Chalcones: Synthetic Chemistry Follows Where Nature Leads

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Review Chalcones: Synthetic Chemistry Follows Where Nature Leads

Hiba A. Jasim 1,2 , Lutfun Nahar 3,* , Mohammad A. Jasim 4 , Sharon A. Moore 5 , Kenneth J. Ritchie 1,* and Satyajit D. Sarker 1

1 Centre for Natural Products Discovery (CNPD), School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, James Parsons Building, Byrom Street, Liverpool L3 3AF, UK; [email protected] (H.A.J.); [email protected] (S.D.S.) 2 Department of Biology, College of Education for Pure Sciences, University of Anbar, Al-Anbar 10081, Iraq 3 Laboratory of Growth Regulators, Institute of Experimental Botany ASCR & Palacký University, Šlechtitel ˚u27, 78371 Olomouc, Czech Republic 4 Department of Biology, College of Education for Women, University of Anbar, Al-Anbar 10081, Iraq; [email protected] 5 Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY, UK; [email protected] * Correspondence: [email protected] (L.N.); [email protected] (K.J.R.); Tel.: +44-(0)-1512312219 (K.J.R.)

Abstract: Chalcones belong to the flavonoid class of phenolic compounds. They form one of the largest groups of bioactive natural products. The potential anticancer, anti-inflammatory, antimicrobial, antioxidant, and antiparasitic properties of naturally occurring chalcones, and their unique chemical structural features inspired the synthesis of numerous chalcone derivatives. In fact, structural features of chalcones are easy to construct from simple aromatic compounds, and it is convenient to perform structural modifications to generate functionalized chalcone derivatives. Many of these synthetic analogs were shown to possess similar bioactivities as their natural counterparts, but Citation: Jasim, H.A.; Nahar, L.; often with an enhanced potency and reduced toxicity. This review article aims to demonstrate how Jasim, M.A.; Moore, S.A.; Ritchie, K.J.; bioinspired synthesis of chalcone derivatives can potentially introduce a new chemical space for Sarker, S.D. Chalcones: Synthetic exploitation for new drug discovery, justifying the title of this article. However, the focus remains on Chemistry Follows Where Nature Leads. Biomolecules 2021, 11, 1203. critical appraisal of synthesized chalcones and their derivatives for their bioactivities, linking to their https://doi.org/10.3390/ interactions at the biomolecular level where appropriate, and revealing their possible mechanisms biom11081203 of action.

Academic Editor: Vladimir Keywords: chalcones; biomolecular interactions; synthesis; natural products; bioactivities; mecha- N. Uversky nisms; anticancer; antimicrobial; phenolics

Received: 31 July 2021 Accepted: 11 August 2021 Published: 13 August 2021 1. Introduction Chalcones are flavonoid-type phenolic phytochemicals, often referred to as ‘open- Publisher’s Note: MDPI stays neutral chain flavonoids’, and biosynthesized via the shikimate pathway [1]. Chalcones are con- with regard to jurisdictional claims in sidered as the biosynthetic precursors of flavonoids. Chemically, chalcones are generally published maps and institutional affil- α,β-unsaturated ketones consisting of two aromatic rings (rings A and B) linked through a iations. three-carbon alkenone unit (Figure1), but these may also include some saturated ketones, commonly known as dihydrochalcones, where instead of a three-carbon alkenone unit, a three-carbon alkanone unit is present. Among the naturally occurring chalcones, the presence of one or more phenolic hydroxyl functionalities is ubiquitous, and prenyl and Copyright: © 2021 by the authors. geranyl substitutions on the aromatic rings are also widely observed. There are several Licensee MDPI, Basel, Switzerland. thousand naturally occurring chalcones reported in the literature [2], and many of those This article is an open access article chalcones were shown to interact with various biomolecules and possess cytoprotective and distributed under the terms and modulatory properties, making them potentially suitable candidates for therapeutic inter- conditions of the Creative Commons ventions in many human ailments. Several patents are also available for chalcones and their Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ derivatives for their activities as anticancer, anti-inflammatory, antimitotic, antioxidant, 4.0/). and cytotoxic properties [3].

Biomolecules 2021, 11, 1203. https://doi.org/10.3390/biom11081203 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, x FOR PEER REVIEW 2 of 38 Biomolecules 2021, 11, x FOR PEER REVIEW 2 of 38 Biomolecules 2021, 11, x FOR PEER REVIEW 2 of 38 BiomoleculesBiomolecules Biomolecules 20212021 20212021,, 1111,, ,11,11 1203x, , FOR xx FORFOR PEER PEERPEER REVIEW REVIEWREVIEW 2 of22 of 37of38 38 38

Biomolecules 2021, 11, x FOR PEER REVIEW 2 of 38

B β B β B BB ββ α A β A α B A α B A α B AAA β α AAA α α BB α αα β B A A α β B α or β ββ or or oror β Figure 1. General structure of chalcones. Figure 1. General structure or of chalcones. FigureFigureFigure 1. 1.1.General GeneralGeneral structure structurestructure of of ofchalcones. chalcones.chalcones. FigureBecause 1. General of structure structural of chalcones. simplicity and therapeutic potential, several bioinspired syn- Because of structural simplicity and therapeutic potential, several bioinspired syn- thesesBecauseBecauseBecause of chalcone of of of structural structuralstructural derivatives simplicity simplicitysimplicity and evaluation and andand therapeutic therapeutictherapeutic of their potential, potential,bioactivitiespotential, several severalseveral were bioinspired bioinspiredbioinspiredreported insyn- syn-syn-the theses of chalcone derivatives and evaluation of their bioactivities were reported in the thesesliteraturethesesthesesBecause of of of chalcone [2]. chalconechalcone of The structural first derivatives derivativesderivatives few simplicity attempts and andand evaluation forevaluationandevaluation th therapeutice synthesis of of of their theirtheir ofpotential, bioactivities chalcobioactivitiesbioactivitiesnes several began were werewere bioinspired in reported reportedreportedthe 1800 in ′ syn-sin in theand thethe literature [2]. The first few attempts for the synthesis of chalcones began in the 1800′s and thesesliteraturecontinuedliteratureliterature of chalcone[2]. [2 [2].through[2].]. The The TheThe first derivatives firstfirst firstthe few fewsubsequentfew attempts attempts attempts and evaluationforcenturies forfor for th ththe the synthesisee synthesissynthesis [4].synthesis of theirIn this of of ofbioactivitieschalco ofreview chalcochalco chalconesnes nesnesarticle, began beganbeganwere began some in reported in inthe inthe theof 1800 the these 18001800 in′ 1800ss ′ and′sssyn-the andand continued through the subsequent centuries [4]. In this review article, some of these syn- literaturecontinuedandthesizedcontinuedcontinued continued [2]. chalconesthrough throughthrough The through first the and thethe few subsequent the subsequenttheirsubsequent attempts subsequent derivatives centuries for centuriescenturies th centuriese were synthesis [4]. [4].[4]. criticallyIn [ 4InIn this]. ofthisthis In chalcoreview this reviewappraisedreview reviewnes article, article,article, began article,for some theirsomeinsome the some of bioactivities, of of1800these thesethese of′s these syn-and syn-synthesized chalcones and their derivatives were critically appraised for their bioactivities, continuedthesizedsynthesizedlinkingthesizedthesized tochalcones throughchalcones chalconestheir chalcones interactions theand andand andsubsequent their theirtheir their derivativesat derivatives derivatives derivativesthe centuries biomolecular were were were [4]. critically In criticallycritically level this reviewwhere appraised appraisedappraisedappraised appropriate,article, for for forfor sometheir their theirtheir andofbioactivities, bioactivities, bioactivities, bioactivities,these revealing syn- linking to their interactions at the biomolecular level where appropriate, and revealing thesizedlinkingtheirlinkinglinking possible to chalcones to to their theirtheir mechanisms interactions interactionsinteractions and their of atderivatives at action.at the thethe biomolecularbiomolecular biomolecularbiomolecular Moreover were critically, this level levellevel review wherewhere whereappraisedwhere article appropriate,appropriate, appropriate,appropriate, forfundamentally their andand bioactivities,andand revealingrevealing revealingrevealing aims to their possible mechanisms of action. Moreover, this review article fundamentally aims to linkingtheirdemonstratetheirtheir possible possible possible possibleto their mechanismshow mechanisms mechanismsinteractionsmechanisms bioinspired of of atof ofaction. action. thesynthesisaction.action. biomolecular Moreover Moreover,MoreoverMoreover of chal, conethis ,, level thisthisthis review derivatives reviewreviewwhere article article articleappropriate, can fundamentally fundamentally fundamentallypotentially and revealing introduce aims aimsaims aims to to to demonstrate how bioinspired synthesis of chalcone derivatives can potentially introduce theirdemonstratetoademonstratedemonstrate demonstratenew possible chemical how mechanisms howhow how space bioinspired bioinspiredbioinspired bioinspired for ofexploitation action. synthesis synthesissynthesis synthesis Moreover forof of ofchal new of chalchal chalcone,cone thisdrugconecone reviewderivatives derivativesdiscovery,derivatives derivatives article can justifying can canfundamentally canpotentially potentiallypotentially potentially the titleintroduce introduce introduceaims intro-of this to a new chemical space for exploitation for new drug discovery, justifying the title of this demonstrateaducearticle. anewa newnew a chemical new chemical chemical chemical how space spacebioinspiredspace space for forfor exploitation forexploitationexploitation synthesis exploitation for of forfor newchal fornewnew cone newdrug drugdrug derivatives drugdiscovery, discovery,discovery, discovery, canjustifying justifyingjustifying potentially justifying the thethe title the introduce titletitle titleof of ofthis ofthisthis article. aarticle.this article.newarticle. article. chemical space for exploitation for new drug discovery, justifying the title of this article.2. Chalcone Synthesis 2. Chalcone Synthesis 2.2. ChalconeChalcone SynthesisSynthesis 2. 2.Chalcone ChalconeChalcones Synthesis Synthesis are considered privileged structures in the medicinal chemistry due to the ChalconesChalcones are are considered considered privileged privileged structures structures in in the the medicinal medicinal chemistry chemistry due due to to the the 2.relative ChalconeChalconesChalconesChalcones ease Synthesis with are areare consideredwhich consideredconsidered they privilegedmay privilegedprivileged be produc structur structurstructured andeseses in inmodified, inthe thethe medicinal medicinalmedicinal reflecting chemistry chemistrychemistry the similar due duedue to to toeasethe thethe relativerelative ease ease with with which which they they may may be be produced produced and and modified, modified, reflecting reflecting the the similar similar ease ease relativewithrelativerelativeChalcones which ease easeease theywith with withare are which considered whichwhich produced they theythey may privileged in maymay nature. be bebe produc producproduc Fromstructured edased and es early andand in modified, themodified, modified,as themedicinal 19th reflecting reflectingreflecting century, chemistry the many thethe similar similarduesimilar research- to ease the easeease withwith which which they they are are produced produced in nature.in nature. From From as earlyas early as the as the 19th 19th century, century, many many researchers research- relativewitherswithwith havewhich whichwhich ease developed they with theythey are whichareare produced producedsyntheticproduced they mayin inchalcones, innature. nature.nature.be produc From FromFrom wied thas as as andearlyKostanecki earlyearly modified, as asas the thethe 19thand 19th19th reflecting century,Tambor century,century, themanybeing manymany similar research-acknowl- research-research- ease haveers developedhave developed synthetic synthetic chalcones, chalcones, with Kostanecki with Kostanecki and Tambor and beingTambor acknowledged being acknowl- as withersedgedersers have whichhavehave as developed the developeddevelopedthey first are to produced synthetic successfully syntheticsynthetic inchalcones, nature.chalcones,chalcones, prepare From wi syntheticwiwith asthth Kostanecki early KostaneckiKostanecki chalcones as the and 19th andand usingTambor century, TamborTambor a method beingmany beingbeing acknowl-research-involving acknowl-acknowl- theedged first toas successfully the first to preparesuccessfully synthetic prepare chalcones synthetic using chalcones a method using involving a method treatment involving of ersedgedtreatmentedgededged have as asas developedthe ofthethe firsto -acetoxychalconefirstfirst to to tosyntheticsuccessfully successfullysuccessfully chalcones, dibromides prepare prepareprepare wisynthetic synthetic syntheticthwith Kostanecki alco chalcones chalconeschalconesholic andalkali using Tamborusingusing [5,6]. a amethod aHowever, methodmethodbeing involvingacknowl- involvinginvolving the cur- o-acetoxychalconetreatment of o-acetoxychalcone dibromides with dibromides alcoholic alkali with [alco5,6].holic However, alkali the[5,6]. current However, methods the ofcur- edgedtreatmentrenttreatmenttreatment methods as the of of of ofirst-acetoxychalcone ooof-acetoxychalcone-acetoxychalcone chalconeto successfully synthesis dibromides dibromidespreparedibromides utilize synthetic anwith withwith alkaline alco alcoalco chalconesholic holicholicbase alkali alkaliandalkali using [5,6].a [5,6].polar[5,6]. a However,method However,However,solvent involving tothe thethecouple cur- cur-cur- chalconerent methods synthesis of chalcone utilize an synthesis alkaline baseutilize and ana alkaline polar solvent base and to couple a polar two solvent compounds to couple treatmentrenttworentrent methods compounds methodsmethods of o -acetoxychalconeof of ofchalcone withchalconechalcone an synthesisaromatic synthesissynthesis dibromides utilizering utilizeutilize each an with anan ,alkaline e.g., alkalinealkaline alco acetophenoneholic base basebase alkali and andand a [5,6]. apolaraand polarpolar However,benzaldehyde, solvent solventsolvent to theto tocouple couple couplecur- and withtwo an compounds aromatic ring with each, an e.g.,aromatic acetophenone ring each and, e.g., benzaldehyde, acetophenone and and to benzaldehyde, produce the core and renttwototwotwo produce methodscompounds compoundscompounds the of core chalconewith withwith chalcone an anan aromaticsynthesis aromaticaromatic nucleus ring utilize ringring (Schem each eacheach an, e.g.,ealkaline,, 1)e.g.,e.g., [7–9].acetophenone acetophenoneacetophenone base Various and aaromatic andpolar andand benzaldehyde, benzaldehyde,solventbenzaldehyde, compounds to couple and and andand chalconeto produce nucleus the core (Scheme chalcone1)[ 7 nucleus–9]. Various (Schem aromatice 1) [7–9]. compounds Various aromatic and different compounds methods and twotodifferentto toproduce producecompoundsproduce methods the thethe core corewithcore usedchalcone chalcone chalconean inaromatic the nucleus nucleusnucleus synthesis ring (Schem (Schem (Schemeach of ,severale e.g., 1)ee 1) 1)[7–9]. acetophenone[7–9].[7–9]. chalcone Various VariousVarious derivatives aromatic aromaticandaromatic benzaldehyde, compounds ( compounds2compounds–10) and andchal- andand useddifferent in the methods synthesis used of severalin the synthesis chalcone of derivatives several chalcone (2–10) andderivatives chalcone (2 itself–10) and (1) arechal- todifferentconedifferent differentproduce itself methods methodsthemethods(1) arecore summarizedused chalcone usedused in in inthe thethenucleus synthesis in synthesissynthesis Table (Schem 1.of of ofseveral e severalseveral 1) [7–9]. chalcone chalconechalcone Various derivatives derivatives derivativesaromatic compounds(2 (–(2210––1010) and)) andand chal- and chal-chal- summarizedcone itself ( in1) Tableare summarized1. in Table 1. differentconeconecone itself itselfitself methods (1 ()(1 1are)) areare summarized used summarizedsummarized in the insynthesis in inTable TableTable 1. of 1.1. several chalcone derivatives (2–10) and chalcone itself (1) are summarized in Table 1.

NaOH NaOHNaOH NaOHEtNaOHNaOH OH Acetophenone NaOHEtEt OH OH Chalcone Acetophenone Benzaldehyde EtEtEt OH OH OH Chalcone Acetophenone Benzaldehyde ChalconeChalcone AcetophenoneAcetophenoneBenzaldehydeBenzaldehydeBenzaldehydeEt OH Chalcone SchemeScheme 1. 1. Synthesis of chalcone. AcetophenoneScheme 1.Synthesis SynthesisBenzaldehyde of of chalcone. chalcone. Chalcone SchemeSchemeScheme 1. 1.1.Synthesis SynthesisSynthesis of of ofchalcone. chalcone.chalcone. TableSchemeTable 1. 1.Synthesis 1. Synthesis Synthesis of of someof some chalcone. chalcone chalcone and and chalcone chalcone derivatives derivatives [7 –[7–9].9]. Table 1. Synthesis of some chalcone and chalcone derivatives [7–9]. TableTableTable 1. 1.1.Synthesis SynthesisSynthesis of of ofsome somesome chalcone chalconechalcone and andand chalcone chalconechalcone derivatives derivativesderivatives [7–9]. [7–9].[7–9]. Reaction Synthesize Chalcone and Its ApproachApproach Compound CompoundTable 1 1 1. Synthesis Compound Compound of some 2 chalcone 2 and chalcone Reaction derivativesConditions [7–9]. Synthesize Chalcone and Its Approach Compound 1 Compound 2 Conditions Reaction Conditions SynthesizeDerivatives Chalcone and Its ApproachApproachApproach Compound Compound Compound 1 11 Compound Compound Compound 2 22 Reaction Reaction Reaction Co CoConditionsnditionsnditions Synthesize Synthesize SynthesizeDerivatives Chalcone ChalconeChalcone and andand Its ItsIts Derivatives ApproachMicrowave Compound 1 Compound 2 ReactionNaOH/MeOH,NaOH/MeOH, Conditions micro- SynthesizeDerivativesDerivativesDerivatives Chalcone and Its Microwave NaOH/MeOH, micro- MicrowaveMicrowaveMicrowave NaOH/MeOH,microwavewaveNaOH/MeOH,NaOH/MeOH, radiation radiation micro- atmicro-micro- 110 Derivatives wave radiation◦ at 110 Microwave NaOH/MeOH,waveatW,wavewave 110 55 radiation W, °C radiationradiation 55 C micro-at atat110 110110 W, 55 °C waveW,I2W,W,-Al 55 5555 2radiation°CO °C3°C , microwave at 110 I2-AlI2-Al2O2O3,3, microwave microwave I22-Al22O33, microwave W,Iradiation2radiation-AlI 55-Al2O °C3O, , for formicrowavemicrowave 8080 s s (1) radiation for 80 s (1) Ionic liquids Iradiation2HBr,-Alradiationradiation2O 3Bmim(OTs),, formicrowave forfor 80 8080 s ss 12 (1) Ionic liquids HBr, Bmim(OTs), 12 (1)(( 11)) IonicIonicIonic liquids liquidsliquids radiationHBr,h,HBr,HBr, 100 Bmim(OTs), °CBmim(OTs),Bmim(OTs), for 80 s 12 1212 HBr,h, 100 Bmim(OTs), °C (1) Ionic liquids HBr,h, h,h,100 100 100 Bmim(OTs),°C °C°C 12 12 h, 100 ◦C h, 100 °C

Biomolecules 2021, 11, 1203 3 of 37

Table 1. Cont. BiomoleculesBiomoleculesBiomoleculesBiomolecules 2021 20212021 2021, 11,, ,1111 ,11 x,, ,xFORx x FORFOR FOR PEER PEERPEER PEER REVIEW REVIEWREVIEW REVIEW 3 3of33 ofof of38 3838 38 Biomolecules Biomolecules 2021 2021, 11, ,11 x ,FOR x FOR PEER PEER REVIEW REVIEW 3 of3 38of 38 BiomoleculesBiomolecules 20212021,, 1111,, xx FORFOR PEERPEER REVIEWREVIEW 33 ofof 3838 Biomolecules Biomolecules BiomoleculesBiomolecules BiomoleculesBiomolecules 2021 2021 2021 20212021 2021, 11,, , 11, 11 11,11x 11, , ,FOR x, x x, x FOR xFOR FORFOR FOR PEER PEER PEER PEERPEER PEER REVIEW REVIEW REVIEW REVIEWREVIEW REVIEW Reaction Synthesize Chalcone and3 Its of333 3 of 3of38 ofof of 38 38 3838 38 Approach Compound 1 Compound 2 Biomolecules 2021, 11, x FOR PEER REVIEW Conditions Derivatives 3 of 38 BiomoleculesBiomolecules 2021 2021, 11,, 11x FOR, x FOR PEER PEER REVIEW REVIEW 3 of3 38 of 38

