Thiazoles and Thiazolidinones As COX/LOX Inhibitors

molecules

Review Thiazoles and Thiazolidinones as COX/LOX Inhibitors

Konstantinos Liaras ID , Maria Fesatidou ID and Athina Geronikaki *

Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University, 54124 Thessaloniki, Greece; [email protected] (K.L.); [email protected] (M.F.) * Correspondence: [email protected]; Tel.: +30-231-099-7616

Academic Editor: Derek J. McPhee Received: 28 February 2018; Accepted: 16 March 2018; Published: 18 March 2018

Abstract: Inflammation is a natural process that is connected to various conditions and disorders such as arthritis, psoriasis, cancer, infections, asthma, etc. Based on the fact that cyclooxygenase isoenzymes (COX-1, COX-2) are responsible for the production of prostaglandins that play an important role in inflammation, traditional treatment approaches include administration of non-steroidal anti-inflammatory drugs (NSAIDs), which act as selective or non-selective COX inhibitors. Almost all of them present a number of unwanted, often serious, side effects as a consequence of interference with the arachidonic acid cascade. In search for new drugs to avoid side effects, while maintaining high potency over inflammation, scientists turned their interest to the synthesis of dual COX/LOX inhibitors, which could provide numerous therapeutic advantages in terms of anti-inflammatory activity, improved gastric protection and safer cardiovascular profile compared to conventional NSAIDs. Thiazole and thiazolidinone moieties can be found in numerous biologically active compounds of natural origin, as well as synthetic molecules that possess a wide range of pharmacological activities. This review focuses on the biological activity of several thiazole and thiazolidinone derivatives as COX-1/COX-2 and LOX inhibitors.

Keywords: thiazole; thiazolidinone; COX; LOX; anti-inﬂammatory

1. Introduction Inflammation is a natural process that is connected to various conditions and disorders such as arthritis, psoriasis, cancer, infections, asthma, etc. Based on the fact that cyclooxygenase isoenzymes (COX-1, COX-2) are responsible for the production of prostaglandins that play an important role in inflammation, traditional treatment approaches include administration of nonsteroidal anti-inflammatory drugs (NSAIDs), which act as selective or non-selective COX inhibitors [1–3]. It is well established that COX-1 inhibitors, such as acetylsalicylic acid, induce gastrointestinal irritation, due to the fact that this particular COX isoenzyme is responsible for the production of gastroprotective prostaglandins. Moreover, this group of drugs can be responsible for increased bleeding diathesis resulted from inhibiting COX-1 catalyzed production of thromboxane A2 (TXA2). The severity of side effects caused by COX-1 or combined COX-1/COX-2 inhibitors (e.g., ibuprofen) concentrated the scientific interest on the production of selective COX-2 inhibitors, inspired by evidence supporting over-expression of this particular isoenzyme during inflammatory conditions. However, the hope for this new generation of drugs to be more effective than their predecessors and with less severe side effects was overshadowed by their association with increased myocardial infarction risk and cardiovascular thrombotic events. These severe side effects are mainly a result of inhibition of COX-2 catalyzed production of prostacyclin (PGI2), a prostaglandin possessing vasodilatory and antiaggregatory properties [4–7].

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Molecules 2018, 23, x 2 of 22 In search for new drugs to avoid side effects, while maintaining high potency over inflammation, In search for new drugs to avoid side effects, while maintaining high potency over scientistsinflammation, turned theirscientists interest turned on leukotrienestheir interest andon leukotrienes lipoxins, which and lipoxins, are produced which via are the produced lipoxygenase via (LOX)the pathwaylipoxygenase and are(LOX) associated pathway with and various are associated procedures with such various as leucocytes procedures activation such as andleucocytes adhesion to vascularactivation endothelium, and adhesion bronchial to vascular asthma endothelium, pathogenesis, bronchial formation asthma ofpathogenesis, edema and gastricformation mucosa of damageedema [ 2and,8,9 gastric]. Consequently, mucosa damage dual [2,8,9]. COX/LOX Consequently, inhibitors dual could COX/LOX provide inhibitors numerous could therapeutic provide advantagesnumerous in termstherapeutic of anti-inflammatory advantages in activity,terms of improved anti-inflammatory gastric protection activity, and improved safer cardiovascular gastric profileprotection compared and tosafer conventional cardiovascular NSAIDs. profile Therefore, compared in theto recentconventional years, aNSAIDs. notable researchTherefore, effort in the in the fieldrecent of dual-acting years, a notable COX/LOX research inhibitors effort within the very field promising of dual-acting results COX/LO has beenX observed inhibitors [10 with,11]. very One of thepromising eminent compounds results has been that wasobserved a result [10,11]. of the One above-mentioned of the eminent scientificcompounds effort that is was licofelone a result (Figure of the 1), a dualabove-mentioned COX/5-LOX scientific inhibitor effort that wasis licofelone under production (Figure 1), a by dual the COX/5-LOX pharmaceutical inhibitor industry, that was with under mixed resultsproduction of phase by III the of pharmaceutical clinical trials for industry, osteoarthritis with mi patientsxed results [12]. of While phase being III of a clinical non-selective trials for COX inhibitor,osteoarthritis it simultaneously patients [12]. inhibits While 5-lipoxygenasebeing a non-sele activatingctive COX protein inhibitor, (FLAP) it simultaneously [13]. It was proved inhibits that polypharmacological5-lipoxygenase activating activity protein of licofelone (FLAP) is [13]. supported It was byproved inhibition that polypharmacological of mPGES-1 [14]. Recently, activity it of was licofelone is supported by inhibition of mPGES-1 [14]. Recently, it was found that licofelone found that licofelone modulates neuroinflammation in the chronic phase of spinal cord injury [15]. It is modulates neuroinflammation in the chronic phase of spinal cord injury [15]. It is believed that this believed that this action is due to elevation of levels of endogenous anti-oxidants and anti-inflammatory action is due to elevation of levels of endogenous anti-oxidants and anti-inflammatory metabolites metabolites in the lesion site. In another publication, the effect of licofelone in intracerebroventricular in the lesion site. In another publication, the effect of licofelone in intracerebroventricular streptozotocin–inducedstreptozotocin–induced cognitive cognitive deficitdeficit inin ratsrats was observed [16]. [16]. Two Two other other compounds compounds that that are are mentionedmentioned in thein literaturethe literature as dual as COX/LOX dual COX/LOX inhibitors inhibitors are thiazol-4(5 are thiazol-4(5H)-one derivatives:H)-one derivatives: darbufelone anddarbufelone CI-987 (Figure and 1CI-987)[17]. (Figure 1) [17].

FigureFigure 1. 1.Chemical Chemical structures structures ofof Licofelone, Darbufelone Darbufelone and and CI-987. CI-987.

It is well established that compounds that contain sulfur atoms play a significant role in living organismsIt is well [18,19]. established In particular, that compounds thiazole thatis a containwell-known sulfur heterocyclic atoms play aromatic a significant compound role in that living organismscontains [ 18sulfur,19]. and In particular, nitrogen atoms thiazole at ispositions a well-known 1 and heterocyclic3 of its five-member aromatic ring, compound respectively that contains [20]. sulfurΤhiazole and nitrogen moiety atomscan be atfound positions in numerous 1 and 3 of biologic its five-memberally active ring, compounds respectively of natural [20]. Thiazole origin (e.g., moiety canthiamine be found [19,20], in numerous mycothiazole biologically [21], cystothiazole active compounds C [22], as well of natural as synthetic origin molecules (e.g., thiamine possessing [19 a,20 ], mycothiazolewide range [ 21of], cystothiazolepharmacological C [22activities], as well such as syntheticas antimicrobial molecules [23–28], possessing antiviral a wide [29,30], range of pharmacologicalantitubercular [23,31], activities anti-inflammatory such as antimicrobial [32–34], anxiolytic [23–28], antiviral[35], anaesthetic [29,30], antitubercular[36], anticonvulsant [23,31 ], anti-inflammatory[37–40], etc.). There [32 is–34 a ],large anxiolytic number [ 35of ],known anaesthetic marketed [36 ],drugs anticonvulsant containing thiazole [37–40 ],rings, etc.). such There as is a largethe anthelmintic number of knowntiabendazole, marketed the antibacterial drugs containing sulfathiazole, thiazole the rings, anticonvulsant such as the riluzole, anthelmintic the tiabendazole,anti-ulcer alizatidine, the antibacterial the antiparkinsonian sulfathiazole, talipexole, the anticonvulsant the antischistosomal riluzole, theniridazole, anti-ulcer the alizatidine,antiviral theritonavir antiparkinsonian and the anti-inflammatory talipexole, the meloxicam. antischistosomal niridazole, the antiviral ritonavir and the anti-inflammatory meloxicam.

