cosmetics

Review Natural and Bioinspired Phenolic Compounds as Tyrosinase Inhibitors for the Treatment of Skin Hyperpigmentation: Recent Advances

Lucia Panzella * and Alessandra Napolitano

Department of Chemical Sciences, University of Naples “Federico II”, I-80126 Naples, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-081-674-131



Received: 1 August 2019; Accepted: 13 September 2019; Published: 1 October 2019


Abstract: One of the most common approaches for control of skin pigmentation involves the inhibition of tyrosinase, a copper-containing enzyme which catalyzes the key steps of melanogenesis. This review focuses on the tyrosinase inhibition properties of a series of natural and synthetic, bioinspired phenolic compounds that have appeared in the literature in the last five years. Both mushroom and human tyrosinase inhibitors have been considered. Among the first class, flavonoids, in particular chalcones, occupy a prominent role as natural inhibitors, followed by hydroxystilbenes (mainly resveratrol derivatives). A series of more complex phenolic compounds from a variety of sources, first of all belonging to the Moraceae family, have also been described as potent tyrosinase inhibitors. As to the synthetic compounds, hydroxycinnamic acids and chalcones again appear as the most exploited scaffolds. Several inhibition mechanisms have been reported for the described inhibitors, pointing to copper chelating and/or hydrophobic moieties as key structural requirements to achieve good inhibition properties. Emerging trends in the search for novel skin depigmenting agents, including the development of assays that could distinguish between inhibitors and potentially toxic substrates of the enzyme as well as of formulations aimed at improving the bioavailability and hence the effectiveness of well-known inhibitors, have also been addressed.

Keywords: pigmentary disorders; mushroom tyrosinase; human tyrosinase; melanin; depigmenting agent; inhibition mechanism; phenolic compounds; resorcinol; hydroxycinammic acids; chalcones

1. Introduction The quest for skin lighteners and agents capable of controlling hyperpigmentation disorders is growing at a sustained pace particularly in Asian countries. Most of the strategies explored so far focus on the control of the activity of tyrosinase, which is the main, rate-limiting enzyme involved in the biosynthesis of melanins, the pigments responsible for skin pigmentation in mammals [1–5]. This work will provide an overview of the tyrosinase inhibition properties of natural phenolic compounds, phenols inspired by active compounds of natural origin, or synthetic phenols as appeared in the literature (data source: SciFinder®, search terms: tyrosinase inhibition) in the last five years. Patents were excluded since the main aim of this review is an update of those compounds that have a potential for further development, though possibly not yet ready for a straightforward use in cosmetics. Beside product efficacy, cytotoxicity, solubility, cutaneous absorption, and stability, other critical issues that should be carefully considered when developing a new tyrosinase inhibitor include adverse effects derived from action of the enzyme itself on the product as largely documented in the recent case of rhododendrol, a depigmenting agent on the market capable of inducing leukoderma [6–8]. In this perspective the different mechanisms by which tyrosinase inhibition occurs will be presented in the following paragraphs.

Cosmetics 2019, 6, 57; doi:10.3390/cosmetics6040057 www.mdpi.com/journal/cosmetics Cosmetics 2019, 6, 57 2 of 33 Cosmetics 2019, 6, x FOR PEER REVIEW 2 of 33

inducing leukoderma [6–8]. In this perspective the different mechanisms by which tyrosinase Giveninhibition the occurs difficulties will be of presented obtaining in mammalian the following tyrosinase, paragraphs. most of the studies have been carried out on fungalGiven (mushroom) the difficulties tyrosinase, of obtaining which mammalian however exhibits tyrosinase, somewhat most of ditheff erentstudies substrate have been specificity carried [9]. Startingout fromon fungal consideration (mushroom) of tyrosinase, the structural which features however of exhibits the most somewhat widely investigateddifferent substrate classes of tyrosinasespecificity inhibitors, [9]. Starting a rationalization from consideration of the of the structural structural requirements features of the to most get widely the inhibitory investigated activity, stemmingclasses also of tyrosinase from model inhibitors, or docking a rationalization studies, will of the be structural offered.Finally, requirements issues to of get toxicity the inhibitory of potential tyrosinaseactivity, inhibitors stemming andalso thefrom limitations model or docking of the instudies, vitro willstudies be offered. using Finally, mushroom issues tyrosinase of toxicity of will be discussedpotential in thetyrosinase perspective inhibitors of developingand the limitations effective of the and in vitro safe tyrosinasestudies using inhibitors. mushroom Datatyrosinase on recent trendswill in be cosmetic discussed formulations in the perspective to improve of developing bioavailability effective and safe effi ciencytyrosinase of well-knowninhibitors. Data tyrosinase on recent trends in cosmetic formulations to improve bioavailability and efficiency of well-known inhibitors will be also presented. tyrosinase inhibitors will be also presented. 2. Skin Pigmentation and Hyperpigmentary Disorders 2. Skin Pigmentation and Hyperpigmentary Disorders SkinSkin pigmentation pigmentation in in humans humans is is dependent dependent main mainlyly on on the the quantity, quantity, type, type, and and distribution distribution of of melaninsmelanins in the in epidermis. the epidermis. The resultingThe resulting pigmentation pigmentation can becan changed be changed by phenomena by phenomena of light of light reflection and direflectionffusion, and or by diffusion, the presence or by ofthe pigments presence ofof api digmentsfferent of kind, a different occasionally kind, occasionally present in thepresent skin in [10 ,11]. Apartthe skin from[10,11]. the hemoglobin and the biliary pigments, melanins are the only pigments to be biosynthesizedApart from in the humans. hemoglobin They and are the producedbiliary pigm inents, melanocytes melanins are lying the inonly the pigments epidermis to be at the dermal-epidermalbiosynthesized junctionin humans. and They then are transferred produced inin the melanocytes form of organelles lying in the termed epidermis melanosomes at the to neighboringdermal-epidermal keratinocytes junction in theand skin then (Figure transferred1)[12 in– 15the]. form of organelles termed melanosomes to neighboring keratinocytes in the skin (Figure 1) [12–15].

COOH NH HO COOH HO 2 NH2 L-tyrosine HO L-dopa O2, Tyr osinase COOH HS Keratinocyte O COOH Melanosome NH2 PHEOMELANIN NH O 2 dopaquinone

HO COOH HO N H leucodopachrome dopaquinone

dopa O Melanocyte COOH O N H dopachrome -CO TRP-2 2 (or DCT)

HO HO COOH HO N HO N H H DHI DHICA TRP-1 [O] [O]

EUMELANIN

FigureFigure 1. Schematic 1. Schematic representation representation of of melanosome melanosome transfers transfers from from melanocytes melanocytes to keratinocytes to keratinocytes and and melanogenesismelanogenesis pathway pathway inside inside melanocytes. melanocytes.

UnderUnder normal normal physiological physiological conditions, conditions, pigmentation pigmentation has a beneficialhas a beneficial effect on theeffect photoprotection on the photoprotection of human skin against harmful UV injury [16]. However increased pigmentation, of human skin against harmful UV injury [16]. However increased pigmentation, especially on the face, such as in the case of melasma, solar lentigo (age spots), and lentigo simplex (freckles), presents a significant cosmetic bother and can cause distress to the affected individual. Increased melanin synthesis and accumulation occurs also in other skin problems and systemic or idiopatic diseases [17–22]. Cosmetics 2019, 6, 57 3 of 33

Hyperpigmentation can also occur through inflammation of the skin, chronic heat exposure, hormonal imbalance, mechanical stimulation, and medication applications.

3. Tyrosinase and its Key Role in Melanin Synthesis Melanogenesis is a complex pathway involving a combination of enzymatic and chemical catalyzed reactions. Melanosomes produce two types of melanin: eumelanin, a brown-black or dark polymer, and pheomelanin, a red-yellow polymer, formed by intervention of cysteine (Figure1). The melanogenesis process is initiated with the oxidation of l-tyrosine to dopaquinone by tyrosinase. The formation of dopaquinone is a rate-limiting step in melanin synthesis because the remainder of the reaction sequence can proceed spontaneously at a physiological pH value. Following its formation, dopaquinone undergoes intramolecular cyclization to produce leucodopachrome. The redox exchange between leucodopachrome and dopaquinone then gives rise to dopachrome and l-3,4-dihydroxyphenylalanine (l-dopa), which is also a substrate for tyrosinase and is oxidized to dopaquinone again by the enzyme. Finally, dopachrome undergoes a rearrangement to give 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) (Figure1). This latter process is catalyzed by tyrosinase related protein-2 (TRP-2), known also as dopachrome tautomerase (DCT). Ultimately, DHI and DHICA are oxidized to melanin pigments. Tyrosinase related protein 1 (TRP-1) is believed to catalyze the oxidation of DHICA to melanin. Although all the three enzymes, tyrosinase, TRP-1, and TRP-2 are involved in the melanogenesis pathway, tyrosinase is exclusively necessary for melanogenesis [11,23–30]. Tyrosinase (EC 1.14.18.1, monophenol, ortho-diphenol: oxygen oxidoreductase) is a multifunctional membrane bound type-3 copper-containing glycoprotein located in the membrane of the melanosome. From the structural point of view, two copper ions are surrounded by three histidine residues that are responsible for the catalytic activity of tyrosinase. Substrates for tyrosinase are generally either phenols, which undergo monooxygenation (monophenolase or cresolase activity), or catechols, which undergo oxidation (diphenolase or catecholase activity), leading in both cases to ortho-quinones (Figure2a) [ 31,32]. Although the view that phenol oxidation involves a hydroxylation step followed by catechol oxidation is still commonly claimed in the literature [33,34], in the monophenolase mechanism the ortho-quinone is formed directly from the phenol, and catechol formation is not an intermediate step [35]. During the catalytic cycle the oxidation states of the copper atoms change to give different forms of the enzyme (Figure2b–d). The active site of the enzyme has three states: oxy, met, and deoxy forms. The oxidation of phenols to ortho-quinones by oxy-tyrosinase is the most important function of the enzyme and it is by this process that l-tyrosine is converted to dopaquinone in the biosynthesis of melanins (Figure2b). Mechanistically, the oxygen of the phenol is believed to bind to CuA followed by electrophilic monooxygenation of the ring leading to a complex in which the substrate is bound to both copper ions. In a further step such complex undergoes homolytic dissociation to give the ortho-quinone and deoxy-tyrosinase. The deoxy-tyrosinase then binds oxygen to regenerate oxy-tyrosinase and the phenol-oxidation cycle continues until the phenol and/or oxygen are depleted [35]. Cosmetics 2019, 6, 57 4 of 33 Cosmetics 2019, 6, x FOR PEER REVIEW 4 of 33

O2 Phenol (b) oxidation

(His) N O N(His) (His) N H2O N(His) (His) N Cu2+ Cu2+ (His) N Cu+ Cu+ (a) (His) N N(His) (His) N N(His) O HO HO OH N(His) N(His) oxy-form deoxy-form + + O R R HO O

Monophenolase (cresolase) Diphenolase (catecholase) R R activity activity O O

H R (His) N H O N(His) (His) N O N(His) (His) N A B Cu Cu (His) N Cu+ Cu+ (His) N N(His) N(His) O (His) N N(His) N(His) O O -O

R R

Catechol Catechol (c)oxidation-I (d) oxidation-II H H (His) N O N(His) (His) N O N(His) (His) N O N(His) (His) N N(His) (His) N 2+ (His) N (His) N Cu2+ Cu Cu2+ Cu2+ Cu2+ Cu2+ (His) N Cu+ Cu+ (His) N N(His) (His) N N(His) (His) N N(His) N(His) O (His) N N(His) N(His) N(His) N(His) oxy-form met-form met-form deoxy-form + + + + HO OH O HO OH O O O

R R R R

H (His) N H (His) N O N(His) (His) N O N(His) O N(His) (His) N N(His) (His) N B (His) N B CuA Cu (His) N 2+ 2+ CuA Cu (His) N + + N(His) Cu Cu N(His) N(His) Cu Cu N(His) (His) N O (His) N (His) N (His) N H N(His) N(His) N(His) N(His) O O O O HO O- HO O-

R R H O R 2 R

FigureFigure 2. (a ) Tyrosinase-catalyzed2. (a) Tyrosinase-catalyzed reactions; reactions; (b–d) oxidation(b–d) oxidation states ofstates tyrosinase of tyrosinase and their and conversions their by phenolsconversions/catechols by phenols/catechols [35]. [35].

Oxy-tyrosinaseOxy-tyrosinase is able is able to oxidize to oxidize catechols catechols in addition in addition to phenols. to phenols. In manyIn many cases, cases, a higher a higher specific activityspecific for catechol activity oxidationfor catechol than oxidation for the than corresponding for the corresponding phenol oxygenation phenol oxygenation has been observedhas been [36]. This isobserved possibly [36]. a This consequence is possibly ofa consequence the ease of of substrate the ease of orientation substrate orient on bindingation on tobinding the activeto the site: whereasactive monohydric site: whereas phenols monohydric bind phenols to CuA, bind catechols to CuA, initially catechols bind initially to the bind active to the site active through site the through the CuB. The oxidation cycle of catechols involves two steps (Figure 2c,d) and in both the CuB. The oxidation cycle of catechols involves two steps (Figure2c,d) and in both the binding of the binding of the catecholic substrate occurs by deprotonation of the adjacent hydroxyl groups such catecholicthat the substrate oxygens occurs are coordinated by deprotonation with the two of theactive adjacent site copper hydroxyl atoms. groups In the suchfirst step, that in the which oxygens are coordinatedoxy-tyrosinase with is converted the two activeto met-tyrosinase site copper (Figure atoms. 2c), In the the catechol/enzyme first step, in which complexoxy dissociates-tyrosinase is convertedwith the to met release-tyrosinase of one of (Figure the oxygen2c), the atoms catechol from/enzyme the peroxy complex conformation dissociates of the with bound the releasedioxygen of one of theyielding oxygen the atoms corresponding from the peroxy ortho-quinone conformation and water. of the The bound resultant dioxygen met form yielding of the enzyme the corresponding retains ortho-quinonethe oxidation and state water. of the The active resultant site coppermet form ions [Cu(II)] of the enzymeto which retainsthe remaining the oxidation oxygen atom state is of the activecoordinated, site copper probably ions [Cu(II)] in a protonated to which theform. remaining Overall, the oxygen catechol atom has isreduced coordinated, the peroxy probably bridge in a protonatedwith formation form. Overall, of water the and catechol has been has oxidized reduced to the an peroxyortho-quinone. bridge In with the formationsecond stage of waterof the and has beencatechol oxidized cycle, to a ansecondortho -quinone.molecule of In catechol the second redu stageces the of active the catechol site Cu(II) cycle, ions a secondto Cu(I) molecule giving of deoxy-tyrosinase and a second molecule of orhto-quinone (Figure 2d). The oxidation states of the catechol reduces the active site Cu(II) ions to Cu(I) giving deoxy-tyrosinase and a second molecule of active site copper ions [Cu(II)] are then restored by binding dioxygen (Figure 2b) [35]. orhto-quinoneTyrosinases (Figure have2d). been The oxidationisolated and states purified of the from active different site coppersources ionssuch [Cu(II)]as plants, are animals, thenrestored and by bindingmicroorganisms. dioxygen Although (Figure2b) many [35]. of them (such as human) have been sequenced, only few have Tyrosinases have been isolated and purified from different sources such as plants, animals, and microorganisms. Although many of them (such as human) have been sequenced, only few have been characterized. Mushroom tyrosinase from Agaricus bisporus is a major and cheap enzyme, with high Cosmetics 2019, 6, x FOR PEER REVIEW 5 of 33 Cosmetics 2019, 6, 57 5 of 33 been characterized. Mushroom tyrosinase from Agaricus bisporus is a major and cheap enzyme, with highsimilarity similarity and homologyand homology compared compared to human to human tyrosinase tyrosinase [1,37 ,38[1,37,38].]. Due toDue the to above-mentioned the above-mentioned good goodproperties, properties, the structural, the structural, functional, functional, and biochemical and biochemical characteristics characteristics of mushroom of mushroom tyrosinase tyrosinase have been havestudied been extensively studied asextensively a model system as a formodel screening system of tyrosinasefor screening inhibitors of tyrosinase and melanogenic inhibitors studies, and melanogenicenzyme-catalyzed studies, reactions, enzyme-catalyzed and enzyme-inhibitor reactions, structural and enzyme-inhibitor studies so far [1structural,39–41]. Tyrosinase studies so from far [1,39–41].A. bisporus Tyrosinaseis a 120 kDa from tetramer, A. bisporus which is a was 120 first kDa isolatedtetramer, by which Bourquelot was firs andt isolated Bertrand by inBourquelot 1895 [42]. andIt has Bertrand three domains in 1895 and [42]. two It copperhas three binding domain sitess composedand two copper of six histidine binding residuessites composed able to interact of six histidinewith molecular residues oxygen able into theinteract active with site. molecular It should be oxygen cautioned in the that active tyrosinase site. It from should mushroom be cautioned is very thatdifferent tyrosinase fromhuman from mushroom tyrosinase. is Mushroom very different tyrosinase from human is a tetramer tyrosinase. enzyme Mushroom present in tyrosinase the cytosol is ofa tetramerthe cells, enzyme while human present tyrosinase in the cytosol is a monomeric of the cells, and while inactive human glycosylated tyrosinase membrane is a monomeric bound form.and inactiveFurthermore, glycosylated tyrosinases membrane from diff erentbound sources form. exhibit Furthermore, quite diff erenttyrosinases substrate from specificity, different e.g., sources human exhibittyrosinase quite shows different higher substrate (up to 6-fold)specificity, affinity e.g., for humanl-DOPA tyrosinase oxidation shows activity higher than the(up mushroomto 6-fold) affinitytyrosinase for [ 31L-DOPA]. In addition, oxidation the aminoactivity acid than sequence the mushroom identity between tyrosinase human [31]. and In mushroomaddition, the tyrosinase amino acidis only sequence very limited identity (23%) between [41]. human and mushroom tyrosinase is only very limited (23%) [41].

4.4. Tyrosinase Tyrosinase Inhibition Inhibition Mechanisms Mechanisms AmongAmong different different types types of of compounds able able to to inhibit inhibit melanogenesis, melanogenesis, such such as as specific specific tyrosinase tyrosinase inactivatorsinactivators and and inhibitors, inhibitors, dopaquinone dopaquinone scavengers, scavengers, alternative alternative enzyme enzyme substrates, substrates, nonspecific nonspecific enzymeenzyme inactivators inactivators and and denaturants, denaturants, only only specific specific tyrosinase tyrosinase inactivators inactivators and and reversible reversible inhibitors inhibitors actuallyactually bind bind to to the the enzyme enzyme and and really really inhibit its activity [1]. [1]. SuicideSuicide inactivators inactivators have have been been widely widely reported reported for for the the control control of of hyperpigmentation hyperpigmentation processes. processes. ToTo explain the suicide inactivation of tyrosinase, mainly two mechanisms have been proposed. It It has has beenbeen suggested suggested that that the the conformational conformational changes changes tri triggeredggered by by the the inhibitor inhibitor compound compound in in the the tertiary tertiary andand quaternary quaternary structures structures of of tyrosinase tyrosinase might might be be th thee real real reason for the suicide inactivation. On On the the otherother hand, itit hashas also also been been proposed proposed that that suicide suicide inactivation inactivation could could occur occur after theafter transfer the transfer of a proton of a protonto the peroxyto the peroxy bridge onbridge the activeon the siteactive of oxy site-tyrosinase of oxy-tyrosinase [1,43–45 [1,43–45].]. AsAs far far as asthe the true true inhibitors inhibitors are concerned, are concerned, four types four of types mechanism of mechanism have been havedescribed: been competitive,described: competitive, uncompetitive, uncompetitive, mixed type mixed (compe type (competitivetitive/uncompetitive),/uncompetitive), and andnoncompetitive. noncompetitive. A competitiveA competitive inhibitor inhibitor can canbind bind to a tofree a enzyme free enzyme and prevents and prevents substrate substrate binding binding to the enzyme to the enzyme active site.active This site. is Thisthe iscase the of case phenolic of phenolic compounds compounds able able to toactact as ascopper copper chelators chelators or or compounds structurallystructurally mimicking mimicking the the substrate substrate of of tyrosinase. tyrosinase. In In contrast, contrast, an an uncompet uncompetitiveitive inhibitor inhibitor can can bind bind onlyonly to to the the enzyme-substrate enzyme-substrate complex, complex, whereas whereas a mi axed mixed inhibitor inhibitor can canbind bind to both to both free enzyme free enzyme and enzyme-substrateand enzyme-substrate complex. complex. Finally, Finally, noncompetiti noncompetitiveve inhibitors inhibitors bind bind to tothe the free free enzyme enzyme and and the the enzyme-substrateenzyme-substrate complex complex with with the the same same equilibrium constant [1,46]. [1,46]. TheThe inhibitory inhibitory strength strength is is generally expressed expressed as as the IC 50 value,value, that that is is the the concentration concentration of of inhibitorinhibitor at at which which 50% 50% of of the the enzyme enzyme activity activity is isinhibited. inhibited. Of course, Of course, it must it must be considered be considered that IC that50 valuesIC50 values may maybe incomparable be incomparable due dueto the to thedifferen differentt assay assay conditions conditions (e.g., (e.g., substrate substrate and and enzyme enzyme concentrations,concentrations, incubation incubation time, time, source source of tyro tyrosinase).sinase). Reference Reference comp compoundsounds commonly commonly used used as as positivepositive controls controls in in the the mushroom mushroom tyrosinase tyrosinase inhibition inhibition assay assay are are kojic kojic acid acid and and ββ-arbutin-arbutin (Figure (Figure 3),3), μ whichwhich however areare veryvery poor poor inhibitors inhibitors (IC (IC50 50> >500 500µ M)M) of of human human tyrosinase tyrosinase [9, 47[9,47].]. Deoxyarbutin Deoxyarbutin has hasbeen been recently recently described described as a novelas a novel tyrosinase tyrosinase inhibitor, inhibitor, with increased with increased skin penetration skin penetration and binding and bindingaffinity toaffinity human to tyrosinasehuman tyrosinase [48–50]. [48–50].

OH O HO OH O O HO HO O OH OH

Kojic acid β-Arbutin μ IC50=6.0 M IC =40 μM 50

FigureFigure 3. Chemical structuresstructures and and IC IC5050values values [9 ][9] against against mushroom mushroom tyrosinase tyrosinase of the of commonlythe commonly used usedreference reference compounds compounds kojic kojic acid andacidβ and-arbutin. β-arbutin.