Claisen-SchmidtClaisen-SchmidtClaisen-SchmidtClaisen-Schmidt BaseBaseBaseBase Claisen-SchmidtClaisen-SchmidtClaisen-Schmidt BaseBaseBase Claisen-SchmidtClaisen-SchmidtClaisen-SchmidtClaisen-SchmidtClaisen-SchmidtClaisen-Schmidt BaseBaseBaseBaseBaseBase Claisen-Schmidt BaseBase Claisen-SchmidtClaisen-Schmidt BaseBase

Using SOCl2 SOCl2/EtOH UsingUsingUsingUsing SOCl SOClSOCl SOCl2 22 2 SOClSOClSOClSOCl2/EtOH22/EtOH2/EtOH/EtOH 2 2 UsingUsingUsing SOCl SOClSOCl2 22 SOClSOClSOCl2/EtOH22/EtOH/EtOH UsingUsing SOClSOCl22 SOClSOCl22/EtOH/EtOH UsingUsingUsingUsing SOCl SOCl SOClSOCl2 2 22 SOClSOClSOClSOCl2/EtOH2/EtOH22/EtOH/EtOH Using SOCl 2 SOClSOCl22/EtOH/EtOH UsingUsing SOCl SOCl2 2 SOClSOCl2/EtOH2/EtOH

AlkynesAlkynesAlkynesAlkynes and andandand al- al-al-al- Amberlyst-15,Amberlyst-15,Amberlyst-15,Amberlyst-15, DCM, DCM,DCM,DCM, AlkynesAlkynes and and al- al- Amberlyst-15,Amberlyst-15, DCM, DCM, dehydesdehydesAlkynesdehydesAlkynes andand al-al- atatAmberlyst-15,atAmberlyst-15, r.t. r.t.r.t. DCM,DCM, dehydesAlkynesAlkynesAlkynesdehydesAlkynesAlkynesAlkynes and and and andandand al- al- al- al-al-al- atAmberlyst-15,Amberlyst-15, Amberlyst-15,atr.t.Amberlyst-15,Amberlyst-15,Amberlyst-15, r.t. DCM, DCM,DCM,DCM,DCM,DCM, dehydesdehydesdehydes at atatr.t. r.t.r.t. Alkynesdehydesdehydesdehydes andand al- Amberlyst-15,atAmberlyst-15, atr.t.at r.t.r.t. DCM,DCM, dehydesAlkynesdehydesdehydes and al- atAmberlyst-15,atat r.t. r.t.r.t. DCM, dehydesAlkynesaldehydes and al- atAmberlyst-15,at r.t. r.t. DCM, dehydesdehydes at r.t.at r.t.

(2(()2(2 2)) ) (2)(2) Sonogashira [PdCl2(PPh3)2], Et3N, (2)(( 22)) SonogashiraSonogashiraSonogashiraSonogashira [PdCl [PdCl[PdCl[PdCl2(PPh22(PPh2(PPh(PPh3)233],)3)2)2 ],2],], Et EtEt3EtN,33N,3N,N, (2)(( 22)) Sonogashira [PdCl2(PPh3)2], Et3N, (2(()22 )) SonogashiracouplingSonogashiracouplingSonogashira [PdClTHF,[PdClTHF,[PdCl2 (PPhheat heat22(PPh(PPh 3 )23],3)) 22],], Et Et3EtN,33N,N, (2) couplingSonogashiracouplingSonogashiracouplingSonogashira THF,[PdClTHF,[PdClTHF,[PdCl heat2(PPh heat heat22(PPh(PPh2 3 ) 2],33)) 322],],2 Et 3EtEtN,33N, N,3 couplingSonogashiracouplingSonogashiraSonogashira THF,[PdClTHF,[PdCl[PdCl heat2 (PPhheat2(PPh(PPh 3)32)],)2], ], EtEtEt3N,3N,N, (2) Sonogashiracouplingcoupling [PdClTHF,THF,2(PPh heatheat3) 2 ], Et3N, (2) (2) couplingcouplingcouplingcouplingcouplingcoupling THF,THF,THF,THF,THF,THF, heat heat heat heat heatheat couplingSonogashiraSonogashira THF,[PdCl[PdCl[PdCl heat22(PPh(PPh2(PPh 3)32)],23 ],)2], EtEt 33N,Et3 N, couplingcoupling THF,THF, heat heat coupling THF, heat

(3(()3(3 3)) ) ((33))( 3) Cross-coupling [PdCl22(dtbpf)], K22CO33, ((33)) Cross-couplingCross-couplingCross-couplingCross-coupling [PdCl[PdCl[PdCl[PdCl2(dtbpf)],2(dtbpf)],2(dtbpf)],(dtbpf)], K K2K COK2CO2COCO3, 3,3, , (3)(( 33)) Cross-coupling [PdCl2(dtbpf)], K2CO3, (3(()33 )) Cross-couplingCross-couplingCross-coupling [PdCl1,4-dioxane,[PdCl1,4-dioxane,[PdCl2(dtbpf)],22(dtbpf)],(dtbpf)], K 2micro- KKCOmicro-22COCO3, 33,, (3) Cross-couplingCross-couplingCross-coupling 1,4-dioxane,[PdCl1,4-dioxane,[PdCl1,4-dioxane,[PdCl2(dtbpf)],22(dtbpf)],(dtbpf)],2 Kmicro-2 micro-KCOKmicro-22COCO23, 33,, 3 Cross-couplingCross-couplingCross-coupling 1,4-dioxane,[PdCl1,4-dioxane,[PdCl[PdCl2(dtbpf)],2(dtbpf)],(dtbpf)], micro- K Kmicro- 2KCO2COCO3,3 , , wave1,4-dioxane,wave1,4-dioxane,2 radiationradiation 2 formicro-micro-for 3 3030 (3) (3) Cross-coupling [PdClwave1,4-dioxane,wave1,4-dioxane,wave1,4-dioxane,1,4-dioxane, (dtbpf)],radiation radiationradiation K micro-for CO micro-formicro-for micro-30 , 30 30 Cross-coupling wave1,4-dioxane,wave[PdCl1,4-dioxane, radiation 2radiation(dtbpf)], formicro- K micro-for 230CO 303, Cross-couplingCross-coupling 1,4-dioxane,[PdClminminwaveminwave[PdCl 2 at at(dtbpf)],at 140radiation 140radiation(dtbpf)],140 °C °C°C K micro- 2CO KforforCO3 , 3030, minwavewavewavewaveminwavewave at radiation 140 at radiation radiationradiation radiation140radiation °C °C for for forfor forfor30 30 3030 3030 wave1,4-dioxane,minminmin1,4-dioxane, at radiation atat140 140140 °C °C°C micro- for micro- 30 min[PdClminmin at2 at140(dtbpf)],at 140140 °C °C °C minwaveminmin at at at140radiation 140140 °C °C°C for 30 minwaveK CO at radiation 140, 1,4-dioxane, °C for 30 ((4(44)) ) Cross-coupling 2 3 (4) minmin at 140at 140 °C °C (4)(( 44)) microwave radiation (4)(( 44()4) ) ◦ (4()4 ) for 30 min at 140 C (4) (4) (4) BFBFBFKKK BFBF3K333 K BFBFBFK3KK Wittig reaction BFBFBF3K33K K Br-, NaOEt, toluene, WittigWittigWittigWittig reaction reactionreaction reaction BFBF3BF33K 3KK Br-Br-Br-Br-, ,, NaOEt, , NaOEt,NaOEt,NaOEt, toluene, toluene,toluene,toluene, WittigWittig reaction reaction BF K3 3 Br-Br-, NaOEt,, NaOEt, toluene, toluene, WittigWittig reactionreaction 3 microwavemicrowaveBr-microwaveBr-,, NaOEt,NaOEt, radiationradiation radiationtoluene,toluene, WittigWittigWittigWittigWittigWittig reaction reaction reaction reaction reactionreaction BFBFK K microwaveBr-Br-Br-Br-microwaveBr-,Br- ,NaOEt,, , , , NaOEt, NaOEt,NaOEt,NaOEt,NaOEt, radiation toluene, radiationtoluene, toluene,toluene,toluene,toluene, 3 3 microwaveformicrowaveformicrowave 5 5 min min radiation radiationradiation Wittig reaction Br-formicrowaveformicrowaveformicrowave, 5microwave NaOEt,min5 5 min min radiation toluene, radiationradiationradiation WittigWittig reaction reaction Br-formicrowaveforforBr-,microwave 5 NaOEt, min 5,5 minminNaOEt, toluene, radiation radiationtoluene, microwaveforforfor 5for min 55 5 minmin min radiation microwaveBr-,formicrowaveforNaOEt, 5 5min min toluene,radiation radiation for 5 min Wittig reaction microwavefor 5 min radiation for 5 min (2(2) ) for 5 min (2()(2 2)) (2)(( 22)) (2()(2( 2(2()2)2 ) ) ) (2) Claisen-Schmidt Zeolite ultrasound (2) Claisen-SchmidtClaisen-SchmidtClaisen-SchmidtClaisen-Schmidt ZeoliteZeoliteZeoliteZeolite ultrasound ultrasoundultrasound ultrasound (2) Claisen-SchmidtClaisen-SchmidtClaisen-Schmidt ZeoliteZeoliteZeolite ultrasound ultrasoundultrasound Claisen-SchmidtClaisen-SchmidtClaisen-SchmidtClaisen-SchmidtClaisen-SchmidtClaisen-Schmidt ZeoliteZeoliteZeoliteZeoliteZeoliteZeolite ultrasound ultrasound ultrasound ultrasound ultrasoundultrasound Claisen-Schmidt Zeolite ultrasound Claisen-SchmidtClaisen-Schmidt ZeoliteZeolite ultrasound ultrasound

Claisen-Schmidt Zeolite ultrasound R = substituent RR R=R =substituent= = substituentsubstituent substituent RRR = == substituent substituentsubstituent R =R substituent = substituent R =R substituent = substituent RR == substituentsubstituent R R=R substituent == substituentsubstituent(5) R R=R Rsubstituent= =substituent= substituentsubstituent R =RR substituent == substituent(substituent5(()5(5 5)) ) R = substituent RR R= =substituent= ( substituent5substituent)( 5) NaOHNaOHNaOH base basebase R = substituent((55)) R = substituent NaOHNaOH base base ((55)()5 (()55 )) R = substituent NaOHNaOHNaOH base basebase R =R substituent =( substituent5) NaOHNaOHNaOHNaOHNaOHNaOH base base base base basebase NaOH base (5) (5) NaOHNaOH base base

(6(6) ) (6()(6 6)) (6)(( 66)) (6()(6( 6(6()6)6 ) ) ) (6) (6) (6) Biomolecules 2021, 11, x FOR PEER REVIEW 3 of 38 BiomoleculesBiomolecules 2021 2021, ,11 11, ,x x FOR FOR PEER PEER REVIEW REVIEW 33 of of 38 38

Claisen-Schmidt Base Claisen-SchmidtClaisen-Schmidt BaseBase

Using SOCl2 SOCl2/EtOH Using SOCl2 SOCl2/EtOH Using SOCl2 SOCl2/EtOH

AlkynesAlkynes and and al- al- Amberlyst-15,Amberlyst-15, DCM, DCM, dehydesAlkynes and al- at r.t.Amberlyst-15, DCM, dehydesdehydes atat r.t.r.t.

(2) ((22)) Sonogashira [PdCl2(PPh3)2], Et3N, Sonogashira [PdCl2(PPh3)2], Et3N, couplingSonogashira THF,[PdCl heat2(PPh 3)2], Et3N, couplingcoupling THF,THF, heatheat

(3) ((33)) Cross-coupling [PdCl2(dtbpf)], K2CO3, Cross-coupling [PdCl2(dtbpf)], K2CO3, Cross-coupling 1,4-dioxane,[PdCl2(dtbpf)], micro- K2CO3, 1,4-dioxane,1,4-dioxane, micro-micro- wavewave radiation radiation for for 30 30 minwave at 140 radiation °C for 30 minmin atat 140140 °C°C

(4)( 4) (4)

BFBF3K K BF33K Wittig reaction Br-, NaOEt, toluene, WittigWittig reactionreaction Br-Br-,, NaOEt,NaOEt, toluene,toluene, microwavemicrowave radiation radiation for microwave5 min radiation forfor 55 minmin

(2) ((22))

BiomoleculesClaisen-Schmidt2021, 11 , 1203 Zeolite ultrasound 4 of 37 Claisen-SchmidtClaisen-Schmidt ZeoliteZeolite ultrasoundultrasound

Table 1. Cont.

R = substituent Reaction Synthesize Chalcone and Its Approach Compound 1R Compound = substituent 2 R = substituent R = substituent Conditions DerivativesRR == substituentsubstituent (5)( 5) NaOH base (5) NaOHNaOH basebase BiomoleculesBiomolecules 2021 2021, 11, 11, x, xFOR FOR PEER PEER REVIEW REVIEW 4 4of of 38 38 Biomolecules 2021, 11, x FOR PEER REVIEW 4 of 38 NaOH base Biomolecules 20212021,, 1111,, xx FORFOR PEERPEER REVIEWREVIEW 44 ofof 3838 Biomolecules BiomoleculesBiomoleculesBiomolecules 2021 2021 20212021, 11,, ,, 11 , 11 11x, , ,FOR, x xxx FOR FORFORFOR PEER PEER PEERPEERPEER REVIEW REVIEW REVIEWREVIEWREVIEW 4 of444 of of38of 38 3838 Biomolecules Biomolecules Biomolecules 2021 20212021,, , 11 1111,, , x xx FOR FORFOR PEER PEERPEER REVIEW REVIEWREVIEW 444 of ofof 38 3838 Biomolecules 2021, 11, x FOR PEER REVIEW 4 of 38

2 2 4 SolventSolventSolvent free free free SiOSiOSiO2, H,2 ,H2 SOHSO2SO4, 80,4 ,80 °C80 °C °C (6) ((66)) 2 2 4 Solvent free SiO22,, HH22SO44,, 8080 °C°C SolventSolventSolvent free freefree SiOSiOSiO2, H222,, 2 HSOH222SOSO4, 80444,, 80 80°C °C °C SolventSolventSolventSolventSolvent free free free freefree SiOSiOSiOSiOSiO, 2H22,2, ,, ,H H HHSOH222SO2SOSOSO, 48044,4, ,, ,80 80 808080°C °C °C °C °C°C Solvent free SiO2, H2SO4, 80 °C

◦ Solvent free SiO2,H2SO4, 80 C

(7()7 (7) )

3 4 (0)(0) 2 3 SuzukiSuzukiSuzuki reaction reaction reaction (PPh(PPh(PPh3)4Pd)3)Pd4(0)Pd, Cs, ,Cs 2CsCOCO2CO3, ,3 , (7) ((77)) toluene (7)((( 77))) toluenetoluene3 4 (0)(0) 2 3 (((7(777))) ) Suzuki reaction (PPh(PPh33))44Pd(0),, (0) Cs(0)Cs22CO33,, SuzukiSuzukiSuzuki reaction reactionreaction (PPh(PPh(PPh3)4Pd333))444PdPd(0),(0)(0) (0)(0)Cs,, Cs2CsCO222COCO3, 333,, (7) SuzukiSuzukiSuzuki reaction reaction reaction (PPh(PPh(PPh(PPh) 33Pd3)3)4)44Pd4Pd, (0)(0)Cs, ,,Cs CsCsCO222CO2CO, 333,3 ,, SuzukiSuzukiSuzuki reaction reactionreaction toluenetoluene(PPh(PPh(PPh )))PdPdPd(0),, , Cs CsCsCOCOCO,, , Suzuki reaction toluene(PPhtoluene3 )4Pd (0), Cs2CO3, Suzuki reaction toluenetoluene(PPhtoluenetoluenetoluenetoluene ) Pd , Cs CO , toluene toluene (0) (PPh3)4Pd , Cs2CO3, toluene

(8()8 (8) )

2, 2 3, PdClPdClPdCl2, Na2,Na Na2COCO2CO3, 3, (8) ((88)) water/acetone (8()((8( 88))) ) PdClwater/acetonewater/acetone2,2, Na22CO3,3, (((888))) PdCl2, Na2CO3, (8) PdClPdClPdCl2, Na2,2,2, Na Na2CO222COCO3, 3,3,3, (8) Suzuki reaction water/acetonePdClPdClPdClPdCl2,2,2,2, Na NaNa Na222CO2COCOCO 3,3,3,3, water/acetonePdClwater/acetone2, Na2CO 3, water/acetonewater/acetonePdClwater/acetonewater/acetonewater/acetoneNa CO PdClwater/acetone2, Na2CO3, water/acetone (1()1 (1) )

Pd Pd Pd ((11)) (1)((( 11))) Pd (((1(111))) ) Pd Pd (1) PdPdPdPdPd Pd Pd (1()1 (1) )

Base-drivenBase-drivenBase-driven KOH/EtOH,KOH/EtOH,KOH/EtOH, heat, heat, heat, 1–5 1–5 1–5 (1) ((1)) ( 1) h (1()((1( 11))) ) Base-driven KOH/EtOH,h h heat, 1–5 ((11)) Base-drivenBase-drivenBase-driven KOH/EtOH,KOH/EtOH,KOH/EtOH, heat, heat,heat, 1–5 1–51–5 (1) Base-drivenBase-drivenBase-drivenBase-driven h KOH/EtOH,KOH/EtOH,KOH/EtOH,KOH/EtOH, heat, heat,heat,heat, 1–5 1–51–51–5 Base-driven h KOH/EtOH,h heat, 1–5 h hhhh KOH/EtOH,h heat, (9()9 (9) ) 1–5 h

((99)) (9)((( 99))) Base-driven (9()((9(999))) ) (9) NaOHNaOHNaOH NaOH NaOHNaOHNaOH NaOHNaOHNaOHNaOHNaOH NaOH

(10) (1010()10 ) ( )