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MoleculesThiazolidinones, 2018, 23, x on the other hand, are derivatives of thiazolidine, a saturated form3 of 22 of thiazole,Molecules with2018, 23 a, x carbonyl group at position 2, 4, or 5. The chemistry of thiazolidinones3 of 22 has Thiazolidinones, on the other hand, are derivatives of thiazolidine, a saturated form of thiazole, drawnwith Thiazolidinones,a scientific carbonyl interestgroup on at the throughposition other hand,2, the 4, or are years 5. derivative Th becausee chemistrys of thisthiazolidine, of thiazolidinones particular a saturated ring has system formdrawn of is scientificthiazole, the core structurewithinterest a carbonyl inthrough a variety groupthe years of at syntheticposition because 2, th compounds4,is orparticular 5. The chemistry withring system a broad of thiazolidinones is th spectrume core structure of has biological drawn in a variety scientific activities, of suchinterestsynthetic as antimycobacterial through compounds the years with[ 41because a, 42broad], antifungal th isspectrum particular [ 43of– ring46biological], system anti-cancer activities, is the [ 47core –such50 structure], anticonvulsantas antimycobacterial in a variety[51 of–53 ], anti-edematoussynthetic[41,42], antifungalcompounds [54], [43–46], antidiarrhealwith a anti-cancerbroad [spectrum55], [47–50] anti-HIV of, bianticonvulsantological [56,57 ],activities, anti-platelet-activating [51–53], such anti-edematousas antimycobacterial factor [54], [58 ], antidiabetic[41,42],antidiarrheal antifungal [59], antihistaminic[55], [43–46],anti-HIV [anti-cancer60 [56,57],], anti-inflammatory anti-platele[47–50], anticonvulsantt-activating [61–63], analgesic factor[51–53], [64[58],, 65anti-edematous], antimicrobialantidiabetic [[54],[59],66–69 ], antidepressantantidiarrhealantihistaminic [70 [55],],[60], etc. anti-HIVanti-inflammatory [56,57], anti-platele [61–63], t-activatinganalgesic [64,65],factor [58],antimicrobial antidiabetic [66–69], [59], antihistaminicantidepressantThis review focuses[70],[60], etc. onanti-inflammatory the biological activity[61–63], of severalanalgesic thiazole [64,65], and thiazolidinoneantimicrobial derivatives[66–69], as COX-1/COX-2antidepressantThis review [70], andfocuses etc. LOX on inhibitors. the biological Literature activity of references several thiazole that are and included thiazolidinone in this derivatives review were foundas COX-1/COX-2 usingThis review mainly focuses and Google LOX on Scholar, theinhibitors. biological Scopus Literature activity and SciFinder ofrefe severalrences (keywords: thiazolethat are and included thiazoles thiazolidinone in COX, this review thiazoles derivatives were LOX, thiazolidinonesasfound COX-1/COX-2 using mainly COX, and thiazolidinonesGoogle LOX Scholar,inhibitors. Scopus LOX, Literature NSAIDs, and Sc refeiFinder inflammation,rences (keywords: that are thiazoles includedthiazoles activity, COX,in this thiazoles thiazolidinonesreview LOX,were activity,foundthiazolidinonesetc.). using mainly COX, Google thiazolidinones Scholar, Scopus andLOX, Sc iFinderNSAIDs, (keywords: inflammation, thiazoles COX,thiazoles thiazoles activity, LOX, thiazolidinonesthiazolidinones activity,COX, etc.).thiazolidinones LOX, NSAIDs, inflammation, thiazoles activity, 2. Thiazolesthiazolidinones as COX/LOX activity, etc.). Inhibitors 2. Thiazoles as COX/LOX Inhibitors 2. TherienThiazoles et as al. COX/LOX [71] reported Inhibitors the synthesis of a series of 5,6-diarylimidazo[2.1-b]thiazole derivatives Therien et al. [71] reported the synthesis of a series of 5,6-diarylimidazo[2.1-b]thiazole and evaluated their possible inhibitory potential against COX-2 and COX-1 enzymes. As a result, derivativesTherien and et evaluatedal. [71] reportedtheir possible the inhibitorysynthesis potentialof a series against of 5,6-diarylimidazo[2.1-b]thiazoleCOX-2 and COX-1 enzymes. As compound 1 (Figure2) was identified as a potent, orally active and selective inhibitor of the COX-2 derivativesa result, compound and evaluated 1 (Figure their 2) possiblewas identified inhibitory as a potentialpotent, orally against active COX-2 and andselective COX-1 inhibitor enzymes. of theAs enzyme. This result was confirmed by in vivo evaluation of anti-inflammatory activity. aCOX-2 result, enzyme. compound This 1 result(Figure was 2) wasconfirmed identified by in as vivo a potent, evaluation orally of active anti-i andnflammatory selective inhibitor activity. of the COX-2 enzyme. This result was confirmed by in vivo evaluation of anti-inflammatory activity.

FigureFigure 2. 2.Chemical Chemical structure structure ofof 5,6-diarylimidazo[2.1-b]thiazole5,6-diarylimidazo[2.1- b]thiazole derivative derivative 1. 1. Figure 2. Chemical structure of 5,6-diarylimidazo[2.1-b]thiazole derivative 1. Woods et al. [72] synthesized a series of 4-substituted thiazole analogues of indomethacin, Woods et al. [72] synthesized a series of 4-substituted thiazole analogues of indomethacin, which whichWoods were ettested al. [72]as inhibitors synthesized of COX-1a series and of CO4-suX-2.bstituted It was thiazole found that anal compoundsogues of indomethacin, are selective werewhichinhibitors tested wereas of inhibitorstestedCOX-2 as while inhibitors of COX-1only moderate of and COX-1 COX-2. COX-1 and ItCO wasacX-2.tivity found It (<57%was that found inhibition compounds that atcompounds 10 are mM) selective was are observed. selective inhibitors of COX-2 while only moderate COX-1 activity (<57% inhibition at 10 mM) was observed. The most inhibitorsThe most activeof COX-2 compounds while only as moderateCOX-2 inhibitors COX-1 acappearedtivity (<57% to be inhibition 2a–c (Figure at 10 3) mM) with was IC50 observed. values of activeThe0.3, compounds1most and active7 nM, respectively.compounds as COX-2 inhibitors as COX-2 appearedinhibitors appeared to be 2a– cto(Figure be 2a–3c )(Figure with IC 3)50 withvalues IC50 ofvalues 0.3, 1of and 7 nM,0.3, respectively.1 and 7 nM, respectively.

Figure 3. Chemical structures of 4-substituted thiazole analogues of indomethacin 2a–c. FigureFigure 3. 3.Chemical Chemical structures structures ofof 4-substituted4-substituted thiazole thiazole analogues analogues of of indomethacin indomethacin 2a–2ac.– c. A series of N-aryl-4-aryl-1,3-thiazole-2-amine derivatives were synthesized by Suh et al. [73] as directA 5-LOXseries of inhibitors. N-aryl-4-aryl-1,3-thiazole-2-amine The SAR and chemical derioptimizationvatives were studies synthesized revealed by Suhthat, et among al. [73] as32 direct 5-LOX inhibitors. The SAR and chemical optimization studies revealed that, among 32

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A series of N-aryl-4-aryl-1,3-thiazole-2-amine derivatives were synthesized by Suh et al. [73] asMolecules direct 5-LOX2018, 23, x inhibitors. The SAR and chemical optimization studies revealed that,4 amongof 22 32Molecules synthesized 2018, 23, compounds,x 3a, N-(3,5-dimethylphenyl)-4-(4-chlorophenyl)-1,3-thiazole-2-amine4 of 22 synthesized compounds, 3a, N-(3,5-dimethylphenyl)-4-(4-chlorophenyl)-1,3-thiazole-2-amine (Figure4), was the most potent LOX inhibitor with 98% inhibition (IC 50 = 127 nM) and 98% inhibition (Figure 4), was the most potent LOX inhibitor with 98% inhibition (IC50 = 127 nM) and 98% inhibition in asynthesized cell-based assay.compounds, Compounds 3a, 3bN-(3,5-dimethylphenyl)-4-(4-chlorophenyl)-1,3-thiazole-2-amineand 3c (Figure4), although possessing strong LOX inhibitory in(Figure a cell-based 4), was assay.the most Compounds potent LOX 3b inhibitor and 3c (Figurewith 98% 4), inhibition although (ICpossessing50 = 127 nM) strong and LOX 98% inhibitoryinhibition activity, with IC50 values of 35 and 25 nM respectively, cell-based assay results showed rather activity,in a cell-based with ICassay.50 values Compounds of 35 and 3b 25and nM 3c (Figurerespectively, 4), although cell-based possessing assay resultsstrong LOXshowed inhibitory rather moderate potential. moderateactivity, with potential. IC50 values of 35 and 25 nM respectively, cell-based assay results showed rather moderate potential.

Figure 4. Chemical structures of N-aryl-4-aryl-1,3-thiazole-2-amine derivatives 3a–c. Figure 4. Chemical structures of N-aryl-4-aryl-1,3-thiazole-2-amine derivatives 3a–c. Figure 4. Chemical structures of N-aryl-4-aryl-1,3-thiazole-2-amine derivatives 3a–c. Carradori et al. [74] reported the synthesis of novel 1-(4-ethyl carboxylate-thiazol-2-yl)-3,5-di(hetero)aryl-2-pyrazoliCarradoriCarradori et al.et [74]al. reported [74] thereported synthesis thene of derivatives novelsynthesis 1-(4-ethyl as potentialof carboxylate-thiazol-2-yl)- inhibitorsnovel of1-(4-ethyl human 3,5-di(hetero)aryl-2-pyrazolineCOXcarboxylate-thiazol-2-yl)-3,5-di(hetero)aryl-2-pyrazoli isoenzymes. In vitro assay derivatives displayed as promis potentialingne inhibitorsselectivity derivatives ofagainst humanas potential COX-1, COX inhibitors isoenzymes.with compound of humanIn vitro4 assay(FigureCOX displayed isoenzymes. 5) possessing promising In thevitro strongest assay selectivity displayed activity against with promis IC COX-1,50ing = 29.60 selectivity with ± 1.58 compound μΜagainst, while COX-1, none4 (Figure withof the 5compound compounds) possessing 4 theexhibited(Figure strongest 5) COX-2possessing activity inhibition. the with strongest IC50 = activity 29.60 with± 1.58 IC50µ =M, 29.60 while ± 1.58 none μΜ, while of the none compounds of the compounds exhibited COX-2exhibited inhibition. COX-2 inhibition.