5. Natural Phenolic Inhibitors of Mushroom Tyrosinase

Cosmetics 2019, 6, 57 6 of 33

Cosmetics5. Natural 2019, Phenolic 6, x FOR PEER Inhibitors REVIEW of Mushroom Tyrosinase 6 of 33 Among natural phenolic compounds acting as tyrosinase inhibitors (Supplementary Materials, Among natural phenolic compounds acting as tyrosinase inhibitors (Supplementary Materials, Table S1), flavonoids are the most representative class. Figure4 shows the structures of the most potent Table S1), flavonoids are the most representative class. Figure 4 shows the structures of the most inhibitors with the corresponding IC50 values against mushroom tyrosinase. Among the different potent inhibitors with the corresponding IC50 values against mushroom tyrosinase. Among the subclasses, the highest activity has been determined for chalcones, with 2,2 ,4,4’-tetrahydroxychalcone different subclasses, the highest activity has been determined0 for chalcones, with exhibiting a very low IC50 value (0.07 µM) [51]. A significant melanogenesis inhibition potential 2,2′,4,4’-tetrahydroxychalcone exhibiting a very low IC50 value (0.07 μM) [51]. A significant has been reported also for galangin (IC50 = 3.55 µM) [52], isoliquiritigenin (IC50 = 4.85 µM) [53], melanogenesis inhibition potential has been reported also for galangin (IC50 = 3.55 μM) [52], kaempferol (IC50 = 5.5 µM) [54], and dihydromorin (IC50= 9.4 µM) [55], belonging to different flavonoid isoliquiritigenin (IC50 = 4.85 μM) [53], kaempferol (IC50 = 5.5 μM) [54], and dihydromorin (IC50= 9.4 subfamilies, but all characterized by at least one resorcinol moiety. IC50 values in the range 20–150 µM μM) [55], belonging to different flavonoid subfamilies, but all characterized by at least one resorcinol have instead been reported for catechins [56–59]. moiety. IC50 values in the range 20–150 μM have instead been reported for catechins [56–59].

Flavonols Chalcones OH HO OH OH OH OH HO O HO O HO HO HO O OH OH CH3 OH OH O O O OH HO OH O OH O OH O OH O OH O Quercetin OH O OH Quercitrin μ Isoliquiritigenin 2,2’,4,4’-Tetrahydroxychalcone IC50=10.73 M [69] IC =45 μM [68] IC =4.85 μM [53] IC =0.07 μM [51] 50 OH 50 50 O HO O O HO HO O HO OH Flavanonols OH OH H C OH OH HO OH 3 Rutin OH O HO OH O HO O HO O OH μ OH IC50=130 M [67] Galangin Kaempferol μ μ IC50=3.55 M [52] IC50=5.5 M[54] OH OH OH O OH O

Dihydromyricetin Dihydromorin Flavones IC =849.88 μM [74] μ 50 IC50=9.4 M [55] OH OH OH OH HO O HO O HO O HO O OH Isoflavones HO HO O HO O OH O OH O OH O O OH Apigenin Baicalein Luteolin 4’,7,8-Trihydroxyflavone μ μ μ μ OH O O IC50=17.3 M [70] IC50=110 M [71] IC50=20.8 M [70] IC50=10.31 M[72] OH OH 3’-Hydroxygenistein Daidzein IC =15.9 μM [75] μ 50 IC50=17.50 M [53] OH OH OH Catechins HO O HO O HO O OH OH OH Catechin Anthocyanins OH OH OH OH μ OH IC50=57.12 M [56] OH OH OH HO O+ OH HO OH HO O OH OH O HO O O CH2OH ProcyanidinB3 OH OH OH HO OH HO μ O IC50=56.58 M [57] OH HO O Cyanidin-3-O-glucoside OH OH μ OH OH O IC50=18.1 M [76] OH OH HO OH OH HO O HO O OH OH OH Epicatechingallate O O μ Flavanones OH ProcyanidinB7 IC50=22.63 M[56] OH OH OH OH μ O O IC50 (monophenolase activity)=31.0 M [59] HO O IC (diphenolase activity)=61.8 μM [59] 50 OH OH OH OH O Gallocatechingallate Epigallocatechingallate Liquiritigenin μ IC =142.40 μM [56] IC50=61.79 M [58] 50 IC =22.0 μM [73] 50

Figure 4. Chemical structures and IC50 values against mushroom tyrosinase of phenolic compounds Figure 4. Chemical structures and IC50 values against mushroom tyrosinase of phenolic compounds belonging to the flavonoid class. Unless otherwise specified, IC50 values refer to the diphenolase belonging to the flavonoid class. Unless otherwise specified, IC50 values refer to the diphenolase activityactivity of of the the enzyme. enzyme.

AnotherAnother major major class class of of mushroom mushroom tyrosinase tyrosinase in inhibitorshibitors is is represented represented by by hydroxystilbenes hydroxystilbenes (Figure(Figure 55).). Several Several derivatives derivatives of of the parent resveratrolresveratrol havehave beenbeen describeddescribed asas potentialpotential μ depigmentingdepigmenting agents,agents, with with oxyresveratrol oxyresveratrol (IC50 = 1.7(ICµM)50 [55= ] and1.7 particularlyM) [55] dihydrooxyresveratrol and particularly μ dihydrooxyresveratrol(IC50 = 0.3 µM) [55] among (IC50 the= most0.3 activeM) [55] compounds. among the Recently, most glycosylationactive compounds. has been Recently, reported glycosylationto improve the has tyrosinase been reported inhibitory to improve activities the oftyro bothsinase resveratrol inhibitory and activities its methylated of both resveratrol analogues andpterostilbene its methylated and pinostilbene analogues pterostilbene [60]. and pinostilbene [60].

CosmeticsCosmetics 2019 2019, ,6 6, ,x x FOR FOR PEER PEER REVIEW REVIEW 77 ofof 3333

OH OH OH OH OH OH Cosmetics 2019, 6, 57 HO HO HO 7 of 33 HO HO HO Dihydrooxyresveratrol Cosmetics 2019, 6, x FOR PEER REVIEW OH OH Dihydrooxyresveratrol 7 of 33 OH OH μ Resveratrol IC50=0.3 μM[55] Resveratrol Oxyresveratrol IC50=0.3 M[55] OH IC =23 μM[63] OH Oxyresveratrol OH OH IC50 =23 μM[63] OH μ OH OH 50 IC50=1.7 μM[55] OH OH IC50=1.7 M[55]OH O OH OH O OH OH OH O OHOH HO O HO OH HO O HO OH HO O HO Dihydrooxyresveratrol HOHO O HO HO OH O HOOH Resveratrol-4’-O-glucosideOH μ Resveratrol IC50=0.3 M[55] OH Oxyresveratrol Resveratrol-4’-O-glucoside OH μ OH OH IC =29 μM[60] IC50=23 M[63] 50 μ Resveratrol-3-O-glucoside μ ICOH50=29 M[60] Resveratrol-3-O-glucoside IC50=1.7 M[55] (piceid) OH OH O OH (piceid)OH OH OH OHOH IC =14 μM[60] OH O OH 50 μ O HOO IC50=14HO M[60] O OH HO O HO O OHOH OH OResveratrol-4’-O-glucosideHO OH OH HO OH μ H3CO IC50=29 M[60] H COResveratrol-3-O-glucoside H3CO Pterostilbene-4’-O-glucoside H3 CO Pterostilbene-4’-O-glucoside 3 (piceid) OH OH OH μ μ Pterostilbene IC50=237 μM [60] IC50=14 M[60] O IC50=237 M [60] Pterostilbene OH μ OCH3 O IC50=653 μM[60] OCH3 OH OC H3 IC50=653 M[60]OH HO OC H3 H3CO OH H CO OH Pterostilbene-4’-O-glucosideOH 3 OH O OH OH HO O IC =237μM [60] PterostilbeneO HOHO O 50 O O μ OH OCH3 HO OH IC50O=653 M[60] OHOH OH OC H3 O HO OH HO OH HO Pinostilbene-3-O-glucoside HO Pinostilbene-3-O-glucosideOH OH O OCH3 μ HO OCH3 IC50=66 μM[60] Pinostilbene-4’-O-glucosideO HO OH O IC50=66 M[60] Pinostilbene-4’-O-glucosideOH OH OH Oμ OH IC50=85 MHO [60] OCH3 IC =85 μM [60] HO HOOCH3 50 HO Pinostilbene-3-O-glucoside OCH3 μ Pinostilbene IC50=66 M[60] Pinostilbene-4’-O-glucoside PinostilbeneOH μ μ IC50=594 M[60] OCH IC50=85 M [60] OCH3 IC =594 μM[60] 3 HO OCH3 50 Pinostilbene IC =594 μM[60] 50 OCH3 50 FigureFigure 5. 5. Chemical Chemical structures structures and and IC IC50 values values (referring (referring to to to to the the diphenolase diphenolase activity activity of of the the enzyme) enzyme) against mushroom tyrosinase of hydroxystilbenes. FigureagainstFigure 5.mushroomChemical 5. Chemical tyrosinase structures structures andof and hydroxystilbenes. IC IC5050values values (referring to to to to the the diphenolase diphenolase activity activity of the of enzyme) the enzyme) againstagainst mushroom mushroom tyrosinase tyrosinase of of hydroxystilbenes. hydroxystilbenes. MovingMoving toto simplesimple phenols,phenols, significantsignificant ininhibitionhibition activityactivity hashas beenbeen describeddescribed forfor 50 μ 50 μ 4-hydroxybenzyl4-hydroxybenzylMovingMoving to simple alcohol alcoholto simple phenols, (IC (IC 50 = phenols,= 6 significant6 μM)M) [61] [61]significant and inhibitionand isoeugenol isoeugenol in activityhibition (IC (IC has50activity = = been33.3 33.3 describedμM)hasM) [62], [62],been which which fordescribed 4-hydroxybenzyl would would forappear appear μ μ morealcoholmore 4-hydroxybenzyl efficientefficient (IC50 = thanthan6 µM) resorcinol resorcinolalcohol [61] and (IC 50 isoeugenol[55][55] = 6 ororM) rhododendr rhododendr[61] (IC and50 isoeugenol= 33.3olol [63][63]µM) (IC themselves.themselves. [6250 =], 33.3 which M) wouldOther[62],Other which inhibitors appearinhibitors would more appearhavehave effi been cientbeen recentlythanrecentlymore resorcinol isolatedisolated efficient [ 55 from fromthan] or rhododendroltheresorcinolthe rootsroots of[55]of DryopterisDryopteris or [63 rhododendr] themselves. crassirhizomacrassirhizomaol [63] Other themselves. [64][64] inhibitors andand Other leavesleaves have inhibitors of beenof PiperPiper recently have aduncumaduncum been isolated [65][65] recently isolated from the roots of Dryopteris crassirhizoma [64] and leaves of Piper aduncum [65] (Figurefrom(Figure the 6). 6). roots of Dryopteris crassirhizoma [64] and leaves of Piper aduncum [65] (Figure6). (Figure 6).

OH HO HO H3CO CH3 OH HO HO H3CO CH3 OH OH HO HO H CO CH OH 3 3 OH HO HO HO HO HO HO HO HO OH OH HO HO HO OH OH Resorcinol Isoeugenol HORhododendrol 4-Hydroxybenzyl alcohol OH OH ResorcinolResorcinol Isoeugenol Rhododendrol 4-Hydroxybenzyl alcohol Pyrogallol IC =162.6 μM [55] Isoeugenol Rhododendrol 4-Hydroxybenzyl alcohol PyrogallolPyrogallol IC50 =162.6μ μM [55] IC =33.33 μM[62] IC =245 μM [63] IC =6 μM [61] μ IC50=162.650 M [55] IC50 =33.33 μM[62]μ IC50 =245 μMμ [63] 50 μ IC50=772 M[77] 50 IC50=33.33 M[62] 50IC50=245 M [63] ICIC5050=6 M [61] [61] ICIC=772=772 μM[77] μM[77] 50 50

Figure 6. Chemical structures and IC50 values (referring to to the diphenolase activity of the enzyme) FigureFigure 6. Chemical 6. Chemical structures structures and and IC IC505050 valuesvalues values (referring (referring to to to to the the diphenolase diphenolase activity activity of the of enzyme)the enzyme) againstagainstagainst mushroom mushroom mushroom tyrosinase tyrosinasetyrosinase tyrosinase of ofof simpleof simplesimple simple phenols. phenols.phenols. phenols.

LowLow IC50 ICvalues50 values against against both both monophenolase monophenolase and di diphenolasephenolase activty activty of mushroom of mushroom tyrosinase tyrosinase LowLow ICIC5050 valuesvalues against against bothboth monophenolasemonophenolase and and didiphenolasephenolase activty activty ofof mushroommushroom tyrosinasetyrosinase have been very recently reported for p-coumaric and caffeic acid [66], belonging to the cinammic havehave been been veryvery recently recentlyrecently reported reportedreported for forforp -coumaric pp-coumaric-coumaric and andand ca ffcaffeiccaffeiceic acid acidacid [66 [66],],[66], belonging belongingbelonging to the toto cinammicthethe cinammiccinammic acid acid family (Figure 7). acidfamilyacid family family (Figure (Figure (Figure7). 7). 7).

O OH OH O O OH OH COOH HO COOH HO O O OH OH O O OH COOH HO COOH HO COOH HO CaffeicCOOH acid HO O OH HO HO HO RosmarinicO acid OH p-Coumaric acid μ μ HO IC50 (monophenolaseHO activity)=1.50Caffeic acid M[66]HO IC50 =24.6 M [70] μ Caffeic acidμ Rosmarinic acid IC50 (monophenolase activity)=0.30HO M[66] IC50 (diphenolaseHO activity)=2.30 M [66]HO Rosmarinic acid p-Coumaric acidμ IC (monophenolase activity)=1.50 μM[66] IC =24.6 μM [70] IC50 (diphenolasep-Coumaric activity)=0.62 acid M[66] IC50 (monophenolaseO activity)=1.50OH μM[66] IC50 =24.6 μM [70] IC (monophenolase activity)=0.30 μM[66] IC50 (diphenolase activity)=2.30 μM [66] 50 IC50 (monophenolase activity)=0.30 μM[66] HOIC50 (diphenolase activity)=2.30 μM [66] OH 50 μ 50 O O IC50 (diphenolase activity)=0.62 μM[66] O OH IC50 (diphenolase activity)=0.62 M[66] O O OH O HOHO OH OHOH HO O O OH H3C O O O HO O VerbascosideO O OH O OH HO HO OH μ HO OH IC50 =324 M [78] OH H3C O HOH3C O Verbascoside HO Verbascoside HO IC =324 μM [78] HO OH IC50 =324 μM [78] Figure 7. Chemical structures and IC50 values againstOH mushroom50 tyrosinase of cinnamic acid derivatives. Unless otherwise specified, IC50 values refer to the diphenolase activity of the enzyme. Figure 7. Chemical structures and IC50 values50 against mushroom tyrosinase of cinnamic acid derivatives. FigureFigure 7.7. ChemicalChemical structuresstructures andand ICIC50 valuesvalues againstagainst mushroommushroom tytyrosinaserosinase ofof cinnamiccinnamic acidacid derivatives.Unless otherwise Unless specified, otherwise IC specified,50 values referIC50 values to the diphenolaserefer to the diphenol activityase of the activity enzyme. of the enzyme. derivatives.The IC Unless50 values otherwise together specified, with structural IC50 values formul refer asto thefor diphenolother phenolicase activity compounds of the enzyme. widely distributed in nature that have been the subject of studies that appeared in the last five years The IC values together with structural formulas for other phenolic compounds widely distributed 5050 TheThe[53,62,63,67–82] ICIC50 valuesvalues are together togetheralso reported withwith in structuralFiguresstructural 4–8. formulformulasas forfor otherother phenolicphenolic compoundscompounds widelywidely in nature that have been the subject of studies that appeared in the last five years [53,62,63,67–82] are distributeddistributed inin naturenature thatthat havehave beenbeen thethe subjectsubject ofof studiesstudies thatthat appearedappeared inin thethe lastlast fivefive yearsyears also reported in Figures4–8. [53,62,63,67–82][53,62,63,67–82] are are also also reported reported in in Figures Figures 4–8. 4–8. A series of more complex phenolic compounds have been isolated from several plants and evaluated as inhibitors against mushroom tyrosinase. The Moraceae family, in particular, has proven to be an important source of potential skin whitening agents [73,83–87] (Figure9), leading to compounds

with in some cases very low IC50 values, such as norartocarpetin (from the stems of Artocarpus rigida, Cosmetics 2019, 6, 57 8 of 33

IC50 = 0.023 µM) [87], morachalcone A (from the twigs of Artocarpus pithecogallus, IC50 = 0.77 µM) [83], and artocarpanone (from the wood of Artocarpus heterophyllous, IC50 = 2.0 µM) [73], all belonging to the flavonoidCosmetics 2019 family, 6, x FOR and PEER characterized REVIEW by the presence of resorcinol ring(s). 8 of 33

O O OH O OH HO CH CH OH 3 3

CH3

OH O OH OH O OH OH O Shikonin μ Aloe emodin Emodin IC50 =26.67 M[62] μ μ IC50 =3.39 M [79] IC50 =187.5 M [80] OCH3 OH OH

HO HO

H3CO O O Enterolactone (+)-Laricilresinol O μ HO IC =21.49 μM[53] IC50 (monophenolase activity)=420 M[81] 50 μ IC50 (diphenolase activity)=124 M[81]

OH OH HO OH HO OH 1,2,3,6-Tetra-O-galloylglucose 1,2,3,4,6-Penta-O-galloylglucose μ μ IC50 =0.29 M [82] IC50 =0.38 M[82] OH O O O O O OH OH HO HO HO O O O O O OH O O O OH HO O O O HO O O O OH OH O OH

OH HO OH OH HO OH HO OH OH

FigureFigure 8.8. Chemical structures and ICIC5050 values against mushroom tyrosinase ofof naturalnatural phenolicphenolic Cosmetics 2019, 6, x FOR PEER REVIEW 9 of 33 compounds.compounds. Unless otherwiseotherwise specified,specified, ICIC5050 values refer to the diphenol diphenolasease activity of the enzyme.

A series of more complex phenolic compounds have been OHisolated from several plants and OH OH HO H3CO O H3CO O evaluated as inhibitors against mushroom tyrosinase. The MoraceaeOH family, in particular, has proven Morachalcone A OCH3 OH OH O to be an important sourceOH of potential skinOH whitening agents μ[73,83–87] (Figure 9), leading to IC50 =0.77 M[83] ArtopithecinC Artopithecin D compounds with in someμ cases very lowμ IC50 values, such as norartocarpetinOH (from the stems of IC50 =37.09 M[83] IC50 =38.14 M[83] H3CO O Artocarpus rigida, IC50 = 0.023 μM) [87], morachalcone A (from the twigs of Artocarpus pithecogallus, OH μ OH μ IC50 = 0.77 M) [83], andHO artocarpanone (from the OHwood of OHArtocarpusO heterophyllous, IC50 = 2.0 M) O O Artocarpin [73], all belonging to the flavonoid family and characterized by theμ presence of resorcinol ring(s). IC50 =722.5 M [84] OH O OCH3 Isobavachalcone OH O μ γ γ IC50 =673.2 M [84] 4’,5-Dihydroxy-6,7-(2,2-dimethylpyrano)-2’-methoxy-8- , -dimethylallylflavone IC =720.1 μM[84] OH 50 OH OH OH

O O HO O H3CO O O OH OH

OH O OH O Norartocarpetin OH O Artocarpanone IC =0.023 μM[87] IC =2.0 μM[73] Cycloheterophyllin 50 50 μ IC50 =104.6 M[84] OH OH HO O O HO O OH O OH OH O HO OH O Steppogenin Artocaepin E μ IC50 =7.5 M [73] μ IC50 =6.7 M[73] HO OH OH HO OH H H OH HO Artoxanthol OH HO μ OH IC50 =5.7 M[85] OH HO Alboctalol HO μ OH IC50 =6.4 M[85] HO OH OH OH

OH HO OH PyranocycloartobiloxanthoneA HO O O μ O IC50 =134 M[86] OH OH OH Chlorophorin OH O CH IC =2.5 μM[85] 3 50

FigureFigure 9. Chemical 9. Chemical structures structures and and IC IC5050values values (referring to to to to the the diphenolase diphenolase activity activity of the of enzyme) the enzyme) againstagainst mushroom mushroom tyrosinase tyrosinase of phenolic of phenolic compounds compounds isolated isolated from fromArtocarpus Artocarpusspecies species (Moraceae (Moraceaefamily). family).

Potent mushroom tyrosinase inhibitors have been isolated also from plants of the genus Morus [55,88–91] (Figure 10): noticeable examples are 2,3′,4-trihydroxydihydrostilbene (IC50 = 0.8 μM) [55], the benzofuran moracin M (IC50 = 8.0 μM) from mulberry (Morus alba) wood [55], and isoprenylated flavanons from Morus nigra, such as kuwanon J (IC50 = 0.17 μM) and sanggenon O (IC50 = 1.15 μM) [91] (Figure 10).

Cosmetics 2019, 6, 57 9 of 33

Potent mushroom tyrosinase inhibitors have been isolated also from plants of the genus Morus [55,88–91] (Figure 10): noticeable examples are 2,30,4-trihydroxydihydrostilbene (IC50 = 0.8 µM) [55], the benzofuran moracin M (IC50 = 8.0 µM) from mulberry (Morus alba) wood [55], and isoprenylated flavanons from Morus nigra, such as kuwanon J (IC50 = 0.17 µM) and sanggenon O (ICCosmetics50 = 1.152019, µ6,M) x FOR [91 PEER] (Figure REVIEW 10). 10 of 33

OH OH OH OCH3 OH HO O HO O OCH OH HO H C 3 Moracin M 3 2,3’,4-Trihydroxydihydrostilbene OH O IC =8.0 μM [55] 50 IC =0.8 μM[55] 5,5’,7-Trihydroxy-2’,4’-dimethoxy-6-methylflavanone 50 OH μ IC50 =44.74 M [88]

HO OH OH HO O OH HO CH3 HO O O OH HO OH OH O Kuwanon C OH O NigragenonE OH O HO O μ μ IC50 =76.2 M [55] Kuwanon G IC50 =21.33 M[90] μ IC50 =67.6 M[89] OH O HO OH OH Chalcomoracin O O OH O IC =2.59 μM[91] 50 OH SanggenonM O OH μ OH IC50 =13.06 M[91] OH O HO O OH

HO OH OH OH OH HO OH OH HO O HO O O HO HO HO O O OH OH O Kuwanon J Sorocein H OH IC =0.17 μM[91] μ 50 IC50 =6.49 M [91]

HO HO

OH OH HO HO O OH HO HO O OH O O O O OH OH OH OH O OH OH O SanggenonC SanggenonO μ IC50 =1.17 M[91] μ IC50 =1.15 M[91]

Figure 10.10. ChemicalChemical structures structures and and IC 50ICvalues50 values (referring (referring to to to the to diphenolase the diphenolase activity activity of the enzyme) of the againstenzyme) mushroom against mushroom tyrosinase tyrosinase of phenolic of compoundsphenolic compounds isolated from isolatedMorus fromspecies Morus (Moraceae species (Moraceaefamily). family). A series of flavonoids derivatives from the root bark of Broussonetia papyrifera, first of all broussoflavonolA series of Jflavonoids (IC50 = 9.29 derivaµM), havetives beenfrom found the root to be bark more of active Broussonetia than kojic papyrifera, acid as inhibitors first of all of thebroussoflavonol monophenolase J (IC acitivty50 = 9.29 of μM), the enzymehave been [92 found] (Figure to be 11 more). Prenylated active than flavanones kojic acid from as inhibitors the roots of Daleathe monophenolase pazensis Rusby acitivty also proved of the to enzyme be quite [92] effective (Figure as mushroom11). Prenylated tyrosinase flavanones inhibitors from [the93]. roots On the of contrary,Dalea pazensis biflavonoids Rusby also not proved containing to be aquite 1,3-benzenediol effective as mushroom from Solanum tyrosinase nigrum inhibitors(Figure 11 [93].) were On only the poorcontrary, tyrosinase biflavonoids inhibitos, not with containing IC50 values a 1,3-benzenediol> 190 µM[94]. from Solanum nigrum (Figure 11) were only poor tyrosinase inhibitos, with IC50 values > 190 μM [94]. A pterocarpan (IC50 = 16.7 μM) and some isoflavones and isoflavans isolated from Dalbergia parviflora (Figure 11) have been also recently reported as inhibitors of the diphenolase activity of mushroom tyrosinase [95].