2 3 ((1010)) AlAl2OAl3O:2O aluminum:3 : aluminumaluminum oxide; oxide;oxide; Bmim BmimBmim (OTs): (OTs): 1-butyl-3-methyl-1(OTs): 1-butyl-3-methyl-11-butyl-3-methyl-1H-imidazoliumHH-imidazolium-imidazolium 4-methylbenzenesulfonate; 4-methylbenzenesulfonate;4-methylbenzenesulfonate; DCM: dichloromethane; (DCM:10DCM:) dichloro-dichloro- EtOH: Al2 O3 : aluminum oxide; Bmim (OTs): 1-butyl-3-methyl-1H-imidazolium 4-methylbenzenesulfonate; DCM:(10(((10(10)10 ))dichloro-) ) 3 2 4 (((101010))) ethanol;methane;methane;methane; Et3 N:EtOH: EtOH: triethylamine;EtOH: ethanol; ethanol; ethanol; NaOEt:Et Et 3N:EtN:3 N:triethylamine; sodium triethylamine; triethylamine; ethoxide; NaOEt: HBr:NaOEt: NaOEt: hydrobromic sodium sodium sodium ethoxide; acid; ethoxide; ethoxide; H2SO HBr:4 :HBr: sulfuricHBr: hydrobromic hydrobromic hydrobromic acid; K2CO acid;3 :acid; potassiumacid; H H2 SOHSO2SO4 carbonate;: sulfuric:4 (:10sulfuric sulfuric) KOH:acid; acid; acid; Al22O33:: aluminumaluminum oxide;oxide; BmimBmim (OTs):(OTs): 1-butyl-3-methyl-11-butyl-3-methyl-1H-imidazolium-imidazolium 4-methylbenzenesulfonate;4-methylbenzenesulfonate; DCM:DCM:(10 dichloro-)dichloro- potassiumAl2AlO232:O 3aluminum3: hydroxide;aluminum oxide; MeOH: oxide; methanol;Bmim Bmim (OTs): Na(OTs):CO 1-butyl-3-methyl-1 :1-butyl-3-methyl-1 sodium carbonate;H NaOH:-imidazoliumH-imidazolium sodium hydroxide; 4-methylbenzenesulfonate; 4-methylbenzenesulfonate; Pd: palladium; PdCl : palladiumDCM: DCM: dichloro- chloride;dichloro- AlAlKAl2AlO22CO2O32O:O 33:aluminum33: :: : 3 aluminumaluminumpotassiumaluminumaluminum oxide; carbonate;oxide;oxide;oxide;oxide; Bmim BmimBmimBmimBmim KOH: (OTs): (OTs):(OTs):(OTs):(OTs): 2potass 1-butyl-3-methyl-1 3 1-butyl-3-methyl-11-butyl-3-methyl-11-butyl-3-methyl-11-butyl-3-methyl-1ium hydroxide;H MeOH:H-imidazoliumHH-imidazolium-imidazolium-imidazolium-imidazolium methanol; 4-methylbenzenesulfonate; 4-methylbenzenesulfonate;4-methylbenzenesulfonate;4-methylbenzenesulfonate; 4-methylbenzenesulfonate;Na2CO2 3:3 sodium carbonate;2 DCM: DCM:DCM: DCM:DCM:NaOH: dichloro- dichloro-dichloro-dichloro-dichloro- sodium methane;K2AlAlCOAlK222OCOOO3:3 33:potassium: : :aluminumaluminumEtOH: aluminumpotassium ethanol; carbonate; oxide;oxide;carbonate;oxide; Et 3Bmim3BmimN:Bmim KOH: triethylamine;KOH: (OTs):(OTs):potass(OTs): potass ium1-butyl-3-methyl-11-butyl-3-methyl-11-butyl-3-methyl-1ium hydroxide;NaOEt: hydroxide; sodium MeOH: MeOH:HHH -imidazolium-imidazolium-imidazoliumethoxide; methanol;0 methanol; HBr: Na 4-methylbenzenesulfonate;4-methylbenzenesulfonate;4-methylbenzenesulfonate; hydrobromicNa2COCO3: sodium: sodium acid; carbonate; carbonate; H22SO 4 4NaOH: : DCM:DCM:DCM:sulfuric NaOH: sodiumdichloro-dichloro-dichloro- acid;sodium methane;PdCl2(PPh3 EtOH:) : bis(triphenylphospine)palladium ethanol; Et3N: triethylamine; dichloride; NaOEt: PdCl sodium(dtbpf): ethoxide; 1,1 -bis(di- HBr:tert-butylphosphino)ferrocene]dichloropalladium; hydrobromic acid; H2SO4:: sulfuricsulfuric acid;acid; Almethane;methane;2O3: aluminum3 2 EtOH:EtOH: ethanol; ethanol;oxide; Bmim3EtEt333N:N: triethylamine;triethylamine;(OTs):2 1-butyl-3-methyl-1 NaOEt:NaOEt: sodium2sodium H-imidazolium ethoxide;ethoxide;2 3 2 HBr: HBr:4-methylbenzenesulfonate; hydrobromichydrobromic acid;acid; 2HH222SOSO 4 DCM:444::: sulfuricsulfuricsulfuric dichloro- acid;acid;acid; methane;hydroxide;methane;hydroxide;methane;methane;methane;hydroxide;(0) EtOH: EtOH: EtOH:EtOH:Pd:EtOH: Pd:Pd: ethanol;palladium; ethanol; ethanol;palladium;ethanol;ethanol;palladium; Et Et Et EtEtN:3PdCl 33N:3N: N:N:PdCltriethylamine;PdCl triethylamine; triethylamine;triethylamine;triethylamine;2: :2palladium : palladiumpalladium NaOEt: NaOEt: NaOEt:NaOEt:NaOEt:chloride; chloride;chloride; sodium sodium sodiumsodiumsodium PdCl PdClPdCl ethoxide; 2 ethoxide;(PPh ethoxide;ethoxide;ethoxide;(PPh2(PPh3)2:) 3)HBr::2bis(triphenylphospine)palladium : HBr: HBr:HBr:bis(triphenylphospine)palladiumHBr:bis(triphenylphospine)palladium hydrobromic hydrobromic hydrobromichydrobromichydrobromic acid; acid; acid;acid;acid; H H HHSOH222SO2SOSOSO: 44sulfuric4:4: : : sulfuric sulfuricsulfuricdichloride;sulfuric dichloride;dichloride; acid; acid; acid;acid;acid; (PPhK22CO)33::Pd potassiumpotassium: tetrakis(triphenylphosphine)palladium(0); carbonate;carbonate; KOH:KOH: potasspotassiumium hydroxide;hydroxide; SiO : silicon MeOH:MeOH: dioxide; methanol;methanol; SOCl : thionyl NaNa22CO chloride;33:: sodiumsodium THF: carbonate;carbonate; tetrahydrofuran. NaOH:NaOH: sodiumsodium K2methane;COK232CO43: potassium33: potassium EtOH: carbonate;ethanol; carbonate; Et KOH:3N: KOH: triethylamine; potass potassiumium hydroxide; NaOEt:hydroxide;2 sodium MeOH: MeOH: ethoxide;methanol; methanol;2 HBr: Na Na2CO hydrobromic22CO3: sodium33(0): sodium carbonate; acid; carbonate; H2SO NaOH:4 NaOH:: sulfuric sodium sodium acid; K2KPdClKCOK222CO2COCO3: 23potassium(dtbpf):323:3: :: potassium potassiumpotassiumpotassium 1,1 carbonate;′-bis(di- carbonate; carbonate;carbonate;carbonate;tert KOH:-butylphosphino)ferrocene]dichloropalladium; KOH: KOH:KOH:KOH: potass potass potasspotasspotassiumiumiumiumium hydroxide; hydroxide; hydroxide;hydroxide;hydroxide; MeOH: MeOH: MeOH:MeOH:MeOH: methanol; methanol; methanol;methanol;methanol; Na(PPh Na NaNaNa2CO2322CO2)CO3CO43Pd4:(0) 3sodium33:3: :: sodium (0) sodiumsodium:sodium tetrakis(triphen carbonate; carbonate; carbonate;carbonate;carbonate; NaOH:ylphosphine)pal- NaOH: NaOH:NaOH:NaOH: sodium sodium sodiumsodiumsodium hydroxide;PdClKKKPdCl22COCOCO2(dtbpf):33:(dtbpf):: : potassium potassiumpotassium Pd: 1,1 ′1,1palladium;-bis(di-′ -bis(di-carbonate; carbonate;carbonate;terttert-butylphosphino)ferrocene]dichloropalladium; PdCl-butylphosphino)ferrocene]dichloropalladium; KOH: KOH:KOH:22: palladiumpotass potasspotassiumiumium hydroxide; hydroxide;hydroxide;chloride; PdCl MeOH: MeOH:MeOH:22(PPh methanol; methanol;methanol;33)22: bis(triphenylphospine)palladium (PPh (PPh Na NaNa3)4Pd22COCOCO) Pd3:3:: : tetrakis(triphensodium sodiumsodium: tetrakis(triphen carbonate; carbonate;carbonate;ylphosphine)pal-ylphosphine)pal- NaOH: NaOH:NaOH: dichloride; sodium sodiumsodium hydroxide;2 3 Pd: palladium; PdCl2:: palladiumpalladium chloride;chloride; PdCl2(PPh(PPh3))2:: bis(triphenylphospine)palladiumbis(triphenylphospine)palladium2 3 dichloride;dichloride; hydroxide;Khydroxide;hydroxide;2CO3: potassium Pd: Pd:Pd: 2 palladium; palladium; palladium;carbonate; PdCl KOH:PdClPdCl2: 2 22potass:palladium: 2 palladiumpalladiumium hydroxide;chloride; chloride;chloride; PdClMeOH: PdClPdCl2(PPh222 (PPh(PPhmethanol;3)2:333 ))222:bis(triphenylphospine)palladium: bis(triphenylphospine)palladiumbis(triphenylphospine)palladium Na2CO3: sodium carbonate; NaOH: dichloride; dichloride;dichloride; sodium hydroxide;ladium(0);hydroxide;ladium(0);hydroxide;hydroxide;hydroxide;ladium(0); SiO Pd: SiO SiOPd:Pd:2Pd:Pd:: silicon:palladium;2 :silicon palladium;siliconpalladium;palladium;palladium; dioxide; dioxide; dioxide; PdCl PdClPdClSOClPdClPdCl SOCl SOCl: 222:2:palladium :: : thionylpalladium:palladium2palladium palladiumpalladium:thionyl thionyl chloride; chloride; chloride; chloride;chloride;chloride;chloride;chloride; THF: THF: THF:PdCl PdCltetrahydrofuran.PdClPdClPdCl tetrahydrofuran. tetrahydrofuran.(PPh222(PPh2(PPh(PPh(PPh(PPh) 33:3) 3))2))22:2:bis(triphenylphospine)palladium :: : bis(triphenylphospine)palladiumbis(triphenylphospine)palladiumbis(triphenylphospine)palladiumbis(triphenylphospine)palladiumbis(triphenylphospine)palladium (0)(0) dichloride; dichloride;dichloride;dichloride;dichloride;dichloride; PdCl22(dtbpf):(dtbpf): 1,11,1′′-bis(di--bis(di-terttert-butylphosphino)ferrocene]dichloropalladium;-butylphosphino)ferrocene]dichloropalladium; (PPh(PPh33))44Pd(0)(0):: (0)tetrakis(triphentetrakis(triphenylphosphine)pal- PdClhydroxide;PdCl2(dtbpf):2(dtbpf): 1,1Pd: 1,1′-bis(di- ′palladium;-bis(di-terttert-butylphosphino)ferrocene]dichloropalladium;-butylphosphino)ferrocene]dichloropalladium; PdCl2: palladium chloride; PdCl2(PPh3)2 :(PPh bis(triphenylphospine)palladium (PPh3)4Pd3)4Pd(0):(0) (0)(0)(0)tetrakis(triphen: tetrakis(triphenylphosphine)pal-ylphosphine)pal- dichloride; PdClPdClhydroxide;PdClPdCl2(dtbpf):222(dtbpf):2(dtbpf):(dtbpf):(dtbpf): 1,1Pd: 1,1 1,11,11,1′-bis(di- ′′-bis(di-′′-bis(di-palladium;-bis(di--bis(di-tertterttertterttert-butylphosphino)ferrocene]dichloropalladium;-butylphosphino)ferrocene]dichloropalladium;-butylphosphino)ferrocene]dichloropalladium;-butylphosphino)ferrocene]dichloropalladium;-butylphosphino)ferrocene]dichloropalladium; PdCl : palladium chloride; PdCl (PPh ) : (PPh bis(triphenylphospine)palladium (PPh (PPh(PPh(PPh3)43Pd33)3))4)44Pd4PdPd:(0) (0)(0)tetrakis(triphen:: :: tetrakis(triphen tetrakis(triphentetrakis(triphentetrakis(triphenylphosphine)pal-ylphosphine)pal-ylphosphine)pal-ylphosphine)pal- dichloride; ladium(0);PdClPdClPdCl222(dtbpf):(dtbpf):(dtbpf): SiO22: 1,1silicon1,11,1′′-bis(di-′-bis(di--bis(di- dioxide;tertterttert-butylphosphino)ferrocene]dichloropalladium;-butylphosphino)ferrocene]dichloropalladium;-butylphosphino)ferrocene]dichloropalladium; SOCl22: thionyl chloride; THF: tetrahydrofuran. (PPh(PPh(PPh 333)))444PdPdPd :: : tetrakis(triphentetrakis(triphentetrakis(triphenylphosphine)pal-ylphosphine)pal-ylphosphine)palladium(0);ladium(0);2 SiOSiO2:: siliconsilicon dioxide;dioxide; SOClSOCl2:: thionylthionyl chloride;chloride; THF:THF: tetrahydrofuran.tetrahydrofuran. 3 4 (0)(0) ladium(0);PdClladium(0);ladium(0);ladium(0);2(dtbpf): SiO SiOSiOSiO2 : 1,1silicon222::: siliconsilicon′silicon-bis(di- dioxide; dioxide;dioxide;dioxide;tert-butylphosphino)ferrocene]dichloropalladium; SOCl SOClSOClSOCl2: thionyl222::: thionylthionylthionyl chloride; chloride;chloride;chloride; THF: THF:THF:THF: tetrahydrofuran. tetrahydrofuran.tetrahydrofuran.tetrahydrofuran. (PPh 3)4Pd : tetrakis(triphenylphosphine)palladium(0);ladium(0);ladium(0);ladium(0); SiO SiO SiOSiO222:2: : :silicon silicon siliconsilicon dioxide; dioxide; dioxide;dioxide;3.3. Molecular3. Molecular Molecular SOCl SOCl SOClSOCl222:2: : :thionyl thionyl thionyl thionylMechanisms Mechanisms Mechanisms chloride; chloride; chloride;chloride; of THF: THF: THF: THF:of ofChalcone Chalcone Chalcone tetrahydrofuran. tetrahydrofuran. tetrahydrofuran.tetrahydrofuran. Actions Actions Actions ladium(0); SiO2: silicon dioxide; SOCl2: thionyl chloride; THF: tetrahydrofuran. 3. MolecularVarious Mechanisms bioactivities of of Chalcone chalcones Actions result from their interactions with several biomol- 3. 3.Molecular3. MolecularMolecularVariousVarious Mechanismsbioactivities Mechanisms Mechanismsbioactivities of of ofchalcones of ofChalcone chalcones ChalconeChalcone result Actions result ActionsActions from from their their interactions interactions with with several several biomol- biomol- 3.ecules3.3.3. Molecular Molecular MolecularMolecular and different Mechanisms Mechanisms MechanismsMechanisms signaling of of ofof Chalcone Chalcone ChalconeChalconepathways. Actions Actions ActionsActions Some of those molecular mechanisms of activi- ecules3.ecules MolecularVarious and and different bioactivities different Mechanisms signaling signaling of chalconesof pathways. Chalcone pathways. result SomeActions Some from of oftheirthose those interactions molecular molecular mechanisms with mechanisms several of biomol- ofactivi- activi- VariousVariousVariousVarious bioactivities bioactivities bioactivitiesbioactivities of of ofofchalcones chalcones chalconeschalcones result result resultresult from from fromfrom their their theirtheir interactions interactions interactionsinteractions with with withwith several several severalseveral biomol- biomol- biomol-biomol- eculestiestiesties of of andVariousofchalconesVariousVarious chalcones chalcones different bioactivitiesbioactivitiesbioactivities are are are signalingdiscussed discussed discussed ofofof pathways. chalconeschalconeschalconesin in inthe the the following following following resultresultresultSome from fromsubsections.offromof subsections. subsections.thosethose theirtheirtheir molecularmolecular interactionsinteractionsinteractions mechanismsmechanisms withwithwith severalseveralseveral ofof activi- activi- biomol-biomol-biomol- eculeseculesecules Variousand andand different differentdifferent bioactivities signaling signalingsignaling of chalconespathways. pathways.pathways. result Some SomeSome from ofof of ofofthosethose thosetheirthosethose molecularmolecular interactions molecularmolecularmolecular mechanismsmechanisms mechanismsmechanismsmechanisms with several ofof of of ofactivi-activi-biomol- activi-activi-activi- tieseculeseculeseculesecules of chalcones and andandand different differentdifferentdifferent are discussed signaling signalingsignalingsignaling in pathways. pathways. pathways.pathways.the following Some SomeSomeSome subsections. of ofofof those thosethosethose molecular molecularmolecularmolecular mechanisms mechanismsmechanismsmechanisms of ofofof activi- activi-activi-activi- tiestieseculesties ofof ofchalconeschalcones andchalcones different areare are discusseddiscussed signalingdiscussed inin pathways. inthethe the followingfollowing following Some subsections.subsections. ofsubsections. those molecular mechanisms of activi- tiesties3.1.tiestiestiesties of of Activation of ofofofchalcones chalcones chalcones chalconeschalconeschalcones of are Nuclearare are areareare discussed discussed discussed discusseddiscusseddiscussed Factor-Erythroid in in in inininthe the the thethethe following following following followingfollowingfollowing 2 p45 subsections.Subunit-Related subsections. subsections. subsections.subsections.subsections. Factor 2 Pathway and 3.1.ties3.1. Activation of Activation chalcones of Nuclearof areNuclear discussed Factor-Erythroid Factor-Erythroid in the following 2 p45 2 p45 Subunit-Related Subunit-Relatedsubsections. Factor Factor 2 Pathway 2 Pathway and and Cellularties of chalcones Defence Genes are discussed in the following subsections. 3.1.CellularCellular Activation Defence Defence of GenesNuclear Genes Factor-Erythroid 2 p45 Subunit-Related Factor 2 Pathway and 3.1.3.1.3.1.3.1. Activation Activation ActivationActivation of of ofNuclearof Nuclear NuclearNuclear Factor-Erythroid Factor-Erythroid Factor-ErythroidFactor-Erythroid 2 2p45 22 p45 p45p45 Subunit-Related Subunit-Related Subunit-RelatedSubunit-Related Factor Factor FactorFactor 2 2Pathway 22 Pathway PathwayPathway and and andand Cellular3.1.3.1.3.1. Activation ActivationActivationNuclear Defence factor-erythroid Genes of ofof Nuclear NuclearNuclear Factor-Erythroid Factor-ErythroidFactor-Erythroid (NF-E2) p45-related 2 22 p45 p45p45 Subunit-Related Subunit-RelatedSubunit-Related factor 2 (Nrf2) Factor FactorFactor is a 2 2 2transcription Pathway PathwayPathway and andand factor, Cellular3.1.CellularCellularNuclear Activation NuclearDefence DefenceDefence factor-erythroid Genesoffactor-erythroid Genes GenesNuclear Factor-Erythroid (NF-E2) (NF-E2) p45-related p45-related 2 p45 Subunit-Related factor factor 2 (Nrf2) 2 (Nrf2) Factor is ais transcription 2a Pathwaytranscription and factor, factor, CellularwhichCellularCellularCellular controls Defence Defence DefenceDefence theGenes Genes GenesGenes expression of a battery of antioxidant genes, all of which have an anti- whichCellularwhichNuclear controls controlsDefence factor-erythroid the Genesthe expression expression (NF-E2) of aof battery a battery p45-related of ofantioxidant antioxidant factorfactor 22genes, (Nrf2)(Nrf2) genes, all isis all of aa transcriptiontranscriptionofwhich which have have an factor,factor, ananti- anti- NuclearNuclearNuclearNuclear factor-erythroid factor-erythroid factor-erythroidfactor-erythroid (NF-E2) (NF-E2) (NF-E2)(NF-E2) p45-related p45-related p45-relatedp45-related factor factor factorfactorfactor 2 2 (Nrf2) 222 (Nrf2) (Nrf2)(Nrf2)(Nrf2) is is isisais a transcription aaa transcription transcriptiontranscriptiontranscription factor, factor, factor,factor,factor, whichoxidantoxidantoxidant controlsNuclearNuclearNuclear response response response thefactor-erythroid factor-erythroidfactor-erythroid element expression element element (ARE) (ARE) (ARE) of (NF-E2) (NF-E2) (NF-E2) ain batteryin theirin their their p45-related p45-relatedpromotp45-related ofpromot promot antioxidanterer erwhich factor factorwhichfactor which genes, allows 2 22allows allows(Nrf2) (Nrf2)(Nrf2) all the theof is istheis binding whicha a abinding transcription bindingtranscriptiontranscription have of of ofNrf2 anNrf2 Nrf2 anti- factor, factor,[10].factor, [10]. [10]. whichwhichwhich Nuclearcontrols controlscontrols factor-erythroidthe thethe expression expressionexpression of (NF-E2) of ofa battery aa batterybattery p45-related of ofofantioxidant antioxidantantioxidant factor genes, 2 genes,genes, (Nrf2) all allall ofis of ofwhicha transcription whichwhich have havehave an anan anti-factor, anti-anti- oxidantwhichwhichwhichwhich response controls controls controlscontrols the the theelementthe expression expression expressionexpression (ARE) of of ofofin a a aatheir battery battery batterybattery promot of of ofof antioxidant antioxidant antioxidantantioxidanter which allows genes, genes, genes,genes, the all all allall ofbinding of ofof which which whichwhich of have have havehave Nrf2 an an anan [10]. anti- anti- anti-anti- oxidantwhichoxidant responsecontrols response theelement element expression (ARE) (ARE) of in a intheir battery their promot promot of antioxidanter erwhich which allows genes, allows the all the bindingof bindingwhich of have ofNrf2 Nrf2 an [10]. anti- [10]. oxidantoxidantoxidantoxidantoxidant response response response responseresponse element element element elementelement (ARE) (ARE) (ARE) (ARE)(ARE) in in in inintheir their their theirtheir promot promot promot promotpromotererer ererwhich which which whichwhich allows allows allows allowsallows the the the thethe binding binding binding bindingbinding of of of ofofNrf2 Nrf2 Nrf2 Nrf2Nrf2 [10]. [10]. [10]. [10].[10]. oxidant response element (ARE) in their promoter which allows the binding of Nrf2 [10]. Biomolecules 2021, 11, 1203 5 of 37

3. Molecular Mechanisms of Chalcone Actions Various bioactivities of chalcones result from their interactions with several biomolecules and different signaling pathways. Some of those molecular mechanisms of activities of chalcones are discussed in the following subsections.