Figure 5. Chemical structure of 1-(4-ethylcarboxylate-thiazol-2-yl)-3,5-di(hetero)aryl-2-pyrazoline FigurederivativeFigure 5. 5.Chemical 4Chemical. structure structure of of 1-(4-ethylcarboxylate-thiazol-2-yl)-3,5-di(hetero)aryl-2-pyrazoline 1-(4-ethylcarboxylate-thiazol-2-yl)-3,5-di(hetero)aryl-2-pyrazoline derivativederivative4. 4. As a continuation of their research on the development of 15-LOX inhibitors [75], a series of new 3,6-diphenylimidazo[2,1-b]thiazol-5-amineAs a continuation of their research on thederivati developmentves were ofdesigned, 15-LOX syntheinhibitorssized [75], and a seriesevaluated of new as As a continuation of their research on the development of 15-LOX inhibitors [75], a series of new inhibitors3,6-diphenylimidazo[2,1-b]thiazol-5-amine of the above enzyme by Tehrani derivatiet al. [76].ves The were study designed, revealed synthe that,sized among and 14 evaluated synthesized as 3,6-diphenylimidazo[2,1-b]thiazol-5-amineandinhibitors tested of derivatives, the above enzyme5a–5d (Figure by Tehrani 6) appeared derivativeset al. [76]. to The be were studythe designed,most revealed potent synthesized that, with among IC50 values and14 synthesized evaluated ranging as inhibitorsbetweenand tested of 11.5–35 thederivatives, above μM. enzymeCompound 5a–5d by(Figure Tehrani5a, with6) appeared et 2,4,4-trimethylpentan-2-yl al. [76 ].to The be studythe most revealed potent pendent that, with group, among IC50 values was 14 synthesizedthe ranging most andactivebetween tested compound, derivatives,11.5–35 μ beingM. Compound5a two–5d times(Figure more5a, 6with) potent appeared 2,4,4-trimethylpentan-2-yl than to reference be the drug most quercetin potent pendent with (IC group,50 IC= 2350 μwasvaluesM). the rangingmost betweenactiveAccording compound, 11.5–35 µ M.to being docking Compound two timesstudies,5a more, with 5a potent 2,4,4-trimethylpentan-2-ylinteracts than referenceproperly drug with quercetin target pendent enzyme(IC50 group,= 23 15-LOX,μM). was the with most activehydrophobic compound,According interactions beingto docking two playing times studies, an more im 5aportant potent interacts thanrole inproperly reference the binding with drug process. quercetintarget enzyme (IC50 =15-LOX, 23 µM). with hydrophobicAccording tointeractions docking studies, playing5a aninteracts important properly role in the with binding target process. enzyme 15-LOX, with hydrophobic interactions playing an important role in the binding process.

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FigureFigure 6. 6.Chemical Chemical structures structures of of 3,6-diphenylimidazo[2,1-b]thiazol-5-amine3,6-diphenylimidazo[2,1-b]thiazol-5-amine derivatives derivatives 5a–5a5d–.5d . Figure 6. Chemical structures of 3,6-diphenylimidazo[2,1-b]thiazol-5-amine derivatives 5a–5d. Elachkar et al. [77] designed and synthesized two novel thiazole derivatives (Figure 7), namely compoundElachkar et6a al.(N-[4-(4-hydroxy-3-methoxyphenyl)-1,3- [77] designed and synthesized two novelthiazol-2-yl]acetamide) thiazole derivatives and (Figure compound7), namely 6b Elachkar et al. [77] designed and synthesized two novel thiazole derivatives (Figure 7), namely compound(4-(2-amino-1,3-thiazol-4-yl)-2-methoxy6a (N-[4-(4-hydroxy-3-methoxyphenyl)-1,3-thiazol-2-yl]acetamide)phenol), with aim to analyze their effect on andCOX compound isoforms. It 6b compound 6a (N-[4-(4-hydroxy-3-methoxyphenyl)-1,3-thiazol-2-yl]acetamide) and compound 6b (4-(2-amino-1,3-thiazol-4-yl)-2-methoxyphenol),was shown, using cell-stably over-expressing COX-1 with and aim blood to analyze platelets, their that effect compound on COX 6a isoforms.was a (4-(2-amino-1,3-thiazol-4-yl)-2-methoxyphenol), with aim to analyze their effect on COX isoforms. It It wasnon-selective shown, using COX-1/COX-2 cell-stably inhibitor, over-expressing while 6b COX-1was a selective and blood COX-2 platelets, inhibitor that with compound similar IC6a50wass was shown, using cell-stably over-expressing COX-1 and blood platelets, that compound 6a was a a non-selective(IC50s 9.01 ± COX-1/COX-20.01 mM and 11.65 inhibitor, ± 6.20 while mM).6b Furtwashermore, a selective these COX-2 compounds inhibitor demonstrated with similar non-selective COX-1/COX-2 inhibitor, while 6b was a selective COX-2 inhibitor with similar IC50s IC anti-inflammatorys (IC s 9.01 ± 0.01 activity mM according and 11.65 to± the6.20 dorsal mM). air Furthermore,pouch model of these inflammation. compounds demonstrated 50(IC50s 509.01 ± 0.01 mM and 11.65 ± 6.20 mM). Furthermore, these compounds demonstrated Docking studies revealed that both compounds 6a and 6b bind to the COX-2 active site in a anti-inﬂammatoryanti-inflammatory activity activity according according to to the the dorsaldorsal air pouch model model of of inflammation. inﬂammation. similar manner as celecoxib. DockingDocking studies studies revealed revealed thatthat bothboth compoundscompounds 6a6a andand 6b6b bindbind to to the the COX-2 COX-2 active active site site in a in a similarsimilar manner manner as as celecoxib. celecoxib.

Figure 7. Chemical structures of compounds 6a (N-[4-(4-hydroxy-3-methoxyphenyl)-1,3-thiazol.-2-yl]acetamide) and 6b Figure 7. Chemical structures of compounds 6a Figure(4-(2-amino-1,3-thiazol-4- 7. Chemical structuresyl)-2-methoxyphenol). of compounds 6a (N-[4-(4-hydroxy-3-methoxyphenyl)-1,3-thiazol.-2-yl]acetamide) (N-[4-(4-hydroxy-3-methoxyphenyl)-1,3-thiazol.-2-yl]acetamide) and 6b and 6b (4-(2-amino-1,3-thiazol-4-yl)-2-methoxyphenol). (4-(2-amino-1,3-thiazol-4-yl)-2-methoxyphenol). Abdelall et al.[17], by modification of the celecoxib molecule, designed and synthesized some thiazolo-celecoxib analogues (7a–7j, Figure 8) and evaluated their anti-inflammatory, COX-1, COX-2 AbdelallAbdelall et et al. al.[17], [17], by by modiﬁcation modification of the celecoxibcelecoxib molecule, molecule, designed designed and and synthesized synthesized some some and 15-LOX inhibitory activity. thiazolo-celecoxibthiazolo-celecoxib analogues analogues ( 7a(7a––7j7j,, Figure Figure8 8))and and evaluatedevaluated their their anti-inflammatory, anti-inﬂammatory, COX-1, COX-1, COX-2 COX-2 andand 15-LOX 15-LOX inhibitory inhibitory activity. activity.

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Figure 8. Structures of thiazolo-celecoxib analogues. Figure 8. Structures of thiazolo-celecoxib analogues. The study of COX-1, COX-2 as well as 15-LOX inhibitory activity revealed that all compounds possessedThe study COX-1, of COX-1, COX-2 COX-2 and 15 as –LOX well inhibitory as 15-LOX potency. inhibitory Compounds activity revealed 7a, 7b, 7e that and all 7i compounds were the possessedmost active COX-1, COX-1 COX-2 inhibitors, and 15 with –LOX IC50 inhibitory values of 4.80–6.30 potency. μΜ Compounds being better7a ,than7b, 7ecelecoxib,and 7i werewhich the mostwas active used COX-1 as a reference inhibitors, drug with (IC IC5050 7.60values μΜ), of but 4.80–6.30 not betterµM beingthan aspirin. better than The celecoxib,same compounds which was usedappeared as a reference to be drugvery (ICpotent50 7.60 COX-2µM), butinhibitors not better (IC50 thans 0.98–1.71 aspirin. μΜ The) samebetter compounds than aspirin, appeared while to be verycompounds potent COX-27a, 7b and inhibitors 7i appeared (IC50s to 0.98–1.71 also be µgoodM) better 15-LOX than inhibitors aspirin, with while IC compounds50s of 3.98–5.417a, 7bμΜand, 7i appearedexhibiting to higher also be potency good 15-LOX than meclofenamate inhibitors with sodium IC50s of 3.98–5.41that was µusedM, exhibiting as a reference higher drug. potency thanNevertheless, meclofenamate two sodiumcompounds that reached was used the as goal a reference of the authors. drug. Compounds Nevertheless, 7a two and compounds 7i possessedreached dual theCOX-2/15-LOX goal of the authors. activity, Compounds despite their7a goodand COX-17i possessed potency. dual This COX-2/15-LOX result proved the activity, rationality despite of the their goodauthors’ COX-1 design. potency. This result proved the rationality of the authors’ design. Oniga et al. [7] designed and synthesized a series of new 2-(trimethoxyphenyl)-thiazoles aiming Oniga et al. [7] designed and synthesized a series of new 2-(trimethoxyphenyl)-thiazoles aiming to develop new, safer and less toxic compounds as NSAIDs. In order to elucidate their mechanism of to develop new, safer and less toxic compounds as NSAIDs. In order to elucidate their mechanism action, the authors performed evaluation of their COX-1/COX-2 inhibitory potency. In addition, of action, the authors performed evaluation of their COX-1/COX-2 inhibitory potency. In addition, docking studies were performed. It was found that four (8a–8d) out of thirteen tested compounds dockingwere the studies most wereactive performed. (Figure 9), even It was though found no that compound four (8a exhibited–8d) out COX-1/COX-2 of thirteen tested activity compounds higher werethan the reference most active drugs. (Figure Docking9), even studies though revealed no compound that compounds exhibited 8a and COX-1/COX-2 8c occupied activityarea close higher to thanthat reference of meloxicam, drugs. forming Docking hydrogen studies bonds revealed with that the compoundskey amino acids8a and Arg120,8c occupied Ser530 of areathe active close to thatsite of of meloxicam, COX-2 enzyme. forming The hydrogen similar behavior, bonds with rega therding key a COX-1 amino acidsactive Arg120,site, was Ser530 observed of thefor activethe siteabove-mentioned of COX-2 enzyme. compounds. The similar Accordin behavior,g to the regarding authors, athis COX-1 is due active to the site, homology was observed similarity for of the above-mentionedactive sites of two compounds. enzymes. The According SAR studies to the revealed authors, that this substitution is due to in the position homology 4 of the similarity phenyl of activering sites is very of two important enzymes. for the The se SARlectivity studies towards revealed the COX-2 that substitution enzyme. in position 4 of the phenyl ring is very important for the selectivity towards the COX-2 enzyme.