Cosmetics 2019, 6, 57 10 of 33 Cosmetics 2019, 6, x FOR PEER REVIEW 11 of 33

HO OH H3CO OH HO OH HO O HO O HO O 2’,4’-Dihydroxy-5’-(1’,1’-dimethylallyl)-8-prenylpinocembrin μ IC50 =2.32 M [93] OH Broussoflavonol J O O OH O OH O IC =9.29 μM [92] 50 4’-Hydroxy-2’-methoxy-5’-(1’,1’-dimethylallyl)-8-prenylpinocembrin μ OH IC50 =49.80 M [93] HO OH O OH O O OH HO OH O OH O O 2',3',5-trihydroxy-5''-methoxy-3''-O- glucosyl-3-4'"-O-biflavone O O μ OH IC50 =207.7 M[94]

O O HO O O OH (8-Hydroxy-3‘-galactosylisoflavone)-2'-8''-(4'''-hydroxyflavone)-biflavone OH O IC =192.0 μM [94] 50 OH

OCH3 HO O H3CO O HO O OH OH HO O OH OH OH OH O OH O O OCH3 OH OCH OCH3 OH Cajanin 3 3,8-Dihydroxy-9-methoxypterocarpan Khrinone B μ 3’-Hydroxy-8-methoxyvestitol IC50 =67.9 M[95] μ μ μ IC50 =16.7 M[95] IC50 =54.0 M [95] IC50 =67.8 M [95]

Figure 11. Chemical structures and IC50 values (referring to to the diphenolase activity of the enzyme) Figure 11. Chemical structures and IC50 values (referring to to the diphenolase activity of the against mushroom tyrosinase of flavonoids isolated from different plants. enzyme) against mushroom tyrosinase of flavonoids isolated from different plants.

A pterocarpan (IC50 = 16.7 µM) and some isoflavones and isoflavans isolated from Dalbergia Increasing attention has been devoted to condensed tannins, which have shown promising parviflora (Figure 11) have been also recently reported as inhibitors of the diphenolase activity of activities as inhibitors of both monophenolase and diphenolase activity of mushroom tyrosinase mushroom tyrosinase [95]. (Table 1) [96–107]. Particularly active were prodelphinidins and procyanidins from the fruit pericarp Increasing attention has been devoted to condensed tannins, which have shown promising of Clausena lansium Skeels [102], as well as the complex mixtures isolated from Persea Americana [106], activities as inhibitors of both monophenolase and diphenolase activity of mushroom tyrosinase Longan bark [99], and from leaves and fruit of Leucaena leucocephala [97]. (Table1)[ 96–107]. Particularly active were prodelphinidins and procyanidins from the fruit pericarp of Clausena lansium Skeels [102], as well as the complex mixtures isolated from Persea Americana [106], Table 1. IC50 values against mushroom tyrosinase reported for condensed tannins isolated from Longan bark [99], and from leaves and fruit of Leucaena leucocephala [97]. different plants.

Table 1. IC50 values against mushroom tyrosinaseIC50 ( reportedμg/mL) for condensed tanninsIC50 (μg/mL) isolated from Source different plants. (Monophenolase Activity) (Diphenolase Activity) Vigna angularis [96] 130.0 35.1 IC (µg/mL) IC (µg/mL) Source 50 50 Leucaena leucocephala [97] (Monophenolase52.3 Activity) (Diphenolase16.1 Activity) Vigna radiata [98] 80 20 Vigna angularis [96] 130.0 35.1 LeucaenaLongan leucocephala [99][ 97] 52.343.7 16.111.5 PrunusVigna radiata cerasifera[98] [100] 80738.37 137.69 20 AnnonaLongan squamosa [99] [101] 43.746.5 11.537.3 PrunusClausena cerasifera lansium[100 [102]] 738.3723.6 137.697.0 Annona squamosa [101] 46.5 37.3 ClausenaFicus lansiumaltissima[102 [104]] 23.6256.7 7.041.3 RhododendronFicus altissima pulchrum[104] [105] 256.7200 41.3200 RhododendronPersea americana pulchrum [106][105] 20040 20019.5 Persea americana [106] 40 19.5 Very potent (IC50 values in the range 0.10–7.5 μM) mushroom tyrosinase inhibitors have been isolated from licorice (Figure 12), the most active belonging to the isoflavan class [108–110]. µ StructurallyVery potent related (IC50 valuescompounds in the and range paeoniflorin 0.10–7.5 M) derivatives mushroom isolated tyrosinase from inhibitors San-Bai have decoction been isolated from licorice (Figure 12), the most active belonging to the isoflavan class [108–110]. Structurally proved less active (IC50 in the range 35.54–171.13 μM) [111] (Figure 12). related compounds and paeoniflorin derivatives isolated from San-Bai decoction proved less active (IC50 in the range 35.54–171.13 µM) [111] (Figure 12).

Cosmetics 2019, 6, 57 11 of 33 Cosmetics 2019, 6, x FOR PEER REVIEW 12 of 33

HO O HO O O O OH O OH O O OH O HO OH OH Glabridin SemilicoisoflavoneB μ μ IC50 =0.25 M [108] AllolicoisoflavoneB IC50 =0.10 M [108] μ IC50 =0.80 M [108]

O O O HO O O HO O OH

GlycybridinK HO OH Glabrene OH O μ μ OCH3 IC50 =2.8 M [109] IC50 =7.5 M [109] 2,’7-dihydroxy-4′-methoxy-8-(3-methyl-2-butenyl)isoflavanone μ IC50 =5.1 M [109]

H3CO O HO O

OCH OCH 3 HO OH 3 HO OH Glyasperin D Glyasperin C μ IC50 =0.15 M[110] μ IC50 =0.2 M[110] OH OH O O OH OH O OH O OH O HO HO O HO O CH2OH

HO OH Liquiritin Liquiritin apioside O O O μ μ IC50 =171.13 M[111] IC50 =88.91 M [111] OH HO HO OH O OH Oxypaeoniflora O O OH O O μ H O IC50 =82.55 M [111] OH O O O HO HO O HO HO O O OH HO O OO HO O H OH Benzoyloxypaeoniflorin OH O μ O Galloylpaeoniflorin IC50 =40.44 M[111] HO O IC =35.54 μM [111] O O 50 HO HO O O O O HO O HO O OH Mudanpioside C O μ IC50 =82.72 M [111] O HO O

FigureFigure 12. ChemicalChemical structures structures and and IC50 IC50 values values (referring (referring to the todiphenolase the diphenolase activity activityof the enzyme) of the enzyme)against mushroom against mushroom tyrosinase tyrosinaseof phenolic of compounds phenolic compounds isolated from isolated Glycyrrhiza from speciesGlycyrrhiza and San-Baispecies anddecoction. San-Bai decoction.

ICIC5050 values in the range 28–42 µμM have been reported for two lignanslignans isolatedisolated fromfrom OpiliaOpilia amentaceaamentacea leavesleaves [[112]112](Figure (Figure 13 13),), whereas whereas particularly particularly e ffeffectiveective against against the the monophenolase monophenolase activity activity of theof the enzyme enzyme were were flavonolignans flavonolignans from from the the seeds seeds of ofSilybum Silybum marianum marianum(IC (IC5050in in thethe rangerange 1.7–4.91.7–4.9 µμM) (Figure(Figure 1313))[ [113]113] asas wellwell as,as, althoughalthough withwith aa lowerlower strength,strength, hydroxylatedhydroxylated phenonesphenones fromfrom SyzygiumSyzygium polyanthumpolyanthum leavesleaves [[114]114] (Figure(Figure 1414).).

Cosmetics 2019, 6, x FOR PEER REVIEW 13 of 33

OCH3

OCH3 O OH HO OH H CO OH OH H CO H Cosmetics 2019, 6, 57 3 3 H OCH3 12 of 33 O O HO O OCH HO O Cosmetics 2019, 6, x FOR PEERHO REVIEW O 3 HO O 13 of 33 OH OH H3CO H3CO Eleutheroside E1 5,5-dimethoxylaricilresinol-4-O-glucopyranoside μ IC50 =28 M[112]OCH μ 3 IC50 =42.1 M [112] OCH3 O OH OH O HO OH O OH H CO OH H CO H 3 OH OH OH3 H OCH3 O O HO OO OCH3 HO O O HO HO O O OH HOHO O O OH OH OH H CO H CO Isosilybin3 A O 3 O Eleutheroside E1 5,5-dimethoxylaricilresinol-4-O-glucopyranoside Isosilybin B μ IC (monophenolase activity)=2.1 μM[113] OH IC50 =28 OHM[112] 50 μ IC50 =42.1 Mμ [112] IC50 (diphenolase activity)=16.7 M [113] OCH3 OCH3 μ OH O IC50 (monophenolaseOH O activity)=4.9 M[113] μ OH O OH IC50 (diphenolase activity)=19.8OH M[113] OH OH O O OCH3 HO O OHOH HO O O OH H HO O H OH Isosilybin A O HO O O OCH3 IC (monophenolase activity)=2.1 μM[113] OH Isosilybin B OH OH 50 H O OH IC (diphenolase activity)=16.7OH μM [113] OCH OCH 50 Silydianin O 3 OH O 2,3-Dehydrosilychristin3 A μ μ μ IC50 (monophenolase activity)=2.1 M [113] IC50 (monophenolaseIC50 (monophenolase activity)=4.9 M[113] activity)=7.6 M[113] μ IC (diphenolase activity)=19.8 μM[113] μ IC50 (diphenolase activity)=16.5OH O M[113] 50 IC50 (diphenolase activity)=35.9 M[113] OH OH OH OH OCH3 OCHOH 3 O H O HO O H O OH HO O OH HO O OCH HO O OCH3 O 3 O OH H OH OH OHOH OH OH Silydianin O OH O 2,3-Dehydrosilychristin A OH O μ OH O μ IC50 (monophenolase activity)=2.1 M [113]Silychristin A IC50 (monophenolase activity)=7.6 M[113] IC (diphenolase activity)=16.5 μM[113] IC (diphenolaseSilybin activity)=35.9 μM[113] 50 μ 50 IC50 (monophenolase activity)=3.2 M[113] IC (monophenolase activity)=1.7 μM [113] μ 50 IC50 (diphenolaseOH activity)=28.8 M [113] OH μ OCH IC50 (diphenolase activity)=12.1 M[113] 3 O O OH HO O OCH HO O O 3 Figure 13. Chemical structures and IC50 values against mushroom tyrosinase of lignans isolated from OH OH OH OH Opilia amentacea and SilybumOH Omarianum. Unless otherwiseOH Ospecified, IC50 values refer to the Silychristin A Silybin diphenolase activity of the enzyme. μ IC50 (monophenolase activity)=3.2 M[113] IC (monophenolase activity)=1.7 μM [113] μ 50 IC50 (diphenolase activity)=28.8 M [113] IC (diphenolase activity)=12.1 μM[113] 50 Higher inhibition against monophenolase than diphenolase activity of mushroom tyrosinase Figure 13. Chemical structures and IC50 valuesvalues against against mushroom mushroom tyrosi tyrosinasenase of lignans isolated from were reported also for xanthohumol and50 other chalcones isolated from Humulus lupulus [115] (Figure Opilia amentaceaamentaceaand andSilybum Silybum marianum marianum. Unless. Unless otherwise otherwise specified, specified, IC values IC50 refer values to the refer diphenolase to the 14). 50 activitydiphenolase of the activity enzyme. of the enzyme.

O O O Higher inhibition againstHO monophenolaseHO than diphenolaseHO activity of mushroom tyrosinase 1-(2,3,5-trihydroxy-4-methylphenyl)hexane-1-one were reported also for xanthohumolμ OH and other chalconesOH isolated from OHHumulus lupulus [115] (Figure IC50 (monophenolase activity)=125.34 M[114] μ OH OH OH IC50 (diphenolase activity)=291.34 M [114] 14). 1-(2,3,5-trihydroxy-4-methylphenyl)octane-1-one (4E)-1-(2,3,5-trihydroxy-4-methylphenyl)dec-4-en-1-one μ μ IC50 (monophenolase activity)=480.51 M [114] IC50 (monophenolase activity)=83.98 M[114] μ μ IC50 (diphenolase activity)=616.31 M[114] IC50 (diphenolase activity)=488.65 M [114] O O O HO HO HO 1-(2,3,5-trihydroxy-4-methylphenyl)hexane-1-one OH OH OH μ OH OH OH IC50 (monophenolase activity)=125.34 M[114]HO OH O OH O OH μ OH OH OH IC50 (diphenolase activity)=291.34 M [114] 1-(2,3,5-trihydroxy-4-methylphenyl)octane-1-one (4E)-1-(2,3,5-trihydroxy-4-methylphenyl)dec-4-en-1-one 4’-O-methylxanthohumol XanthohumolC Xanthohumol μ μ O O IC50 (monophenolaseO activity)=480.51O M [114] IC50O (monophenolaseO activity)=83.98 M[114] μ IC50 (diphenolase activity)=616.31 M[114] μ IC (diphenolase activity)=488.65 μM [114]μ IC (monophenolase activity)=15.4 μM [115] IC50 (monophenolase activity)=34.3 M[115]50 IC50 (monophenolase activity)=20.6 M[115] 50 μ μ μ IC50 (diphenolase activity)=70.5 M[115] IC50 (diphenolase activity)=41.3 M [115] IC50 (diphenolase activity)=31.1 M[115] OH OH OH OH OH HO OH O OH O OH HO O O OH 6-Prenylnaringenin Xanthohumol 4’-O-methylxanthohumol XanthohumolC O O Flavokawain C O O IC (monophenolaseO O activity)=38.1 μM [115] OH O 50 IC μ(diphenolase activity)=77.2 μM[115] μ IC (monophenolaseO O activity)=15.4 μM [115] IC50 (monophenolase activity)=34.350 M[115] IC50 (monophenolase activity)=20.6 M[115] 50 μ μ μ μ IC50 (diphenolase activity)=70.5 M[115] IC50 (diphenolase activity)=41.3 M [115] IC50 (diphenolaseIC50 (monophenolase activity)=31.1 activity)=60.2 M[115] M [115] μ IC50 (diphenolase activity)=106.7 M[115] OH OH OH OH OH HO O O OH HO O XanthohumolO B OH 6-Prenylnaringenin IC (monophenolase activity)=22.1 μM[115] Isoxanthohumol 50 Flavokawain C μ μ IC50 (monophenolase activity)=38.1 M [115] IC50 (diphenolase activity)=46.7 M[115] IC (monophenolase activity)=77.4OH O μM [115] O O 50 IC (diphenolaseO O activity)=77.2 μM[115] O O IC (diphenolase activity)=157.4 μ50M [115] μ 50 IC50 (monophenolase activity)=60.2 M [115] μ IC50 (diphenolase activity)=106.7 M[115] Figure 14. ChemicalChemical structures structures and IC 50 valuesvaluesOH against againstOH mushroom mushroom tyro tyrosinasesinase of of phenolic phenolicOH compounds compounds O OH HO O isolatedisolated from SyzygiumXanthohumol polyanthum B and Humulus lupulus. μ Isoxanthohumol IC50 (monophenolase activity)=22.1 M[115] μ IC50 (diphenolase activity)=46.7 M[115] IC (monophenolase activity)=77.4 μM [115] O O 50 O O IC (diphenolase activity)=157.4 μM [115] SeveralHigher inhibitionp-coumarate against esters monophenolase from Breynia thanofficinalis50 diphenolase leaves activityhave been of mushroom describedtyrosinase as mushroom were reported also for xanthohumol and other chalcones isolated from Humulus lupulus [115] (Figure 14). tyrosinase inhibitors, the most active of which being seguinoside A p-coumarate (IC50 = 16.9 μM) SeveralFigure 14.p -coumarateChemical structures esters and from IC50Breynia values against officinalis mushroomleaves havetyrosinase been of described phenolic compounds as mushroom isolated from Syzygium polyanthum and Humulus lupulus. tyrosinase inhibitors, the most active of which being seguinoside A p-coumarate (IC50 = 16.9 µM) [116]

Several p-coumarate esters from Breynia officinalis leaves have been described as mushroom tyrosinase inhibitors, the most active of which being seguinoside A p-coumarate (IC50 = 16.9 μM)

Cosmetics 2019, 6, 57 13 of 33 Cosmetics 2019, 6, x FOR PEER REVIEW 14 of 33

(Figure[116] (Figure 15), whereas 15), whereas less elessffective effectiv weree were feruloyl feruloyl sucrose sucrose esters esters from fromOryza Oryza sativa sativaroots roots [ 117[117]] andand epicatechinepicatechin glucosydesglucosydes isolatedisolated fromfrom BreyniaBreynia fruticosafruticosa[ [118]118] (Figure(Figure 15 15).). Cosmetics 2019, 6, x FOR PEER REVIEW 14 of 33

O [116] (Figure 15), whereas less effective were feruloyl sucrose estersO from Oryza sativa roots [117] and HO epicatechin glucosydes isolated fromO O Breynia fruticosaOH [118] (Figure 15). O Butyl p-coumarate HO HO O μ O IC50 =75.4 M[116] O O O HO O O O HO O O OH O HO OH HO O Butyl p-coumarate HO Methylp-coumarate SeguinosideHO A p-coumarateO μ O IC50 =75.4 M[116] IC =143.6 μM[116] IC =16.9 μM[116] 50 O 50 O HO O O OH

O HO OH HO O O OH Methylp-coumarate Seguinoside A p-coumarate O OH IC O=143.6 μM[116] IC =16.9 μM[116] 50 50 O O O HO HO HO OH HO O HO O O OH OH O O OH Robustaside A Glucopyranose-1,6-di-O-p-coumaroyl ester O μ OH O μ IC50 =69.1 M [116] IC50 =156.6 M[116] O O O HO HO HO HO OOH HO O O OH OH OH OH OH Robustaside A Glucopyranose-1,6-di-O-p-coumaroyl ester O H3CO O μ O H3CO μ O IC50 =69.1 M [116] IC50 =156.6 M[116] O O O OH OHO O OH O OH HO HO HO O O HO O O O HOH3CO O O H3CO OH O 3-Acetyl-7-methoxyepicatechin-5-O-(6-isobutanoyl)glucopyranosidO e O O 3-Acetyl-7-methoxyepicatechin-5-O-[6-(2-methylbutanoyl)]glucopyO ranoside μ O O IC50 (monophenolase activity)=890HO M[118] HO IC (monophenolase activity)=820 μM [118] HO μ O O HO 50 O O IC50 (diphenolase activity)=770 M [118]OH OH μ IC50 (diphenolase activity)=750 M[118] 3-Acetyl-7-methoxyepicatechin-5-O-(6-isobutanoyl)glucopyranoside 3-Acetyl-7-methoxyepicatechin-5-O-[6-(2-methylbutanoyl)]glucopyranoside O μ O IC50 (monophenolase activity)=890 M[118] IC (monophenolase activity)=820 μM [118] μ 50 IC50 (diphenolase activity)=770 M [118] μ O O IC50 (diphenolase activity)=750 M[118] O O HO O HO HO O O OO O O OH O HO OH O O OOH O O OH O HO O O HO O O O O O O HO O OH O O OH 3,6-Diferuloyl-3’,6’-diacetylsucroseO OH O HO OH O OH OH O O OCH3 O Smilaside A OCH3 μ O O O O IC50 =47.33 M [117] μ O OH O IC50 =45.13 M [117]OH 3,6-Diferuloyl-3’,6’-diacetylsucrose OCH3 Smilaside A OCH3 μ H3CO H3CO IC50 =47.33 M [117] μ IC50 =45.13 M [117] HO HO H3CO H3CO HO HO FigureFigure 15.15. Chemical structuresstructures andand ICIC5050 values against mushroom tyrosinasetyrosinase of phenolic compoundscompounds isolatedisolatedFigure fromfrom 15. Breynia ChemicalBreynia andand structures OryzaOryza sativaandsativa IC50 species.species. values against UnlessUnless mushroom otherwiseotherwise tyro specified,specified,sinase of phenolic ICIC5050 values compounds refer toto thethe diphenolasediphenolaseisolated activityfromactivity Breynia ofof thethe and enzyme.enzyme. Oryza sativa species. Unless otherwise specified, IC50 values refer to the diphenolase activity of the enzyme. Interestingly,Interestingly, polyamine polyamine derivatives derivatives comprising comprising coumaroyl coumaroyl and caandffeoyl caffeoyl moieties moieties from beefrom pollen bee of QuercusInterestingly, mongolica have polyamine been also derivatives described comprising as tyrosinase coumaroyl inhibitors and [caffeoyl119]. moieties from bee pollenpollen of Quercus of Quercus mongolica mongolica have have been been also also described described asas tyrosinase tyrosinase inhibitors inhibitors [119]. [119]. Finally, moderate-high activity has been very recently reported for phenylethylchromones isolated Finally,Finally, moderate-high moderate-high activity activity has has beenbeen very recentlyrecently reported reported for for phenylethylchromones phenylethylchromones fromisolatedisolated the from agarwood from the theagarwood ofagarwoodAquilaria of of Aquilaria plantsAquilaria [plants120 plants,121 [120,121]] and anthraquinones and and anthraquinones anthraquinones from fromCassia from Cassia Cassia tora toraseeds seedstora seeds[ 122] (Figure[122][122] (Figure 16 ).(Figure 16). 16).