3.1. Activation of Nuclear Factor-Erythroid 2 p45 Subunit-Related Factor 2 Pathway and Cellular Defence Genes

Biomolecules 2021, 11, x FOR PEER REVIEWNuclear factor-erythroid (NF-E2) p45-related factor 2 (Nrf2) is a transcription factor,5 of 38 which controls the expression of a battery of antioxidant genes, all of which have an antioxidant response element (ARE) in their promoter which allows the binding of Nrf2 [10]. The ARE-Nrf2 complex leads to induction of cell expression of cell defense genes. such asThe glutathione ARE-Nrf2 S-transferasecomplex leads (GST), to induction hemoxygenase-1 of cell expression (HO-1), andof cell xenobiotic defense genes. metabolizing such as enzymeglutathione (NAD(P)H: S-transferase quinone (GST), oxidoreductase hemoxygena 1) (NQO1)se-1 (HO-1), [11–13 and]. Kim xenobiotic et al. [14 ]metabolizing synthesized aenzyme series of (NAD(P)H: chalcone derivatives, quinone oxidoreductase and among them, 1) (NQO1) a new chalcone [11–13]. derivative Kim et al. (11 [14]) (Figure synthe-2) wassized found a series to possessof chalcone the bestderivatives, Nrf2 activation and among properties them, anda new could chalcone induce derivative Nrf2 nuclear (11) translocation.(Figure 2) was This found chalcone to possess salt the (11 )best was Nrf2 shown activation to induce properties gene expression and could of induce antioxidant Nrf2 enzymesnuclear translocation. and attenuate This inﬂammatory chalcone salt responses (11) was inshown activated to induce microglia. gene expression There has of been an- antioxidant increasing enzymes number and of attenuate publications inflammatory that detail theresponses relationship in activated between microglia. chalcones There and Nrf2,has been with an several increasing studies number reporting of publications the ability that of chalcones detail the to relationship induce Nrf2. between The ability chal- ofcones synthetic and Nrf2, and with natural several chalcones studies to reporting activate thethe Nrf2ability signaling of chalcones pathway to induce was reviewedNrf2. The recentlyability of [ 15synthetic]. and natural chalcones to activate the Nrf2 signaling pathway was reviewed recently [15]. HCl

(11)

FigureFigure 2.2. A synthetic chalconechalcone derivativederivative asas anan Nrf2Nrf2 activator.activator.

AjiboyeAjiboye etet al.al. [[16]16] reportedreported thatthat naturalnatural chalconeschalcones lophironeslophirones BB ((1212)) andand CC ((1313)) couldcould 0 0 induceinduce Nrf2 (Figure 33).). In addi addition,tion, the the natural natural chalcone, chalcone, 3,4,2 3,4,2′,4′,4-tetrahydroxychalcone-tetrahydroxychalcone 4′- 0 4O--Oβ-D-glucopyranoside-β-D-glucopyranoside (14 (),14 was), was noted noted to increase to increase the thelevel level of NQO1 of NQO1 [NAD(P) [NAD(P) H: qui- H: quinonenone oxidoreductase oxidoreductase 1] in 1] Hepa in Hepa 1c1c7 1c1c7 cells [17]. cells Martinez [17]. Martinez et al. [18] et reported al. [18] reported that chalcone that chalcone(1) could (increase1) could glutathione increase glutathione (GSH), HO-1, (GSH), and HO-1, Nrf2 and(Figure Nrf2 3). (Figure Furthermore,3). Furthermore, other re- 0 0 0 othersearchers researchers found 2-chloro-4 found 2-chloro-4′,6′-dimethoxy-2,6 -dimethoxy-2′-hydroxychalcone-hydroxychalcone (15), a synthetic (15), a syntheticchalcone, chalcone,to increase to GSH increase levels GSH by enhancing levels by enhancing its biosynthesis its biosynthesis [19]. The ability [19]. The to induce ability activation to induce activationof Nrf2 was of exploited Nrf2 was to exploited assess potential to assess canc potentialer chemopreventive cancer chemopreventive activity of licorice activity sam- of licoriceples collected samples from collected different from geographical different geographical locations [20]. locations In fact, [20 th].e In structural fact, the structural diversity diversitythat exists that among exists synthetic among synthetic and natural and chalcones, natural chalcones, ease of structural ease of structural modification, modiﬁcation, and the α β andpresence the presence of α,β-unsaturated of , -unsaturated carbonyl carbonyl functionality functionality (pharmacophore) (pharmacophore) make makethese thesecom- compoundspounds suitable suitable drug drug candidates candidates or can or canlead lead to targeting to targeting of Nrf2-dependent of Nrf2-dependent disease. disease. 3.2. Activation of the Nuclear Factor-Kappa B (NF-κB) PI3K/Akt Signaling Pathway The transcription factor, nuclear factor-kappa B PI3K/Akt (NF-κB), is a heterodimer consisting of p50 and p65 subunits, and is central to the functioning of the immune system. It has a role to play in the expression of immunoglobulin-k. NF-κB is activated by extracellular promoters, such as growth factors and inﬂammatory cytokines. The extracellular promoters switch on NF-κB signaling through dissolution and phosphorylation of the inhibiting I-κB protein. Allowing NF-κB to enter the nucleus and regulate cell cycle and apoptosis-related gene expression [21]. Biomolecules 2021, 11, 1203 6 of 37 Biomolecules 2021, 11, x FOR PEER REVIEW 6 of 38

FigureFigure 3. 3.Chalcones Chalcones that that induce induce transcriptiontranscription factors: chalcone chalcone (1 (1),), lophirone lophirone B B(12 (12) and) and C C(13 (13) induce) induce the the Nrf2 Nrf2 pathway, pathway, whilewhile synthetic synthetic chalcones chalcones DK-139 DK-139 ( 24(24),), L6H9 L6H9 ((2525)) andand DMPF-1DMPF-1 ( 26)) induce induce the the NF- NF-κκBB pathway. pathway.

3.2. ActivationSeveral studies of the Nuclear have examined Factor-Kappa the effectB (NF- ofκB) chalcones PI3K/Akt onSignaling NF-κB Pathway signaling as a plausi- ble wayThe to transcription modulate inflammation factor, nuclear and factor-kappa cancer, and B PI3K/Akt found that (NF- severalκB), is natural a heterodimer chalcones, e.g.,consisting butein of(16 p50), calomelanone and p65 subunits, (17), and flavokawain is central Cto ( 18the), functioning homobutein of (19 the), immune 4-hydroxychalcone system. 0 (20It has), 4 -hydroxychalconea role to play in the ( 21expression), isoliquiritigenin of immunoglobulin-k. (22), 4-methoxychalcone NF-κB is activated (2), and by phloretin extra- (23cellular) (Figure promoters,4) have such the abilityas growth to suppressfactors and NF- inflammatoryκB signaling cytokines. [22]. Similarly, The extracellular NF-κB ac- 0 0 tivationpromoters could switch be on stimulated NF-κB signaling by several through synthetic dissolution chalcones, and phosphorylation such as 2-hydroxy-3 of the in-,5,5 - 0 trimethoxychalconehibiting I-κB protein. (DK-139) Allowing(24 )[NF-23],κB (E to)-2,6-diﬂuoro-4 enter the nucleus-methoxychalcone and regulate cell (L6H9) cycle (25 and)[24 ], Biomolecules 2021, 11, x FOR PEER REVIEW 7 of 38 andapoptosis-related 3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one gene expression [21]. (DMPF-1) (26)[25] (FigureSeveral3). studies have examined the effect of chalcones on NF-κB signaling as a plau- sible way to modulate inflammation and cancer, and found that several natural chalcones, e.g., butein (16), calomelanone (17), flavokawain C (18), homobutein (19), 4-hydroxychalcone (20), 4’-hydroxychalcone (21), isoliquiritigenin (22), 4-methoxychalcone (2), and phloretin (23) (Figure 4) have the ability to suppress NF-κB signaling [22]. Similarly, NF- κB activation could be stimulated by several synthetic chalcones, such as 2-hydroxy- 3’,5,5’-trimethoxychalcone (DK-139) (24) [23], (E)-2,6-difluoro-4′-methoxychalcone (L6H9) Butein (16) R = H (25) [24], and 3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one (DMPF-1) Homobutein (19) R = Me Calomelanone (17) R = R’ = Me; R’’ = H (26) [25] (Figure 3). Flavokawain C (18) R = R’ = R’’ = Me Phloretin (23) R = R’ = R’’ = H

Isoliquiritigenin (22) 4-Hydroxychalcone (20) R = H 4′-Hydroxychalcone (21) 4-Methoxychalcone (2) R = Me

Figure Figure4. Examples 4. Examples of some of naturally some naturally occurring occurring chalcones chalcones that induce that inducethe NF- theκB NF-pathway.κB pathway.

3.3. Effects on the Cell Cycle Many researchers have investigated the effects of synthetic and natural chalcones on the cell cycle [26–30]. Dimethyl-cardamonin (27) was shown to arrest cell cycle in the G1 phase by decreased expression of cyclin D1, CDK4 (cyclin-dependent kinase 4), and phospho-Rb [30], while Hseu et al. [29] reported that the chalcone flavokawain B (28) could cause cell cycle arrest in the G2/M phase in human oral carcinoma cells. Studies conducted by Maioral et al. [31] established the importance of chalcone (2E)- 1-(2,5-dimethoxy-phenyl)-3-(1-naphthyl)-2-propene-1-one (29) in blocking the G2/M phase in human leukemia cell lines, i.e., NB4, K562, and Kasumi cell lines, and the G0/G1 phase in the human T-cell leukemia cell line CEM, the human lung cancer cell line U937, and the S phase in Jurkat cell lines. In addition, Kello et al. [32] found that the chalcones (E)-2-(4′-methoxybenzylidene)-1-benzosuberone (30) and (E)-2-(3′,4′-dimethoxy-benzylidene)-1-tetralone (31) could be responsible for cell cycle arrest at the G2/M phase in Caco- 2 cells. Two synthetic chalcones, (E)-1-(4-aminophenyl)-3-(2,3-dimethoxyphenyl)-prop-2- en-1-one (32) and (E)-1-(4-aminophenyl)-3-phenylprop-2-en-1-one) (33), were studied for their effects on the cell cycle of the human erythroleukemic cell line K562 and it was observed that both chalcones acted as inhibitors of the cell cycle [33]. The cell cycle distribution of cervical cancer (HeLa) cells treated with the synthetic chalcone L1 (39) was analyzed by flow cytometry, revealing its ability to induce cell cycle arrest in the G2/M phase after 24 h of treatment [26], while chalcone (1) and licochalcone A (40) were found to induce the cell cycle arrest in the G1 phase in the MCF-7 breast cancer cells [27]. A summary of the effects of different chalcones on the cell cycle is shown in Figure 5, and the structures of chalones that influence the cell cycle are presented in Figure 6. Biomolecules 2021, 11, 1203 7 of 37

3.3. Effects on the Cell Cycle Many researchers have investigated the effects of synthetic and natural chalcones on the cell cycle [26–30]. Dimethyl-cardamonin (27) was shown to arrest cell cycle in the G1 phase by decreased expression of cyclin D1, CDK4 (cyclin-dependent kinase 4), and phospho-Rb [30], while Hseu et al. [29] reported that the chalcone ﬂavokawain B (28) could cause cell cycle arrest in the G2/M phase in human oral carcinoma cells. Studies conducted by Maioral et al. [31] established the importance of chalcone (2E)-1- (2,5-dimethoxy-phenyl)-3-(1-naphthyl)-2-propene-1-one (29) in blocking the G2/M phase in human leukemia cell lines, i.e., NB4, K562, and Kasumi cell lines, and the G0/G1 phase in the human T-cell leukemia cell line CEM, the human lung cancer cell line U937, and the S phase in Jurkat cell lines. In addition, Kello et al. [32] found that the chalcones (E)-2- (40-methoxybenzylidene)-1-benzosuberone (30) and (E)-2-(30,40-dimethoxy-benzylidene)- 1-tetralone (31) could be responsible for cell cycle arrest at the G2/M phase in Caco-2 cells. Two synthetic chalcones, (E)-1-(4-aminophenyl)-3-(2,3-dimethoxyphenyl)-prop-2-en- 1-one (32) and (E)-1-(4-aminophenyl)-3-phenylprop-2-en-1-one) (33), were studied for their effects on the cell cycle of the human erythroleukemic cell line K562 and it was observed that both chalcones acted as inhibitors of the cell cycle [33]. The cell cycle distribution of cervical cancer (HeLa) cells treated with the synthetic chalcone L1 (39) was analyzed by ﬂow cytometry, revealing its ability to induce cell cycle arrest in the G2/M phase after 24 h of treatment [26], while chalcone (1) and licochalcone A (40) were found to induce the cell cycle arrest in the G1 phase in the MCF-7 breast cancer cells [27]. A summary of the effects Biomolecules 2021, 11, x FOR PEER REVIEWof different chalcones on the cell cycle is shown in Figure5, and the structures of chalones8 of 38

that inﬂuence the cell cycle are presented in Figure6.

Figure 5.5. The effect ofof naturalnatural andand syntheticsynthetic chalconeschalcones onon thethe cellcell cycle.cycle. GroupGroup A:A: ChalconesChalcones arrestarrest thethe cellcell cyclecycle atat thethe GG11/S phase, phase, i.e., i.e., dimethyl dimethyl cardamonin cardamonin ( 27))[ [30],30], tetramethoxychalcone (34)[) [28],28], 20′-hydroxy-2,3,40′,6,60′-tetramethoxychalcone (35(35)[) 34[34],], and and tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline tetrahydro-[1,2,4]triazolo[3,4-a]isoquino- chalconesline chalcones (36)[ (3536].) [35]. Group Group B: Chalcones B: Chalcones that arrestthat arrest the cell the cycle cell cycle at the at G 2the/M G phase2/M phase chalcone chalcone (1)[29 (1],) isoliquiritigenin[29], isoliquiritigenin (22)[36 (22], (2) E[36],)-3-(acridin-9-yl)-1-(2,6-dimethoxyphenyl)prop-2-en-1-one (2E)-3-(acridin-9-yl)-1-(2,6-dimethoxyphenyl)prop-2-en-1-one (37)[37], and(37) quinazolinone-chalcone[37], and quinazolinone-chalcone (38)[38]. (38) [38].

(E)-1-(4-Aminophenyl)-3-(2,3-dimethoxyphenyl)-prop-2-en-1-one (32)

(2E)-3-(Acridin-9-yl)-1-(2,6-di- R = R’ = OMe methoxyphenyl)prop-2-en-1-one (E)-1-(4-Aminophenyl)-3-phenylprop-2-en-1-one) (33) R = R’ = H (37)

(E)-2-(3′,4′-Dimethoxy-benzylidene)-1-tetralone (31) (2E)-1-(2,5-Dimethoxy-phenyl)-3-(1-naphthyl)-2-propene-1-one (29)

Flavokawain B (28) 2′-Hydroxy-2,3,4′,6′-tetramethoxychal- Dimethyl cardamonin (27) cone (35) Biomolecules 2021, 11, x FOR PEER REVIEW 8 of 38

Figure 5. The effect of natural and synthetic chalcones on the cell cycle. Group A: Chalcones arrest the cell cycle at the G1/S phase, i.e., dimethyl cardamonin (27) [30], tetramethoxychalcone (34) [28], 2′-hydroxy-2,3,4′,6′-tetramethoxychalcone (35) [34], and tetrahydro-[1,2,4]triazolo[3,4-a]isoquino- Biomolecules 2021, 11, 1203 line chalcones (36) [35]. Group B: Chalcones that arrest the cell cycle at the G2/M phase chalcone (1) 8 of 37 [29], isoliquiritigenin (22) [36], (2E)-3-(acridin-9-yl)-1-(2,6-dimethoxyphenyl)prop-2-en-1-one (37) [37], and quinazolinone-chalcone (38) [38].

(E)-1-(4-Aminophenyl)-3-(2,3-dimethoxyphenyl)-prop-2-en-1-one (32)

(2E)-3-(Acridin-9-yl)-1-(2,6-di- R = R’ = OMe methoxyphenyl)prop-2-en-1-one (E)-1-(4-Aminophenyl)-3-phenylprop-2-en-1-one) (33) R = R’ = H (37)

(E)-2-(3′,4′-Dimethoxy-benzylidene)-1-tetralone (31) (2E)-1-(2,5-Dimethoxy-phenyl)-3-(1-naphthyl)-2-propene-1-one (29)

Biomolecules 2021, 11, x FOR PEER REVIEW 9 of 38 Flavokawain B (28) 2′-Hydroxy-2,3,4′,6′-tetramethoxychal- Dimethyl cardamonin (27) cone (35)

Licochalcone A (40) L1 (39)

(E)-2-(4′-Methoxybenzylidene)-1-benzosuberone (30)

Quinazolinone-chalcone (38)

Tetramethoxychalcone (34)

Tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline chalcones (36) Figure 6. Structures of some chalcones that interfere with the cell cycle. Figure 6. Structures of some chalcones that interfere with the cell cycle.