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Molecules 2018, 23, x 7 of 22 Molecules 2018, 23, x 7 of 22

FigureFigure 9. 9.Chemical Chemical structuresstructures of of compounds compounds 8a8a–d–.d . Figure 9. Chemical structures of compounds 8a–d. NovelNovel 4,5-diarylthiazoles 4,5-diarylthiazolesFigure COX-1 COX-1 9. Chemical inhibitorsinhibitors structures were reportedof reported compounds by by Abdelazeem 8a Abdelazeem–d. and and co-workers co-workers [78]. [78 ]. These Novelcompounds 4,5-diarylthiazoles were designed COX-1 and inhibitors synthesized were reported in order by Abdelazeemto be tested and as co-workers COX inhibitors [78]. These compounds were designed and synthesized in order to be tested as COX inhibitors analogously analogouslyTheseNovel compounds to 4,5-diarylthiazoles mofezolac were and designed FR122047 COX-1 and inhibitors (Figure synthesized were10), which reported in order lack by a toAbdelazeemgastric be tested damaging andas co-workersCOX profile. inhibitors [78]. to mofezolacTheseanalogously compounds and to FR122047 mofezolac were (Figure anddesigned FR122047 10 ),and which (Figure synthesized lack 10), a which gastric in orderlack damaging a gastricto be damaging proﬁle.tested as profile.COX inhibitors analogously to mofezolac and FR122047 (Figure 10), which lack a gastric damaging profile.

FigureFigureFigure 10. 10. 10.Chemical Chemical Chemical structures structures structures of ofof COXCOX inhibitors Mofezolac MofezolacMofezolac and andand FR122047 FR122047FR122047. . . Figure 10. Chemical structures of COX inhibitors Mofezolac and FR122047. TheseThese compounds compounds were were alsoalso evaluatedevaluated for anti-inflammatory andand analgesic analgesic activities. activities. This This These compounds were also evaluated for anti-inflammatory and analgesic activities. This study studystudy revealedThese revealed compounds that that two two compounds, werecompounds, also evaluated 9a9a andand 9b for (Figure anti-inflammatory 11)11) werewere the the mostand most analgesic potent potent COX-1 COX-1activities. inhibitors inhibitors This revealed that two compounds, 9a and 9b (Figure 11) were the most potent COX-1 inhibitors with IC withstudywith IC IC50 revealed values50 values of that of 0.42 0.42 two and and compounds, 0.32 0.32 μ μMM and and9a and moderatemoderate 9b (Figure COX-2 11) inhibitors inhibitorswere the mostwith with ICpotent IC50s50 s10.71 10.71COX-1 and and inhibitors 9.23 9.23 μM, μM, 50 values of 0.42 and 0.32 µM and moderate COX-2 inhibitors with IC s 10.71 and 9.23 µM, respectively. respectively.withrespectively. IC50 values The The studiesof studies 0.42 andconcerning concerning 0.32 μM ulcerogenicity ulcerogenicityand moderate revealedCOX-2 inhibitors a a significantly significantly50 with tolerableIC tolerable50s 10.71 gastric gastricand 9.23 profile. profile. μM, The studiesrespectively. concerning The studies ulcerogenicity concerning revealedulcerogenicity a significantly revealed a significantly tolerable gastric tolerable profile. gastric profile.

Figure 11. Chemical structures of 4,5-diarylthiazoles 9a and 9b. Figure 11. Chemical structures of 4,5-diarylthiazoles 9a and 9b. FigureFigure 11. 11.Chemical Chemical structures structures of 4,5-diarylthiazoles 4,5-diarylthiazoles 9a 9aandand 9b. 9b. As a continuation of their previous research [78], Abdelazeem et al. [79] synthesized a series of novelAsAs adiphenyl continuationa continuation thiazole of of derivativestheir their previous previous aiming researchresearch to evaluate [78],, AbdelazeemAbdelazeemtheir anticancer et et al. activity.al. [79] [79] synthesized synthesized a seriesa series of of novelAsnovel adiphenylTaking continuation diphenyl into thiazole thiazole account of derivatives their derivatives the previous growing aiming aiming researchinterest toto evaluateevaluate of [78 sc],ientific Abdelazeemtheirtheir anticancer anticancercommunity et activity. activity. al. in [ 79studying] synthesized the potential a series of novelanticancer diphenylTakingTaking intoactivity thiazoleinto account account of derivatives COX-2 the the growinggrowinginhibitors, aiming interestinterest the to evaluateau ofthors scientificientific evaluated their anticancercommunitycommunity anti-inflammatory activity.in in studying studying and the the alsopotential potential COX anticancerTakinganticancerinhibitory intoactivity activityactivity account of ofof COX-2 compoundsCOX-2 the growing inhibitors,inhibitors, 10a– interest10g thethe (Figures au ofthors scientific 12 evaluatedevaluated and 13) community that anti-inflammatoryanti-inflammatory possessed in studyingthe bestand and anticanceralso thealso COX potential COX anticancerinhibitoryprofileinhibitory activityagainst activity activity a ofpanel of ofCOX-2 compounds compoundsof cancer inhibitors, cell 10a10a lines––10g10g the(MCF-7, (Figures(Figures authors HT-29, 1212 evaluated andand A549). 13)13) thatthat anti-inflammatory possessed possessed the the best best andanticancer anticancer also COX profile against a panel of cancer cell lines (MCF-7, HT-29, A549). inhibitory profile activity against a of panel compounds of cancer cell10a lines–10g (MCF-7,(Figures HT-29, 12 and A549). 13 ) that possessed the best anticancer profile against a panel of cancer cell lines (MCF-7, HT-29, A549). Molecules 2018, 23, 685 8 of 21 Molecules 2018, 23, x 8 of 22 Molecules 2018, 23, x 8 of 22

FigureFigure 12. 12.Chemical Chemical structures structures ofof diphenyl thiazole thiazole derivatives derivatives 10a10a–10c–10c. . Figure 12. Chemical structures of diphenyl thiazole derivatives 10a–10c. The most active as COX-1 inhibitor was 10b (IC50 = 4.8 μM), while 10f, the most active The most active as COX-1 inhibitor was 10b (IC = 4.8 µM), while 10f, the most active anticancer anticancerThe most compound active asagainst COX-1 previously inhibitor mentionedwas 10b50 (IC cell50 =lines 4.8 μ(withM), whileIC50 = 10f0.96, the μM most as COX-2active µ compoundinhibitor)anticancer against showedcompound previously the highestagainst mentioned selectivitypreviously cellindex mentioned lines concerning (with cell IC 50thislines= 0.96particular (withM IC as 50isoenzymeCOX-2 = 0.96 inhibitor)μ Mcompared as COX-2 showed to thediclofenac.inhibitor) highest selectivity showed Based onthe index thehighest fact concerning selectivitythat all thistested index particular compounds concerning isoenzyme showedthis particular compared a good isoenzyme COX-2 to diclofenac. selectivity, compared Based the to on theauthorsdiclofenac. fact that came all Based tested to theon compounds theconclusion fact that showed that all theretested a good mighcompounds COX-2t be selectivity,an showedimportant the a good authorscorrelation COX-2 came between selectivity, to the conclusion cancer the thattreatmentauthors there mightcame and theto be inhibitionthe an importantconclusion of the correlation thatabove-mentioned there migh betweent COXbe canceran isoform. important treatment correlation and the between inhibition cancer of the above-mentionedtreatment and the COX inhibition isoform. of the above-mentioned COX isoform.

Figure 13. Chemical structures of diphenyl thiazole derivatives 10d–10g . FigureFigure 13. 13.Chemical Chemical structures structures ofof diphenyl thiazole thiazole derivatives derivatives 10d10d–10g–10g. . 3. Thiazolidinones as COX/LOX Inhibitors 3. Thiazolidinones as COX/LOX Inhibitors 3. ThiazolidinonesOttana et al. as COX/LOX[80], with Inhibitors the aim to ameliorate the activity of lead compound (2R,2Ottana′S)3,3′-(1,2-ethanediyl)bis(2-(3,4-dimethoxyphenyl)-thiazolidin-4-one et al. [80], with the aim to ameliorate the activity [81],of leadmade compound some Ottana et al. [80], with the aim to ameliorate the activity of lead compound (2R,20S)3,30-(1,2- modifications(2R,2′S)3,3′-(1,2-ethanediyl)bis(2-(3,4-dimethoxyphenyl)-thiazolidin-4-one such as removal of 3-methoxygroups of the benzene ring, retaining[81], themade 4-methoxy some ethanediyl)bis(2-(3,4-dimethoxyphenyl)-thiazolidin-4-onemodifications such as removal of 3-methoxygroups of the [benzene81], made ring, some retaining modiﬁcations the 4-methoxy such as removal of 3-methoxygroups of the benzene ring, retaining the 4-methoxy groups. The synthesized

Molecules 2018, 23, 685 9 of 21

Molecules 2018, 23, x 9 of 22 compound 11 (Figure 14) was screened for its anti-inflammatory activity as well as for its Molecules 2018, 23, x 9 of 22 gastrointestinalgroups. The synthesized safety [82 compound]. The authors 11 (Figure evaluated 14) was screened the new for compound, its anti-inflammatory after corresponding activity as well as for its gastrointestinal safety [82]. The authors evaluated the new compound, after modifications,groups. The forsynthesized its possible compound COX-1/COX-2 11 (Figure inhibitory 14) was activity.screened It for was its foundanti-inflammatory that the novel activity compound as corresponding modifications, for its possible COX-1/COX-2 inhibitory activity. It was found that the is a better COX-2 inhibitor than the lead compound of this class, as it was observed inthe human novelwell ascompound for its gastrointestinalis a better COX-2 safety inhibitor [82]. than The the authors lead compound evaluated of thisthe class,new ascompound, it was observed after wholecorresponding blood assay modifications, and computational for its possible studies. COX-1/COX-2 The selectivity inhibitory index COX-1/COX-2activity. It was found appeared that the to be inthe human whole blood assay and computational studies. The selectivity index COX-1/COX-2 novel compound is a better COX-2 inhibitor than the lead compound of this class, as it was observed moreappeared than 30 to times be more higher than than 30 thattimes of ahigher previously than that mentioned of a previously lead compound. mentioned Based lead on compound. the findings, inthe human whole blood assay and computational studies. The selectivity index COX-1/COX-2 theBased authors on confirmedthe findings, the the well-established authors confirmed fact the that we overproductionll-established fact of that COX-2 overproduction derived prostaglandins of COX-2 appeared to be more than 30 times higher than that of a previously mentioned lead compound. playderived a role prostaglandins in acute inflammation. play a role in acute inflammation. Based on the findings, the authors confirmed the well-established fact that overproduction of COX-2 derived prostaglandins play a role in acute inflammation.