6,8-dihydroxy-2-[2-(4-methoxyphenyl)ethyl]chromone μ OH IC50 =51.5 Mμ [120] OH IC50 =51.5 M [120] OCH3 OCH3 OH OCH3 OCH3 OHO O H3CO O O O H3CO O HO HO HO HO O HOOH O HO O 6-Hydroxy-7-methoxy-2-[2-(3-hydroxy-4-methoxyphenyl)ethyl]chromone O OH O O 5,6-Dihydroxy-2-(2-phenylethyl)chromone μ 6-Hydroxy-7-methoxy-2-[2-(3-hydroxy-4-methoxyphenyl)ethyl]chromIC50 =89.0 M [120]one 5,6-Dihydroxy-2-(2-phenylethyl)chromoneIC =172.6 μM[121] IC =89.0 μM [120] 50 50 μ IC50 =172.6 M[121] O O O

H3CO CH3 CH3 CH3 O O O H CO CH CH CH 3 H3CO OH3 H3CO OH 3 OGlu 3 CH3O O OCH3 OH O OCH3 OH O OCH3 H CO OH H CO OH OGlu 3 Chrysoobtusin 3 CH3O O OCH3 7-MethoxyobtusifolinOH O OCH3 Obtusifolin-2-O-glucosideOH O OCH3 IC =3.0 μM [122] 50 μ μ Chrysoobtusin IC50 =7.0 M [122] IC50 =9.2 M [122] 7-Methoxyobtusifolin Obtusifolin-2-O-glucoside IC =3.0 μM [122] 50 IC =7.0 μM [122] IC =9.2 μM [122] FigureFigure 16. Chemical 16. Chemical structures structures and and IC50 IC50 values values (referring(referring to50 to the the diphenolase diphenolase activity activity50 of the of enzyme) the enzyme) against mushroom tyrosinase of phenolic compounds isolated from Aquilaria and Cassia tora species. againstFigure 16. mushroom Chemical tyrosinase structures of and phenolic IC50 values compounds (referring isolated to the from diphenolaseAquilaria and activityCassia of torathe species.enzyme) against mushroom tyrosinase of phenolic compounds isolated from Aquilaria and Cassia tora species.

Cosmetics 2019, 6, 57 14 of 33 Cosmetics 2019, 6, x FOR PEER REVIEW 15 of 33

6.6. Synthetic Phenolic Inhibitors of Mushroom Tyrosinase InIn thethe lastlast yearsyears severalseveral studiesstudies havehave beenbeen directeddirected toto thethe developmentdevelopment ofof novelnovel tyrosinasetyrosinase inhibitorsinhibitors inspiredinspired by by natural natural sca scaffolds,ffolds, which which should should overcome overcome stability, stability, efficacy, efficacy, and isolationand isolation yield issues.yield issues. One of theOne main of exploitedthe main sca exploitedffolds is hydroxycinnamicscaffolds is hydroxycinnamic acid: indeed several acid: hydroxycinnamic indeed several acidhydroxycinnamic analogues have acid been analogues synthesized have through been synthesized the most disparate through approaches the most disparate [123–141 ],approaches leading in some[123–141], cases leading to very potent in some mushroom cases to very tyrosinase potent inhibitors mushroom (Figure tyrosinase 17), such inhibitors as 2,4-dihydroxycinnamides (Figure 17), such as (IC2,4-dihydroxycinnamides50 = 0.0112–0.16 µM) [132 (IC,13350 ].= A thiophenyl0.0112-0.16 derivativeμM) [132,133]. of 2,4-dihydroxycinnamic A thiophenyl derivative acid has alsoof exhibited2,4-dihydroxycinnamic a very low IC 50acidvalue has (0.013 alsoµ M)exhibited against a the very monophenolase low IC50 value activity (0.013 of theμM) enzyme against [134 the]. Anmonophenolase IC50 value of activity 1.10 µM of for the the enzyme monophenolase [134]. An activity IC50 value of mushroom of 1.10 μ tyrosinaseM for the hasmonophenolase been instead calculatedactivity of mushroom for a cyclopentanone tyrosinase has compound been instead related calculated to 3-hydroxy-4-methoxycinnamic for a cyclopentanone compound acid related [135]. Quiteto 3-hydroxy-4-methoxycinnami low IC50 values have beenc acid reported [135]. also Quite for low dihydrolipoic IC50 values acid have conjugates been reported of caff eicalso acid for anddihydrolipoic its methylester acid [136conjugates,137], as of well caffeic as for acid thiochromanone and its methylester compounds [136,137], [138], diamides as well [ 139as], for or estersthiochromanone [140,141] related compounds to p-coumaric [138], diamides acid. [139], or esters [140,141] related to p-coumaric acid.

IC =0.14 μM [132] X,Y= (CH2)2NMe(CH2)2 50 μ X,Y= (CH2)2O( CH2)2 IC50 =0.06 M [132] μ OH O X=H, Y= cyclopentyl IC50 =0.12 M [132] X μ N X=H, Y= cyclohexyl IC50 =0.16 M [132] Y IC =0.0256 μM [133] HO X=H, Y= phenyl 50 μ X,Y= ethyl IC50 =0.0112 M [133]

O COOH OH O HO SH S S O H CO HO 3 OH OR HO IC50 (monophenolase activity)= OCH HO IC50 (monophenolase activity)= 3 R=H 1.10 μM [135] R=H, IC (monophenolase activity) =2.0 μM, IC (diphenolase activity) =3.22 μM [137] 0.013 μM [134] 50 R= methyl 50 μ μ R=methyl, IC50 (monophenolaseactivity) =0.83 M,IC50 (diphenolase activity) =0.05 M [136]

O O O n Br [ ] N N H H HO S HO OH μ μ IC50 =4.1 M [138] n=2-4, IC50 =3.4-6.5 M [139]

O O

O O O

HO HO

H3CO IC =2.0 μM [140] IC =10.6 μM [140] 50 50

FigureFigure 17.17. ChemicalChemical structures structures and and IC IC5050 valuesvalues against against mushroom tyrosinase of syntheticsynthetic hydroxycinnamichydroxycinnamic acid derivatives.derivatives. Unless otherwise specified,specified, ICIC5050 values refer to thethe diphenolasediphenolase activityactivity ofof thethe enzyme.enzyme.

SimilarSimilar scaffolds scaffolds are are chalcones chalcones [142–156], [142–156 characte], characterizedrized by an enone by an moiety enone linked moiety to a phenyl linked toring a as phenylwell. Particularly ring as active well. as Particularly mushroom tyrosinase active as inhibitors mushroom are 2,2 tyrosinase′,4,4′-tetrahydroxychalcone inhibitors are 2,2(IC050,4,4 = 00.08-tetrahydroxychalcone μM) and its derivatives (IC50 = [149],0.08 µ followedM) and its by derivatives azachalcones [149 ],(IC followed50 = 1.70–2.30 by azachalcones μM) [150], (ICchalcone50 = 1.70–2.30 oximes (ICµM)50 = [1504.5–8], chalconeμM) [151], oximes and a (ICchalcone50 = 4.5–8 basedµ M)pyrazoline [151], and(IC50 a = chalcone 4.72 μM) based [152] pyrazoline(Figure 18).(IC Quite50 = low4.72 ICµ50M) values [152] have (Figure been 18 ).reported Quite lowalso ICfor50 chalcone-21values have (IC been50 = 6.8 reported μM) [153], also for6-methoxy-3,4-dihydronaphthalenone chalcone-21 (IC50 = 6.8 µM) [153], 6-methoxy-3,4-dihydronaphthalenone chalcone-like derivatives (IC50 chalcone-like= 6.19 μ derivativesM) [154], (ICaminochalcones50 = 6.19 µM) [[155],154], aminochalconesand indenone chal [155cone-like], and indenone derivatives chalcone-like [156] (Figure derivatives 18). [156] (Figure 18).

Cosmetics 2019, 6, 57 15 of 33 Cosmetics 2019, 6, x FOR PEER REVIEW 16 of 33

HO OH OH HO OH OH O O OH HO O OH OH OH O OH O IC =0.08 μM [149] 50 μ OH IC50 =0.11 M [149] μ IC50 =5.66 M [149]

OH OH OH O NO2 OH N N

N OH OH N N HO HO μ μ μ μ IC50 =1.70 M [150] IC50 =2.30 M [150] IC50 =4.77 M [151] IC50 =7.89 M [151]

O OH OH O N O O OH N HN Cl O O OH O IC =4.72 μM [152] 50 Chalcone-21 O μ μ IC50 =6.8 M [153] IC50 =6.19 M [154] N

OH OCH3 OH NH2 OH

NH2 O O O O OCH3 OH HO OH μ IC50 =9.75 M [155] μ IC50 =7.82 M [155] IC =12.3 μM [156] μ 50 IC50 =8.2 M [156]

FigureFigure 18. 18. ChemicalChemical structures structures and and IC IC5050 valuesvalues (referring (referring to to the the diphenolase diphenolase activity activity of of the the enzyme) enzyme) againstagainst mushroom mushroom tyrosinase tyrosinase of of synthetic synthetic chalcone chalcone derivatives. derivatives.

AsAs to to other other natural natural phenol-inspi phenol-inspiredred synthetic synthetic compounds compounds [157–161], [157–161], the the best best results results have have been been reportedreported for for a a carvacrol carvacrol derivative derivative cont containingaining a a 3,5-dihydroxyphenyl 3,5-dihydroxyphenyl moiety (IC 50 == 0.01670.0167 μµM)M) [159] [159 ] (Figure(Figure 19). 19). Good Good inhibition inhibition proper propertiesties have have been been exhibited exhibited also also by by some some rhododendrol rhododendrol glycosides glycosides Cosmetics(IC(IC50 201950 = =0.56–9.15, 0.56–9.156, x FOR PEER μM)µM) REVIEW[160] [160 and] and eugenol eugenol derivatives derivatives (IC (IC50 50ca.ca. 8 μ 8M)µM) [161] [161 (Figure] (Figure 19). 19 ). 17 of 33 Of course, the most potent inhibitory activity is still attributed to resorcinol derivatives

[162–170], although these compounds often suffer from toxicityOH OR concerns (the case of rhododendrol HO O μ is emblematic [6–8]) (see below). LowO IC50 values (0.39–3.62 M) have been reported for resorcinol O HO alkyl glucosides [166] (Figure 19),OH whereasO thiamidol, which is currently one of the most potent skin μ R= Glc, Xyl, Cel or Mal IC50 =0.0167 M [159] μ 50 μ depigmenting agent on the market, is not so active againstIC50 =1.51-2.30 mushroom M [160] tyrosinase (IC = 108 M) [9].

Alkyl resorcinols, such as 4-butylresorcinolHO or 4-hexylresorcinol, also exhibitedOH very low IC50 values O OH [ ]n O O O OHμ (Figure 19), particularly against the monophenolaseO activity (IC50 = 0.077OH M for 4-butylresorcinol) HO O OCH3 HO 50 μ n=3-14 [167,168]. Rather low IC valuesIC50 =8 have M [161] been determined also for resveratrol derivatives such as IC =0.39-3.62 μM [166] μ50 (E)-2,3-bis(4-hydroxyphenyl)acrylonitrileO (IC50 = 5.06 M) [169] and dihydrooxyresveratrol S OH OH glucosides [170] (Figure 19). NH N Thiamidol HO OH HO HO μ μ IC50 =0.56 M [167] IC50 =108 M[9] μ IC50 =0.33 M [168]

OR2 CN OH OHOR1 OR 1 HO OH RHO2O IC =5.06 μM [169] R1=R2=Glc, IC =12.80 μM [170] 50 OH 50 R1=Glc,R2=H, IC =2.63 μM [170] 50

FigureFigure 19. Chemical 19. Chemical structures structures and IC and50 values IC50 values (referring (referring to theto diphenolase the diphenolase activity activity of theof enzyme) the enzyme) againstagainst mushroom mushroom tyrosinase tyrosinase of synthetic of synthetic phenolic phenolic compounds. compounds.

CoumarinsOf course, are theanother most potentclass of inhibitory compounds activity able is to still efficiently attributed inhibit to resorcinol mushroom derivatives tyrosinase [162– 170], [171–174].although Coumarin these dimers compounds and derivatives often suff coerntaining from toxicity a tetracyclic concerns skeleton (the exhibited case of IC rhododendrol50 values in is the rangeemblematic 1.7–2.9 [μ6M–8 ])[172] (see (Figure below). 20), Low whereas IC50 values even higher (0.39–3.62 activityµM) has have been been reported reported for synthetic for resorcinol 3-heteroarylcoumarins [173] and umbelliferone-thiazolidinedione hybrids [174] (Figure 20).

OH R= IC =1.7 μM [172] H 50 μ R= IC50 =1.2 M [172] H O

O R OH O

O O

OH OH S OH S Br

O HO O O HO O O O O μ IC50 =0.38 M [173] IC =0.15 μM [173] μ O 50 IC50 =1.8 M [172] O O

OH N OH S HO O O μ IC50 =0.25 M [174] O

Figure 20. Chemical structures and IC50 values (referring to the diphenolase activity of the enzyme) against mushroom tyrosinase of synthetic coumarin derivatives.

7. Human and Animal Tyrosinase Phenolic Inhibitors In the last five years, several natural and synthetic phenolic compounds have been described also as inhibitors of tyrosinase from animal and human sources. Most of these studies used B16 murine melanoma cell lines as a model [52,55,75,85,95,96,99,114,122,123,127–129,132–135,138,139,151,153,155,163,175–205], although some papers using zebrafish as an in vivo whole animal model have also been published [55,116,206]. As to the human sources, data on inhibition of human recombinant or purified tyrosinase [9,207], human melanoma cells [130,136], normal human melanocytes [208–211], or human skin models consisting of reconstructed three-dimensional human epidermis [212–215] have been published

Cosmetics 2019, 6, x FOR PEER REVIEW 17 of 33

OH OR HO O O O HO OH O μ R= Glc, Xyl, Cel or Mal IC50 =0.0167 M [159] μ IC50 =1.51-2.30 M [160]

HO OH O OH [ ]n O O O OH O OH HO O OCH3 HO μ n=3-14 IC50 =8 M [161] μ IC50 =0.39-3.62 M [166] O S OH OH NH N Thiamidol Cosmetics 2019, 6, 57 HO OH HO HO 16 of 33 μ μ IC50 =0.56 M [167] IC50 =108 M[9] μ IC50 =0.33 M [168]

OR2 CN OH alkyl glucosides [166] (Figure 19), whereas thiamidol,OHOR1 which is currently one of the most OR 1 potent skin depigmenting agentHO on the market, is not soOH active against mushroom tyrosinase RHO2O IC =5.06 μM [169] R1=R2=Glc, IC =12.80 μM [170] (IC50 = 108 µM) [9]. Alkyl50 resorcinols,OH such as 4-butylresorcinol50 or 4-hexylresorcinol, also 1 2 μ R =Glc,R =H, IC50 =2.63 M [170] exhibited very low IC50 values (Figure 19), particularly against the monophenolase activity

(ICFigure50 = 0.07719. ChemicalµM for structures 4-butylresorcinol) and IC50 values [167 (referring,168]. Rather to the diphenolase low IC50 values activity have of the been enzyme) determined alsoagainst for resveratrol mushroom derivativestyrosinase of such synthetic as (E)-2,3-bis(4-hydroxyphenyl)acrylonitrile phenolic compounds. (IC50 = 5.06 µM) [169] and dihydrooxyresveratrol glucosides [170] (Figure 19). CoumarinsCoumarins are another are another class of class compounds of compounds able to efficiently able to inhibit efficiently mushroom inhibit tyrosinase mushroom [171–174].tyrosinase Coumarin[171–174 dimers]. Coumarin and derivatives dimers and co derivativesntaining a tetracyclic containing skeleton a tetracyclic exhibited skeleton IC50 exhibited values in IC 50 thevalues range 1.7–2.9 in the range μM [172] 1.7–2.9 (FigureµM[ 20),172] whereas (Figure 20even), whereas higher activity even higher has been activity reported has been for reportedsynthetic for 3-heteroarylcoumarinssynthetic 3-heteroarylcoumarins [173] and umbelliferone-thiazolidinedione [173] and umbelliferone-thiazolidinedione hybrids [174] hybrids (Figure [ 17420).] (Figure 20).

OH R= IC =1.7 μM [172] H 50 μ R= IC50 =1.2 M [172] H O

O R OH O

O O

OH OH S OH S Br

O HO O O HO O O O O μ IC50 =0.38 M [173] IC =0.15 μM [173] μ O 50 IC50 =1.8 M [172] O O

OH N OH S HO O O μ IC50 =0.25 M [174] O

FigureFigure 20. 20.ChemicalChemical structures structures and and IC50 IC values50 values (referring (referring to the to thediphenolase diphenolase activity activity of the of theenzyme) enzyme) againstagainst mushroom mushroom tyrosinase tyrosinase of synthetic of synthetic coumarin coumarin derivatives. derivatives. 7. Human and Animal Tyrosinase Phenolic Inhibitors 7. Human and Animal Tyrosinase Phenolic Inhibitors In the last five years, several natural and synthetic phenolic compounds have been described In the last five years, several natural and synthetic phenolic compounds have been described also as inhibitors of tyrosinase from animal and human sources. Most of these studies used B16 also as inhibitors of tyrosinase from animal and human sources. Most of these studies used B16 murine melanoma cell lines as a model [52,55,75,85,95,96,99,114,122,123,127–129,132–135,138,139,151, murine melanoma cell lines as a model 153,155,163,175–205], although some papers using zebrafish as an in vivo whole animal model have [52,55,75,85,95,96,99,114,122,123,127–129,132–135,138,139,151,153,155,163,175–205], although some also been published [55,116,206]. As to the human sources, data on inhibition of human recombinant papers using zebrafish as an in vivo whole animal model have also been published [55,116,206]. As or purified tyrosinase [9,207], human melanoma cells [130,136], normal human melanocytes [208–211], to the human sources, data on inhibition of human recombinant or purified tyrosinase [9,207], or human skin models consisting of reconstructed three-dimensional human epidermis [212–215] have human melanoma cells [130,136], normal human melanocytes [208–211], or human skin models been published (Figure 21). The results of clinical trials have also been reported for well recognized consisting of reconstructed three-dimensional human epidermis [212–215] have been published skin depigmenting agents [216,217] such as thiamidol, that, as stated also above, is one of the most striking examples of a pigmentation inhibitor exhibiting significant higher activity on human than on mushroom tyrosinase [9,218]. This nicely exemplifies the differential effects of tyrosinase inhibitors on the human and mushroom enzymes, likely due to the presence of additional amino acids in the hydrophobic substrate-binding pocket of mushroom tyrosinase [218]. Cosmetics 2019, 6, x FOR PEER REVIEW 18 of 33

(Figure 21). The results of clinical trials have also been reported for well recognized skin depigmenting agents [216,217] such as thiamidol, that, as stated also above, is one of the most striking examples of a pigmentation inhibitor exhibiting significant higher activity on human than on mushroom tyrosinase [9,218]. This nicely exemplifies the differential effects of tyrosinase inhibitors on the human and mushroom enzymes, likely due to the presence of additional amino Cosmetics 2019, 6, 57 17 of 33 acids in the hydrophobic substrate-binding pocket of mushroom tyrosinase [218].

O HO OH O N OH S HO O S NH N Bis(4-hydroxybenzyl)sulfide (T1) 20% inhibition at 50 μM [209] O HO OH 2-hydroxypyridine-N-oxide-embedded 6-hydroxyaurone Thiamidol μ IC50 =0.35 M [207] μ OH IC50 =1.1 M[9] OH HO HO OH O O O Sulfuretin N H O IC =20 μM [208] O 50 2-[2-methyl-5-(propan-2-yl)anilino]-2-oxoethyl-(2E)-3-(2,4-hydroxyphenyl)prop-2-enoate 91.9% inhibition at 135 μM [130] OH COOH HO SO O OCH 3 OH 3 S SH O HO O HO OCH3 OH O H CO Pectolinarigenin HO 3 Luteolin 7-sulfate OH O 53.1% inhibition at 30 μM [213] 2-S-lipoylcaffeic acid methyl ester (LCAME) IC =16 μM [210] IC =34.7 μM [136] 50 50 OH OH OH H3CO O OH H CO O O 3 OH HO O HO HO OH OH O HO Swertiajaponin OH O OH O HO HO O Spinosin OH HO CN

O CN HO H CO COOCH 3 S 3 2-(3,4-dihydroxybenzylidene)malononitrile (BMN11) NHCOCH HO 3

OCH3 Methyl-2-acetylamino-3-(4-hydroxyl-3,5-dimethoxybenzoylthio)propanoate (MAHDP)