3.4. Effects3.4. Effects on Apoptosis on Apoptosis ApoptosisApoptosis is a isform a form of programmed of programmed cell cell death death in inmulticellular multicellular organisms, organisms, governed governed by by aa series series of of biochemical eventsevents [39[39].]. Several Several studies studies have have examined examined the the effect effect of chalconesof chal- on conesapoptosis on apoptosis to establish to establish whether whether chalcones chalco inducenes induce cell death cell death through through apoptosis apoptosis or necrosis. or necrosis. One of the early studies reported that chalcones (1) could induce apoptosis through enhancing the pro-apoptotic molecules, Bax and Bak, whilst reducing anti-apoptotic Bcl proteins (Figure 7) [40]. Chen et al. [41] demonstrated that the natural chalcone lonchocarpin (41) decreased cell proliferation via activation of caspase-3, caspase-9, and Bax (Figure 7). The synthetic chalcone, (2E)-3-(2-naphthyl)-1-(3′-methoxy-4′-hydroxy-phenyl)-2-propen-1-one (42), could block the G2/M phase, in addition to increasing p53 and Bax expression, thus bringing about caspase-3 activation and cell death [42]. Furthermore, it was shown that a synthetic chalcone (2E)-1-(2,5-dimethoxy-phenyl)- 3-(1-naphthyl)-2-propene-1-one (29) could induce cell death in human acute leukemia cell lines [31]. A recent study by Novilla et al. (2017) pointed out that synthetic chalcones (E)- 1-(4-aminophenyl)-3-(2,3-dimethoxy-phenyl)-prop-2-en-1-one (32) and (E)-1-(4-aminophenyl)-3-phenylprop-2-en-1-one) (33) could induce expression of caspase-3 in K562 cells. Additionally, another synthetic chalcone derivative, (E)-3-(4-methoxyphenyl)-2-methyl- 1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (43), was proposed as useful against prostate cancer as it was noted to cause cell cycle arrest and apoptosis (Figure 7) [43]. The structures of chalones that can influence apoptosis are presented in Figure 8. Biomolecules 2021, 11, 1203 9 of 37

One of the early studies reported that chalcones (1) could induce apoptosis through enhancing the pro-apoptotic molecules, Bax and Bak, whilst reducing anti-apoptotic Bcl proteins (Figure7)[ 40]. Chen et al. [41] demonstrated that the natural chalcone lonchocarpin (41) decreased cell proliferation via activation of caspase-3, caspase-9, and Bax (Figure7). The synthetic chalcone, (2E)-3-(2-naphthyl)-1-(30-methoxy-40-hydroxy-phenyl)-2-propen-1-one Biomolecules 2021, 11, x FOR PEER (REVIEW42), could block the G2/M phase, in addition to increasing p53 and Bax expression,10 of thus38

bringing about caspase-3 activation and cell death [42].

Biomolecules 2021, 11, x FOR PEER REVIEW 10 of 38

FigureFigure 7. 7.Schematic Structures diagram of some chalcones showing howthat interfere chalcones with induce the cell apoptosis. cycle.

Furthermore, it was shown that a synthetic chalcone (2E)-1-(2,5-dimethoxy-phenyl)- 3-(1-naphthyl)-2-propene-1-one (29) could induce cell death in human acute leukemia cell lines [31]. A recent study by Novilla et al., (2017) pointed out that synthetic chalcones (E)-1-(4-aminophenyl)-3-(2,3-dimethoxy-phenyl)-prop-2-en-1-one (32) and (E)-1-(4- aminophenyl)-3-phenylprop-2-en-1-one) (33) could induce expression of caspase-3 in K562 cells. Additionally,Lonchocarpin another (41) synthetic chalcone(2E)-3-(2-Naphthyl)-1-(3 derivative, (E)-3-(4-methoxyphenyl)-2-′-methoxy-4′-hydroxy- methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-onephenyl)-2-propen-1-one (43), was proposed as (42 useful) against

prostate cancer as it was noted to cause cell cycle arrest and apoptosis (Figure7)[ 43]. The Figurestructures 7. Structures of chalonesof some chalcones that can that inﬂuence interfere apoptosis with the cell are cycle. presented in Figure8.

(E)-3-(4-Methoxyphenyl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (43)

Figure 8. Structures of some chalcones that influence apoptosis. Lonchocarpin (41) (2E)-3-(2-Naphthyl)-1-(3′-methoxy-4′-hydroxy- 3.5. Binding with the Estrogenic Receptor (ER) phenyl)-2-propen-1-one (42) Chalcones, especially several natural chalcones present in food plants, are known to possess estrogenic properties, which are mediated by their interactions with the estrogenic receptor (ER) [44,45]. Isoliquiritigenin (22), a natural chalcone that is usually found in licorice, was shown to have estrogen receptor α-dependent growth-promoting effects on breast cancer cells [44]; its estrogenic effect was established using the hormone-sensitive MCF-7 breast cancer and steroid-independent HeLa cells. This chalcone was found to transactivate(E)-3-(4-Methoxyphenyl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one the endogenous estrogen receptor α in MCF-7 cells, supported (43 )by its ability Figure to8. Structuresinduce the of down-regulation some chalcones that of estrogeninfluence receptorapoptosis. α protein levels and the up-regulation Figureof pS2 8. mRNA.Structures Furthermore, of some chalcones it was that shown inﬂuence that this apoptosis. chalcone could exert agonistic effect 3.5. Binding3.5.for Binding both with estrogen the with Estrogenic the receptor Estrogenic Receptor isoforms. Receptor (ER) In (ER) silico studies performed with the chalcone 2′,4′- dihydroxy-6-methoxy-3,5-dimethylchalcone (44) (Figure 9), a component of the leaves of Chalcones, especially several natural chalcones present in food plants, are known to EugeniaChalcones, aquea established especially its several interaction natural with chalcones estrogen present receptor in αfood [45,46]. plants, Another are knownsimilar to possess estrogenic properties, which are mediated by their interactions with the estro- possessvirtual estrogenic screening of properties, 2′,3′,4′-trihydroxychalcone which are mediated (45)by showed their interactionsthat this chalcone with theacted estrogenic as an genic receptor (ER) [44,45]. Isoliquiritigenin (22), a natural chalcone that is usually found estrogen receptor ligand that could modulate the activity of 17β-estradiol [47]. in licorice, was shown to have estrogen receptor α-dependent growth-promoting effects on breast cancer cells [44]; its estrogenic effect was established using the hormone-sensitive MCF-7 breast cancer and steroid-independent HeLa cells. This chalcone was found to transactivate the endogenous estrogen receptor α in MCF-7 cells, supported by its ability to induce the down-regulation of estrogen receptor α protein levels and the up-regulation of pS2 mRNA. Furthermore, it was shown that this chalcone could exert agonistic effect for both estrogen receptor isoforms. In silico studies performed with the chalcone 2′,4′- dihydroxy-6-methoxy-3,5-dimethylchalcone (44) (Figure 9), a component of the leaves of Eugenia aquea established its interaction with estrogen receptor α [45,46]. Another similar virtual screening of 2′,3′,4′-trihydroxychalcone (45) showed that this chalcone acted as an estrogen receptor ligand that could modulate the activity of 17β-estradiol [47]. Biomolecules 2021, 11, 1203 10 of 37

receptor (ER) [44,45]. Isoliquiritigenin (22), a natural chalcone that is usually found in licorice, was shown to have estrogen receptor α-dependent growth-promoting effects on breast cancer cells [44]; its estrogenic effect was established using the hormone-sensitive MCF-7 breast cancer and steroid-independent HeLa cells. This chalcone was found to transactivate the endogenous estrogen receptor α in MCF-7 cells, supported by its ability to induce the down-regulation of estrogen receptor α protein levels and the up-regulation of pS2 mRNA. Furthermore, it was shown that this chalcone could exert agonistic effect for both estrogen receptor isoforms. In silico studies performed with the chalcone 20,40- dihydroxy-6-methoxy-3,5-dimethylchalcone (44) (Figure9), a component of the leaves of Eugenia aquea established its interaction with estrogen receptor α [45,46]. Another similar Biomolecules 2021, 11, x FOR PEER REVIEW 0 0 0 11 of 38 virtual screening of 2 ,3 ,4 -trihydroxychalcone (45) showed that this chalcone acted as an estrogen receptor ligand that could modulate the activity of 17β-estradiol [47].

2′,4′-Dihydroxy-6-methoxy-3,5-dimethylchalcone (44)

Chalcone 47

2′,3′,4′-Trihydroxychalcone (45) 4,2′,4′-Trihydroxychalcone (46) Figure 9. Examples of chalcones that bind to estrogenic receptors Figure 9. Examples of chalcones that bind to estrogenic receptors.

BranhamBranham et al. et [48] al. [used48] used the estrogen the estrogen receptor–ligand receptor–ligand binding binding assay to assay assess to the assess rel- the ativerelative binding binding affinity affinity of five of chalcones, five chalcones, i.e., chalcone i.e., chalcone (1), 4-hydroxychalcone (1), 4-hydroxychalcone (20), 4′ (-hy-20), 40- droxychalconehydroxychalcone (21), phloretin (21), phloretin (23), (and23), and4,2′,4 4,2′-trihydroxychalcone0,40-trihydroxychalcone (46), ( 46and), anda significant a significant levellevel of binding of binding with with the the estrogen estrogen receptor receptor αα waswas observed observed with all thesethese chalcones.chalcones. In In this thisstudy, study, a preliminarya preliminary attempt attempt was was made made todescribe to describe possible possible structure–activity structure–activity relationships rela- tionshipsof the chalconesof the chalcones usedin used the in study. the study. Chalcone Chalcone (1) was (1 found) was found to bind to withbind thewith estrogen the estrogenreceptor receptor with awith weaker a weaker affinity affinity than thatthan ofthat the of monohydroxylated the monohydroxylated chalcones chalcones20 and 20 21, andwhereas 21, whereas multiple multiple hydroxylation, hydroxylation, e.g., e.g., in chalconein chalcone46 ,46 appeared, appeared to to have have decreased decreased the the bindingbindingaffinity. affinity. Several Several chalcone-phenylpyran-2-one chalcone-phenylpyran-2-one derivatives derivatives bearing bearing a N a,N N,N-dimethyl-di- methylethylamine ethylamine side side chain, chai forn, example,for example, chalcone chalcone47, 47 were, were synthesized synthesized as estrogenas estrogen receptor re- ceptormodulators modulators [49]. [49]. All synthesizedAll synthesized chalcone chalcone derivatives derivatives showed showed selectivity selectivity toward toward estrogen estrogenreceptor receptorα, and α among, and among the compounds, the compounds, the derivative the deri withvative 2,6-dichloro with 2,6-dichloro functionalities func- (47) tionalitiesshowed (47 the) showed strongest the affinity strongest toward affinity the receptor.toward the receptor.

4. Bioactivity4. Bioactivity of Chalcones of Chalcones ChalconesChalcones are areknown known as biologically as biologically active active molecules. molecules. Different Different studies studies with with natural natural andand synthetic synthetic chalcones chalcones have have demonstrated demonstrated their their bioactivities bioactivities in vitro,in vitro in ,vivo,in vivo and, and most most recentlyrecently in silico. in silico. Major Major bioactivities bioactivities of chalcones of chalcones include include their activities their activities as anticancer, as anticancer, antidiabetic,antidiabetic, antimicrobial, antimicrobial, and antioxidant and antioxidant agents. agents. Moreover, Moreover, various various chalcones chalcones were were shownshown to possess to possess antiparasitic antiparasitic properties. properties. Most Most of their of their activities, activities, particularly particularly their theiranti- an- cancerticancer potential, potential, is associated is associated with some with someof the ofbiomolecular the biomolecular mechanisms mechanisms outlined outlined in Ta- in ble Table1 in this1 in article. this article. Bioactivities Bioactivities of chalcones of chalcones are described are described with specific with speciﬁc examples examples in the in following subsections. Figure 10 presents the chemical structures of those bioactive chalcones, unless the structures are shown earlier in this article, whilst Table 2 summarizes various bioactivities of naturally occurring chalcones [50–81].

Biomolecules 2021, 11, 1203 11 of 37

the following subsections. Figure 10 presents the chemical structures of those bioactive Biomolecules 2021, 11, x FOR PEER REVIEW 12 of 38 chalcones, unless the structures are shown earlier in this article, whilst Table2 summarizes various bioactivities of naturally occurring chalcones [50–81].

Cardamonin (48)

[2′,4′-Dihydroxy-6′-methoxychalcone] Deoxydihydroxanthoangelol H (49)

2,6-Dihydroxy-4-methoxychalcone (52) 2′,4′-Dihydroxychalcone (51) Dihydrochalcone diglycoside (50)

(E)-1-(2,4-Dihydroxy-3-(3-methylbut-2-en-1-yl)phenyl)-3-phenylprop-2-en- 2′,6′-Dihydroxy-4′-methoxychalcone (54) 1-one (53)

3,2′-Dihydroxy-2,4,4′,6′-tetramethoxychalcone (55) R = OH 2′-Hydroxy-2,4,4′,6′-tetramethoxychalcone (56) R = H 2′-Hydroxy-2,3,4,4′,6′-pentamethoxychalcone (57)) R = OMe

1-(5,7-Dihydroxy-2,2,6-trimethyl-2H-1-benzopyran-8-yl)-3-phenyl-2-propen-1-one [58]

Echinantin (59) Flavokawain A (60) [4,4′-Dihydroxy-6-methoxychalcone] [2′,4,4′-Trimethoxy-5′-hydroxychalcone]

4-Hydroxyderricin (62) R = Me

2′-Hydroxy-4′,5′-dimethoxychalcone (61) Isobavachalcone (63) R = H

Figure 10. Cont. Biomolecules 2021, 11, 1203 12 of 37 Biomolecules 2021, 11, x FOR PEER REVIEW 13 of 38

Isosalipurposide (66)

4′-Hydroxyrottlerin (64) R = OH Rottlerin (65) R = H Licochalcone B (68) R = H Tetrahydroxy-methoxychalcone (69) R = OH

Licoagrochalcone A (70)

Kamalachalcone E (67) Licochalcone C (71)

Licochalcone D (72)

Licochalcone G (73) OH O

H O O OH OH

Mallotophilippens C (74) R = H

Mallotophilippens D (75) R = OH Mallotophilippens E (76)

Naringenin chalcone (78) [2′,4, 4′,6′-Tetrahydroxychalcone] Marein (77)

Figure 10. Cont. Biomolecules 2021, 11, 1203 13 of 37 Biomolecules 2021, 11, x FOR PEER REVIEW 14 of 38

2′,3,4,4′-Tetrahydroxy-3′-(6-hydroxy-3,7-dimethyl-7-octadienyl)chalcone (79) R = OH 2′,4′,4-Trihydroxy-3′-(6-hydroxy-3,7-dimethyl-7-octadienyl)chalcone (80) R = H

2′,4′,4-Trihydroxy-3′-[2-hydroxy-7-methyl-3-methylene-6-octenyl-chalcone (81)

2,3,4-Trimethoxy-2′-hydroxychalcone (82) Xanthoangelol (83) R = R’ = H Xanthoangel F (84) R = Me; R’ = H 2′,3,4,4′-Tetrahydroxy-3′-geranylchalcone (85) R = H; R’- OH

Xanthoangelol B (86) R = H Xanthoangelol G (87) R = Me

Xanthodeistal A (88) Xanthoangelol D (89) R = OH Xanthoangelol E (90) R = OOH

Xanthoangelol J (92)

Xanthoangelol I (91)

FigureFigure 10. Structures 10. Structures of some of some naturally naturally occurring occurring bioactive bioactive chalcones. chalcones.

TableTable 2. Bioactivities 2. Bioactivities of some of some naturally naturally occurring occurring chalcones. chalcones.

BioactivitiesBioactivities Chalcones Chalcones Sources References References Anti-acetylcholinesterase IsosalipurposideIsosalipurposide (66 ()66 ) Acacia cyanophylla [50] Anti-acetylcholinesterase Acacia cyanophylla [50] NaringeninNaringenin chalcone chalcone (78 ()78 ) Anti-arthritic Cardamonin (48) Boesenbergia rotunda [51] Anti-arthritic Cardamonin (48) Boesenbergia rotunda [51] Biomolecules 2021, 11, 1203 14 of 37

Table 2. Cont.

Bioactivities Chalcones Sources References Toxicodendron vernicifluum [52] Butein (16) Butea dahlia [22,53] Calomelanone (17) Stevia lucida Deoxydihydroxanthoangelol H (49) Angelica keiskei [54] 2,6-Dihydroxy-4-methoxychalcone (52) Dimethyl-cardamonin (27) Syzygium campanulatum [55] Echinantin (59) Piper methysticum & Alpinia pricei Flavokawain A (60) [56] Piper methysticum Flavokawain B (28) Flavokawain B (28) Alpinia pricei [57] Flavokawain C (18) Piper methysticum [22,53] Homobutein (19) Butea frondosa 20-Hydroxy-40,50-dimethoxychalcone (61) Sarcandra hainanensis [58] Anticancer 4-Hydroxychalcone (20) Glycyrrhiza glabra [22,53] 40-Hydroxychalcone (21) 4-Hydroxyderricin (62) [59] Angelica keiskei Isobavachalcone (63)[54] Isobavachalcone (63) Psoralea corylifolia [60] Piper methysticum [57] Isoliquiritigenin (22) Alpinia pricei Glycyrrhiza glabra [22,53] Isosalipurposide (66) Helichrysum maracandicum [61] Lonchocarpin (41) Pongamia pinnata [41] Marein (77) Glycyrrhiza glabra [22,53] 4-Methoxychalcone (2) Phloretin (23) Stevia lucida [22,53] 2,3,4-Trimethoxy-20-hydroxychalcone (82) Piper methysticum [62] Xanthoangelol (83) [59] Xanthoangelol I (91) Angelica keiskei [54] Xanthoangelol J (92) 20,60-Dihydroxy-40-methoxychalcone (54) Piper claussenianum [63] Antidiabetic 4-Hydroxyderricin (62) Angelica keiskei [64] Xanthoangelol (83) Flavokawain B (28) Alpinia pricei [65] Isoliquiritigenin (22) Licoagrochalcone A (70) Glycyrrhiza inflata [66] Licochalcone B (68) Anti-inflammatory Licochalcone C (71) Glycyrrhiza glabra [67] Mallotophilippens C (74) Mallotophilippens D (75) Mallotus philippinensis [68] Mallotophilippens E (76) Biomolecules 2021, 11, 1203 15 of 37

Table 2. Cont.

Bioactivities Chalcones Sources References Antimicrobial 20,40-Dihydroxychalcone (51) Zuccagnia punctata [69] 3,20-Dihydroxy-2,4,40,60- tetramethoxychalcone (55) Piper hispidum [70] 0 0 0 Antibacterial 2 -Hydroxy-2,4,4 ,6 - tetramethoxychalcone (56) 20-Hydroxy-2,3,4,40,60- pentamethoxychalcone (57) Isoliquiritigenin (22) Apis mellifera [71] 1-(5,7-Dihydroxy-2,2,6-trimethyl-2H-1- benzopyran-8-yl)-3- Mallotus philippinensis [72] phenyl-2-propen-1-one [58] 3,20-Dihydroxy-2,4,40,60- tetramethoxychalcone (55) 20-Hydroxy-2,4,40,60- tetramethoxychalcone (56) Piper hispidum [70] 20-Hydroxy-2,3,4,40,60- pentamethoxychalcone (57) 40-Hydroxyrottlerin (64) Mallotus philippinensis [72] Isoliquiritigenin (22) Apis mellifera [71] Antifungal Kamalachalcone E (67) Mallotus philippinensis [72] Rottlerin (65) 20,3,4,40-Tetrahydroxy-30- geranylchalcone (85) 20,3,4,40-Tetrahydroxy-30-(6-hydroxy-3,7- dimethyl-7-octadienyl)chalcone (79) 20,40,4-Trihydroxy-30-geranylchalcone (83) [xanthoangelol] Artocarpus nobilis [73] 20,40,4-Trihydroxy-30-(6-hydroxy-3,7- dimethyl-7-octadienyl)chalcone (80) 20,40,4-Trihydroxy-30-[2-hydroxy-7- methyl-3- methylene-6-octenyl-chalcone] (81) Dihydrochalcone diglycoside (50) Thalassodendrin ciliatum [74] Echinantin (59) Glycyrrhiza inflata [75] Isoliquiritigenin (22) Quercus coccifera [76] Licochalcone A (40) Glycyrrhiza inflata [75] Licochalcone B (68) Quercus coccifera [76] Antiviral Licochalcone D (72) Glycyrrhiza inflata [76] Licochalcone G (73) Quercus coccifera Tetrahydroxy-methoxychalcone (69)[76] Xanthoangelol (83) Xanthoangelol F (84) Angelica keiskei [77] Xanthoangelol D (89) Xanthoangelol E (90) Biomolecules 2021, 11, 1203 16 of 37

Table 2. Cont.