Figure 14. Chemical structure of 4-thiazolidinone derivative 11. Figure 14. Chemical structure of 4-thiazolidinone derivative 11. Vigorita et al. [83]Figure performed 14. Chemical conformational structure of 4-thiazolidinonestudies as well derivativeas in situ 11molecular. dynamics on Vigorita et al. [83] performed conformational studies as well as in situ molecular dynamics on previously synthesized [81] 3,3′-(1,2-ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones 12 previouslyVigorita synthesized et al. [83] [ 81performed] 3,30-(1,2-ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones conformational studies as well as in situ molecular dynamics on 12 (Figure 15), which were obtained as racemic mixtures (a) and mesomeric (b) forms RR, SS, RS, in previously synthesized [81] 3,3′-(1,2-ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones 12 (Figureorder 15 to), better which understand were obtained the binding as racemic mode mixtures of these (a) forms and mesomeric to the active (b) center forms ofRR the, SS enzymes., RS, in orderIt (Figure 15), which were obtained as racemic mixtures (a) and mesomeric (b) forms RR, SS, RS, in to betterwas found understand that the theSS bindingenantiomer mode exhibited of these the forms highest to thebind activeing affinity center score of the with enzymes. interaction It was order to better understand the binding mode of these forms to the active center of the enzymes. It foundenergy that of the −47.15SS enantiomer kcal/mol, while exhibited the RR theenantiomer highest showed binding low affinity affinity score for withboth interactionCOX isoforms. energy The of was found that the SS enantiomer exhibited the highest binding affinity score with interaction −47.15meso kcal/mol,form RS, although while the ableRR toenantiomer interact with showed both enzy lowmes, affinity showed, for both however, COX higher isoforms. affinity The for meso energy of −47.15 kcal/mol, while the RR enantiomer showed low affinity for both COX isoforms. The formCOX-2RS, althoughwith interaction able to energy interact −46.88 with kcal/mol. both enzymes, showed, however, higher affinity for COX-2 meso form RS, although able to interact with both enzymes, showed, however, higher affinity for with interactionThe authors, energy after− 46.88in vitro kcal/mol. evaluation of COX-1/COX-2 inhibitory activity, concluded that COX-2 with interaction energy −46.88 kcal/mol. affinityThe authors, order towards after in COX-1/COX-2 vitro evaluation is offollowing COX-1/COX-2 the order inhibitory SS > RS > activity, RR, in concludedagreement thatwith affinitythe The authors, after in vitro evaluation of COX-1/COX-2 inhibitory activity, concluded that ordertheoretical towards results COX-1/COX-2 as well as previous is following in vivo the data order [82]. SS > RS > RR, in agreement with the theoretical affinity order towards COX-1/COX-2 is following the order SS > RS > RR, in agreement with the results asTheoretical well as previous results inindicated vivo data SS [82> ].RS > RR affinity order towards COX-2 isoenzyme, in theoretical results as well as previous in vivo data [82]. agreement with in vitro and previous in vivo pharmacological results. TheoreticalTheoretical results results indicated indicated SS >SS RS > >RS RR > affinity RR affinity order towardsorder towards COX-2 isoenzyme,COX-2 isoenzyme, in agreement in withagreement in vitro andwith previous in vitro and invivo previous pharmacological in vivo pharmacological results. results.

Figure 15. Chemical structures of racemic mixtures (a) and mesomeric (b) forms of

3,3′-(1,2-ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinone 12. FigureFigure 15. 15.Chemical Chemical structures structures of racemicof racemic mixtures mixtures (a) and(a) and mesomeric mesomeric (b) forms(b) forms of 3,3 0of-(1,2- ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinoneAs3,3′ -(1,2-ethanediyl)-bis[2-(3,4-dima continuation of their previousethoxyphenyl)-4-thiazolidinone work [80], Ottana 12. et 12 al.. [84] reported the design and synthesis of 2-imino-4-thiazolidinones 13a, 13b and 5-arylidene-2-imino-4-thiazolidinones 14a–14f As a continuation of their previous work [80], Ottana et al. [84] reported the design and (FigureAs a continuation16), which ofwere their evaluated previous workfor thei [80r], Ottanain vivo et anti-inflammatory al. [84] reported theactivity design by and synthesis of 2-imino-4-thiazolidinones 13a, 13b and 5-arylidene-2-imino-4-thiazolidinones 14a–14f carrageenan-induced paw edema and pleurisy assays in rats [85,86]. Compound 14a, synthesis(Figure of16), 2-imino-4-thiazolidinones which were evaluated13a , for13b andtheir 5-arylidene-2-imino-4-thiazolidinonesin vivo anti-inflammatory activity14a by–14f 5-(3-methoxypnenyliden)-2-phenylimino-3-propyl-4-thiazolidine, exhibited very good (Figurecarrageenan-induced 16), which were evaluatedpaw edema for theirandin pleurisy vivo anti-inﬂammatory assays in rats activity [85,86]. by carrageenan-inducedCompound 14a, pawanti-inflammatory edema and pleurisy activity in assays this assay. in rats With [85 the,86 aim]. Compound of investigating14a ,their 5-(3-methoxypnenyliden)-2- possible mechanism of 5-(3-methoxypnenyliden)-2-phenylimino-3-propyl-4-thiazolidine, exhibited very good anti-inflammatory activity in this assay. With the aim of investigating their possible mechanism of

Molecules 2018, 23, 685 10 of 21 phenylimino-3-propyl-4-thiazolidine,Molecules 2018, 23, x exhibited very good anti-inﬂammatory activity in this10 of assay. 22 Molecules 2018, 23, x 10 of 22 With the aim of investigating their possible mechanism of action, their ability to inhibit COX-1 action, their ability to inhibit COX-1 and COX-2 was assessed in the murine monocyte/macrophage andaction, COX-2 their was ability assessed to inhibit in the COX-1 murine and monocyte/macrophage COX-2 was assessed in the J774 murine cell line monocyte/macrophage [87]. Finally, the most J774 cell line [87]. Finally, the most promising among the tested compounds, 14d, was successfully promisingJ774 cell amongline [87]. the Finally, tested the compounds, most promising14d, wasamong successfully the tested dockedcompounds, into the14d, active was successfully site of COX-2 docked into the active site of COX-2 enzyme, having as reference the known selective COX-2 enzyme,docked having into the as referenceactive site the of knownCOX-2 selectiveenzyme, COX-2having inhibitoras reference SC-558. the known selective COX-2 inhibitor SC-558. inhibitor SC-558. 13a 13b InIn this this assay, assay, compounds compounds 13aand and 13b exhibitedexhibited only a a weak weak inhibition inhibition of of COX-1 COX-1 isoform isoform in all in all In this assay, compounds 13a and 13b exhibited only a weak inhibition of COX-1 isoform in all testedtested doses, doses, without without inhibiting inhibiting COX-2. COX-2. TheThe introduction of of a a (Z (Z)-5-arylidene)-5-arylidene group group generally generally gave gave tested doses, without inhibiting COX-2. The introduction of a (Z)-5-arylidene group generally gave riserise to theto the inhibition inhibition of of COX-2 COX-2 without without reaching,reaching, however, the the levels levels of of the the reference reference drugs. drugs. rise to the inhibition of COX-2 without reaching, however, the levels of the reference drugs.

Figure 16. Chemical structures of 2-imino-4-thiazolidinone derivatives 13a, 13b and FigureFigure 16. 16.Chemical Chemical structures structures of 2-imino-4-thiazolidinone of 2-imino-4-thiazolidinone derivatives derivatives13a, 13b 13aand, 13b 5-arylidene- and 5-arylidene-2-imino-4-thiazolidinone derivatives 14a–14f. 2-imino-4-thiazolidinone5-arylidene-2-imino-4-thiazolidinone derivatives 14a derivatives–14f. 14a–14f. Taranalli et al. [88] synthesized 11 thiazolidine-4-one compounds, 15a–h (Figure 17), and tested Taranalli et al. [88] synthesized 11 thiazolidine-4-one compounds, 15a–h (Figure 17), and tested theirTaranalli anti-inflammatory et al. [88] synthesized activity in 11 vitro thiazolidine-4-one (COX-1 and compounds,COX-2 inhibition)15a–h (Figureand in 17vivo), and their anti-inflammatory activity in vitro (COX-1 and COX-2 inhibition) and in vivo tested(carrageenan-induced their anti-inﬂammatory paw edema activity and cottonin vitro pellet-induced(COX-1 and granulomas COX-2 inhibition)in rats). Most and of inthe vivo (carrageenan-induced paw edema and cotton pellet-induced granulomas in rats). Most of the (carrageenan-inducedcompounds showed significant paw edema inhibition and cotton of edema pellet-induced and granuloma granulomas dry weight, in and, rats). concerning Most of in the compounds showed significant inhibition of edema and granuloma dry weight, and, concerning in compoundsvitro COX-1 showed and COX-2 signiﬁcant inhibition, inhibition half of ofthe edema compounds and granuloma tested showed dry maximum weight, and, inhibition concerning of vitro COX-1 and COX-2 inhibition, half of the compounds tested showed maximum inhibition of in vitroCOX-2,COX-1 comparable and COX-2 to nimesulide. inhibition, However, half of the all compounds tested compounds tested showed did not maximum inhibit the inhibition COX-1 of COX-2, comparable to nimesulide. However, all tested compounds did not inhibit the COX-1 enzyme. COX-2,enzyme. comparable to nimesulide. However, all tested compounds did not inhibit the COX-1 enzyme.