Figure 21. Chemical structures and inihibitory potency (where available) of the main human tyrosinaseFigure 21. inhibitors.Chemical structures and inihibitory potency (where available) of the main human tyrosinase inhibitors. Of course, care should be taken when cellular or in vivo models are considered, since several alternativeOf course, or additional care should biochemical be taken mechanisms when cellular can beor operative,in vivo models involving are e.g.,considered, tyrosinase since expression several andalternative interference or additional with the complex biochemical signaling mechanisms pathways incan melanogenesis, be operative, which involving could resulte.g., intyrosinase melanin reductionexpression as and well. interference As an example, with the it hascomplex been reportedsignaling thatpathways both ferulic in melanogenesis, and caffeic acid which inhibited could melaninresult in productionmelanin reduction in B16 melanomaas well. As cells,an example, but ferulic it has acid been reduced reported tyrosinase that both activity ferulic byand directly caffeic bindingacid inhibited to the enzyme,melanin whereas production no binding in B16 was melanoma observed cells, in the but case ferulic of caff eicacid acid reduced [177]. Aparttyrosinase from theactivity direct by inhibition directly ofbinding tyrosinase to the activity, enzyme, the wherea anti-melanogenics no binding activity was ofobserved resorcinol in inthe B16F10 case of cells caffeic has beenacid attributed[177]. Apart to thefrom inhibition the direct of cAMPinhibition signaling of ty androsinase activation activity, of p38 the MAPK anti-melanogenic [179]. The same activity applies of e.g.,resorcinol to moracin in B16F10 J [181 cells], 4,5-dica has beenffeoylquinic attributed acid to [the183 ],inhibition chrysin [of187 cAMP], casuarictin signaling [178 and], and activation synthetic of compoundsp38 MAPK [[179].135,136 The,153 same,197], applies which havee.g., beento moracin reported J [181], to both 4,5-dicaffeoylquinic inhibit intracellular acid tyrosinase [183], chrysin activity and[187], regulate casuarictin melanogenesis-related [178], and synthetic protein compounds expression. [135,136,153,197], which have been reported to both Ininhibit any intracellular case, there is tyrosinase no doubt activity that human and regulate tyrosinase melanogenesis-re inhibitors arelated really protein important expression. in the perspectiveIn any ofcase, cosmetics there is development. no doubt that human tyrosinase inhibitors are really important in the perspective of cosmetics development. 8. Structural Requirements for the Design of Tyrosinase Inhibitors 8. StructuralSeveral inhibitionRequirements mechanisms for the Design have been of reportedTyrosinase for Inhibitors the tyrosinase inhibitors described above, highlightingSeveral theinhibition importance mechanisms of key structural have been moieties reported as responsible for the tyrosinase for the observed inhibitors effects. described As an example,above, highlighting in silico analysis the importance showed that of key the structural flavonoids moieties spinosin as and resp swertiajaponinonsible for the act observed as competitive effects. inhibitorsAs an example, of the enzymein silico byanalysis binding showed to the activethat th sitee flavonoids through hydrogen spinosin bondingand swertiajaponin and hydrophobic act as interactionscompetitive inhibitors [212,214], of as the is the enzyme case alsoby binding for condensed to the active tannins site fromthrough diff erenthydrogen sources bonding based and on molecularhydrophobic docking interactions [96,98 ,99[212,214],]. Chelation as is the of copper case also ions for by condensed adjacent hydroxyltannins from groups different on the sources B ring has also been suggested as a feasible inhibition mechanism for proanthocyanidins [101,102,106]. Copper chelation as well as hydrophobic and hydrogen bonding within the active site resulting in secondary structural changes have been validated for brazilein, too [190]. Generally, the number and location of phenolic hydroxyl groups significantly affect the tyrosinase inhibitory activity in the case of flavonoids [62]. The presence of sugar moieties as well as the glycosylation pattern is also important: Cosmetics 2019, 6, 57 18 of 33 for example, flavanol containing 5-O- and 7-O-sugar moieties are more potent inhibitors compared to related not glycosylated compounds [118]. Interestingly, quercetin-3-O-α-L-rhamnopyranoside possesses tyrosinase inhibition acitivity whereas 3-glycosylated flavonols were not active, suggesting that the rhamnosyl group at C-3 played an indispensable role in the anti-tyrosinase activity [59]. The impact of chemical structure on the tyrosinase inhibition properties is emblematic also in the case of hydroxystilbene compounds, in which the presence of the inter-ring double bond, or of methylated or glucosylated phenolic moieties strongly affect the IC50 value [55,60,63]. The presence of the sulfur atom able to chelate the copper ions has been described as essential for the inhibitory activity in the case of bis(4-hydroxybenzyl) sulfide from Gastrodia elata [209]. An interaction driven mainly by electrostatic forces has instead been brought forth in the case of aloe-emodin, and this would induce changes in conformation of the enzyme preventing binding of the substrate [79]. Interactions with specific amino acid residues in the active site pocket of the enzyme have been evidenced by molecular dynamics simulation in the case of pyrogallol [77] and quercetin-7-O-α-L-rhamnoside [182]. Binding via Met280 residue has been in particular predicted for baicalein [71]. In the case of obtusin derivatives, different interactions inside and/or outside the active site of the enzyme have been proposed [122]. Interactions with specific amino acids in the tyrosinase binding pocket has been predicted also for synthetic inhibitors, such as hydroxylated chalcone derivatives [151,155], 2-(3, 4-dihydroxybenzylidene) malononitrile [215], or carvacrol derivatives featuring a 2,4-dihydroxyphenyl moiety, able to interact with amino acid HIS85 through the 2-hydroxy group [159]. Other important structural requirements have been also underlined: for example, a three carbons tether with a diamide-link in dimeric cynnamoyl analogues is required to efficiently inhibit melanin production on α-MSH stimulated B16F1 cells [139]. The same has been reported for the alkyl spacer in the case of resorcinol alkyl glucosides [166]. The presence of resorcinol and glucose moieties has also reported to be important [162]. Hydrogen bonds and aromatic (hydrophobic) interactions with tyrosinase have been predicted by docking simulation for the potent inhibitor MHY2081 [129].

9. New Trends in the Search for Tyrosinase Inhibitors Recently, a rather large number of studies have been directed to the development of novel assays for the search and assessment of tyrosinase inhibitors. These have been prompted in part by the need to avoid interferences due to color development associated to the oxidation of phenolic compounds acting as substrates of mushroom tyrosinase [219,220]. As an example, a colorimetric assay based on a combination of chitosan-stabilized platinum nanoparticels, catechol, tyrosinase, and 3,3’,5,5’-tetramethylbenzidine as the probe being oxidized to a yellow diamine has been proposed [221]. A microreactor-detector based on the use of a gold disk for tyrosinase immobilization and a carbon disk as a working electrode able to amperometrically detect dopaquinone formation starting from l-tyrosine has also been described [222]. Immobilized tyrosinase has been used also coupled to capillary electrophoresis [223,224]. A different approach is based on thin layer chromatography (TLC) bioautographic assay, with the reported advantages of a low cost and sensitive methodology [225], whereas ultrafiltration coupled with HPLC has been proposed as a strategy for identification of specific inhibitors of the enzyme [226]. The use of dopamine functionalized quantum dots exhibiting strong fluorescence undergoing quenching upon dopamine oxidation by the enzyme have also been proposed [227]. Alternatives to mushroom tyrosinase have also been developed, such as recombinant tyrosinase from Polyporus arcularius overproduced in Escherichia coli [228]. Perhaps one of the main drawbacks of the “classic” mushroom tyrosinase inhibition assay is that it does not enable to distinguish between skin whitening tyrosinase inhibitors and leukoderma inducing phenols, that is compounds which are readily oxidized by the enzyme leading to the generation of cytotoxic reactive quinones [229]. To this aim, a convenient screening method was reported, involving spectrophotometric monitoring of the incubation mixtures followed by reduction with NaBH4 and Cosmetics 2019, 6, 57 19 of 33

HPLC analysis. Under these conditions it was indeed possible to differentiate potential toxic enzyme substrates, such as rhododendrol, raspberry ketone, and p-susbstitued phenols, from tyrosinase inhibitors like ellagic acid [38]. Another issue to take into account is the possibility that the inhibitor compound may react with dopaquinone to give an adduct that is not further oxidized. In this way dopaquinone is subtracted from the melanogenic pathway and a decrease of pigmentation is observed though the activity of the enzyme that has not been affected to any extent. This could be the case of compounds comprising a resorcinol moiety [230], like phenylethyl resorcinol and resveratrol derivatives, or a thiazolidine unit that may undergo ring opening disclosing the thiol functionality [231]. Of course, the possible toxicity associated with the occurrence of this diverted reaction pathways should be carefully evaluated. Another emerging research trend is the development of new formulations for improving the bioavaialability and hence the efficiency of tyrosinase inhibitors to be used as skin depigmenting agents. As an example, a polyethylene glycol/polycaprolactone (PEG/PCL) copolymer has shown good encapsulation efficiency toward the potent skin lightening agent adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxybenzamide (known as AP736) [232]. On the same line, hybrid poly (lactic-co-glycolic acid) (PLGA) microspheres have been proposed to improve the encapsulation and control the release of amphiphilic compounds such as phenylethyl resorcinol, leading to 40% enhancement of tyrosinase inhibition in mouse melanoma cells [233]. Ethosomes formulations as well as nanostructured lipid carriers (NLCs) with high encapsulation efficiency and stability have also been developed for the delivery of phenylethyl resorcinol into the skin, exhibiting higher tyrosinase inhibition compared to other formulations in B16 melanoma cells [234,235]. Increased loading and chemical stability was achieved also by the use of smartPearls combined with the UV abosorber Tinosorb S [236]. SmartPearls consisting of mesoporus silica particles have been combined also with glabridin to enhance its water solubility by a factor higher than four and therefore improve its dermal bioavailability [237]. A 20-fold increase of tyrosinase inhibition activity has also been reported for a glabridin/hydroxypropyl-β-cyclodextrin inclusion complex [238]. Gallic acid-loaded cationic niosomes composed of Brij 52/cholesterol/cetyltrimethylammonium bromide at 7:3:0.65 have shown high stability and tyrosinase inhibition in B16F10 melanoma cells, due to controlled release of the phenol over 24 h [239]. Monoolein and lauroylcholine chloride-based vesicles have proven efficient at delivering 3-hydroyxcoumarin to the deeper skin layers [240]. NLCs as well as solid lipid nanoparticles (SLNs) have been employed instead for resveratrol encapsulation, enhancing its tyrosinase inhibitory activity [241,242] Good results have been obtained also with nanoparticles from calli of resveratrol-enriched rice [243]. SLNs for encapsulation of curcumin and a synthetic inhibitor, (Z)-5-(2,4-dihydroxy benzylidene)thiazolidine-2,4-dione (MHY498), have also been described [244,245]. Improved performance as a cosmetic ingredient has been finally reported for dextran-rosmarinic acid conjugates [246].

10. Conclusions and Perspectives The regulation of melanogenesis is highly complex and a number of cellular factors are involved in this process. Tyrosinase, the central enzymatic system of melanogenesis, catalyzing the rate-limiting step of the pathway, has become one of the most important targets for the control of hyperpigmentary disorders of pathological or cosmetic relevance. As a result, in recent years, an impressive number of inhibitors have been reported that exert their action at the level of tyrosinase. In general, given the availability and the ease of purification, tyrosinase from Agaricus bisporus mushroom is the most frequently used model for screening potential candidates in the development of skin-whitening substances, while human and mouse melanocytic lysates are used to a lesser extent. Cosmetics 2019, 6, 57 20 of 33

It is interesting to note that despite the diversity of natural inhibitors, a large number of tyrosinase inhibitors are phenolic in nature. Many researchers have designed appropriate scaffolds inspired by the structure of natural compounds and developed novel synthetic inhibitors. A valuable support in these studies has been provided by the molecular docking approach that allowed to rationalize the critical structural elements responsible for the inhibitory activity of natural compounds providing a guide for the design of more effective synthetic bioinspired inhibitors. In particular, from the survey of the recent literature reported in this paper the presence of at least one 2,4-dihydroxyphenyl (resorcinol) moiety stands as an essential factor to achieve effective tyrosinase inihibition properties. However, hydroxycinnamic acids possibily “activated” by suitable substituents are emerging as valid alternative depigmenting agents which, even though in most cases are of synthetic origin, should not, in principle, present toxicity issues associated with the entrapment of dopaquinone as briefly discussed in the previous paragraphs. More in general, there are several issues that should be carefully considered in the development of the research in the field of tyrosinase inhibitors for the treatment of skin hyperpigmentation. At present, though a wide range of tyrosinase inhibitors from natural and synthetic sources have been reported, only a few of them, in addition to being effective, are known as safe compounds. No significant advances concerning toxicity issues of tyrosinase inhibitors seem to emerge from the literature survey carried out for this review, the relevant papers just reporting the results of in vitro cytotoxicity experiments [49,52,75,81,95,126,129,131–133,136,137,147,163,176–178,184,185,192,198,202, 203,207,210,212,214,215,239,240,242,245] and only a few of in vivo experiments on zebrafish [130,206, 209]. Therefore, it is essential to examine the efficacy and safety of inhibitors by checking e.g., whether or not the candidate inhibitor is substrate of tyrosinase being modified on exposure to the enzyme. Once this first level of safety assessment has been passed, in vivo experiments using reconstructed three-dimensional human epidermis that has mostly replaced animal models tests should be carried out before the compound could be considered for clinical trials in the perspectives of its use in medicinal and cosmetic applications. Future directions of the research on pigmentation control by tyrosinase modulation also include the development of highly specific assays of the enzymatic activity as well as the appropriate use of innovative formulations for boosting the efficacy of the inhibitors by enhancing their bioavailability.

Supplementary Materials: The following are available online at http://www.mdpi.com/2079-9284/6/4/57/s1, Table S1: Main natural phenolic inhibitors of mushroom tyrosinase. Author Contributions: L.P. and A.N. wrote the paper. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest.

References

1. Zolghadri, S.; Bahrami, A.; Hassan Khan, M.T.; Munoz-Munoz, J.; Garcia-Molina, F.; Garcia-Canovas, F.; Saboury, A.A. A comprehensive review on tyrosinase inhibitors. J. Enzyme Inhib. Med. Chem. 2019, 34, 279–309. [CrossRef][PubMed] 2. Kumari, S.; Tien Guan Thng, S.; Kumar Verma, N.; Gautam, H.K. Melanogenesis inhibitors. Acta Dermatol. Venereol. 2018, 98, 924–931. [CrossRef][PubMed] 3. Pillaiyar, T.; Namasivayam, V.; Manickam, M.; Jung, S.H. Inhibitors of melanogenesis: An updated review. J. Med. Chem. 2018, 61, 7395–7418. [CrossRef][PubMed] 4. Gunia-Krzy˙zak,A.; Popiol, J.; Marona, H. Melanogenesis inhibitors: Strategies for searching for and evaluation of active compounds. Curr. Med. Chem. 2016, 23, 3548–3574. [CrossRef][PubMed] 5. Lee, S.Y.; Baek, N.; Nam, T.G. Natural, semisynthetic and synthetic tyrosinase inhibitors. J. Enzyme Inhib. Med. Chem. 2016, 31, 1–13. [CrossRef][PubMed] 6. Ito, S.; Wakamatsu, K. Biochemical mechanism of rhododendrol-induced leukoderma. Int. J. Mol. Sci. 2018, 19, 552. Cosmetics 2019, 6, 57 21 of 33

7. Gabe, Y.; Miyaji, A.; Kohno, M.; Hachiya, A.; Moriwaki, S.; Baba, T. Substantial evidence for the rhododendrol-induced generation of hydroxyl radicals that causes melanocyte cytotoxicity and induces chemical leukoderma. J. Dermatol. Sci. 2018, 91, 311–316. [CrossRef][PubMed] 8. Abe, Y.; Okamura, K.; Kawaguchi, M.; Hozumi, Y.; Aoki, H.; Kunisada, T.; Ito, S.; Wakamatsu, K.; Matsunaga, K.; Suzuki, T. Rhododenol-induced leukoderma in a mouse model mimicking Japanese skin. J. Dermatol. Sci. 2016, 81, 35–43. [CrossRef] 9. Mann, T.; Gerwat, W.; Batzer, J.; Eggers, K.; Scherner, C.; Wenck, H.; Stäb, F.; Hearing, V.J.; Röhm, K.H.; Kolbe, L. Inhibition of human tyrosinase requires molecular motifs distinctively different from mushroom tyrosinase. J. Investig. Dermatol. 2018, 138, 1601–1608. [CrossRef] 10. Ito, S.; Wakamatsu, K.; d’Ischia, M.; Napolitano, A.; Pezzella, A. Structure of melanins. In Melanins and Melanosomes: Biosynthesis, Biogenesis, Physiological, and Pathological Functions; Riley, P.A., Borovansky, J., Eds.; Wiley-VCH: Weinheim, Germany, 2011; pp. 167–185. 11. Panzella, L.; Ebato, A.; Napolitano, A.; Koike, K. The late stages of melanogenesis: Exploring the chemical facets and the application opportunities. Int. J. Mol. Sci. 2018, 19, 1753. [CrossRef] 12. Serre, C.; Busuttil, V.; Botto, J.M. Intrinsic and extrinsic regulation of human skin melanogenesis and pigmentation. Int. J. Cosmet. Sci. 2018, 40, 328–347. [CrossRef][PubMed] 13. Hurbain, I.; Romao, M.; Sextius, P.; Bourreau, E.; Marchal, C.; Bernerd, F.; Duval, C.; Raposo, G. Melanosome distribution in keratinocytes in different skin types: Melanosome clusters are not degradative organelles. J. Investig. Dermatol. 2018, 138, 647–656. [CrossRef][PubMed] 14. Tadokoro, R.; Takahashi, Y. Intercellular transfer of organelles during body pigmentation. Curr. Opin. Genet. Dev. 2017, 45, 132–138. [CrossRef] 15. Thong, H.Y.; Jee, S.H.; Sun, C.C.; Boissy, R.E. The patterns of melanosome distribution in keratinocytes of human skin as one determining factor of skin colour. Br. J. Dermatol. 2003, 149, 498–505. [CrossRef] [PubMed] 16. Brenner, M.; Hearing, V.J. The protective role of melanin against UV damage in human skin. Photochem. Photobiol. 2008, 84, 539–549. [CrossRef] 17. Zubair, R.; Lyons, A.B.; Vellaichamy, G.; Peacock, A.; Hamzavi, I. What’s new in pigmentary disorders. Dermatol. Clin. 2019, 37, 175–181. [CrossRef] 18. Maeda, K. Large melanosome complex is increased in keratinocytes of solar lentigo. Cosmetics 2017, 4, 49. [CrossRef] 19. Plensdorf, S.; Livieratos, M.; Dada, N. Pigmentation disorders: Diagnosis and management. Am. Fam. Physician 2017, 96, 797–804. 20. Ferreira Cestari, T.; Pinheiro Dantas, L.; Catucci Boza, J. Acquired hyperpigmentations. An. Bras. Dermatol. 2014, 89, 11–25. [CrossRef] 21. Yamaguchi, Y.; Hearing, V.J. Melanocytes and their diseases. Cold Spring Harb. Perspect. Med. 2014, 4, a017046. [CrossRef] 22. Cardinali, G.; Kovacs, D.; Picardo, M. Mechanisms underlying post-inflammatory hyperpigmentation: Lessons from solar lentigo. Ann. Dermatol. Venereol. 2012, 139, S148–S152. [CrossRef] 23. Raper, H.S. The tyrosinase-tyrosine reaction. Production from tyrosine of 5,6-dihydroxyindole and 5,6-dihydroxyindole-2-carboxylic acid—The precursors of melanin. Biochem. J. 1927, 21, 89–96. [CrossRef] [PubMed] 24. Mason, H.S. The chemistry of melanin. Mechanism of the oxidation of dihydroxyphenylalanine by tyrosinase. J. Biol. Chem. 1948, 172, 83–99. [PubMed] 25. Ito, S.; IFPCS. The IFPCS presidential lecture: A chemist’s view of melanogenesis. Pigment Cell Res. 2003, 16, 230–236. [CrossRef][PubMed] 26. Micillo, R.; Panzella, L.; Koike, K.; Monfrecola, G.; Napolitano, A.; d’Ischia, M. “Fifty shades” of black and red or how carboxyl groups fine tune eumelanin and pheomelanin properties. Int. J. Mol. Sci. 2016, 17, 746. [CrossRef][PubMed] 27. Panzella, L.; Napolitano, A.; d’Ischia, M. Is DHICA the key to dopachrome tautomerase and melanocyte functions? Pigment Cell Melanoma Res. 2011, 24, 248–249. [CrossRef][PubMed] 28. Jimenez-Cervantes, C.; Solano, F.; Kobayashi, T.; Urabe, K.; Hearing, V.J.; Lozano, J.A.; Garcia-Borron, J.C. A new enzymatic function in the melanogenic pathway. The 5,6-dihydroxyindole-2-carboxylic acid oxidase activity of tyrosinase related protein-1 (TRP1). J. Biol. Chem. 1994, 269, 17993–18001. [PubMed] Cosmetics 2019, 6, 57 22 of 33

29. Olivares, C.; Solano, F. New insights into the active site structure and catalytic mechanism of tyrosinase and its related proteins. Pigment Cell Melanoma Res. 2009, 22, 750–760. [CrossRef][PubMed] 30. Niu, C.; Aisa, H.A. Upregulation of melanogenesis and tyrosinase activity: Potential agents for vitiligo. Molecules 2017, 22, 1303. [CrossRef][PubMed] 31. Pillaiyar, T.; Manickam, M.; Namasivayam, V. Skin whitening agents: Medicinal chemistry perspective of tyrosinase inhibitors. J. Enzyme Inhib. Med. Chem. 2017, 32, 403–425. [CrossRef][PubMed] 32. Solano, F. On the metal cofactor in the tyrosinase family. Int. J. Mol. Sci. 2018, 19, 633. [CrossRef][PubMed] 33. Citek, C.; Lyons, C.T.; Wasinger, E.C.; Stack, T.D.P. Self-assembly of the oxy-tyrosinase core and the fundamental components of phenolic hydroxylation. Nat. Chem. 2012, 4, 317–322. [CrossRef][PubMed] 34. Fujieda, N.; Yabuta, S.; Ikeda, T.; Oyama, T.; Muraki, N.; Kurisu, G.; Itoh, S. Crystal structures of copper-depleted and copper-bound fungal pro-tyrosinase: Insights into endogenous cysteine-dependent copper incorporation. J. Biol. Chem. 2013, 288, 22128–22140. [CrossRef][PubMed] 35. Ramsden, C.A.; Riley, P.A. Tyrosinase: The four oxidation states of the active site and their relevance to enzymatic activation, oxidation and inactivation. Bioorg. Med. Chem. 2014, 15, 2388–2395. [CrossRef] 36. Hernández-Romero, D.; Sanchez-Amat, A.; Solano, F. A tyrosinase with an abnormally high tyrosine hydroxylase/dopa oxidase ratio. FEBS J. 2006, 273, 257–270. [CrossRef][PubMed] 37. Vanitha, M.; Soundhari, C. Isolation and characterisation of mushroom tyrosinase and screening of herbal extracts for anti-tyrosinase activity. Int. J. ChemTech Res. 2017, 10, 1156–1167. 38. Ito, S.; Wakamatsu, K. A convenient screening method to differentiate phenolic skin whitening tyrosinase inhibitors from leukoderma-inducing phenols. J. Dermatol. Sci. 2015, 80, 18–24. [CrossRef] 39. Ioni¸tă, E.; Aprodu, I.; Stănciuc, N.; Râpeanu, G.; Bahrim, G. Advances in structure-function relationships of tyrosinase from Agaricus bisporus—Investigation on heat-induced conformational changes. Food Chem. 2014, 156, 129–136. [CrossRef] 40. Ismaya, W.T.; Tandrasasmita, O.M.; Sundari, S.; Diana; Lai, X.; Retnoningrum, D.S.; Dijkstra, B.W.; Tjandrawinata, R.R.; Rachmawati, H. The light subunit of mushroom Agaricus bisporus tyrosinase: Its biological characteristics and implications. Int. J. Biol. Macromol. 2017, 102, 308–314. [CrossRef] 41. Ismaya, W.T.; Rozeboom, H.J.; Weijn, A.; Mes, J.J.; Fusetti, F.; Wichers, H.J.; Dijkstra, B.W. Crystal structure of Agaricus bisporus mushroom tyrosinase: Identity of the tetramer subunits and interaction with tropolone. Biochemistry 2011, 50, 5477–5486. [CrossRef] 42. Bourquelot, E.; Bertrand, G. La laccase dans les champignons. Compt. Rendus. 1895, 121, 783–786. 43. Muñoz-Muñoz, J.L.; Garcia-Molina, F.; Varon, R.; Garcia-Ruíz, P.A.; Tudela, J.; Garcia-Cánovas, F.; Rodríguez-López, J.N. Suicide inactivation of the diphenolase and monophenolase activities of tyrosinase. IUBMB Life 2010, 62, 539–547. [CrossRef][PubMed] 44. Haghbeen, K.; Saboury, A.A.; Karbassi, F. Substrate share in the suicide inactivation of mushroom tyrosinase. Biochim. Biophys. Acta 2004, 1675, 139–146. [CrossRef][PubMed] 45. Land, E.J.; Ramsden, C.A.; Riley, P.A. The mechanism of suicide-inactivation of tyrosinase: A substrate structure investigation. Tohoku J. Exp. Med. 2007, 212, 341–348. [CrossRef][PubMed] 46. Chang, T.S. An updated review of tyrosinase inhibitors. Int. J. Mol. Sci 2009, 10, 2440–2475. [CrossRef] [PubMed] 47. Solano, F.; Briganti, S.; Picardo, M.; Ghanem, G. Hypopigmenting agents: An updated review on biological, chemical and clinical aspects. Pigment Cell Res. 2006, 195, 550–571. [CrossRef][PubMed] 48. Hamed, S.H.; Sriwiriyanont, P.; deLong, M.A.; Visscher, M.O.; Wickett, R.R.; Boissy, R.E. Comparative efficacy and safety of deoxyarbutin, a new tyrosinase inhibiting agent. J. Cosmet. Sci. 2006, 57, 291–308. [PubMed] 49. Tofani, R.P.; Sumirtapura, Y.C.; Darijanto, S.T. Formulation, characterisation, and in vitro skin diffusion of nanostructured lipid carriers for deoxyarbutin compared to a nanoemulsion and conventional cream. Sci. Pharm. 2016, 84, 634–645. [CrossRef][PubMed] 50. Garcia-Jimenez, A.; Teruel-Puche, J.A.; Garcia-Ruiz, P.A.; Saura-Sanmartin, A.; Berna, J.; Garcia-Canovas, F.; Rodriguez-Lopez, J.N. Structural and kinetic considerations on the catalysis of deoxyarbutin by tyrosinase. PLoS ONE 2017, 12, e0187845. [CrossRef][PubMed] 51. Zhang, L.; Tao, G.; Chen, J.; Zheng, Z.P. Characterization of a new flavone and tyrosinase inhibition constituents from the twigs of Morus Alba L. Molecules 2016, 21, 1130. [CrossRef] Cosmetics 2019, 6, 57 23 of 33