Bioactivities Chalcones Sources References Xanthoangelol B (86) Xanthoangelol G (87) Xanthodeistal A (88) Licochalcone C (71) Glycyrrhiza glabra [67] Antioxidant Isosalipurposide (66) Acacia cyanophylla [50] Naringenin chalcone (78) (E)-1-(2,4-Dihydroxy-3-(3-methylbut-2- en-1-yl)phenyl)-3- Lonchocarpus sp. [78] phenylprop-2-en-1-one (53) Antiparasitic Flavokawain B (28) Polygonum ferrugineum [79] Licochalcone C (71) Glycyrrhiza glabra [80] Licoagrochalcone A (70) Erythrina abyssinica [81] Mallotophilippens C (74) Immunoregulatory Mallotophilippens D (75) Mallotus philippinensis [68] Mallotophilippens E (76)

4.1. Anticancer and Cancer Chemopreventive Activity Several investigations have revealed the bioactivity of chalcones against cancer, either as a cancer chemopreventive agent or as a potential cancer curative agent. However, most of those investigations were in vitro or in silico. Both natural (Figure 10; Table2) and synthetic chalcones acted as anticancer agents through the mechanisms sated in Table1, and mainly the induction of cancer/tumor cell death, predominantly by apoptosis. Research groups who are interested in the cytotoxicity of chalcones, such as Sumiyoshi et al. [59], reported that two chalcone derivatives, xanthoangelol (83) and 4-hydroxyderricin (62), isolated from Angelica keiskei roots could inhibit metastasis and the growth of a tumor. In addition, twenty-one natural chalcones were investigated by Orlikova et al. [22] for their ability to inhibit NF-κB in K562 cells. They found that butein (16), calomelanone (17), flavokawain C (18), homobutein (19), 4-hydroxychalcone (20), 40-hydroxychalcone (21), isoliquiritigenin (22), marein (77), 4-methoxychalcone (2), and phloretin (23) had the ability to inhibit histone deacetylase enzyme (HDAC), and NF-κB. Inspired by the anticancer potential of naturally occurring chalcones, several synthetic chalcone analogs were produced and assessed for their anticancer properties. For example, Sakagami et al. [82] reported the synthesis of fifteen chalcones (Figure 11), and showed their ability to act as selective anticancer agents in several human oral squamous cancer cell lines, such as HSC-2, HSC-3, HSC-4, and Ca9-22. Anticancer activity and possible mechanisms of action of 20-hydroxy-40,50-dimethoxychalcone (61), isolated from Sarcandra hainanensis, were investigated using the lung cancer cell lines, e.g., H322M, H460, H358, H1792 and H157. It was shown that chalcone 61 could increase the level of cellular reactive oxygen species (ROS) and induce cell apoptosis. Ramirez-Tagle et al. [62] used 30-bromo-3,4-dimethoxychalcone (107) and 2,3,4-trimethoxy- 20-hydroxychalcone (82) on mouse hepatocytes (HepM) and human hepatoma cells (HepG2 and Huh-7) and found that both chalcones could lead to cellular apoptosis and to an increase ROS levels. Synthetic chalcone (E)-1-(2-hydroxyphenyl)-3-(4-methyl-phenyl)-prop- 2-en-1-one (108) was identified as a chemopreventive agent with the results indicating that it could decrease the extent of DNA damage [83]. Biomolecules 2021, 11, x FOR PEER REVIEW 17 of 38

(62), isolated from Angelica keiskei roots could inhibit metastasis and the growth of a tumor. In addition, twenty-one natural chalcones were investigated by Orlikova et al. [22] for their ability to inhibit NF-κB in K562 cells. They found that butein (16), calomelanone (17), flavokawain C (18), homobutein (19), 4-hydroxychalcone (20), 4’-hydroxychalcone (21), isoliquiritigenin (22), marein (77), 4-methoxychalcone (2), and phloretin (23) had the ability to inhibit histone deacetylase enzyme (HDAC), and NF-κB. Inspired by the anticancer potential of naturally occurring chalcones, several synthetic chalcone analogs were produced and assessed for their anticancer properties. For

Biomolecules 2021, 11, 1203 example, Sakagami et al. [82] reported the synthesis of fifteen chalcones (Figure 11),17 and of 37 showed their ability to act as selective anticancer agents in several human oral squamous cancer cell lines, such as HSC-2, HSC-3, HSC-4, and Ca9-22.

2′,4-Dihydroxychalcone (93) R = H; R’ = OH 4-Bromo-2′-hydroxychalcone (94) R = H; R’ = Br 4-Chloro-2′-hydroxychalcone (95) R = H; R’ = Cl 4-Fluoro-2′-hydroxychalcone (96) R = H; R’ = F 2′-Hydroxychalcone (6) R = R’ = H 2′-Hydroxy-4-methoxychalcone (97) R = H; R’ = OMe 2′-Hydroxy-3,4-dimethoxychalcone (98) R = R’ = OMe

4-Bromo-2′-hydroxy-4′-methoxychalcone (99) R = H; R’ = Br 2′,4-Dihydroxy-4′methoxychalcone (100) R = H; R’ = OH 2′-Hydroxy-4,4′-dimethoxyflavone (101) R = H; R’ = OMe 2′-Hydroxy-4′-methoxychalcone (102) R = R’ = H 2′-Hydroxy-3,4,4′-trimethoxyflavone (103) R = R’ = OMe

4,4′-Dimethoxychalcone (104) R = R’ = H 2,4,4′-Trimethoxychalcone (105) R = H; R’ = OMe 2′,4,4′-Trimethoxychalcone (106) R = OMe; R’ = H

(E)-1-(2-Hydroxyphenyl)-3-(4-methyl-phenyl)- 3′-Bromo-3,4-dimethoxychalcone (107) prop-2-en-1-one) (108) Figure 11. Structures of some synthetic chalcones with anticancer potential. Figure 11. Structures of some synthetic chalcones with anticancer potential.

4.2. Antidiabetic Activity Some naturally occurring chalcones were shown to possess antidiabetic properties. For example, 20,60-dihydroxy-40-methoxychalcone (52), isolated from the ﬂowers of Piper claussenianum [63], and 4-hydroxyderricin (62), and xanthoangelol (83) from Angelica keiskei, were found to have antidiabetic properties [64]. Chalcone 52 exhibited its antidiabetic properties through producing a hypoglycemic effect in streptozotocin-induced diabetes in rats. It was observed that this compound could reduce blood glucose levels from 277.4 mg/dL before treatment to 158.8 mg/dL after 12 days of treatment. Both 4-hydroxyderricin (62) and xanthoangelol (83) displayed insulin-like behavior via a pathway that is not dependent on the activation of peroxisome proliferator-activated receptor-γ [64], whereas chalcone 62 could prevent the progression of diabetes in genetically diabetic KK-Ay mice. The antidiabetic effect of naturally occurring chalcones prompted several bioinspired syntheses of chalcone analogs, which were subsequently tested for their antidiabetic poten- Biomolecules 2021, 11, 1203 18 of 37

tial. For instance, synthetic chalcones, (E)-1,3-dip-tolylprop-2-en-1-one (114), 4,5-dihydro-3,5- dip-tolylpyrazole-1-carbothioamide (110), 4,5-dihydro-3,5-dip-tolylpyrazole-1-carboxamide (111), (4,5-dihydro-3,5-dip-tolylpyrazol-1-yl)(phenyl)methanone (112), 4,5-dihydro-1-phenyl- 3,5-dip-tolyl-1H-pyrazole (113), and 3,5-bis(4-methylphenyl)-1-(phenylsulfonyl)-4,5-dihydro- 1H-pyrazole (109), were shown to act as hypoglycemic agents by decreasing the level of blood glucose in alloxan-induced diabetic rats [84]. Among these chalcone derivatives, 4,5-dihydro-1-phenyl-3,5-dip-tolyl-1H-pyrazole (113) produced the most prominent antidiabetic effect. In addition, Chinthala et al. [85] synthesized twenty chalcone derivatives, three of which (115–117) (Figure 12) were found to exert α-glucosidase-inhibitory activity (IC50 = 67.7–102.1 µM). Based on the obtained results with these chalcone derivatives, it was Biomolecules 2021, 11, x FOR PEER REVIEWassumed that the presence of aliphatic chain length up to five carbons (n-pentyl) attached19 of 38 to

the triazole ring might be optimum for generating α-glucosidase activity.

4,5-Dihydro-3,5-dip-tolylpyrazole-1-carbothioamide (110) 3,5-bis(4-Methylphenyl)-1-(phenylsulfonyl)- 4,5-dihydro-1H-pyrazole (109)

4,5-Dihydro-3,5-dip-tolylpyrazole-1-carboxamide (111)

(4,5-Dihydro-3,5-dip-tolylpyrazol-1-yl)(phenyl)methanone (112)

(E)-1,3-Dip-tolylprop-2-en-1-one (114)

4,5-Dihydro-1-phenyl-3,5-dip-tolyl-1H-pyrazole (113)

Chalcone 1,2,3-triazole derivatives Chalcone-triazole 1 (115) R = 2C2H5-phenyl; R’ = H; R’’ = OH Chalcone-triazole 2 (116) R = n-pentyl; R’ = H; R’’ = OH Chalcone-triazole 3 (117) R = n-pentyl; R’ = OH; R’’ = H

FigureFigure 12. 12. StructuresStructures of of some some synthetic synthetic antidiabetic antidiabetic chalcones. chalcones.

4.3. Anti-Inflammatory Activity Naturally occurring chalcones are phenolic compounds, and often possess one or more phenolic hydroxyl functionality in their structures, which generally offer them with the inherent free-radical-scavenging properties that can be useful against oxidative stress. It is known that oxidative stress is associated with inflammatory responses. Thus, any reduction in oxidative stress is expected to inhibit inflammatory responses. Chalcones with free-radical-scavenging properties were shown to also possess anti-inflammatory properties. The examples of naturally occurring anti-inflammatory chalcones could include flavokawain B (28) and isoliquirigenin (22) from Alpinia pricei [65], licoagrochalcone A (70) and licochalcone B (68) from Glycyrrhiza inflata [66], licochalcone C (71) from Glycyr- rhiza glabra [67], and mallotophilippens C-E (74–76) from Mallotus philippinensis [68]. It was shown that flavokawain B (28) could inhibit the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-induced murine leukemia macrophage Biomolecules 2021, 11, 1203 19 of 37

4.3. Anti-Inflammatory Activity Naturally occurring chalcones are phenolic compounds, and often possess one or more phenolic hydroxyl functionality in their structures, which generally offer them with the inherent free-radical-scavenging properties that can be useful against oxidative stress. It is known that oxidative stress is associated with inflammatory responses. Thus, any reduction in oxidative stress is expected to inhibit inflammatory responses. Chalcones with free-radical-scavenging properties were shown to also possess anti-inflammatory properties. The examples of naturally occurring anti-inflammatory chalcones could include flavokawain B (28) and isoliquirigenin (22) from Alpinia pricei [65], licoagrochalcone A (70) and licochalcone B (68) from Glycyrrhiza inflata [66], licochalcone C (71) from Glycyrrhiza glabra [67], and mallotophilippens C-E (74–76) from Mallotus philippinensis [68]. It was shown that flavokawain B (28) could inhibit the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-induced murine leukemia macrophage RAW 264.7 cells [65]. Furthermore, this chalone dose-dependently decreased the secretion of TNF-R and inhibited the expression of iNOS (inducible nitric oxide synthase) and COX2 (cyclooxygenase 2) proteins. Flavokawain B (28) was also found to block the nuclear translocation NF-κB and thus decrease NF-κB protein levels in the nucleus. Similar anti-inflammatory activity was observed with the chalcone 28 in vivo using a mouse model, where the pre-administration of a 200 mg/kg compound could reduce the NO concentration and significantly suppress LPS-induced iNOS, COX-2, and NF-κB proteins expression in mouse liver. Licoagrochalcone A (70) and licochalcone B (68) showed prominent anti-inflammatory activity with IC50 values of 9.35 and 8.78 µM, respectively, on LPS-induced NO production. Additionally, chalcone 70 showed potent inhibitory effect on NF-κB transcription [66]. Mallotophilippens C-E (74–76) were found to inhibit NO production in activated RAW 264.7 cells and the expression of iNOS, COX2, IL-6 (interleukin 6), and IL-1β mRNA [68], suggesting that these compounds might exert their anti-inflammatory properties through inactivation of NF-κB. Anti-inflammatory properties of naturally occurring chalcones, as exemplified above, prompted bioinspired synthesis of several chalcone analogs as anti-inflammatory agents [86–89]. Over two decades ago, several 20-hydroxychalcones and 20,50-dihydroxychalcones (Figure 13) were synthesized and their anti-inflammatory properties were ascertained by observation of their in vitro inhibitory effects on the activation of mast cells, neutrophils, microglial cells, and macrophages [86]. Among these synthetic chalcones, 2,20-hydroxychalcone (124) emerged as the most potent anti-inflammatory agent that could inhibit the release of β- glucuronidase (IC50 = 1.6 µM) and lysozyme (IC50 = 1.4 µM) from rat neutrophils. Later, eleven chalcone derivatives (Figure 13) were synthesized by the Claisen–Schmidt condensation of acetophenones and aromatic aldehydes, or produced with suitable dihydrochalcone and alkyl bromide, or prepared in one-pot synthesis involving acetophenone and aromatic aldehyde under ultrasonication [87], and their anti-inflammatory potential was assessed. Chalcone derivatives 125, 132, 133, and 136 showed a considerable level of inhibition on the release of β-glucuronidase or lysozyme from rat neutrophils stimulated with appropriate stimuli; chalcones 125 and 133 inhibited superoxide anion production in rat neutrophils; and chalcones 123, 128, and 135 could inhibit NO production. Jantan et al. [88] reported the synthesis of chalcone derivatives and showed their potential as inhibitors of secretory phospholipase A2, cyclooxygenases, lipoxygenase, and pro-inflammatory cytokines by a series of in vitro enzyme inhibition and in silico assays. Chalcone derivatives with 4-methylamino-ethanol functionality appeared to be the most potent ones. Most recently, a synthetic chalcone (139) (Figure 13) was demonstrated to possess antioxidant, anti-inflammatory, and neuroprotective properties [89]. This chalcone could attenuate LPS-induced inflammation in RAW 264.7 macrophages. BiomoleculesBiomolecules 2021, 11, x2021 FOR, 11 PEER, 1203 REVIEW 21 of 38 20 of 37

4-Chloro-2′-hydroxychalcone (118) R = R’’ = R’’’ = H; R’ = OH; R’’’’ = Cl 4-Chloro-2′5′-dimethoxychalcone (119) R = R’ = OMe; R’’ = R’’’ = H; R’’’’ = Cl 4-Chloro-2′5′-diethoxychalcone (120) R = R’ = OEt; R’’ = R’’’ = H; R’’’’ = Cl 4-Chloro-2′5′-dipropyloxychalcone (121) R = R’ = OPr; R’’ = R’’’ = H; R’’’’ = Cl 4-Chloro-2′5′-dibutyloxychalcone (122) R = R’ = OBu; R’’ = R’’’ = H; R’’’’ = Cl 3,4-Dichloro-2′-hydroxychalcone (123) R = R’’ = H; R’ = OH; R’’’ = R’’’’ = Cl 2,2′-Dihydroxychalcone (124) R = R ‘’’ = R’’’’ = H; R’ = R’’ = OH 2′,4-Dihydroxychalcone (125) R = R’’ = R’’’ = H; R’ = R’’’’ = OH 4,5′-Dimethoxy-2′-hydroxychalcone (126) R = R’’’ = OMe; R’ = OH; R’’ = R’’’ = H 3,4-Dihydroxy-2′,5′-dimethoxychalcone (127) R = R’ = OMe: R ‘’ = H; R’’’ = R’’’’ = OH 4-Hydroxy-2′,5′-dimethoxychalcone (128) R = R’ = OMe; R’’ = R’’’ = H; R’’’’ = OH 2′-Hydroxy-4-chloro-5′-methoxychalcone (129) R = OMe; R’ = OH; R’’ = R’’’ = H; R’’’’ = Cl 2′-Hydroxy-4-methy-5′-methoxychalcone (130) R = OMe; R’ = OH; R’’ = R’’’ = H; R’’’’ = Me 3,4,5′-Trimethoxy-2′-hydroxychalcone (131) R = R’’’ = R’’’’ = OMe; R’ = OH; R’’ = H

2′-Hydroxy-thiochalcone 1 (132) 2′-Hydroxy-thiochalcone 2 (133)

Thiochalcone (134)

Nitrogen ring containing chalcone (136)

2′,5′,4-Trihydroxy-3,5-di-isopropyl-chalcone (135) OMe

4-Chloro-2′,5′-dihydroxychalcone (137) R = Cl 2′-Hydroxy-4-methoxychalcone (139) 2′,5′-Dihydroxychalcone (138) R = H

Figure 13.Figure Structures 13. Structures of some ofsynthetic some synthetic anti-inflammatory anti-inﬂammatory chalcones. chalcones.

4.4. Antimicrobial4.4. Antimicrobial Activity Activity There areThere several are several reports reports available available in the in literature the literature describing describing the antimicrobial the antimicrobial ac- activity tivity ofof natural natural and and synthetic synthetic chalcones; chalcones; thes thesee activities activities include include their their activity activity against against sev- several eral pathogenicpathogenic bacterial, bacterial, fungal, fungal, and and viral viral species. species. Figure Figure 10 andand TableTable2 present2 present some some examples Biomolecules 2021, 11, 1203 21 of 37

of naturally occurring antimicrobial chalcones. Here, the antimicrobial activity of chalcones is discussed under three subsections: antibacterial, antifungal, and antiviral chalcones.