Figure 17. Chemical structures ofthiazolidine-4-one derivatives 15a–h. FigureFigure 17. 17.Chemical Chemical structuresstructures ofthiazolidine-4-one derivatives derivatives 15a15a–h–. h. In their study, Geronikaki et al. [89] reported the computer aided design, synthesis and In their study, Geronikaki et al. [89] reported the computer aided design, synthesis and biological evaluation of nine novel 5-arylidene-4-thiazolidinone derivatives that were chosen as biologicalIn their study,evaluation Geronikaki of nine et novel al. [89 5-arylidene-4-] reported thethiazolidinone computer aided derivative design,s synthesisthat were and chosen biological as candidates out of 22 compounds predicted to be COX/5-LOX dual inhibitors. It was found that evaluationcandidates of nineout of novel 22 compounds 5-arylidene-4-thiazolidinone predicted to be COX/5-LOX derivatives dual that inhibitors. were chosen It was as candidates found that out compounds 16a, 16b (Figure 18) were dual COX-1/LOX inhibitors (IC50s 158 μM/116 μM and 125 of 22compounds compounds 16a, predicted16b (Figure to 18) be COX/5-LOXwere dual COX-1/LOX dual inhibitors. inhibitors It (IC was50s found 158 μM/116 that compounds μM and 12516a , μM/125.9 μΜ, respectively), while compound 16c appeared to be the COX-1 inhibitor (IC50 = 141 16bμM/125.9(Figure 18μΜ), were respectively), dual COX-1/LOX while compound inhibitors 16c appeared (IC50s 158 toµ beM/116 the COX-1µM and inhibitor 125 µ M/125.9(IC50 = 141µ M, μM). respectively),μM). while compound 16c appeared to be the COX-1 inhibitor (IC50 = 141 µM).

Molecules 2018, 23, 685 11 of 21 Molecules 2018, 23, x 11 of 22

Molecules 2018, 23, x 11 of 22 Molecules 2018, 23, x 11 of 22

Figure 18. Chemical structures of 5-arylidene-4-thiazolidinones 16a–c. Figure 18. Chemical structures of 5-arylidene-4-thiazolidinones 16a–c. Hofmann andFigure co-workers 18. Chemical [90] reported structures the of design 5-arylidene-4-thiazolidinones, virtual screening for 16a LOX–c. inhibitory activity andHofmann synthesis and of co-workers Figurea series 18. Chemicalof [ 9035] reported5-benzylidene-2-phenylthiazolinones. structures the of design, 5-arylidene-4-thiazolidinones virtual screening These for 16a LOX–c . compounds inhibitory were activity andevaluated synthesisHofmann in of intact a and series polymorphonuclearco-workers of 35 5-benzylidene-2-phenylthiazolinones. [90] reported leukocytes the design (PMNL), virtual and screening a cell-free These for assay. compounds LOX inhibitory were activity evaluated in intactand ItHofmannsynthesis polymorphonuclear was found andof aco-workersthat series compound leukocytesof [90]35 reported5-benzylidene-2-phenylthiazolinones. 17a (PMNL) (Figure the design and19) acaused, cell-free virtual potent screening assay. inhibition forThese LOX of compoundsinhibitory 5-LOX product activity were evaluated in intact polymorphonuclear leukocytes (PMNL) and a cell-free assay. formationandIt wassynthesis found in intact thatof PMNLa compoundseries and of in3517a cell-free 5-benzylidene-2-phenylthiazolinones.(Figure PMNL 19) caused S100 with potent IC50 inhibitionvalues of 2 of Theseand 5-LOX 0.5 compounds μ productM, respectively. formation were It was found that compound 17a (Figure 19) caused potent inhibition of 5-LOX product in intactInevaluated order PMNL to in improve intact and in polymorphonuclear activity, cell-free the PMNL authors S100 leukocytes made with se ICveral 50(PMNL)values modifications and of 2 a andcell-free 0.5on theµ assay.M, parent respectively. compound In order that to improveledformation toIt several activity,was in foundintact derivatives, the authorsPMNLthat compound among and made in whichcell-free several 17a th (FigurePMNLe modiﬁcations most S100potent19) withcaused was on IC thefound 50potent values parent to be inhibitionof compound compound2 and 0.5 of μ M, that17b5-LOX respectively. (Figure led product to several 19), In order to improve activity, the authors made several modifications on the parent compound that derivatives,exhibitingformation among inthe intact strongest which PMNL theLOX and most inhibitoryin cell-free potent activity wasPMNL found S100with to with IC be50 compoundsIC 0.0950 values μΜ ofand17b 2 and0.28(Figure 0.5 μΜ μ 19M,in), respectively.both exhibiting assaysthe ledIn order to several to improve derivatives, activity, among the authorswhich th madee most se potentveral modifications was found to beon compoundthe parent 17bcompound (Figure that19), strongest(intact PMNL LOX inhibitory and in cell-free activity PMNL with S100). IC50s 0.09 µM and 0.28 µM in both assays (intact PMNL and in exhibiting the strongest LOX inhibitory activity with IC50s 0.09 μΜ and 0.28 μΜ in both assays cell-freeled to PMNLseveral S100).derivatives, among which the most potent was found to be compound 17b (Figure 19), (intactexhibiting PMNL the and strongest in cell-free LOX PMNL inhibitory S100). activity with IC50s 0.09 μΜ and 0.28 μΜ in both assays (intact PMNL and in cell-free PMNL S100).

Figure 19. Chemical structures of 5-benzylidene-2-phenylthiazolinones 17a, 17b.

HofmannFigureFigure et 19.al. 19. Chemical [91],Chemical taking structures structures into ofofaccount 5-benzylidene-2-phenylthiazolinones5-benzylidene-2-phenylthiazolinones their previous promising 17a 17afindings, 17b, 17b. . regarding ligand-based virtualFigure 19.screening Chemical of structures 5-benzylidene-2-phenyl-5 of 5-benzylidene-2-phenylthiazolinonesH-thiazol-4-one derivatives 17a, 17b. [92] as LOX Hofmann et al. [91], taking into account their previous promising findings regarding inhibitors,Hofmann introduced et al. [91], takingstructur intoal modifications account their previouson compound promising 17a. ﬁndingsThis led regardingto the discovery ligand-based of ligand-basedHofmann virtual et al. screening [91], taking of 5-benzylidene-2-phenyl-5 into account their previousH-thiazol-4-one promising derivatives findings [92] regarding as LOX virtualderivative screening 18 (Figure of 5-benzylidene-2-phenyl-5 20), which was investigatedH-thiazol-4-one for its molecular derivatives pharmacological [92] asproperties. LOX inhibitors, inhibitors,ligand-based introduced virtual screening structur alof 5-benzylidene-2-phenyl-5modifications on compoundH-thiazol-4-one 17a. This led derivatives to the discovery [92] as LOX of introduced structural modiﬁcations on compound 17a. This led to the discovery of derivative 18 derivativeinhibitors, 18introduced (Figure 20), structur whichal was modifications investigated onfor compoundits molecular 17a pharmacological. This led to the properties. discovery of (Figure 20), which was investigated for its molecular pharmacological properties. derivative 18 (Figure 20), which was investigated for its molecular pharmacological properties.

Figure 20. Chemical structure of 5-benzylidene-2-phenyl-5H-thiazol-4-one derivative 18.