52. Chung, K.W.; Jeong, H.O.; Lee, E.K.; Kim, S.J.; Chun, P.; Chung, H.Y.; Moon, H.R. Evaluation of antimelanogenic activity and mechanism of galangin in silico and in vivo. Biol. Pharm. Bull. 2018, 41, 73–79. [CrossRef][PubMed] 53. Morgan, A.M.A.; Jeon, M.N.; Jeong, M.H.; Yang, S.Y.; Kim, Y.H. Chemical components from the stems of Pueraria lobata and their tyrosinase inhibitory activity. Nat. Prod. Sci. 2016, 22, 111–116. [CrossRef] 54. Solimine, J.; Garo, E.; Wedler, J.; Rusanov, K.; Fertig, O.; Hamburger, M.; Atanassov, I.; Butterweck, V. Tyrosinase inhibitory constituents from a polyphenol enriched fraction of rose oil distillation wastewater. Fitoterapia 2016, 108, 13–19. [CrossRef][PubMed] 55. Chaita, E.; Lambrinidis, G.; Cheimonidi, C.; Agalou, A.; Beis, D.; Trougakos, I.; Mikros, E.; Skaltsounis, A.L.; Aligiannis, N. Anti-melanogenic properties of Greek plants. A novel depigmenting agent from Morus alba wood. Molecules 2017, 22, 514. [CrossRef][PubMed] 56. Tang, H.; Cui, F.; Li, H.; Huang, Q.; Li, Y. Understanding the inhibitory mechanism of tea polyphenols against tyrosinase using fluorescence spectroscopy, cyclic voltammetry, oximetry, and molecular simulations. RSC Adv. 2018, 8, 8310–8318. [CrossRef] 57. Renda, G.; Ozel, A.; Barut, B.; Korkmaz, B.; Soral, M.; Kandemir, U.; Liptaj, T. Bioassay guided isolation of active compounds from Alchemilla barbatiflora Juz. Rec. Nat. Prod. 2018, 12, 76–85. [CrossRef] 58. Lall, N.; Kishore, N.; Momtaz, S.; Hussein, A.; Naidoo, S.; Nqephe, M.; Crampton, B. Extract from Ceratonia siliqua exhibits depigmentation properties. Phytother. Res. 2015, 29, 1729–1736. [CrossRef][PubMed] 59. Kakumu, Y.; Yamauchi, K.; Mitsunaga, T. Identification of chemical constituents from the bark of Larix kaempferi and their tyrosinase inhibitory effect. Holzforschung 2019, 73, 637–643. [CrossRef] 60. Uesugi, D.; Hamada, H.; Shimoda, K.; Kubota, N.; Ozaki, S.; Nagatani, N. Synthesis, oxygen radical absorbance capacity, and tyrosinase inhibitory activity of glycosides of resveratrol, pterostilbene, and pinostilbene. Biosci. Biotech. Biochem. 2017, 81, 226–230. [CrossRef][PubMed] 61. Popova, I.E.; Morra, M.J. Sinapis alba seed meal as a feedstock for extracting the natural tyrosinase inhibitor 4-hydroxybenzyl alcohol. Ind. Crops Prod. 2018, 124, 505–509. [CrossRef] 62. Zuo, A.R.; Cao, S.W.; Zuo, A.R.; Dong, H.H.; Shu, Q.L.; Zheng, L.X.; Yu, X.Y.; Yu, Y.Y.; Cao, S.W. The antityrosinase and antioxidant activities of flavonoids dominated by the number and location of phenolic hydroxyl groups. Chin. Med. 2018, 13, 51. [CrossRef][PubMed] 63. Hagiwara, K.; Okura, M.; Sumikawa, Y.; Hida, T.; Kuno, A.; Horio, Y.; Yamashita, T. Biochemical effects of the flavanol-rich lychee fruit extract on the melanin biosynthesis and reactive oxygen species. J. Dermatol. 2016, 43, 1174–1183. [CrossRef][PubMed] 64. Pham, V.C.; Kim, O.; Lee, J.H.; Min, B.S.; Kim, J.A. Inhibitory effects of phloroglucinols from the roots of Dryopteris crassirhizoma on melanogenesis. Phytochem. Lett. 2017, 21, 51–56. [CrossRef] 65. Luyen, B.T.T.; Thao, N.P.; Widowati, W.; Fauziah, N.; Maesaroh, M.; Herlina, T.; Kim, Y.H. Chemical constituents of Piper aduncum and their inhibitory effects on soluble epoxide hydrolase and tyrosinase. Med. Chem. Res. 2017, 26, 220–226. [CrossRef] 66. Crespo, M.I.; Chaban, M.F.; Lanza, P.A.; Joray, M.B.; Palacios, S.M.; Vera, D.M.A.; Carpinella, M.C. Inhibitory effects of compounds isolated from Lepechinia meyenii on tyrosinase. Food Chem. Toxicol. 2019, 125, 383–391. [CrossRef][PubMed] 67. Kishore, N.; Twilley, D.; Blom van Staden, A.; Verma, P.; Singh, B.; Cardinali, G.; Kovacs, D.; Picardo, M.; Kumar, V.; Lall, N. Isolation of flavonoids and flavonoid glycosides from Myrsine africana and their inhibitory activities against mushroom tyrosinase. J. Nat. Prod. 2018, 81, 49–56. [CrossRef] 68. Abed, S.A.; Sirat, H.M.; Taber, M. Tyrosinase inhibition, anti-acetylcholinesterase, and antimicrobial activities of the phytochemicals from Gynotroches axillaris Blume. Pak. J. Pharm. Sci. 2016, 29, 2071–2078. [PubMed] 69. Omar, S.H.; Scott, C.J.; Hamlin, A.S.; Obied, H.K. Biophenols: Enzymes (β-secretase, cholinesterases, histone deacetylase and tyrosinase) inhibitors from olive (Olea europaea L.). Fitoterapia 2018, 128, 118–129. [CrossRef] 70. Kim, D.H.; Lee, J.H. Comparative evaluation of phenolic phytochemicals from perilla seeds of diverse species and screening for their tyrosinase inhibitory and antioxidant properties. S. Afr. J. Bot. 2019, 123, 341–350. [CrossRef] 71. Guo, N.; Wang, C.; Shang, C.; You, X.; Zhang, L.; Liu, W. Integrated study of the mechanism of tyrosinase inhibition by baicalein using kinetic, multispectroscopic and computational simulation analyses. Int. J. Biol. Macromol. 2018, 118, 57–68. [CrossRef] Cosmetics 2019, 6, 57 24 of 33

72. Shang, C.; Zhang, Y.; You, X.; Guo, N.; Wang, Y.; Fan, Y.; Liu, W. The effect of 7,8,4’-trihydroxyflavone on tyrosinase activity and conformation: Spectroscopy and docking studies. Luminescence 2018, 33, 681–691. [CrossRef][PubMed] 73. Nguyen, H.X.; Nguyen, N.T.; Nguyen, M.H.K.; Le, T.H.; Do, T.N.V.; Hung, T.M.; Nguyen, M.T.T. Tyrosinase inhibitory activity of flavonoids from Artocarpus heterophyllous. Chem. Cent. J. 2016, 10, 2. [CrossRef] [PubMed] 74. Chen, J.; Liu, S.; Huang, Z.; Huang, W.; Li, Q.; Ye, Y. Molecular inhibitory mechanism of dihydromyricetin on mushroom tyrosinase. J. Biomol. Struct. Dyn. 2018, 36, 3740–3752. [CrossRef][PubMed]

75. Ding, H.Y.; Chiang, C.M.; Tzeng, W.M.; Chang, T.S. Identification of 30-hydroxygenistein as a potent melanogenesis inhibitor from biotransformation of genistein by recombinant Pichia pastoris. Process. Biochem. 2015, 50, 1614–1617. [CrossRef] 76. Casedas, G.; Les, F.; Gonzalez-Burgos, E.; Gomez-Serranillos, M.P.; Smith, C.; Lopez, V. Cyanidin-3-O-glucoside inhibits different enzymes involved in central nervous system pathologies and type-2 diabetes. S. Afr. J. Bot. 2019, 120, 241–246. [CrossRef] 77. Xiong, S.L.; Lim, G.T.; Yin, S.J.; Lee, J.; Si, Y.X.; Yang, J.M.; Park, Y.D.; Qian, G.Y. The inhibitory effect of pyrogallol on tyrosinase activity and structure: Integration study of inhibition kinetics with molecular dynamics simulation. Int. J. Biol. Macromol. 2019, 121, 463–471. [CrossRef][PubMed] 78. Boghrati, Z.; Naseri, M.; Rezaie, M.; Pham, N.; Quinn, R.J.; Tayarani-Najaran, Z.; Iranshahi, M. Tyrosinase inhibitory properties of phenylpropanoid glycosides and flavonoids from Teucriumpolium L. var. gnaphalodes. Iran. J. Basic Med. Sci. 2016, 19, 804–811. 79. Zeng, H.J.; Liu, Z.; Hu, G.Z.; Qu, L.B.; Yang, R. Investigation on the binding of aloe-emodin with tyrosinase by spectral analysis and molecular docking. Spectrochim. Acta Mol. Biomol. Spectrosc. 2019, 211, 79–85. [CrossRef][PubMed] 80. Lu, T.M.; Ko, H.H. A new anthraquinone glycoside from Rhamnus nakaharai and anti-tyrosinase effect of 6-methoxysorigenin. Nat. Prod. Res. 2016, 30, 2655–2661. [CrossRef] 81. Kim, S.S.; Park, K.J.; JooAn, H.; Choi, Y.H. Inhibitory kinetics of enterolactone on mushroom tyrosinase. Der. Pharma Chem. 2016, 8, 124–130. 82. Magid, A.A.; Schmitt, M.; Prin, P.C.; Pasquier, L.; Voutquenne-Nazabadioko, L. In vitro tyrosinase inhibitory and antioxidant activities of extracts and constituents of Paeonia lactiflora Pall. flowers. Nat. Prod. J. 2017, 7, 237–245. [CrossRef] 83. Wang, Y.; Xu, L.Y.; Liu, X.; Feng, L.H.; Zhou, Z.W.; He, X.R.; Ren, G. Artopithecins A-D, prenylated 2-arylbenzofurans from the twigs of Artocarpus pithecogallus and their tyrosinase inhibitory activities. Chem. Pharm Bull. 2018, 66, 1199–1202. [CrossRef] 84. Abdullah, S.A.; Jamil, S.; Basar, N.; Abdul, L.; Siti, M.; Mohd Arriffin, N. Flavonoids from the leaves and heartwoods of Artocarpus lowii King and their bioactivities. Nat. Prod. Res. 2017, 31, 1113–1120. [CrossRef] [PubMed] 85. Jin, Y.J.; Lin, C.C.; Lu, T.M.; Li, J.H.; Chen, I.S.; Kuo, Y.H.; Ko, H.H. Chemical constituents derived from Artocarpus xanthocarpus as inhibitors of melanin biosynthesis. Phytochemistry 2015, 117, 424–435. [CrossRef] 86. Lathiff, S.M.A.; Jemaon, N.; Abdullah, S.A.; Jamil, S. Flavonoids from Artocarpus anisophyllus and their bioactivities. Nat. Prod. Commun. 2015, 10, 393–396. [CrossRef] 87. Nguyen, M.T.T.; Le, T.H.; Nguyen, H.X.; Dang, P.H.; Do, T.N.V.; Abe, M.; Takagi, R.; Nguyen, N.T. Artocarmins G-M, prenylated 4-chromenones from the stems of Artocarpus rigida and their tyrosinase inhibitory activities. J. Nat. Prod. 2017, 80, 3172–3178. [CrossRef][PubMed] 88. Duc, L.V.; Thanh, T.B.; Thu, H.L.T.; Bach, N.V. Chemical constituents and tyrosinase inhibitory activity of aqueous fraction of the leaves of Morus alba L. from Vietnam. Int. J. Pharmacogn. 2018, 5, 399–403. 89. Koirala, P.; Seong, S.H.; Zhou, Y.; Shrestha, S.; Jung, H.A.; Choi, J.S. Structure-activity relationship of the tyrosinase inhibitors kuwanon G, mulberrofuran G, and albanol B from Morus species: A kinetics and molecular docking study. Molecules 2018, 23, 1413. [CrossRef][PubMed] 90. Xu, L.; Huang, C.; Wu, C.; Huang, T.; Jia, A.; Hu, X. Chiral separation, absolute configuration, and bioactivity of two pairs of flavonoid enantiomers from Morus nigra. Phytochemistry 2019, 16333–16337. [CrossRef] [PubMed] 91. Hu, X.; Yu, M.H.; Yan, G.R.; Wang, H.Y.; Hou, A.J.; Lei, C. Isoprenylated phenolic compounds with tyrosinase inhibition from Morus nigra. J. Asian Nat. Prod. Res. 2018, 20, 488–493. [CrossRef] Cosmetics 2019, 6, 57 25 of 33

92. Tian, J.L.; Liu, T.L.; Xue, J.J.; Hong, W.; Zhang, Y.; Zhang, D.X.; Cui, C.C.; Liu, M.C.; Niu, S.L. Flavanoids derivatives from the root bark of Broussonetia papyrifera as a tyrosinase inhibitor. Ind. Crops Prod. 2019, 138, 111445. [CrossRef] 93. Santi, M.D.; Peralta, M.A.; Mendoza, C.S.; Cabrera, J.L.; Ortega, M.G. Chemical and bioactivity of flavanones obtained from roots of Dalea pazensis Rusby. Bioorg. Med. Chem. Lett. 2017, 27, 1789–1794. [CrossRef] [PubMed] 94. Sabudak, T.; Ozturk, M.; Alpay, E. New bioflavonoids from Solanum nigrum L. by anticholinesterase and anti-tyrosinase activities-guided fractionation. Rec. Nat. Prod. 2017, 11, 130–140. 95. Promden, W.; Viriyabancha, W.; Monthakantirat, O.; Umehara, K.; Noguchi, H.; Umehara, K.; Noguchi, H.; De-Eknamkul, W. Correlation between the potency of flavonoids on mushroom tyrosinase inhibitory activity and melanin synthesis in melanocytes. Molecules 2018, 9, 1403. [CrossRef][PubMed] 96. Chai, W.M.; Wei, Q.M.; Deng, W.L.; Zheng, Y.L.; Chen, X.Y.; Huang, Q.; Chong, O.Y.; Peng, Y.Y. Anti-melanogenesis properties of condensed tannins from Vigna angularis seeds with potent antioxidant and DNA damage protection activities. Food Funct. 2019, 10, 99–111. [CrossRef][PubMed] 97. Chen, H.; Song, W.; Sun, K.K.; Du, H.W.; Wei, S.D. Structure elucidation and evaluation of antioxidant and tyrosinase inhibitory effect and mechanism of proanthocyanidins from leaf and fruit of Leucaena leucocephala. J. Wood Chem. Technol. 2018, 38, 430–444. [CrossRef] 98. Chai, W.M.; Ou-Yang, C.; Huang, Q.; Lin, M.Z.; Wang, Y.X.; Xu, K.L.; Huang, W.Y.; Pang, D.D. Antityrosinase and antioxidant properties of mung bean seed proanthocyanidins: Novel insights into the inhibitory mechanism. Food Chem. 2018, 260, 27–36. [CrossRef] 99. Chai, W.M.; Huang, Q.; Lin, M.Z.; Chong, O.Y.; Huang, W.Y.; Wang, Y.X.; Xu, K.L.; Feng, H.L. Condensed tannins from Longan bark as inhibitor of tyrosinase: Structure, activity, and mechanism. J. Agric. Food Chem. 2018, 66, 908–917. [CrossRef] 100. Song, W.; Qin, S.T.; Fang, F.X.; Gao, Z.J.; Liang, D.D.; Liu, L.L.; Tian, H.T.; Yang, H.B. Isolation and purification of condensed tannin from the leaves and branches of Prunus cerasifera and its structure and bioactivities. Appl. Biochem. Biotechnol. 2018, 185, 464–475. [CrossRef] 101. Chai, W.M.; Lin, M.Z.; Wang, Y.X.; Xu, K.L.; Huang, W.Y.; Pan, D.D.; Zou, Z.R.; Peng, Y.Y. Inhibition of tyrosinase by cherimoya pericarp proanthocyanidins: Structural characterization, inhibitory activity and mechanism. Food Res. Int. 2017, 100, 731–739. [CrossRef] 102. Chai, W.M.; Lin, M.Z.; Feng, H.L.; Zou, Z.R.; Wang, Y.X. Proanthocyanidins purified from fruit pericarp of Clausena lansium (Lour.) Skeels as efficient tyrosinase inhibitors: Structure evaluation, inhibitory activity and molecular mechanism. Food Funct. 2017, 8, 1043–1051. [CrossRef][PubMed] 103. Song, W.; Zhu, X.F.; Ding, X.D.; Yang, H.B.; Qin, S.T.; Chen, H.; Wei, S.D. Structural features, antioxidant and tyrosinase inhibitory activities of proanthocyanidins in leaves of two tea cultivars. Int. J. Food Prop. 2017, 20, 1348–1358. [CrossRef] 104. Deng, Y.T.; Liang, G.; Shi, Y.; Li, H.L.; Zhang, J.; Mao, X.M.; Fu, Q.R.; Peng, W.X.; Chen, Q.X.; Shen, D.Y. Condensed tannins from Ficus altissima leaves: Structural, antioxidant, and antityrosinase properties. Process. Biochem. 2016, 51, 1092–1099. [CrossRef] 105. Chai, W.M.; Wang, R.; Wei, M.K.; Zou, Z.R.; Deng, R.G.; Liu, W.S.; Peng, Y.Y. Proanthocyanidins extracted from Rhododendron pulchrum leaves as source of tyrosinase inhibitors: Structure, activity, and mechanism. PLoS ONE 2015, 10, e0145483. [CrossRef][PubMed] 106. Chai, W.M.; Wei, M.K.; Wang, R.; Deng, R.G.; Zou, Z.R.; Peng, Y.Y. Avocado proanthocyanidins as a source of tyrosinase inhibitors: Structure characterization, inhibitory activity, and mechanism. J. Agric. Food Chem. 2015, 63, 7381–7387. [CrossRef] 107. Gong, C.F.; Wang, Y.X.; Wang, M.L.; Su, W.C.; Wang, Q.; Chen, Q.X.; Shi, Y. Evaluation of the structure and biological activities of condensed tannins from Acanthus ilicifolius Linn and their effect on fresh-cut fuji apples. Appl. Biochem. Biotechnol. 2019.[CrossRef][PubMed] 108. Lin, Y.; Kuang, Y.; Li, K.; Wang, S.; Song, W.; Qiao, X.; Sabir, G.; Ye, M. Screening for bioactive natural products from a 67-compound library of Glycyrrhiza inflate. Bioorg. Med. Chem. 2017, 25, 3706–3713. [CrossRef] 109. Li, K.; Ji, S.; Song, W.; Kuang, Y.; Lin, Y.; Tang, S.; Cui, Z.; Qiao, X.; Yu, S.; Ye, M. Glycybridins A-K, bioactive phenolic compounds from Glycyrrhiza glabra. J. Nat. Prod. 2017, 80, 334–346. [CrossRef] Cosmetics 2019, 6, 57 26 of 33