4.4.1. Antibacterial Activity Antibacterial activity of naturally occurring chalcones is well-documented in the literature [69,70] (Table2). For example, 2 0,40-dihydroxychalcone (51) isolated from Zuccagnia punctata; 3,20-dihydroxy-2,4,40,60-tetramethoxychalcone (55), 20-hydroxy-2,4,40,60-tetramethoxychalcone (56), and 20-hydroxy-2,3,4,40,60-pentamethoxychalcone (57) from Piper hispidum; and isoliquiritigenin (22) from the Brazilian propolis (Apis melifera) were shown to possess antibacterial properties [69–71]. 20,40-Dihydroxychalcone (51) was found active against the Gram-positive and Gram-negative bacterial species, including Acinetobacter baumannii, Enter- obacter cloacae, Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens, and Stenotrophomonas maltophilia, which have MIC values ranging between 0.10 µg/mL and 100 µg/mL [69]. 3,20-Dihydroxy-2,4,40,60-tetramethoxychalcone (55), 20-hydroxy-2,4,40,60- tetramethoxychalcone (56) and 20-hydroxy-2,3,4,40,60-pentamethoxychalcone (57) were shown active against Staphylococcus aureus with MIC values in the range of 125–250 µg/mL [70], whilst the antibacterial activity isoliquiritigenin (22) was observed against Actinomyces naes- lundii, Staphylococcus aureus, and Streptococcus mutans (MIC = 15.6–62.5 µg/mL) [71]. The antibacterial activity of natural chalcones inspired synthetic chemists to attempt bioinspired synthesis of antibacterial chalcone derivatives. For example, a decade ago, Solankee et al. [90] investigated synthetic triazine-based chalcones (Figure 14) as antibacterial agents, and reported inhibition of the growth of Bacillus cereus, Enterobac- ter cloacae, Escherichia coli, Listeria monocytogenes, Micrococcus flavus, Pseudomonas aeruginosa, Salmonella typhimurium, and Staphylococcus aureus. However, except for the furanyl derivative (143), the activity of other compounds was rather weak. Chu et al. [91] resynthesized 29 cationic chalcones with varying aryl substitutions, and diversity in the N,N-dimethyl alkylamine length, and tested all compounds against Enterococcus faecalis, Escherichia coli, Salmonella enterica and Staphylococcus aureus. Chalcone derivatives, (E)-N-(2-((4-cinnamoylphenyl)amino)-2-oxoethyl)-N,N-dimethyloctan-1-aminium chloride (145) and (E)-N-(2-((4-(3-(2-fluorophenyl)acryloyl)phenyl)amino)-2-oxoethyl)-N,N- dimethyloctan-1-aminium chloride (146) (Figure 14), demonstrated a considerable level of growth inhibitory activity against both Gram-negative and Gram-positive bacteria, including the drug-resistant New Delhi metallo-β-lactamase-1 (NDM), Klebsiella pneumoniae carbapenemase (KPC), and methicillin-resistant Staphylococcus aureus (MRSA) strains. While (E)-N-(2-((4-cinnamoylphenyl)amino)-2-oxoethyl)-N,N-dimethyloctan-1-aminium chloride (145) was most active against E. coli (MIC = 2 µg/mL), derivative 146 showed the most prominent activity against S. aureus (MIC = 0.5 µg/mL). This finding demonstrated the potential applications of chalcone peptidomimetics as a new class of antibacterial agents. Most recently, a series of β-chalcone derivatives (147–158) (Figure 14) was synthesized using various substituted amines by the Claisen-Schmidt condensation reaction in basic condition, and evaluated for antibacterial activity against different species of bacteria, including Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella enterica and Staphylococcus pneumoniae [92]. Among these synthetic chalcone derivatives, compound 148 emerged as the most potent antibacterial agent which was particularly effective against E. coli (MIC = 125 µg/mL). In silico studies established DNA binding and molecular docking of these compounds. There are several other examples of synthesis antibacterial chalcones and assessment of their modes of action available in the literature [93–97]. BiomoleculesBiomolecules 2021, 11, x FOR2021 ,PEER11, 1203 REVIEW 23 of 38 22 of 37

Triazine chalcone 1 (140) R = NO2; R’ = H Triazine chalcone 2 (141) R = Cl; R’ = H Triazine chalcone 3 (142) R = H; R’ = OMe O

H N

N N

N N N H H

Triazine chalcone 4 (143) R = Furanyl Triazine chalcone 5 (144) R = Thienyl

(E)-N-(2-((4-cinnamoylphenyl)amino)-2-oxoethyl)-N,N-dimethyloctan-1-aminium chloride (145) R = H (E)-N-(2-((4-(3-(2-Fluorophenyl)acryloyl)phenyl)amino)-2-oxoethyl)-N,N-dimethyloctan-1-aminium chloride (146) R = F

β-Chalcone derivative d (150) R = NO2 β-Chalcone derivative e (151) R = Br

β-Chalcone derivative a (147) R = NO2; R’ = H β-Chalcone derivative b (148) R = H; R’ = Me β-Chalcone derivative c (149) R = H; R’ = NO2

Figure 14. Cont. Biomolecules 2021, 11, 1203 23 of 37 Biomolecules 2021, 11, x FOR PEER REVIEW 24 of 38

β-Chalcone derivative f (152) R = NO2; R’ = H β-Chalcone derivative i (155) R = NO2; R’ = H β-Chalcone derivative g (153) R = H; R’ = Me β-Chalcone derivative j (156) R = H; R’ = NO2 β-Chalcone derivative h (154) R = Br; R’ = H β-Chalcone derivative k (157) R = Br; R’ = H

β-Chalcone derivative l (158) Figure 14. Structures of some synthetic antibacterial chalcones. Figure 14. Structures of some synthetic antibacterial chalcones.

4.4.2. Antifungal4.4.2. Antifungal Activity Activity ChalconesChalcones are known are to known possess to possess antifungal antifungal properties. properties. One of One the ofearly the earlystudies studies on on an- antifungaltifungal activities activities of naturally of naturally occurring occurring chalcones chalcones was conducted was conducted by Jayasinghe by Jayasinghe et al. et al. [73] [73] (Table(Table 2). 2In). Inthat that work, work, several several chalcones chalcones (79 ( 79–81–81, 83, 83 andand 8585)) were were isolated fromfrom thethe leaves of leaves ofArtocarpus Artocarpus nobilis nobilis, and, and assessed assessed for fungicidalfor fungicidal activities activities against againstCladosporium Cladosporium cladosporioides . cladosporioidesAll those. All chalcones those chalcones showed showed fungicidal fungicidal activity (2–15activityµg/spot) (2–15 μ ing/spot) the thin in layerthe thin chromatog- layer chromatographyraphy (TLC) bio-authography (TLC) bio-authography method. method. 1-(5,7-Dihydroxy-2,2,6-trimethyl-2H-1-benzopyran- 1-(5,7-Dihydroxy-2,2,6-trimethyl- 2H-1-benzopyran-8-yl)-3-phenyl-2-propen-1-one8-yl)-3-phenyl-2-propen-1-one [58], 40-hydroxyrottlerin [58], 4′-hydroxyrottlerin (64), kamalachalcone (64), ka- E (67) and malachalconerottlerin E ( (6765)), and isolated rottlerin from ( the65), fruitsisolated of Mallotus from the philippinensis fruits of Mallotus, were tested philippinensis for antifungal, ac- were testedtivity for against antifungal several activity human against pathogenic several fungus human [72]. pathogenic Chalcone 58 fungusand the [72]. chalcone Chal- dimer 67 cone 58 andshowed the chalcone significant dimer antifungal 67 showed properties significant (IC50 = antifungal 4–16 µg/mL) properties against (ICAspergillus50 = 4–16 fumigates μg/mL) againstand Cryptococcus Aspergillus neoformans fumigates. and Both Cryptococcus compounds wereneoformans particularly. Both compounds effective against wereCryptococ- particularlycus neoformanseffective against(IC50 =Cryptococcus 4 µg/mL). However,neoformans none (IC50 of = those4 μg/mL). chalcones However, displayed none anyof notice- those chalconesable antifungal displayed activity any noticeable against Aspergillus antifungal flavus activity, A. niger, against Candida Aspergillus albicans, flavus C. glabrata, A. , and niger, CandidaC. tropicalis albicans,[72 C.]. 3,2glabrata0-Dihydroxy-2,4,4, and C. tropicalis0,60-tetramethoxychalcone [72]. 3,2′-Dihydroxy-2,4,4 (55′),,6′ 2-tetrameth-0-hydroxy-2,4,40,60- oxychalconetetramethoxychalcone (55), 2′-hydroxy-2,4,4 (56), and′,6′-tetramethoxychalcone 20-hydroxy-2,3,4,40,60-pentamethoxychalcone (56), and 2′-hydroxy- (57) were 2,3,4,4′,6′shown-pentamethoxychalcone active against C. albicans (57) werewith shown MIC active values against in the rangeC. albicans of 250-500 with MICµg/mL val- [70]. ues in the rangeThese of 250-500 initial findingsμg/mL [70]. on antifungal properties of natural chalcones led the way to Thesebioinspired initial findings synthesis on antifungal of several proper other chalconeties of natural analogs chalcones with antifungal led the way activities. to Just bioinspiredover synthesis two decades of several ago, other Lopez chalcone et al. [98 analogs] synthesized with antifungal 41 chalcone activities. derivatives, Just over 11 of which two decades(1, 159 ago,–168 Lopez) (Figure et al. 15 [98]) were synthesized found active 41 chalcone against derivatives, dermatophytes, 11 of e.g.,whichEpidermophy- (1, 159–168)ton (Figure floccosum 15) were, Microsporum found active canis, against M. gypseum, dermatophytes, Trichophyton e.g., mentagrophytes Epidermophytonand floc-T. rubrum cosum, Microsporum(MIC = 1.5–12.5 canis,µ g/mL)M. gypseum,These Trichophyton chalcones (1 ,mentagrophytes159–168) showed and inhibitory T. rubrum properties (MIC = against 1.5–12.5 polymersμg/mL) These of the chalcones fungal cell (1, 159 wall.–168 However,) showed none inhibitory of these properties chalcones against was activepoly- against mers of theAspergillus fungal cell niger, wall. A. However, fumigatyus, none A. flavus, of these Candida chalcones albicans, was active Cryptococcus against neoformans Asper- and gillus niger,Saccharomyces A. fumigatyus, cerevisiae A. flavus,. Antifungal Candida activityalbicans, ofCryptococcus 12 further synthetic neoformans chalcones, and Saccharo- albeit some of myces cerevisiaethem are. Antifungal actually natural activity chalcones, of 12 further were synthetic tested against chalcones,Penicillium albeit chrsogenumsome of them, A. niger, A. are actuallyfluvus naturaland Anthrobortys chalcones, oligosporawere tested, and against (E)-1-(4-hydroxyphenyl)-3-phenylprop-2-en-1-one Penicillium chrsogenum, A. niger, A. fluvus and(21 Anthrobortys), were found oligospora active against, and (E)-P. chrsogenum1-(4-hydroxyphenyl)-3-phenylprop-2-en-1-oneand A. nigar,(E)-1-(4-hydroxyphenyl)-3-(4- (21), weremethoxyphenyl)prop-2-en-1-one found active against P. chrsogenum (169 and) displayed A. nigar, fungicidal(E)-1-(4-hydroxyphenyl)-3-(4- effect against P. chrsogenum methoxyphenyl)prop-2-en-1-one (169) displayed fungicidal effect against P. chrsogenum Biomolecules 2021, 11, 1203 24 of 37 Biomolecules 2021, 11, x FOR PEER REVIEW 25 of 38

andand 1-(4-hydroxyphenyl)-3-(4-methoxyphenyl)propan-1-one 1-(4-hydroxyphenyl)-3-(4-methoxyphenyl)propan-1-one (170 (170) )was was active active against against A.A. nigerniger [99][99 ](Figure (Figure 15). 15).

Chalcone (1) R = R’ = R’’= R’’’= H 2,4-Dichloro-chalcone (159) R = R’’ = Cl; R’ = R’’’ = H 2,3-Dimethoxychalcone (160) R = R’ = OMe; R’’ = R’’’ = H 2,4-Dimethoxychalcone (161) R’ = R’’’ = H; R = R’’ = OMe 3,4-Dimethoxychalcone (162) R = R’’’ = H; R’ = R’’ = OMe 3-Methoxychalcone (163) R = R’’ = R’’’ = H; R’ = OMe 4-Methoxychalcone (164) R = R’ = R’’’ = H; R’’ = OMe 4-Methylchalcone (165) R = R’ = R’’’ = H; R’’ = Me 2-Nitro-chalcone (166) R = NO2; R’= R’’ = R’’’ = H 4-Nitro-chalcone (167) R = R’= R’’’ = H; R’’ = NO2

4′-Bromo-4-methoxychalcone (168) (E)-1-(4-Hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (169)

1-(4-Hydroxyphenyl)-3-(4-methoxyphenyl)pro-

pan-1-one (170) (E)-2-(3′,4′,5′-Trimethoxy-benzylidene)-1- tetralone (171)

(E)-2-(3′,4′-Dimethoxy-benzylidene)-1-tetralone (31) R = H; R’ = R’’ = OMe (E)-2-Benzylidene-1-tetralone (172) R = R’ = R’’ = H (E)-2-(2′-Chloro-benzylidene)-1-tetralone (173) R = Cl; R’ = R’’ = H (E)-2-(3′-Chloro-benzylidene)-1-tetralone (174) R = R’’ = H; R’ = Cl (E)-2-(4′-Chloro-benzylidene)-1-tetralone (175) R = R’ = H; R’’ = Cl (E)-2-(4′-Bromo-benzylidene)-1-tetralone (176) R = R’ = H; R’’ = Br (E)-2-(4′-Fluoro-benzylidene)-1-tetralone (177) R = R’ = H; R’’ = F (E)-2-(4′-Methoxy-benzylidene)-1-tetralone (178) R = R’ = H; R’’ = OMe (E)-2-(2′,4′-Dichloro-benzylidene)-1-tetralone (179) R = R’’ = Cl; R’ = H

FigureFigure 15. 15. StructuresStructures of of some some synthetic synthetic antifungal antifungal chalcones. chalcones.

GuptaGupta et et al. al. [100] [100 ]synthesize synthesizedd 10 10 chalcone chalcone derivatives derivatives (31 (31, ,171171––177177) )(Figure (Figure 15) 15) and and testedtested for for their their antifungal antifungal properties. properties. None None of of these these chalcones chalcones were were active active against against A.A. niger niger andand C.C. albicans albicans, ,but but showed showed strong strong fungicidal fungicidal activity activity (MIC (MIC = = 1.5 1.5–50.0 – 50.0 μµg/mL) against against the the dermatophytedermatophyte MicrosporumMicrosporum gypseum gypseum. .It It is is noteworthy noteworthy that that ( (EE)-2-benzylidene-1-tetralone)-2-benzylidene-1-tetralone (172(172) )and and ( (EE)-2-(4)-2-(4′-chloro-benzylidene)-1-tetralone0-chloro-benzylidene)-1-tetralone ((175)) exhibitedexhibited betterbetter antifungalantifungal activity activity than the positive control ketoconazole, a well-known antifungal drug. It appeared that Biomolecules 2021, 11, 1203 25 of 37

than the positive control ketoconazole, a well-known antifungal drug. It appeared that the addition of a Cl functionality at C-40 of these compounds could enhance the antifungal potency. There are several other publications available to date that describe the synthesis and antifungal activity of chalcone derivatives having versatile chemical features [101–104].

4.4.3. Antiviral Activity Chalcones were demonstrated to possess antiviral properties, which is thought to be exerted mainly by the disruption of the different stage of viral replication cycle, the inhibition of viral or cell enzymes, and/or the induction of apoptosis. One of the earliest studies on the antiviral activities of naturally occurring chalcones was conducted about two decades ago by Ochiumi et al. [76] (Table2). In that study, naturally occurring chalcones, including licochalcone A (40), licochalcone B (68), and tetrahydroxy-methoxychalcone (69), were found to suppress TPA (12-O-tetradecanoylphorbol-13-acetate)-induced HIV promoter activity, and it was suggested that these chalcones could be used as templates for the development of novel anti-HIV drugs. Later, licochalcone A (40), licochalcone D (72), and licochalcone G (73), isolated from G. inflata, were reported to possess antiviral properties against influenza virus [75]. Similarly, echinantin (59) and isoliquiritigenin (22) from the same plant were also active against this virus. The antiviral activity was measured by their noncompetitive neuraminidase inhibitory activity. Among these chalcones, echinantin (59) was the most potent one with an IC50 value in the range of 2.19–5.80 µg/mL against various strains of the influenza virus, e.g., H1N1, H9N2, novel H1N1 (WT), and oseltamivir- resistant novel H1N1 (H274Y), expressed in 293T cells. In another study, dihydrochalcone diglycoside (50), isolated from the seagrass Thalassodendrin ciliatum, showed antiviral activity against the influenza A virus [74], and is assumed to have resulted from the electronic interactions between atomic charges within this compound in both aromatic rings and pseudo-receptor structures in the cells which prevent the attachment and penetration of the virus to the cell. Several alkylated chalcones, including xanthoangelol (83), xanthoangelols B, D-G (84–87), and xanthodeistal (88), isolated from Angelica keiskei (Table2), were shown to possess significant antiviral properties [77], as evident from their inhibitory activity against cysteine proteases of SARS-CoV viruses. Among these compounds, xanthoangelol E(90), containing the perhydroxyl group, exhibited the most potent inhibitory activity PRO PRO against SARS-CoV 3CL and PL with IC50 values of 11.4 and 1.2 µM. Promising antiviral properties of various naturally occurring chalcones tempted synthetic chemists to indulge in bioinspired synthesis of chalcone derivatives with potential antiviral properties. Such efforts have recently been further intensified with the emergence of various deadly respiratory viruses, and viral diseases including the current COVID-19 pandemic. Several studies have identified the activity of synthetic chalcones against different viruses. For example, Cole et al. [105] synthesized several O-benzyl-substituted chalcones, e.g., 1-(2-benzyloxy-6-hydroxyphenyl)-3-(5-bromo-2-methoxyphenyl)-propenone) (180), and determined their antiviral properties, suggesting that these compounds could be used for the prevention or treatment of human immunodeficiency virus (HIV) infections, whilst Mateeva et al. [106] investigated several synthetic chalcones (183–189)(Figure 16) as antiviral agents, and showed that all chalcones at a concentration of 5 µM could inhibit, albeit at variable potencies, the translation of hepatitis C virus. The inhibition of phos- phorylated rsp6 (ribosomal protein S6) and S6K1 (ribosomal protein S6 kinase beta-1) by these chalcones could dampen hepatitis C virus translation. This inhibition potentially was mediated through inhibition of mTOR (mechanistic target of rapamycin), which is a protein kinase that regulates cell growth, survival, and metabolism. BiomoleculesBiomolecules2021 2021, ,11 11,, 1203 x FOR PEER REVIEW 2726 of of38 37

1-(2-Benzyloxy-6-hydroxyphenyl)-3-(5-bromo-2-methoxyphenyl)-propenone (180)

1-(2-Benzyloxy-6-hydroxyphenyl)-3-(5-bromo-2-ethoxyphenyl)-propenone (181) 1-(2-Benzyloxy-6-hydroxyphenyl)-3-(5-chloro-2-ethoxyphenyl)-propenone (182)

2′,3,4,4′,5-Pentamethoxy-6-hydroxychalcone 3′,5′-Dibromo-3,4-dimethoxy-6′-hydorxychal- (183) R = H cone (186) R = R’ = Br 2′,3,4,4′,5-Pentamethoxy-5′-methyl-6-hydroxy- 3′,5′-Dichloro-3,4-dimethoxy-6′-hydorxychal- chalcone (184) R = Me cone (187) R = R’ = Cl 2′,3,4,4′,5-Pentamethoxy-5′-hexyl-6-hydroxy- 3′-Methyl-5′-nitro-3,4-dimethoxy-6′-hydorxychalcone (185) R = C6H11 chalcone (188) R = NO2; R’ = Me

3′,5′-Dichloro-3,4,5-trimethoxy-6′-hydorxychalcone (189)

Chalcone derivative containing a purine ether functionality (190)

Figure 16. Structures of of some some synthetic synthetic antiviral antiviral chalcones. chalcones.

1-(2-Benzyloxy-6-hydroxyphenyl)-3-(5-bromo-2-methoxyphenyl)-propenone (180(180) was) foundwas found to be to the be mostthe most potent potent as an as antiviralan antivi agent,ral agent, and and could could inhibit inhibit several several clinical clinical iso- latesisolates of of HIV HIV in in a dose-dependenta dose-dependent fashion fashion with with IC IC5050 values of around around 5 5 μµMM[ [105].105]. This This ﬁndingfinding led to further modification modiﬁcation of of this this structure structure (180 (180) )to to enhance enhance antiviral antiviral potency potency and and reduce toxicity towards normal normal human human cells, cells, which which resulted resulted in in the the synthesis synthesis of of two two more more antiviral chalcones chalcones (181 (181) )and and (182 (182). ).Both Both chalcones chalcones (181 (181 andand 182182) at )a at concentration a concentration of 10 of 10 µM offered >92% inhibition of viral propagation without impacting host cell viability. Biomolecules 2021, 11, 1203 27 of 37

It appeared that halogenation at C-5 is an essential requirement for the activity of these benzoyloxychalcones. An ethoxy substituent in (181) and (182), instead of a methoxy in 180, offered increased efﬁcacy, and a balance between high antiviral potency and low toxicity to host cells. Most recently, Fu et al. [107] synthesized 28 chalcone derivatives containing a purine ether functionality, and derivative (190) (Figure 16) emerged as the best candidate to effectively inhibit the infectivity of tobacco mosaic virus in vivo with an EC50 value of 65.8 µg/mL. It was demonstrated that this chalcone derivative could destroy the integrity of tobacco mosaic virus. A docking study suggested that the antiviral activity of (190) might depend on its strong binding afﬁnity to tobacco mosaic virus coat protein (TMV-CP). There are several other reports on antiviral properties of synthetic chalcone derivatives available in the literature to date, including a few excellent review articles on this topic [108–110].