A pharmacologicalFigure 20. Chemical profile structure was studiedof 5-benzylidene-2-phenyl-5 both in a cell-basedH-thiazol-4-one system using derivative human 18 PMNL. and cell-freeFigure assaysFigure 20. utilizing 20.Chemical Chemical PMNL structure structure homogenates, of of 5-benzylidene-2-phenyl-5 5-benzylidene-2-phenyl-5 S100 preparationsHH-thiazol-4-one-thiazol-4-one of the homogenates derivative derivative and18.18 partially. purifiedA pharmacological recombinant 5-LOX. profile It waswas foundstudied that both derivative in a cell-based 18 seems system to be ausing promising human novel PMNL 5-LOX and cell-free assays utilizing PMNL homogenates, S100 preparations of the homogenates and partially inhibitorA pharmacological with IC50 values profile in the nMwas concentrations studied both inrange a cell-based in intact cellssystem and using cell-free human assays. PMNL It would and A pharmacological proﬁle was studied both in a cell-based system using human PMNL and bepurifiedcell-free interesting assaysrecombinant to utilizingpoint 5-LOX.out PMNL that It compound washomogenates, found 18 that had S100 derivative a completely preparations 18 seems different of tothe be mode homogenates a promising of action andnovelcompared partially 5-LOX to cell-free assays utilizing PMNL homogenates, S100 preparations of the homogenates and partially previouslyinhibitorpurified recombinantwith studied IC50 values inhibitors 5-LOX. in the Itof nMwas this concentrations found class. that Neve derivativertheless, range in 18 thisintact seems compound cells to andbe a cell-free promisingappeared assays. tonovel be It highlywould5-LOX puriﬁed recombinant 5-LOX. It was found that derivative 18 seems to be a promising novel 5-LOX selectivebeinhibitor interesting forwith 5-LOX. toIC poin50 values t out inthat the compound nM concentrations 18 had a completelyrange in intact different cells and mode cell-free of action assays. compared It would to inhibitorpreviouslybe interestingAs with a continuation studied IC to50 poinvalues inhibitorst out of in thattheir the compound nMofprevious this concentrations class. work 18 hadNeve [89], artheless, completely range Eleftheriou in this intact different compoundand cells co-workers mode and appeared cell-free of action[93], assays.based tocompared be onhighly It wouldthe to beknowledge interestingselectivepreviously for thatstudied to5-LOX. point balanced inhibitors out thatmodulation compoundof this ofclass. several18 Nevehad targrtheless, a completelyets is crucialthis compound different in the treatment mode appeared of of action multifactorialto be compared highly to previouslydiseasesselectiveAs a for andcontinuation studied5-LOX. knowing inhibitors of the their inflammation ofprevious this class. work mechanis Nevertheless, [89], Eleftherioums, proposed this and compound co-workersthat balanced appeared [93], inhibitionbased to beon highly theof selectiveCOX-1/COX-2knowledgeAs for a 5-LOX.continuation that and balanced LOX ofenzymes modulationtheir previous could of be severalwork a promising [89], targ Eleftheriouets approach is crucial andfor in theco-workers treatmenttreatment [93], ofof inflammation. multifactorialbased on the Thus,diseasesknowledgeAs aa continuationfragment–basedand that knowing balanced ofthe modulationlibrary, their inflammation previous focused of several workmechanison targCOX-1, [89etsms,], is EleftheriouCOX-2 crucialproposed inand the that andLOX treatment balanced co-workersinhibition, of multifactorialinhibition by [93 ],using basedof COX-1/COX-2diseases and andknowing LOX enzymesthe inflammation could be a promisingmechanisms, approach proposed for the that treatment balanced of inflammation.inhibition of on the knowledge that balanced modulation of several targets is crucial in the treatment of Thus,COX-1/COX-2 a fragment–based and LOX enzymes library, could focused be a promisingon COX-1, approach COX-2 forand the LOX treatment inhibition, of inflammation. by using Thus, a fragment–based library, focused on COX-1, COX-2 and LOX inhibition, by using

Molecules 2018, 23, 685 12 of 21 multifactorial diseases and knowing the inﬂammation mechanisms, proposed that balanced inhibition of COX-1/COX-2 and LOX enzymes could be a promising approach for the treatment of inﬂammation.Molecules 2018, Thus,23, x a fragment–based library, focused on COX-1, COX-2 and LOX inhibition,12 by of using 22 chemoinformaticsMolecules 2018, 23, x assays was created. As a result, 23 new benzothiazol-2-yliminothiazolidin-4-ones12 of 22 chemoinformatics assays was created. As a result, 23 new benzothiazol-2-yliminothiazolidin-4-ones were designed and synthesized in order to evaluate their inhibitory activity on the above-mentioned were designed and synthesized in order to evaluate their inhibitory activity on the above-mentioned enzymes.chemoinformatics The evaluation assays of was inhibitory created. activities As a resu revealedlt, 23 new that benzothiazol-2-yliminothiazolidin-4-ones most of the compounds showed potency wereenzymes. designed The andevaluation synthesized of inhibitory in order toactivities evaluate revealed their inhibitory that most activity of the on thecompounds above-mentioned showed against COX-1, with the best being compounds 19a, 19b and 19c (Figure 21), with IC50 values of 0.018, potency against COX-1, with the best being compounds 19a, 19b and 19c (Figure 21), with IC50 0.31enzymes. and 0.51 The mM, evaluation respectively. of inhibitory Regarding activities COX-2, itrevealed was observed that most that of the the strongest compounds inhibitory showed effect potencyvalues of against 0.018, 0.31 COX-1, and 0.51with mM, the respectively.best being compounds Regarding COX-2,19a, 19b it wasand observed19c (Figure that 21), the withstrongest IC50 was exhibited by compound 19a (58.8% inhibition), while, as far as LOX inhibition was concerned, valuesinhibitory of 0.018, effect 0.31 was and exhibited 0.51 mM, by respectively.compound 19a Re (58.8%garding inhibition), COX-2, it was while, observed as far asthat LOX the inhibition strongest almost all tested thiazolidinones were more potent than their thiazolyl analogues [89], having as a inhibitorywas concerned, effect almostwas exhibited all tested by thiazolidinonescompound 19a (58.8%were more inhibition), potent while,than their as far thiazolyl as LOX analoguesinhibition more potent compound 19d with IC = 17.7 µM. was[89], concerned,having as a almostmore potent all tested compound thiazolidinones50 19d with wereIC50 = more17.7 μΜ potent. than their thiazolyl analogues [89], having as a more potent compound 19d with IC50 = 17.7 μΜ.

FigureFigure 21. 21.Chemical Chemical structures structures ofof benzothiazol-2-yliminothiazolidin-4-onesbenzothiazol-2-yliminothiazolidin-4-ones 19a19a– d–. d. Figure 21. Chemical structures of benzothiazol-2-yliminothiazolidin-4-ones 19a–d. Unsal-Tan et al. [94] reported the design of a series of novel Unsal-Tan et al. [94] reported the design of a series of novel 2-aryl-3-(4-sulfamoyl/ 2-aryl-3-(4-sulfamoyl/methylsulfonylphenylamino)-4-thiazolidinones with the aim to develop new methylsulfonylphenylamino)-4-thiazolidinonesUnsal-Tan et al. [94] reported withthe design the aim of toa developseries newof selectivenovel 2-aryl-3-(4-sulfamoyl/methylsulfonylphenylamino)-4-thiazolidinonesselective cyclooxygenase-2 inhibitors using molecular modeling studies with by the the aim MOE to program.develop newThe cyclooxygenase-2 inhibitors using molecular modeling studies by the MOE program. The designed selectivedesigned cyclooxygenase-2thiazolidinone derivatives inhibitors with using reasonable molecular binding modeling modes studies and by high the docking MOE program. scores were The thiazolidinone derivatives with reasonable binding modes and high docking scores were synthesized designedsynthesized thiazolidinone and evaluated derivatives for their with reasonableCOX-1/COX-2 binding inhibitory modes andactivities high dockingwith NS-398 scores wereand and evaluated for their COX-1/COX-2 inhibitory activities with NS-398 and indomethacine used as synthesizedindomethacine and used evaluated as reference for compounds.their COX-1/COX-2 The activity inhibitory of these thiazolidinonesactivities with wasNS-398 relatively and referenceindomethacinemoderate compounds. against used COX-1 as The reference enzyme, activity compounds.with of these the be thiazolidinonesst Theactivity activity demonstrated of was thes relativelye thiazolidinones by compound moderate 20awas against (IC relatively50 = COX-138.9 enzyme, with the best activity demonstrated by compound 20a (IC = 38.9 µM). On the other hand, moderateμΜ). On the against other COX-1 hand, enzyme,COX-2 inhibitory with the beactivityst activity appeared demonstrated to be slightly50 by compound better than 20a COX-1, (IC50 = with38.9 COX-2μΜthe ).best inhibitory On activity the other activityshown hand, by appeared COX-2 compound inhibitory to be20b slightly (IC activity50 = 14.4 better a ppearedμM) than followed COX-1,to be byslightly withcompound thebetter best 20cthan activity (IC COX-1,50 = 20 shown μwithM). by compoundtheThe best above-mentioned activity20b (IC shown50 = 14.4compounds by compoundµM) followed are 20b presented (IC by50 compound = 14.4in Figure μM) followed 20c22. (IC50 by= 20compoundµM). The 20c above-mentioned (IC50 = 20 μM). compoundsThe above-mentioned are presented compounds in Figure are22. presented in Figure 22.

Figure 22. Chemical structures of 2-aryl-3-(4-sulfamoyl/methylsulfonylphenylamino)-4-thiazolidinones 20a–20c. FigureFigure 22. 22.Chemical Chemical structures structures of of 2-aryl-3-(4-sulfamoyl/methylsulfonylphenylamino)-4-thiazolidinones 2-aryl-3-(4-sulfamoyl/methylsulfonylphenylamino)-4-thiazolidinones 20a20a–20c–20c. . Based on their previous studies [89], Apostolidis and co-workers [95] described the synthesis of novelBased 5-arylidene-2-(1,3-thiazol-2 on their previous studies-ylimino)-1,3-thiazolidin-4-ones [89], Apostolidis and co-workers intr oducing[95] described different the substituentssynthesis of novelinBased position 5-arylidene-2-(1,3-thiazol-2 on their4 of previousthiazole ring studies and-ylimino)-1,3-thiazolidin-4-ones [ 89evaluated], Apostolidis their andanti-inflammatory, co-workers introducing [95 ]COX-1/COX-2 described different the substituents and synthesis LOX of novelininhibitory position 5-arylidene-2-(1,3-thiazol-2-ylimino)-1,3-thiazolidin-4-ones activities. 4 of thiazole In general, ring alland compounds evaluated showedtheir anti-inflammatory, moderate introducing to low inhibitoryCOX-1/COX-2 different activity substituents and against LOX in positioninhibitoryall three 4 of enzymes. thiazoleactivities. Nevertheless, ring In general, and evaluated all compounds compounds their anti-inﬂammatory,21a showed and 21b moderate (Figure COX-1/COX-2to 23) low demonstrated inhibitory and activity good LOX activity inhibitoryagainst activities.allagainst three COX-1 Inenzymes. general, with Nevertheless, IC all50 compoundss 16 and 10 compounds μΜ showed, respectively. 21a moderate and 21b to (Figure low inhibitory 23) demonstrated activity againstgood activity all three enzymes.against COX-1 Nevertheless, with IC50 compoundss 16 and 10 μΜ21a, respectively.and 21b (Figure 23) demonstrated good activity against COX-1 with IC50s 16 and 10 µM, respectively.