110. Ji, S.; Li, Z.; Song, W.; Wang, Y.; Liang, W.; Li, K.; Tang, S.; Wang, Q.; Qiao, X.; Zhou, D.; et al. Bioactive constituents of Glycyrrhiza uralensis (licorice): Discovery of the effective components of a traditional herbal medicine. J. Nat. Prod. 2016, 79, 281–292. [CrossRef] 111. Tao, Y.; Su, D.; Du, Y.; Li, W.; Cai, B.; Di, L.; Shi, L.; Hu, L. Magnetic solid-phase extraction coupled with HPLC-Q-TOF-MS for rapid analysis of tyrosinase binders from San-Bai decoction by Box-Behnken statistical design. RSC Adv. 2016, 6, 109730–109741. [CrossRef] 112. Magid, A.A.; Abdellah, A.; Pecher, V.; Pasquier, L.; Harakat, D.; Voutquenne-Nazabadioko, L. Flavonol glycosides and lignans from the leaves of Opilia amentacea. Phytochem. Lett. 2017, 21, 84–89. [CrossRef] 113. Kim, J.Y.; Kim, J.Y.; Jenis, J.; Li, Z.P.; Ban, Y.J.; Baiseitova, A.; Park, K.H. Tyrosinase inhibitory study of flavonolignans from the seeds of Silybum marianum (Milk thistle). Bioorg. Med. Chem. 2019, 27, 2499–2507. [CrossRef][PubMed] 114. Setyawati, A.; Hirabayashi, K.; Yamauchi, K.; Hattori, H.; Mitsunaga, T.; Batubara, I.; Heryanto, R.; Hashimoto, H.; Hotta, M. Melanogenesis inhibitory activity of components from Salam leaf (Syzygium polyanthum) extract. J. Nat. Med. 2018, 72, 474–480. [CrossRef][PubMed] 115. Kim, D.W.; Woo, H.S.; Kim, J.Y.; Ryuk, J.A.; Park, K.H.; Ko, B.S. Phenols displaying tyrosinase inhibition from Humulus lupulus. J. Enzyme Inhib. Med. Chem. 2016, 31, 742–747. [PubMed] 116. Sasaki, A.; Yamano, Y.; Sugimoto, S.; Otsuka, H.; Matsunami, K.; Shinzato, T. Phenolic compounds from the leaves of Breynia officinalis and their tyrosinase and melanogenesis inhibitory activities. J. Nat. Med. 2018, 72, 381–389. [CrossRef][PubMed] 117. Cho, J.G.; Cha, B.J.; Seo, W.D.; Jeong, R.H.; Shrestha, S.; Kim, J.Y.; Kang, H.C.; Baek, N.I. Feruloyl sucrose esters from Oryza sativa roots and their tyrosinase inhibition activity. Chem. Nat. Compd. 2015, 51, 1094–1098. [CrossRef] 118. Peng, W.W.; Wang, Z.Q.; Ji, M.Y.; Liao, Z.L.; Liu, Z.Q.; Wu, P. Tyrosinase inhibitory activity of three new glycosides from Breynia fruticosa. Phytochem. Lett. 2017, 22, 1–5. [CrossRef] 119. Kim, S.B.; Liu, Q.; Ahn, J.H.; Jo, Y.H.; Turk, A.; Hong, I.P.; Han, S.M.; Hwang, B.Y.; Lee, M.K. Polyamine derivatives from the bee pollen of Quercus mongolica with tyrosinase inhibitory activity. Bioorg. Chem. 2018, 81, 127–133. [CrossRef] 120. Yang, L.; Yang, Y.L.; Dong, W.H.; Li, W.; Wang, P.; Cao, X.; Yuan, J.Z.; Chen, H.Q.; Mei, W.L.; Dai, H.F. Sesquiterpenoids and 2-(2-phenylethyl)chromones respectively acting as α-glucosidase and tyrosinase inhibitors from agarwood of an Aquilaria plant. J. Enzyme Inhib. Med. Chem. 2019, 34, 853–862. [CrossRef] [PubMed] 121. Zhao, Y.M.; Yang, L.; Dong, W.H.; Li, W.; Chen, H.Q.; Wang, H.; Cai, C.H.; Gai, C.J.; Mei, W.L.; Dai, H.F. Three new 2-(2-phenylethyl)chromone derivatives from agarwood of Aquilaria crassna Pierre ex Lecomte (Thymelaeaceae) in Laos. Phytochem. Lett. 2019, 32, 134–137. [CrossRef] 122. Lee, G.Y.; Cho, B.O.; Shin, J.Y.; Jang, S.I.; Cho, I.S.; Kim, H.Y.; Park, J.S.; Cho, C.W.; Kang, J.S.; Kim, J.H.; et al. Tyrosinase inhibitory components from the seeds of Cassia tora. Arch. Pharm. Res. 2018, 41, 490–496. [CrossRef][PubMed] 123. Ullah, S.; Park, Y.; Park, C.; Lee, S.; Kang, D.; Yang, J.; Akter, J.; Chun, P.; Moon, H.R. Antioxidant, anti-tyrosinase and anti-melanogenic effects of (E)-2,3-diphenylacrylic acid derivatives. Bioorg. Med. Chem. 2019, 27, 2192–2200. [CrossRef][PubMed] 124. Gur, Z.T.; Senol, F.S.; Shekfeh, S.; Orhan, I.E.; Banoglu, E.; Caliskan, B. Novel piperazine amides of cinnamic acid derivatives as tyrosinase inhibitors. Lett. Drug Des. Discov. 2019, 16, 36–44. [CrossRef] 125. Kim, S.J.; Yang, J.; Lee, S.; Park, C.; Kang, D.; Akter, J.; Ullah, S.; Kim, Y.J.; Chun, P.; Moon, H.R. The tyrosinase inhibitory effects of isoxazolone derivatives with a (Z)-β-phenyl-α, β-unsaturated carbonyl scaffold. Bioorg. Med. Chem. 2018, 26, 3882–3889. [CrossRef][PubMed] 126. Yang, J.K.; Lee, E.; Hwang, I.J.; Yim, D.B.; Han, J.; Lee, Y.S.; Kim, J.H. β-Lactoglobulin peptide fragments conjugated with caffeic acid displaying dual activities for tyrosinase inhibition and antioxidant effect. Bioconjugate Chem. 2018, 29, 1000–1005. [CrossRef][PubMed] 127. Jung, H.J.; Lee, M.J.; Park, Y.J.; Noh, S.G.; Lee, A.K.; Moon, K.M.; Lee, E.K.; Bang, E.J.; Park, Y.J.; Kim, S.J.; et al. A novel synthetic compound, (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-iminothiazolidin-4-one (MHY773) inhibits mushroom tyrosinase. Biosci. Biotech. Biochem. 2018, 82, 759–767. [CrossRef][PubMed] Cosmetics 2019, 6, 57 27 of 33

128. Bang, E.; Lee, E.K.; Noh, S.G.; Jung, H.J.; Moon, K.M.; Park, M.H.; Park, Y.J.; Hyun, M.K.; Lee, A.K.; Kim, S.J.; et al. In vitro and in vivo evidence of tyrosinase inhibitory activity of a synthesized (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-thioxothiazolidin-4-one (5-HMT). Exp. Dermatol. 2019, 28, 734–737. [CrossRef][PubMed] 129. Kang, K.H.; Lee, B.; Son, S.; Yun, H.Y.; Moon, K.M.; Jeong, H.O.; Kim, D.H.; Lee, E.K.; Choi, Y.J.; Kim, D.H.; et al. (Z)-2-(Benzo[d]thiazol-2-ylamino)-5-(substituted benzylidene)thiazol-4(5H)-one derivatives as novel tyrosinase inhibitors. Biol. Pharm. Bull. 2015, 38, 1227–1233. [CrossRef] 130. Abbas, Q.; Ashraf, Z.; Hassan, M.; Nadeem, H.; Latif, M.; Afzal, S.; Seo, S.Y. Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies. Drug Des. Devel. Ther. 2017, 11, 2029–2046. [CrossRef][PubMed] 131. Ashraf, Z.; Rafiq, M.; Seo, S.Y.; Babar, M.M.; Zaidi, N.U. Synthesis, kinetic mechanism and docking studies of vanillin derivatives as inhibitors of mushroom tyrosinase. Bioorg. Med. Chem. 2015, 23, 5870–5880. [CrossRef] 132. Ullah, S.; Park, C.; Ikram, M.; Kang, D.; Lee, S.; Yang, J.; Park, Y.; Yoon, S.; Chun, P.; Moon, H.R. Tyrosinase inhibition and anti-melanin generation effect of cinnamamide analogues. Bioorg. Chem. 2019, 87, 43–55. [CrossRef][PubMed] 133. Ullah, S.; Kang, D.; Lee, S.; Ikram, M.; Park, C.; Park, Y.; Yoon, S.; Chun, P.; Moon, H.R. Synthesis of cinnamic amide derivatives and their anti-melanogenic effect in α-MSH-stimulated B16F10 melanoma cells. Eur. J. Med. Chem. 2019, 161, 78–92. [CrossRef][PubMed] 134. Kim, C.S.; Noh, S.G.; Park, Y.; Kang, D.; Chun, P.; Chung, H.Y.; Jung, H.J.; Moon, H.R. A potent tyrosinase inhibitor, (E)-3-(2,4-dihydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one, with anti-melanogenesis properties in α-MSH and IBMX-induced B16F10 melanoma cells. Molecules 2018, 23, 2725. [CrossRef][PubMed] 135. Jung, H.J.; Lee, A.K.; Park, Y.J.; Lee, S.; Kang, D.; Jung, Y.S.; Chung, H.Y.; Moon, H.R. (2E,5E)-2,5-Bis(3-hydroxy-4-methoxybenzylidene) cyclopentanone exerts anti-melanogenesis and anti-wrinkle activities in B16F10 melanoma and Hs27 fibroblast cells. Molecules 2018, 23, 1415. [CrossRef] [PubMed] 136. Micillo, R.; Sires-Campos, J.; Garcia-Borron, J.C.; Panzella, L.; Napolitano, A.; Olivares, C. Conjugation with dihydrolipoic acid imparts caffeic acid ester potent inhibitory effect on dopa oxidase activity of human tyrosinase. Int. J. Mol. Sci. 2018, 19, 2156. [CrossRef] 137. Micillo, R.; Pistorio, V.; Pizzo, E.; Panzella, L.; Napolitano, A.; d’Ischia, M. 2-S-lipoylcaffeic acid, a natural product-based entry to tyrosinase inhibition via catechol manipulation. Biomimetics 2017, 2, 15. [CrossRef] 138. Bang, E.; Noh, S.G.; Ha, S.; Jung, H.J.; Kim, D.H.; Lee, A.K.; Hyun, M.K.; Kang, D.; Lee, S.; Park, C.; et al. Evaluation of the novel synthetic tyrosinase inhibitor (Z)-3-(3-bromo-4-hydroxybenzylidene) thiochroman-4-one (MHY1498) in vitro and in silico. Molecules 2018, 23, 3307. [CrossRef] 139. Ha, J.H.; Park, S.N. Dimeric cinnamoylamide analogues for regulation of tyrosinase activity in melanoma cells: A role of diamide-link chain length. Bioorg. Med. Chem. 2018, 26, 6015–6022. [CrossRef] 140. Sheng, Z.; Ge, S.; Xu, X.; Zhang, Y.; Wu, P.; Zhang, K.; Xu, X.; Li, C.; Zhao, D.; Tang, X. Design, synthesis and evaluation of cinnamic acid ester derivatives as mushroom tyrosinase inhibitors. Medchemcomm 2018, 9, 853–861. [CrossRef] 141. Sheng, Z.; Ge, S.; Xu, X.; Zhang, Y.; Wu, P.; Zhang, K.; Xu, X.; Li, C.; Zhao, D.; Tang, X. Correction: Design, synthesis and evaluation of cinnamic acid ester derivatives as mushroom tyrosinase inhibitors. Medchemcomm 2018, 9, 897. [CrossRef] 142. Aliabadi, R.S.; Mahmoodi, N.O.; Ghafoori, H.; Roohi, H.; Pourghasem, V. Design and synthesis of novel bis-hydroxychalcones with consideration of their biological activities. Res. Chem. Intermediat. 2018, 44, 2999–3015. [CrossRef] 143. Suthar, S.K.; Bansal, S.; Narkhede, N.; Guleria, M.; Alex, A.T.; Joseph, A. Design, synthesis and biological evaluation of oxindole-based chalcones as small-molecule inhibitors of melanogenic tyrosinase. Chem. Pharm. Bull. 2017, 65, 833–839. [CrossRef][PubMed] 144. Radhakrishnan, S.K.; Shimmon, R.G.; Conn, C.; Baker, A.T. Inhibitory kinetics of azachalcones and their oximes on mushroom tyrosinase: A facile solid-state synthesis. Chem. Biodivers. 2016, 13, 531–538. [CrossRef] [PubMed] 145. Radhakrishnan, S.; Shimmon, R.; Conn, C.; Baker, A. Development of hydroxylated naphthylchalcones as polyphenol oxidase inhibitors: Synthesis, biochemistry and molecular docking studies. Bioorg. Chem. 2015, 63, 116–122. [CrossRef][PubMed] Cosmetics 2019, 6, 57 28 of 33

146. Radhakrishnan, S.; Shimmon, R.; Conn, C.; Baker, A. Integrated kinetic studies and computational analysis on naphthyl chalcones as mushroom tyrosinase inhibitors. Bioorg. Med. Chem. Lett. 2015, 25, 4085–4091. [CrossRef][PubMed] 147. Suthar, S.K.; Aggarwal, V.; Chauhan, M.; Sharma, A.; Bansal, S.; Sharma, M. Molecular docking and biological evaluation of hydroxy-substituted (Z)-3-benzylideneindolin-2-one chalcones for the lead identification as tyrosinase inhibitors. Med. Chem. Res. 2015, 24, 1331–1341. [CrossRef] 148. Zheng, Z.P.; Zhang, Y.N.; Zhang, S.; Chen, J. One-pot green synthesis of 1,3,5-triarylpentane-1,5-dione and triarylmethane derivatives as a new class of tyrosinase inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 795–798. [CrossRef][PubMed] 149. Dong, X.; Zhang, Y.; He, J.L.; Zhang, S.; Zeng, M.M.; Chen, J.; Zheng, Z.P. Preparation of tyrosinase inhibitors and antibrowning agents using green technology. Food Chem. 2016, 197, 589–596. [CrossRef] 150. Radhakrishnan, S.K.; Shimmon, R.G.; Conn, C.; Baker, A.T. Azachalcones: A new class of potent polyphenol oxidase inhibitors. Bioorg. Med. Chem. Lett. 2015, 25, 1753–1756. [CrossRef][PubMed] 151. Radhakrishnan, S.K.; Shimmon, R.G.; Conn, C.; Baker, A.T. Evaluation of novel chalcone oximes as inhibitors of tyrosinase and melanin formation in B16 cells. Archiv der Pharmazie 2016, 349, 20–29. [CrossRef] 152. Qin, H.L.; Shang, Z.P.; Jantan, I.; Tan, O.U.; Hussain, M.A.; Sher, M.; Bukhari, S.N.A. Molecular docking studies and biological evaluation of chalcone based pyrazolines as tyrosinase inhibitors and potential anticancer agents. RSC Adv. 2015, 5, 46330–46338. [CrossRef] 153. Kim, B.H.; Park, K.C.; Park, J.H.; Lee, C.G.; Ye, S.K.; Park, J.Y. Inhibition of tyrosinase activity and melanin production by the chalcone derivative 1-(2-cyclohexylmethoxy-6-hydroxy-phenyl)-3-(4-hydroxymethyl- phenyl)-propenone. Biochem. Biophys. Res. Commun. 2016, 480, 648–654. [CrossRef][PubMed] 154. Ranjbar, S.; Akbari, A.; Edraki, N.; Khoshneviszadeh, M.; Hemmatian, H.; Firuzi, O.; Khoshneviszadeh, M. 6-Methoxy-3,4-dihydronaphthalenone chalcone-like derivatives as potent tyrosinase inhibitors and radical scavengers. Lett. Drug Des. Discov. 2018, 15, 1170–1179. [CrossRef] 155. Radhakrishnan, S.; Shimmon, R.; Conn, C.; Baker, A. Design, synthesis and biological evaluation of hydroxy substituted amino chalcone compounds for antityrosinase activity in B16 cells. Bioorg. Chem. 2015, 62, 117–123. [CrossRef][PubMed] 156. Radhakrishnan, S.; Shimmon, R.; Conn, C.; Baker, A. Inhibitory kinetics of novel 2,3-dihydro-1H-inden-1-one chalcone-like derivatives on mushroom tyrosinase. Bioorg. Med. Chem. Lett. 2015, 25, 5495–5499. [CrossRef] 157. Brotzman, N.; Xu, Y.; Graybill, A.; Cocolas, A.; Ressler, A.; Seeram, N.P.; Ma, H.; Henry, G.E. Synthesis and tyrosinase inhibitory activities of 4-oxobutanoate derivatives of carvacrol and thymol. Bioorg. Med. Chem. Lett. 2019, 29, 56–58. [CrossRef][PubMed] 158. Ashraf, Z.; Rafiq, M.; Seo, S.Y.; Kwon, K.S.; Babar, M.M.; Zaidi, N.U. Kinetic and in silico studies of novel hydroxy-based thymol analogues as inhibitors of mushroom tyrosinase. Eur. J. Med. Chem. 2015, 98, 203–211. [CrossRef] 159. Ashraf, Z.; Rafiq, M.; Nadeem, H.; Hassan, M.; Afzal, S.; Waseem, M.; Afzal, K.; Latip, J. Carvacrol derivatives as mushroom tyrosinase inhibitors; synthesis, kinetics mechanism and molecular docking studies. PLoS ONE 2017, 12, e0178069. [CrossRef] 160. Iwadate, T.; Nihei, K. Rhododendrol glycosides as stereospecific tyrosinase inhibitors. Bioorg. Med. Chem. 2015, 23, 6650–6658. [CrossRef] 161. Ali, A.; Ashraf, Z.; Kumar, N.; Rafiq, M.; Jabeen, F.; Park, J.H.; Choi, K.H.; Lee, S.; Seo, S.Y.; Choi, E.H.; et al. Influence of plasma-activated compounds on melanogenesis and tyrosinase activity. Sci. Rep. 2016, 6, 21779. [CrossRef] 162. Matsumoto, T.; Nakajima, T.; Iwadate, T.; Nihei, K. Chemical synthesis and tyrosinase-inhibitory activity of isotachioside and its related glycosides. Carbohydr. Res. 2018, 465, 22–28. [CrossRef][PubMed] 163. Kim, D.H.; Kim, S.J.; Ullah, S.; Yun, H.Y.; Chun, P.; Moon, H.R. Design, synthesis, and antimelanogenic effects of (2-substituted phenyl-1,3-dithiolan-4-yl) methanol derivatives. Drug Des. Devel. Ther. 2017, 11, 827–836. [CrossRef][PubMed] 164. Wang, Y.; Hao, M.M.; Sun, Y.; Wang, L.F.; Wang, H.; Zhang, Y.J.; Li, H.Y.; Zhuang, P.W.; Yang, Z. Synergistic promotion on tyrosinase inhibition by antioxidants. Molecules 2018, 23, 106. [CrossRef][PubMed] 165. Li, Q.; Yang, H.; Mo, J.; Sun, H.; Chen, Y.; Wu, Y.; Kang, C.; Sun, Y. Identification by shape-based virtual screening and evaluation of new tyrosinase inhibitors. PeerJ 2018, 6, e4206. [CrossRef][PubMed] Cosmetics 2019, 6, 57 29 of 33

166. Ishioka, W.; Oonuki, S.; Iwadate, T.; Nihei, K. Resorcinol alkyl glucosides as potent tyrosinase inhibitors. Bioorg. Med. Chem. Lett. 2019, 29, 313–316. [CrossRef] 167. Garcia-Jimenez, A.; Teruel-Puche, J.A.; Ortiz-Ruiz, C.V.; Berna, J.; Tudela, J.; Garcia-Canovas, F. 4-n-butylresorcinol, a depigmenting agent used in cosmetics, reacts with tyrosinase. IUBMB Life 2016, 68, 663–672. [CrossRef] 168. Ortiz-Ruiz, C.V.; Berna, J.; Rodriguez-Lopez, J.N.; Tomas, V.; Garcia-Canovas, F. Tyrosinase-catalyzed hydroxylation of 4-hexylresorcinol, an antibrowning and depigmenting agent: A kinetic study. J. Agric. Food Chem. 2015, 63, 7032–7040. [CrossRef][PubMed] 169. Ismail, T.; Shafi, S.; Srinivas, J.; Sarkar, D.; Qurishi, Y.; Khazir, J.; Alam, M.S.; Kumar, H.M.S. Synthesis and tyrosinase inhibition activity of trans-stilbene derivatives. Bioorg. Chem. 2016, 64, 97–102. [CrossRef] 170. Tanaka, Y.; Suzuki, M.; Kodachi, Y.; Nihei, K. Molecular design of potent, hydrophilic tyrosinase inhibitors based on the natural dihydrooxyresveratrol skeleton. Carbohydr. Res. 2019, 472, 42–49. [CrossRef] 171. Ashraf, Z.; Rafiq, M.; Seo, S.Y.; Babar, M.M.; Zaidi, N.U. Design, synthesis and bioevaluation of novel umbelliferone analogues as potential mushroom tyrosinase inhibitors. J. Enzyme Inhib. Med. Chem. 2015, 30, 874–883. [CrossRef] 172. Kamauchi, H.; Noji, M.; Kinoshita, K.; Takanami, T.; Koyama, K. Coumarins with an unprecedented tetracyclic skeleton and coumarin dimers from chemically engineered extracts of a marine-derived fungus. Tetrahedron 2018, 74, 2846–2856. [CrossRef] 173. Pintus, F.; Matos, M.J.; Vilar, S.; Hripcsak, G.; Varela, C.; Uriarte, E.; Santana, L.; Borges, F.; Medda, R.; Di Petrillo, A.; et al. New insights into highly potent tyrosinase inhibitors based on 3-heteroarylcoumarins: Anti-melanogenesis and antioxidant activities, and computational molecular modeling studies. Bioorg. Med. Chem. 2017, 25, 1687–1695. [CrossRef][PubMed] 174. Molnar, M.; Kovac, T.; Strelec, I. Umbelliferone-thiazolidinedione hybrids as potent mushroom tyrosinase inhibitors. Int. J. Pharm. Res. Allied Sci. 2016, 5, 305–310. 175. Santi, M.D.; Peralta, M.A.; Puiatti, M.; Cabrera, J.L.; Ortega, M.G. Melanogenic inhibitory effects of triangularin in B16F0 melanoma cells, in vitro and molecular docking studies. Bioorg. Med. Chem. 2019, 27, 3722–3728. [CrossRef] 176. Lee, J.Y.; Cho, Y.R.; Park, J.H.; Ahn, E.K.; Jeong, W.; Shin, H.S.; Kim, M.S.; Yang, S.H.; Oh, J.S. Anti-melanogenic and anti-oxidant activities of ethanol extract of Kummerowia striata: Kummerowia striata regulate anti-melanogenic activity through down-regulation of TRP-1, TRP-2 and MITF expression. Toxicol. Rep. 2019, 6, 10–17. [CrossRef][PubMed] 177. Maruyama, H.; Kawakami, F.; Lwin, T.T.; Imai, M.; Shamsa, F. Biochemical characterization of ferulic acid and caffeic acid which effectively inhibit melanin synthesis via different mechanisms in B16 melanoma cells. Biol. Pharm. Bull. 2018, 41, 806–810. [CrossRef][PubMed] 178. Goenka, S.; Ceccoli, J.; Simon, S.R. Anti-melanogenic activity of ellagitannin casuarictin in B16F10 mouse melanoma cells. Nat. Prod. Res. 2019, 1–6. [CrossRef] 179. Kang, M.; Park, S.H.; Oh, S.W.; Lee, S.E.; Yoo, J.A.; Nho, Y.H.; Lee, S.; Han, B.S.; Cho, J.Y.; Lee, J. Anti-melanogenic effects of resorcinol are mediated by suppression of cAMP signaling and activation of p38 MAPK signaling. Biosci. Biotech. Biochem. 2018, 82, 1188–1196. [CrossRef] 180. Wu, Q.Y.; Wong, Z.C.F.; Wang, C.; Fung, A.H.Y.; Wong, E.O.Y.; Chan, G.K.L.; Dong, T.T.X.; Chen, Y.; Tsim, K.W.K. Isoorientin derived from Gentiana veitchiorum Hemsl. flowers inhibits melanogenesis by down-regulating MITF-induced tyrosinase expression. Phytomedicine 2019, 57, 129–136. 181. Li, H.X.; Park, J.U.; Su, X.D.; Kim, K.T.; Kang, J.S.; Kim, Y.R.; Kim, Y.H.; Yang, S.Y. Identification of anti-melanogenesis constituents from Morus alba L. leaves. Molecules 2018, 23, 2559. [CrossRef] 182. Park, S.; Jegal, J.; Chung, K.W.; Jung, H.J.; Noh, S.G.; Chung, H.Y.; Ahn, J.; Kim, J.; Yang, M.H. Isolation of tyrosinase and melanogenesis inhibitory flavonoids from Juniperus chinensis fruits. Biosci. Biotech. Biochem. 2018, 82, 2041–2048. [CrossRef][PubMed] 183. Ha, J.H.; Park, S.N. Mechanism underlying inhibitory effect of six dicaffeoylquinic acid isomers on melanogenesis and the computational molecular modeling studies. Bioorg. Med. Chem. 2018, 26, 4201–4208. [CrossRef][PubMed] 184. Oh, T.I.; Yun, J.M.; Park, E.J.; Kim, Y.S.; Lee, Y.M.; Lim, J.H. Plumbagin suppresses α-MSH-induced melanogenesis in B16F10 mouse melanoma cells by inhibiting tyrosinase activity. Int. J. Mol. Sci. 2017, 18, 320. [CrossRef][PubMed] Cosmetics 2019, 6, 57 30 of 33