4.5. Antioxidant Activity Antioxidants are compounds that can stop or prevent oxidative processes. They can be natural compounds as well as synthetic products. Antioxidants are effective in the manage- ment of oxidative stress, which is considered as one of the major causes of several chronic and life-threatening diseases. External supply of antioxidants is important for human health, and often achieved through regular diets containing plenty of fruits and vegetables. However, there are times when the additional supply of antioxidants in formulated forms may become essential. Plants have long been known as a source of antioxidants, and the phenolic and polyphenolic compounds are a major class of natural antioxidants. Most of the naturally occurring chalcones are phenolic compounds, which possess significant free-radical-scavenging and antioxidant properties. For example, lichochalcone C (71)[67] from Glycyrrhiza glabra and naringenin chalcone (78) and its glucoside, isosalipurposide (66), from Acacia cyanophylla [50] were shown to possess antioxidant properties (Table2). Similarly, several chalcones (79–81, 83, and 85) were isolated from the leaves of Artocarpus nobilis, and were demonstrated to have antioxidant activity [73]. The antioxidant activity of isosalipurposide (66) was established by the 1,1-diphenyl-2-hydrazyl (DPPH) assay, the 2,20-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) cation radical-scavenging assay, and the reducing power assay. The aglycone of glycoside 66, commonly known as naringenin chalcone (78), could have enhanced antioxidant potency because of the presence of an additional phenolic hydroxyl group. Additionally, this chalcone (66) was shown active against acetylcholinesterase with an IC50 value of 52.04 µg/mL [50]. Lichochalcone C (71) at a concentration of 50 µM was found to significantly influence the antioxidant network activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) activity [67]. The geranylated chalcones (79–81, 83, and 85) showed strong qualitative radical-scavenging activity in the TLC-based DPPH assay [73]. Both the naturally occurring chalcones, and several synthetic chalcones, and their derivatives, were shown to possess antioxidant properties of varied potencies based on structural variations and diversity. Most recently, from a series of synthetic β-chalcone derivatives, chalcone (148) (Figure 14) was studied for its antioxidant activity using the DPPH and hydrogen-peroxide (H2O2) assays [92]; this chalcone showed significant antioxidant (radical-scavenging) activity with the IC50 values of 298 and 530 µg/mL, respectively, in the DPPH and H2O2 assays. Wang et al. [111] synthesized 41 chalcone derivatives and assessed their dual antioxidant mechanisms. Among the compounds, chalcone 191 (Figure 17) was found to be the most potent one, and showed cytoprotection of H2O2-induced oxidative damage in phaeochromocytoma (PC12) cells through free- radical-scavenging (as confirmed from the DPPH assay) and activation of the Nrf2/ARE antioxidant pathway at the same time. This chalcone (191) also displayed a noticeable effect against ischemia/reperfusion-related brain injury in animals. It was suggested that 2,5-dimethoxy-3040-dihydroxychalcone (191) could act through dual antioxidant mechanisms, and could be considered as a direct and indirect antioxidant. A total of 26 chalcone derivatives with alkyl-substituted pyrazine heterocycle were synthesized and assessed for Biomolecules 2021, 11, x FOR PEER REVIEW 29 of 38

ischemia/reperfusion-related brain injury in animals. It was suggested that 2,5-di- Biomolecules 2021, 11, 1203 28 of 37 methoxy-3′4′-dihydroxychalcone (191) could act through dual antioxidant mechanisms, and could be considered as a direct and indirect antioxidant. A total of 26 chalcone derivatives with alkyl-substituted pyrazine heterocycle were synthesized and assessed for their radical-scavengingtheir radical-scavenging as well as cellular as well antiox as cellularidant capacity, antioxidant impacting capacity, the impactinggrowth of thecells growth of exposed cellsto H exposed2O2 [112]. to Three H2O2 of[112 these]. Three synt ofhetic these chalcone synthetic analogs chalcone (192 analogs–194) ((Figure192–194 17)) (Figure 17) exhibitedexhibited DPPH-radical-scavenging DPPH-radical-scavenging activity (IC activity50 = 39–186 (IC50 =μM) 39–186 throughµM) a through single electron a single electron transfer followedtransfer followedby a proton by atransfer proton mechanism, transfer mechanism, as revealed as revealedin the density in the functional density functional theory (DFT)theory modeling. (DFT) modeling. Clearly, chalcone Clearly, chalcone193 was the193 mostwas theactive most free-radical-scavenger active free-radical-scavenger with an ICwith50 value an IC of50 39value μM ofin 39theµ DPPHM in the assay. DPPH Earlier, assay. Lahsasni Earlier, Lahsasniet al. [113] et synthesized al. [113] synthesized a a library oflibrary chalcone of chalconederivatives derivatives and chalcone and chalcone195 emerged195 emergedas the most as thepotent most antioxidant potent antioxidant among theamong analogs, the analogs,and the activity and the was activity better was than better that than of the that well-known of the well-known antioxidant antioxidant ascorbic acidascorbic in the acid DPPH in the assay. DPPH assay.

Chalcone-pyrazine analog a (192) R = H

2,5-Dimethoxy-3′4′-dihydroxychalcone (191) Chalcone-pyrazine analog b (193) R = Isopropyl Chalcone-pyrazine analog c (194) R = Isobutyl

Chalcone long-chain fatty acid ester (195)

C12H25

Chacone-phenothoazine derivative a (196) Ar = 4-Dimethyl-aminophenyl Chacone-phenothoazine derivative b (197) Ar = 4-Chlorophenyl Chacone-phenothoazine derivative c (198) Ar = 4-Methoxyphenyl Chacone-phenothoazine derivative d (199) Ar = 3,4-Dimethoxyphenyl Chacone-phenothoazine derivative e (200) Ar = 2-Furfuyl Chacone-phenothoazine derivative f (201) Ar = 3-Thienyl Chacone-phenothoazine derivative g (202) Ar = 3,4,5-Trimethoxyphenyl Figure 17. Structures of some synthetic antioxidant chalcones. Figure 17. Structures of some synthetic antioxidant chalcones.

2′-Hydroxy-4-methoxychalcone20-Hydroxy-4-methoxychalcone (139), a recently (139), a recentlysynthesized synthesized chalcone, chalcone, showed showeda a considerableconsiderable antioxidant antioxidant activity [89]. activity It wa [89s found]. It was to foundbe able to to be attenuate able to attenuate LPS-induced LPS-induced oxidativeoxidative stress and stress promote and promote antioxidant antioxidant defense defense in RAW264.7 in RAW264.7 macrophages. macrophages. 2′-Hy- 20-Hydroxy- droxy-4-methoxychalcone4-methoxychalcone pretreatment pretreatment at at a aconcentration concentration range range of 0.01—1.00.01-–1.0 µμMM couldcould augment augment thethe nuclear nuclear expression expression of of Nrf2 Nrf2 in ain concentration-dependent a concentration-dependent manner. manner. An increased An in- level of creased levelthe downstreamof the downstream antioxidant antioxidant protein protein heme heme oxygen oxygen SE-1 wasSE-1 also was observed.also observed. Additionally, Additionally,this pretreatmentthis pretreatment was foundwas found to signiﬁcantly to significantly increase increase the levels the levels of non-enzymatic of non-en- antioxi- zymatic antioxidantdant GSH (glutathione) GSH (glutathione) in LPS-stimulated in LPS-stimulated RAW 264.7RAW cells.264.7 Zahranicells. Zahrani et al. [et114 al.] reported [114] reportedthe synthesis the synthesis of several of several chalcone-based chalcone-based phenothiazine phenothiazine derivatives derivatives and their and antioxidant their po- antioxidanttentials potentials based onbased the DPPHon the assay;DPPH seven assay; of seven these compoundsof these compounds (196–202) showed(196–202 promising) DPPH-radical-scavenging activity. There are several other reports depicting the synthesis and antioxidant properties of chalcone derivatives available in the literature, most of which possess DPPH-radical-scavenging properties [115–118]. Biomolecules 2021, 11, 1203 29 of 37

4.6. Antiparasitic Activity Parasites are organisms that live and feed on another living being, e.g., animals, hu- mans, insects, or plants, and most often cause harm to the host organism. Parasitic diseases, such as like leishmaniasis and malaria, remain a major global health concern, and research consequently continues in the search for effective and affordable drugs to combat various parasitic diseases. Some naturally occurring chalcones were shown to possess antiparasitic activities (Table2). For example, flavokawain B ( 28), isolated from Polygonum ferrugineum [79]; (E)-1-(2,4-dihydroxy-3-(3-methylbut-2-en-1-yl)phenyl)-3-phenylprop-2-en-1- one (53) from Lonchocarpus sp. [78]; licoagrochalcone A (70) from Erythrina abyssinica [81]; and licochalcone C (71) isolated from Glycyrrhiza glabra [80] were found to possess significant antiparasitic/antiprotozoal properties. A protozoa can be free-living or parasitic. Most of the disease-causing protozoa are parasitic. Even free-living protozoa when entering other cells and tissues of living being become parasitic. While licochalcone C (71) was found active against malarial parasite Plasmodium falciparum, chalcone 53 showed activity against Leishmania and Trypanosoma species. Flavokawain B (28) demonstrated trypanocidal activity against Trypanosoma cruzi and T. bruceii, with IC50 values of 9.5 µM and 4.8 µM, respectively [79], whereas licoagrochalcone A (70) was shown to have antiplasmodial activity against chloroquine-sensitive and chloroquin-resistant strains of Plasmodium falciparum; the IC50 values were determined as 12.7 and 12.0 µM, respectively [81]. Two other chalcones from Erythrina abyssinica, homobutein (19) (IC50 = 15.0 and 16.1 µM, respectively) and 5-prenylated derivative of butein (16) (IC50 = 10.3 and 11.2 µM, respectively) were also active against both strains for Plasmodium falciparum. Inspired by the observed antiparasitic activity of naturally occurring chalcones, several synthetic chalcones with potential antiparasitic activity were introduced. Ugwu et al. [119] reported that several synthetic chalcone derivatives of the structural classes chromanochal- cones, chromeno-dehydrochalcones, quinolinyl chalcones, morachalcones, prenylated chalcones, chromenochalcones, quinoxaline chalcones, chalcone sulphonamides, and lic- ochalcones could exhibit antimalarial activity, and some of them were even active against chloroquin-resistant P. falciparaum. Structures of some of those antimalarial chalcone derivatives (203–207) are presented in Figure 18. Yadav et al. [120] synthesized 27 antimalarial chalcones, and from the antiplasmodial screening of these compounds, chalcone derivative 1-(4-benzimidazol-1-yl-phenyl)-3-(2, 4-dimethoxy-phenyl)-propen-1-one (208) appeared as the most potent one with an IC50 value of 1.1 µg/mL against P. falciparum. Among the 27 compounds tested, the presence of two methoxyl functionalities at positions 2 and 4 appeared to be optimum for antimalarial activity followed by 3,4-dimethoxy and 2,5- dimethoxy with moderate activity. It was noted that 3,4,5-trimethoxy series of derivatives displayed weak activity, probably because of the stearic hindrance at the binding site of the enzyme. Several dimeric chalcone derivatives were synthesized and their antimalarial potential was evaluated using in vitro globin hydrolysis, β-hematin formation, and murine Plasmodium berghei [121]. Among the deimeric chalcone derivatives, 1,1-bis-[(30,40- N-(urenylphenyl)-3-(3”,4”,5”-trimethoxyphenyl)]-2-propen-1-one (209) (Figure 18) was found to be the most active antimalarial candidate. Quinolinone-chalcone derivatives were synthesized and assessed for their antiparasitic activity against the mammalian stages of Trypanosoma brucei and Leishmania infantum [122]. Among the compounds, quinolinone-chalcone derivative 210 exhibited the most prominent activity against both parasites, particularly against Leishmania infantum (IC50 = 1.3 µM). An- other derivative (211) (Figure 18) showed significant trypanocidal activity (IC50 = 2.6 µM). These are just a few examples of antiparasitic synthetic chalcone derivatives, and there are many more examples are available in the literature [123,124]. Biomolecules 2021, 11, 1203 30 of 37 Biomolecules 2021, 11, x FOR PEER REVIEW 31 of 38

Antimalarial quinolinyl chalcone (203)

Antimalarial prenylated chalcone (204)

Antimalarial chromenochalcone (205)

Antimalarial chromeno-dihydrochalcone (206)

Antimalarial quinoxaline chalcone (207) 1-(4-Benzimidazol-1-yl-phenyl)-3-(2, 4-dimethoxyphenyl)-propen-1-one (208)

1,1-Bis-[(3′,4′-N-(urenylphenyl)-3-(3″,4″,5″-trimethoxyphenyl)]-2-propen-1-one (209)

Trypanocidal quinolinone-chalcone derivative (210) Quinolinone-chalcone derivative (210) Figure 18. Structures of some synthetic antiparasitic chalcones. Figure 18. Structures of some synthetic antiparasitic chalcones.

Quinolinone-chalcone4.7. Immunoregulatory derivatives Activity were synthesized and assessed for their antiparasitic activity against the mammalian stages of Trypanosoma brucei and Leishmania infantum Natural chalcones mallotophilippens (74–76) displayed immunoregulatory activ- [122]. Among the compounds, quinolinone-chalcone derivative 210 exhibited the most ity [68]. The immunomodulatory activity of synthetic sulfonamide chalcone derivatives prominent activity against both parasites, particularly against Leishmania infantum (IC50 = in mice infected with ﬁlarial parasites, including Brugia malayi, has recently been stud- 1.3 μM). Another derivative (211) (Figure 18) showed significant trypanocidal activity ied [125]. Lee et al. [126] reviewed the potential immunomodulatory effects of natural and (IC50 = 2.6 μM). These are just a few examples of antiparasitic synthetic chalcone deriva- synthetic chalcones, and several synthetic chalcone derivatives were reported to possess tives, and there are many more examples are available in the literature [123,124]. immunomodulatory properties, mediated through multiple mechanisms, e.g., actions on 4.7. Immunoregulatory Activity Biomolecules 2021, 11, x FOR PEER REVIEW 32 of 38

Natural chalcones mallotophilippens (74–76) displayed immunoregulatory activity [68]. The immunomodulatory activity of synthetic sulfonamide chalcone derivatives in

Biomolecules 2021, 11, 1203 mice infected with filarial parasites, including Brugia malayi, has recently been studied31 of 37 [125]. Lee et al. [126) reviewed the potential immunomodulatory effects of natural and synthetic chalcones, and several synthetic chalcone derivatives were reported to possess immunomodulatory properties, mediated through multiple mechanisms, e.g., actions on dendriticdendritic cells, cells, neutrophils, neutrophils, basophils, basophils, innate innate lymphoid lymphoid cells, cells, microglial microglial cells, cells, and and T T cells. cells. FigureFigure 1919 showsshows some some examples examples of of syntheti syntheticc immunomodulatory immunomodulatory ch chalconealcone derivatives.

2′,5′-Dihydroxy2-naphthylchalcone (211)

(E)-1-[2-Hydroxy-4-methoxy-3-(morpholinomethyl)phenyl]-3-(pyridin-2-yl)prop-2-en-1-one (212)

E)-1-[4-ethoxy-2-hydroxy-5-(morpho- 1-(2,3,4-Trimethoxyphenyl)-3-[3-(2-chloroquino- linomethyl)phenyl]-3-(pyridin-2-yl)prop- linyl)]-2-propen-1-one (214) 2-en-1-one (213)

2′,5′-Dihydroxy-2-furfurylchalcone (215) 3-Phenyl-1-(2,4,6-tris(methoxymethoxy)-phenyl)prop-2-yn-1-one (216)

2′,4-Dihydroxy-6′-isopentyloxychalcone (217)

FigureFigure 19. 19. StructuresStructures of of some some synthetic synthetic immunomodulatory immunomodulatory chalcones. chalcones.

SyntheticSynthetic chalconechalcone analogs, analogs, including including 20,50-dihydroxy2-naphthylchalcone 2′,5′-dihydroxy2-naphthylchalcone (211), could (211 act), couldon neutrophil act on neutrophil degranulation degranulation and superoxide and superoxide anion generation, anion generation, while heterocyclic while chalcones,heterocy- clicnamely chalcones, (E)-1-[2-hydroxy-4-methoxy-3-(morpholinomethyl)phenyl]-3-(pyridin-2-yl)prop-2- namely (E)-1-[2-hydroxy-4-methoxy-3-(morpholinomethyl)phenyl]-3- (pyridin-2-yl)prop-2-en-1-oneen-1-one (212) and (E)-1-[4-ethoxy-2-hydroxy-5-(morpholinomethyl)phenyl]-3-(pyridin-2- (212) and (E)-1-[4-ethoxy-2-hydroxy-5-(morpholinomethyl)phenyl]-3-(pyridin-2-yl)prop-2-en-1-oneyl)prop-2-en-1-one (213) (Figure 19), were found (213) to (Figure inhibit 19), the were generation found ofto superoxideinhibit the anion and elastases [126]. Similarly, 1-(2,3,4-trimethoxyphenyl)-3-(3-(2-chloroquinolinyl)-2- propen-1-one (214) could suppress the production of elastase and superoxide anion, and LTB4- (leukotriene B4) release in human neutrophils. The N-formylmethionyl-leucyl-phenylalanine (fMLP)-stimulated respiratory burst in neutrophils was found to be inhibited by the synthetic chalcone analog, 20,50-dihydroxy-2-furfurylchalcone (215). An unusual synthetic chalcone Biomolecules 2021, 11, 1203 32 of 37

derivative, 3-phenyl-1-(2,4,6- tris(methoxymethoxy)phenyl)prop-2-yn-1-one (216), was shown to possess immunomodulatory properties, whereas 20,4-dihydroxy-60-isopentyloxychalcone (217) could modulate an innate immune response [126]. These are just a few examples of synthetic chalcone derivatives that can modulate an immune response, and there are many more similar examples available in the literature [127].

5. Conclusions Over the years, thousands of chalcones and their derivatives were isolated from natural sources, and many of those were screened for potential bioactivities, mainly including anticancer, anti-inﬂammatory, antimicrobial, antioxidant, and antiparasitic properties. The d of bioactive naturally occurring chalcones has inspired total or partial synthesis of chalcone analogs as well as minor structural modiﬁcations of natural chalcones forming a large collection of bioactive synthetic chalcone derivatives, some of which have enhanced bioactivities and/or reduced toxicities compared to relevant natural chalcones. This review article has demonstrated how bioinspired synthesis of chalcone derivatives can potentially introduce a new chemical space for the exploitation for new drug discovery.

Author Contributions: All authors contributed equally to collation of relevant information from extensive literature search. Additionally, L.N. and K.J.R. prepared, edited and submitted the manuscript as corresponding authors. All authors have read and agreed to the published version of the manuscript. Funding: Lutfun Nahar (L.N.) gratefully acknowledges the financial support of the European Regional Development Fund—Project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868). Data Availability Statement: All relevant data were presented as an integral part of this manuscript. Acknowledgments: Lutfun Nahar gratefully acknowledges the financial support of the European Regional Development Fund—Project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868). The Government of Iraq is thanked for a PhD scholarship to Hiba Jasim. Conflicts of Interest: The authors declare no conflict of interest.

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