185. Wang, S.T.; Chang, W.C.; Hsu, C.; Su, N.W. Antimelanogenic effect of urolithin A and urolithin B, the colonic metabolites of ellagic acid, in B16 melanoma cells. J. Agric. Food Chem. 2017, 65, 6870–6876. [CrossRef] [PubMed] 186. Abdul Hamid, M.; Abu Bakar, N.; Park, C.S.; Ramli, F.B.; Sulaiman, W.R.W. Inhibitory effect and molecular mechanism of an anti-tyrosinase in B16F1 melanoma cells by α-mangostin, isolated from mangosteen pericarp. J. Food Nutr. Res. 2016, 4, 820–827. 187. Zhu, L.; Lu, Y.; Yu, W.G.; Zhao, X.; Lu, Y.H. Anti-photoageing and anti-melanogenesis activities of chrysin. Pharm. Biol. 2016, 54, 2692–2700. [CrossRef] 188. Nasr, B.N.; Chaabane, F.; Sassi, A.; Chekir-Ghedira, L.; Ghedira, K. Effect of apigenin-7-glucoside, genkwanin and naringenin on tyrosinase activity and melanin synthesis in B16F10 melanoma cells. Life Sci. 2016, 144, 80–85. [CrossRef] 189. Campos, P.M.; Prudente, A.S.; Horinouchi, C.D.; Cechinel-Filho, V.; Favero, G.M.; Cabrini, D.A.; Otuki, M.F. Inhibitory effect of GB-2a (I3-naringenin-II8-eriodictyol) on melanogenesis. J. Ethnopharmacol. 2015, 174, 224–229. [CrossRef] 190. Hridya, H.; Amrita, A.; Sankari, M.; George Priya Doss, C.; Gopalakrishnan, M.; Gopalakrishnan, C.; Siva, R. Inhibitory effect of brazilein on tyrosinase and melanin synthesis: Kinetics and in silico approach. Int. J. Biol. Macromol. 2015, 81, 228–234. [CrossRef] 191. Yamauchi, K.; Mitsunaga, T.; Itakura, Y.; Batubara, I. Extracellular melanogenesis inhibitory activity and the structure-activity relationships of ugonins from Helminthostachys zeylanica roots. Fitoterapia 2015, 104, 69–74. [CrossRef] 192. Imen, M.; Chaabane, F.; Nadia, M.; Soumaya, K.; Kamel, G.; Leila, C.G. Anti-melanogenesis and antigenotoxic activities of eriodictyol in murine melanoma (B16-F10) and primary human keratinocyte cells. Life Sci. 2015, 135, 173–178. [CrossRef][PubMed] 193. Jeong, J.Y.; Liu, Q.; Kim, S.B.; Jo, Y.H.; Mo, E.J.; Yang, H.H.; Song, D.H.; Hwang, B.Y.; Lee, M.K. Characterization of melanogenesis inhibitory constituents of Morus alba leaves and optimization of extraction conditions using response surface methodology. Molecules 2015, 20, 8730–8741. [CrossRef][PubMed] 194. Lee, S.M.; Chen, Y.S.; Lin, C.C.; Chen, K.H. Hair dyes resorcinol and lawsone reduce production of melanin in melanoma cells by tyrosinase activity inhibition and decreasing tyrosinase and microphthalmia-associated transcription factor (MITF) expression. Int. J. Mol. Sci. 2015, 16, 1495–1508. [CrossRef][PubMed] 195. Mustapha, N.; Bzeouich, I.M.; Ghedira, K.; Hennebelle, T.; Chekir-Ghedira, L. Compounds isolated from the aerial part of Crataegus azarolus inhibit growth of B16F10 melanoma cells and exert a potent inhibition of the melanin synthesis. Biomed. Pharmacother. 2015, 69, 139–144. [CrossRef][PubMed] 196. Cho, J.G.; Huh, J.; Jeong, R.H.; Cha, B.J.; Shrestha, S.; Lee, D.G.; Kang, H.C.; Kim, J.Y.; Baek, N.I. Inhibition effect of phenyl compounds from the Oryza sativa roots on melanin production in murine B16-F10 melanoma cells. Nat. Prod. Res. 2015, 29, 1052–1054. [CrossRef][PubMed] 197. Kuo, Y.H.; Chen, C.C.; Wu, P.Y.; Wu, C.S.; Sung, P.J.; Lin, C.Y.; Chiang, H.M. N-(4-methoxyphenyl) caffeamide-induced melanogenesis inhibition mechanisms. BMC Complement. Altern. Med. 2017, 17, 71. [CrossRef][PubMed] 198. Ullah, S.; Park, Y.; Ikram, M.; Lee, S.; Park, C.; Kang, D.; Yang, J.; Akter, J.; Yoon, S.; Chun, P.; et al. Design, synthesis and anti-melanogenic effect of cinnamamide derivatives. Bioorg. Med. Chem. 2018, 26, 5672–5681. [CrossRef][PubMed] 199. Lee, S.J.; Son, Y.H.; Lee, K.B.; Lee, J.H.; Kim, H.J.; Jeong, E.M.; Park, S.C.; Kim, I.G. 4-n-butylresorcinol enhances proteolytic degradation of tyrosinase in B16F10 melanoma cells. Int. J. Cosmet.Sci. 2017, 39, 248–255. [CrossRef] 200. Ullah, S.; Akter, J.; Kim, S.J.; Yang, J.; Park, Y.; Chun, P.; Moon, H.R. The tyrosinase-inhibitory effects of 2-phenyl-1,4-naphthoquinone analogs: Importance of the (E)-β-phenyl-α, β-unsaturated carbonyl scaffold of an endomethylene type. Med. Chem. Res. 2019, 28, 95–103. [CrossRef] 201. Wang, W.; Zhang, Y.; Nakashima, S.; Wang, T.; Yoshikawa, M.; Matsuda, H. Inhibition of melanin production by anthracenone dimer glycosides isolated from Cassia auriculata seeds. J. Nat. Med. 2019, 73, 439–449. [CrossRef] 202. Son, S.; Kim, H.; Yun, H.Y.; Kim, D.H.; Ullah, S.; Kim, S.J.; Kim, Y.J.; Kim, M.S.; Yoo, J.W.; Chun, P.; et al. (E)-2-Cyano-3-(substituted phenyl)acrylamide analogs as potent inhibitors of tyrosinase: A linear β-phenyl-α,β-unsaturated carbonyl scaffold. Bioorg. Med. Chem. 2015, 23, 7728–7734. [CrossRef][PubMed] Cosmetics 2019, 6, 57 31 of 33

203. Kuo, Y.H.; Chen, C.C.; Lin, P.; You, Y.J.; Chiang, H.M. N-(4-bromophenethyl) caffeamide inhibits melanogenesis by regulating AKT/glycogen synthase kinase 3 beta/microphthalmia-associated transcription factor and tyrosinase-related protein 1/tyrosinase. Curr. Pharm. Biotechnol. 2015, 16, 1111–1119. [CrossRef] [PubMed] 204. Lu, T.M.; Ko, H.H.; Ng, L.T.; Hsieh, Y.P. Free-radical-scavenging, antityrosinase, and cellular melanogenesis inhibitory activities of synthetic isoflavones. Chem. Biodivers. 2015, 12, 963–979. [CrossRef][PubMed] 205. Jeong, H.J.; Lee, C.S.; Choi, J.; Hong, Y.D.; Shin, S.S.; Park, J.S.; Lee, J.H.; Lee, S.; Yoon, K.D.; Ko, J. Flavokawains B and C, melanogenesis inhibitors, isolated from the root of Piper methysticum and synthesis of analogs. Bioorg. Med. Chem. Lett. 2015, 25, 799–802. [CrossRef][PubMed] 206. Veselinovic, J.B.; Veselinovic, A.M.; Ilic-Tomic, T.; Davis, R.; O’Connor, K.; Pavic, A.; Nikodinovic-Runic, J. Potent anti-melanogenic activity and favorable toxicity profile of selected 4-phenyl hydroxycoumarins in the zebrafish model and the computational molecular modeling studies. Bioorg. Med. Chem. 2017, 25, 6286–6296. [CrossRef][PubMed] 207. Haudecoeur, R.; Carotti, M.; Gouron, A.; Maresca, M.; Buitrago, E.; Hardre, R.; Bergantino, E.; Jamet, H.; Belle, C.; Reglier, M.; et al. 2-Hydroxypyridine-N-oxide-embedded aurones as potent human tyrosinase inhibitors. ACS Med. Chem. Lett. 2017, 8, 55–60. [CrossRef] 208. Zhou, Z.; Hou, J.; Xiong, J.; Li, M. Characterization of sulfuretin as a depigmenting agent. Fundam. Clin. Pharmacol. 2019, 33, 208–215. [CrossRef] 209. Chen, W.C.; Tseng, T.S.; Hsiao, N.W.; Lin, Y.L.; Wen, Z.H.; Tsai, C.C.; Lee, Y.C.; Lin, H.H.; Tsai, K.C. Discovery of highly potent tyrosinase inhibitor, T1, with significant anti-melanogenesis ability by zebrafish in vivo assay and computational molecular modeling. Sci. Rep. 2015, 5, 7995. [CrossRef] 210. Kwak, J.Y.; Seok, J.K.; Suh, H.J.; Choi, Y.H.; Hong, S.S.; Kim, D.S.; Boo, Y.C. Antimelanogenic effects of luteolin 7-sulfate isolated from Phyllospadix iwatensis Makino. Br. J. Dermatol. 2016, 175, 501–511. [CrossRef] 211. Kwak, J.Y.; Park, S.; Seok, J.K.; Liu, K.H.; Boo, Y.C. Ascorbyl coumarates as multifunctional cosmeceutical agents that inhibit melanogenesis and enhance collagen synthesis. Arch. Dermatol. Res. 2015, 307, 635–643. [CrossRef] 212. Moon, K.M.; Hwang, Y.H.; Yang, J.H.; Ma, J.Y.; Lee, B. Spinosin is a flavonoid in the seed of Ziziphus jujuba that prevents skin pigmentation in a human skin model. J. Funct. Foods 2019, 54, 449–456. [CrossRef] 213. Lee, S.; Lee, D.H.; Kim, J.C.; Um, B.H.; Sung, S.H.; Jeong, L.S.; Kim, Y.K.; Kim, S.N. Pectolinarigenin, an aglycone of pectolinarin, has more potent inhibitory activities on melanogenesis than pectolinarin. Biochem. Biophys. Res. Commun. 2017, 493, 765–772. [CrossRef][PubMed] 214. Lee, B.; Moon, K.M.; Lee, B.S.; Yang, J.H.; Park, K.I.; Cho, W.K.; Ma, J.Y. Swertiajaponin inhibits skin pigmentation by dual mechanisms to suppress tyrosinase. Oncotarget 2017, 8, 95530–95541. [CrossRef] [PubMed] 215. Lee, B.; Moon, K.M.; Lim, J.S.; Park, Y.; Kim, D.H.; Son, S.; Jeong, H.O.; Kim, D.H.; Lee, E.K.; Chung, K.W.; et al. 2-(3,4-dihydroxybenzylidene)malononitrile as a novel anti-melanogenic compound. Oncotarget 2017, 8, 91481–91493. [CrossRef] 216. Ha, J.H.; Jeong, Y.J.; Xuan, S.H.; Lee, J.Y.; Park, J.; Park, S.N. Methyl-2-acetylamino-3-(4-hydroxyl-3,5- dimethoxybenzoylthio) propanoate suppresses melanogenesis through ERK signaling pathway mediated MITF proteasomal degradation. J. Dermatol. Sci. 2018, 91, 142–152. [CrossRef][PubMed] 217. Arrowitz, C.; Weber, T.; Schoelermann, A.M.; Mann, T.; Jiang, L.I.; Kolbe, L. Effective tyrosinase inhibition by thiamidol results in significant improvement of mild to moderate melasma. J. Investig. Dermatol. 2019, 139, 1691–1698. [CrossRef][PubMed] 218. Hornyak, T.J. Next time, save mushrooms for the pizza! J. Investig. Dermatol. 2018, 138, 1470–1472. [CrossRef] 219. Mayr, F.; Sturm, S.; Ganzera, M.; Waltenberger, B.; Martens, S.; Schwaiger, S.; Schuster, D.; Stuppner, H. Mushroom tyrosinase-based enzyme inhibition assays are not suitable for bioactivity-guided fractionation of extracts. J. Nat. Prod. 2019, 82, 136–147. [CrossRef] 220. Gasowska-Bajger, B.; Wojtasek, H. Reactions of flavonoids with o-quinones interfere with the spectrophotometric assay of tyrosinase activity. J. Agric. Food Chem. 2016, 64, 5417–5427. [CrossRef] 221. Deng, H.H.; Lin, X.L.; He, S.B.; Wu, G.W.; Wu, W.H.; Yang, Y.; Lin, Z.; Peng, H.P.; Xia, X.H.; Chen, W. Colorimetric tyrosinase assay based on catechol inhibition of the oxidase-mimicking activity of chitosan-stabilized platinum nanoparticles. Mikrochim. Acta 2019, 186, 1–7. [CrossRef] Cosmetics 2019, 6, 57 32 of 33

222. Vandeput, M.; Patris, S.; Silva, H.; Parsajoo, C.; Dejaeghere, B.; Martinez, J.A.; Kauffmann, J.M. Application of a tyrosinase microreactor-detector in a flow injection configuration for the determination of affinity and dynamics of inhibitor binding. Sens. Actuator. B Chem. 2017, 248, 385–394. [CrossRef] 223. Cheng, M.; Chen, Z. Screening of tyrosinase inhibitors by capillary electrophoresis with immobilized enzyme microreactor and molecular docking. Electrophoresis 2017, 38, 486–493. [CrossRef][PubMed] 224. Tang, L.; Zhang, W.; Zhao, H.; Chen, Z. Tyrosinase inhibitor screening in traditional Chinese medicines by electrophoretically mediated microanalysis. J. Sep. Sci. 2015, 38, 2887–2892. [CrossRef][PubMed] 225. Zhou, J.; Tang, Q.; Wu, T.; Cheng, Z. Improved TLC bioautographic assay for qualitative and quantitative estimation of tyrosinase inhibitors in natural products. Phytochem. Anal. 2017, 28, 115–124. [CrossRef] 226. Wang, Z.; Hwang, S.H.; Huang, B.; Lim, S.S. Identification of tyrosinase specific inhibitors from Xanthium strumarium fruit extract using ultrafiltration-high performance liquid chromatography. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2015, 1002, 319–328. [CrossRef] 227. Chai, L.; Zhou, J.; Feng, H.; Tang, C.; Huang, Y.; Qian, Z. Functionalized carbon quantum dots with dopamine for tyrosinase activity monitoring and inhibitor screening: In vitro and intracellular investigation. ACS Appl. Mater. Interfaces 2015, 7, 23564–23574. [CrossRef] 228. Markova, E.; Kotik, M.; Krenkova, A.; Man, P.; Haudecoeur, R.; Boumendjel, A.; Hardre, R.; Mekmouche, Y.; Courvoisier-Dezord, E.; Reglier, M.; et al. Recombinant tyrosinase from Polyporus arcularius: Overproduction in Escherichia coli, characterization, and use in a study of aurones as tyrosinase effectors. J. Agric. Food Chem. 2016, 64, 2925–2931. [CrossRef] 229. Ortiz-Ruiz, C.V.; Garcia-Molina, M.; Serrano, J.T.; Tomas-Martinez, V.; Garcia-Canovas, F. Discrimination between alternative substrates and inhibitors of tyrosinase. J. Agric. Food Chem. 2015, 63, 2162–2171. [CrossRef] 230. Crescenzi, O.; Napolitano, A.; Prota, G.; Peter, M.G. Oxidative coupling of dopa with resorcinol and phloroglucinol: Isolation of adducts with an unusual tetrahydromethanobenzofuro [2,3-d] azocine skeleton. Tetrahedron 1991, 47, 6243–6250. [CrossRef] 231. Napolitano, A.; Micillo, R.; Monfrecola, G. Melanin pigmentation control by 1,3-thiazolidines: Does NO scavenging play a critical role? Exp. Dermatol. 2016, 25, 596–597. [CrossRef] 232. Shin, H.J.; Beak, H.S.; Il Kim, S.; Joo, Y.H.; Choi, J. Development and evaluation of topical formulations for a novel skin whitening agent (AP736) using Hansen solubility parameters and PEG-PCL polymers. Int. J. Pharm. 2018, 552, 251–257. [CrossRef][PubMed] 233. Jeon, S.H.; Na, Y.G.; Lee, H.K.; Cho, C.W. Hybrid polymeric microspheres for enhancing the encapsulation of phenylethyl resorcinol. J. Microencapsul. 2019, 36, 130–139. [CrossRef][PubMed] 234. Limsuwan, T.; Boonme, P.; Khongkow, P.; Amnuaikit, T. Ethosomes of phenylethyl resorcinol as vesicular delivery system for skin lightening applications. BioMed Res. Int. 2017, 8310979. [CrossRef][PubMed] 235. Kim, B.S.; Na, Y.G.; Choi, J.H.; Kim, I.; Lee, E.; Kim, S.Y.; Lee, J.Y.; Cho, C.W. The improvement of skin whitening of phenylethyl resorcinol by nanostructured lipid carriers. Nanomaterials 2017, 7, 241. [CrossRef] 236. Koepke, D.; Mueller, R.H.; Pyo, S.M. Phenylethyl resorcinol smartLipids for skin brightening—Increased loading & chemical stability. Eur. J. Pharm. Sci. 2019, 137, 104992. 237. Hespeler, D.; Kaltenbach, J.; Pyo, S.M. Glabridin smartPearls—Silica selection, production, amorphous stability and enhanced solubility. Int. J. Pharm. 2019, 561, 228–235. [CrossRef] 238. Wei, Y.; Zhang, J.; Zhou, Y.; Bei, W.; Li, Y.; Yuan, Q.; Liang, H. Characterization of glabridin/hydroxypropyl-β-cyclodextrin inclusion complex with robust solubility and enhanced bioactivity. Carbohydr. Polym. 2017, 159, 152–160. [CrossRef] 239. Chaikul, P.; Khat-udomkiri, N.; Iangthanarat, K.; Manosroi, J.; Manosroi, A. Characteristics and in vitro anti-skin aging activity of gallic acid loaded in cationic CTAB noisome. Eur. J. Pharm. Sci. 2019, 131, 39–49. [CrossRef] 240. Schlich, M.; Fornasier, M.; Nieddu, M.; Sinico, C.; Murgia, S.; Rescigno, A. 3-hydroxycoumarin loaded vesicles for recombinant human tyrosinase inhibition in topical applications. Colloids Surf. B Biointerfaces 2018, 171, 675–681. [CrossRef] 241. Fachinetti, N.; Rigon, R.B.; Eloy, J.O.; Sato, M.R.; dos Santos, K.C.; Chorilli, M. Comparative study of glyceryl behenate or polyoxyethylene 40 stearate-based lipid carriers for trans-resveratrol delivery: Development, characterization and evaluation of the in vitro tyrosinase inhibition. AAPS PharmSciTech 2018, 19, 1401–1409. [CrossRef] Cosmetics 2019, 6, 57 33 of 33

242. Rigon, R.B.; Fachinetti, N.; Chorilli, M.; Severino, P.; Santana, M.H.A. Skin delivery and in vitro biological evaluation of trans-resveratrol-loaded solid lipid nanoparticles for skin disorder therapies. Molecules 2016, 21, 116. [CrossRef][PubMed] 243. Lee, T.H.; Kang, J.H.; Seo, J.O.; Baek, S.H.; Moh, S.H.; Chae, J.K.; Park, Y.U.; Ko, Y.T.; Kim, S.Y.Anti-melanogenic potentials of nanoparticles from calli of resveratrol-enriched rice against UVB-induced hyperpigmentation in guinea pig skin. Biomol. Ther. 2016, 24, 85–93. [CrossRef][PubMed] 244. Shrotriya, S.; Ranpise, N.; Satpute, P.; Vidhate, B. Skin targeting of curcumin solid lipid nanoparticles-engrossed topical gel for the treatment of pigmentation and irritant contact dermatitis. Artif. Cells Nanomed. Biotechnol. 2018, 46, 1471–1482. [CrossRef][PubMed] 245. Al-Amin, M.; Cao, J.; Naeem, M.; Banna, H.; Kim, M.S.; Jung, Y.; Chung, H.Y.; Moon, H.R.; Yoo, J.W. Increased therapeutic efficacy of a newly synthesized tyrosinase inhibitor by solid lipid nanoparticles in the topical treatment of hyperpigmentation. Drug Des. Devel. Ther. 2016, 10, 3947–3957. [CrossRef] 246. Parisi, O.I.; Malivindi, R.; Amone, F.; Ruffo, M.; Malanchin, R.; Carlomagno, F.; Piangiolino, C.; Nobile, V.; Pezzi, V.; Scrivano, L.; et al. Safety and efficacy of dextran-rosmarinic acid conjugates as innovative polymeric antioxidants in skin whitening: What is the evidence? Cosmetics 2017, 4, 28. [CrossRef]

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).