Molecules 2018, 23, x 12 of 22

chemoinformatics assays was created. As a result, 23 new benzothiazol-2-yliminothiazolidin-4-ones were designed and synthesized in order to evaluate their inhibitory activity on the above-mentioned enzymes. The evaluation of inhibitory activities revealed that most of the compounds showed potency against COX-1, with the best being compounds 19a, 19b and 19c (Figure 21), with IC50 values of 0.018, 0.31 and 0.51 mM, respectively. Regarding COX-2, it was observed that the strongest inhibitory effect was exhibited by compound 19a (58.8% inhibition), while, as far as LOX inhibition was concerned, almost all tested thiazolidinones were more potent than their thiazolyl analogues [89], having as a more potent compound 19d with IC50 = 17.7 μΜ.

Figure 21. Chemical structures of benzothiazol-2-yliminothiazolidin-4-ones 19a–d.

Unsal-Tan et al. [94] reported the design of a series of novel 2-aryl-3-(4-sulfamoyl/methylsulfonylphenylamino)-4-thiazolidinones with the aim to develop new selective cyclooxygenase-2 inhibitors using molecular modeling studies by the MOE program. The designed thiazolidinone derivatives with reasonable binding modes and high docking scores were synthesized and evaluated for their COX-1/COX-2 inhibitory activities with NS-398 and indomethacine used as reference compounds. The activity of these thiazolidinones was relatively moderate against COX-1 enzyme, with the best activity demonstrated by compound 20a (IC50 = 38.9 μΜ). On the other hand, COX-2 inhibitory activity appeared to be slightly better than COX-1, with the best activity shown by compound 20b (IC50 = 14.4 μM) followed by compound 20c (IC50 = 20 μM). The above-mentioned compounds are presented in Figure 22.

Figure 22. Chemical structures of 2-aryl-3-(4-sulfamoyl/methylsulfonylphenylamino)-4-thiazolidinones 20a–20c.

Based on their previous studies [89], Apostolidis and co-workers [95] described the synthesis of novel 5-arylidene-2-(1,3-thiazol-2-ylimino)-1,3-thiazolidin-4-ones introducing different substituents in position 4 of thiazole ring and evaluated their anti-inflammatory, COX-1/COX-2 and LOX inhibitory activities. In general, all compounds showed moderate to low inhibitory activity against Moleculesall three2018 ,enzymes.23, 685 Nevertheless, compounds 21a and 21b (Figure 23) demonstrated good activity13 of 21 against COX-1 with IC50s 16 and 10 μΜ, respectively.

Molecules 2018, 23, x 13 of 22

MoleculesFigure 2018 23., Chemical23, x structures of 5-arylidene-2-(1,3-thiazol-2-ylimino)-1,3-thiazolidin-4-ones 21a, 1321b of. 22 Figure 23. Chemical structures of 5-arylidene-2-(1,3-thiazol-2-ylimino)-1,3-thiazolidin-4-ones 21a, Figure21b. 23. Chemical structures of 5-arylidene-2-(1,3-thiazol-2-ylimino)-1,3-thiazolidin-4-ones 21a, Abdelazeem21b. et al. [96] synthesized and evaluated the in vivo and in vitro anti-inflammatory activityAbdelazeem of a series ofet diphenylthiazole–thiazolidinoneal. [96] synthesized and evaluated hybrids.the in vivo The and evaluation in vitro anti-inflammatory of COX-1/COX-2 inhibitoryactivityAbdelazeem potencyof a series revealedet ofal. diphenylthiazole–thiazo[96] that, synthesized in general, and all evaluated compoundslidinone thehybrids. in demonstrated vivo The and evaluation in vitro moderate anti-inflammatory of COX-1/COX-2 to high activity. It wasactivityinhibitory shown of potencya thatseries the revealed of potencydiphenylthiazole–thiazo that, of in compounds general, all compoundslidinone depends hybrids. on demonstrated the The substituent evaluation moderate on of the to COX-1/COX-2 high thiazolidinone activity. ring.inhibitoryIt was Thus, shown replacement potency that therevealed potency of five that, membered of incompounds general, thiophene all depend compounds rings on the with demonstrated substituent pyridine oron moderate phenylthe thiazolidinone ringsto high significantly activity. ring. Thus, replacement of five membered thiophene ring with pyridine or phenyl rings significantly increasedIt was shown the COX-1 that the inhibitory potency activityof compounds and selectivity. depends on the substituent on the thiazolidinone ring. increased the COX-1 inhibitory activity and selectivity. Thus,Consequently, replacement compounds of five membered22a and thiophene22b (Figure ring with24) appeared pyridine or to phenyl be the rings most significantly potent COX-1 increasedConsequently, the COX-1 compounds inhibitory activity 22a and and 22b selectivity. (Figure 24) appeared to be the most potent COX-1 inhibitors with IC50 values of 3.51 and 2.03 µM, respectively. The introduction of the bulky naphthyl inhibitorsConsequently, with IC50 valuescompounds of 3.51 22a and and 2.03 22b μΜ ,(Figure respectively. 24) appeared The introduction to be the of most the bulky potent naphthyl COX-1 group in position 5 of thiazolidinone ring resulted in compound 22c (Figure 24) with strong COX-2 inhibitorsgroup in position with IC 505 valuesof thiazolidi of 3.51none and ring2.03 resultedμΜ, respectively. in compound The introduction22c (Figure 24) of thewith bulky strong naphthyl COX-2 inhibition (IC = 3.84 µM). These in vitro results are in accordance with results of in vivo experiments groupinhibition in position 50(IC50 = 5 3.84of thiazolidi μΜ). Thesenone ringin vitro resulted results in compound are in ac cordance22c (Figure with 24) withresults strong of in COX-2 vivo and molecular docking. inhibitionexperiments (IC and50 = molecular 3.84 μΜ docking.). These in vitro results are in accordance with results of in vivo experiments and molecular docking.

FigureFigure 24. 24.Chemical Chemical structures structures ofof diphenylthiazole–thiazolidinonediphenylthiazole–thiazolidinone hybrids hybrids 22a22a–c–. c. Figure 24. Chemical structures of diphenylthiazole–thiazolidinone hybrids 22a–c. As part of their ongoing studies on the synthesis of safe anti-inflammatory agents, Abdellatif et As part of their ongoing studies on the synthesis of safe anti-inﬂammatory agents, al. [97]As designedpart of their and ongoing synthesized studies two on series the synthesis of new thiazolidin-4-ones of safe anti-inflammatory as potential agents, COX-2 Abdellatif selective et Abdellatif et al. [97] designed and synthesized two series of new thiazolidin-4-ones as potential COX-2 al.inhibitors. [97] designed Among and the synthesized synthesized two compounds, series of ne 23aw thiazolidin-4-ones and 23b (Figure 25)as potentialexhibited COX-2 in general, selective the selective inhibitors. Among the synthesized compounds, 23a and 23b (Figure 25) exhibited in general, inhibitors.strongest in Among vitro COX-2 the synthesized potential (ICcompounds,50s 2.3 and 23a1.9 μΜand, respectively)23b (Figure 25)and exhibited selectivity in (SIsgeneral, 4.56 andthe the strongest in vitro COX-2 potential (IC50s 2.3 and 1.9 µM, respectively) and selectivity (SIs 4.56 and strongest5.68, respectively). in vitro COX-2 Nevertheless, potential these(IC50s two2.3 andcompounds 1.9 μΜ, respectively)showed good and COX-1 selectivity inhibitory (SIs 4.56 activity and 5.68, respectively). Nevertheless, these two compounds showed good COX-1 inhibitory activity (IC s 5.68,(IC50 srespectively). 10.5 and 10.8 μΜNevertheless,, respectively) these as well.two Itcompounds should be notedshowed that good these COX-1 results inhibitorywere in agreement activity 50 10.5 and 10.8 µM, respectively) as well. It should be noted that these results were in agreement with (ICwith50s in 10.5 vivo and and 10.8 molecular μΜ, respectively) docking data. as well. It should be noted that these results were in agreement in vivowith andin vivo molecular and molecular docking docking data. data.

Figure 25. Chemical structures of thiazolidinone derivatives 23a, 23b.

FigureFigure 25. 25.Chemical Chemical structuresstructures of thiazolidinone derivatives derivatives 23a23a, 23b, 23b. . Ashour et al. [98] presented the synthesis and evaluation of in vitro/in vivo anti-inflammatory activityAshour of etnew al. [98]pyrazolyl presented benzenesulfonami the synthesis anddes ev aluationlinked ofto inpolysubstituted vitro/in vivo anti-inflammatory pyrazoles and activitythiazolidinones. of new Among pyrazolyl these twobenzenesulfonami series of compounds,des linked thiazolidinone to polysubstituted derivatives andpyrazoles specifically and thiazolidinones.compounds 24a Amongand 24b these(Figure two 26) series appeared of compounds, to be the mostthiazolidinone potent COX-1/COX-2 derivatives andinhibitors specifically (IC50s compounds 24a and 24b (Figure 26) appeared to be the most potent COX-1/COX-2 inhibitors (IC50s

Molecules 2018, 23, 685 14 of 21

Ashour et al. [98] presented the synthesis and evaluation of in vitro/in vivo anti-inﬂammatory activity of new pyrazolyl benzenesulfonamides linked to polysubstituted pyrazoles and thiazolidinones. Among these two series of compounds, thiazolidinone derivatives and speciﬁcally Molecules 2018, 23, x 14 of 22 compounds 24a and 24b (Figure 26) appeared to be the most potent COX-1/COX-2 inhibitors (IC50s Molecules 2018, 23, x µ 14 of 22 5.6/1.525.6/1.52 and and 4.5/1.06 4.5/1.06 μΜM,, SIs SIs 3.68 3.68 and and 4.24, 4.24, respectively). respectively). It shou It shouldld be mentioned be mentioned that, in that, general, in general, the the enzymatic inhibitory activity coincided with the results of the rat paw edema assay. 5.6/1.52enzymatic and inhibitory 4.5/1.06 μΜ activity, SIs 3.68 coincided and 4.24, with respectively). the results of It theshou ratld paw be mentioned edema assay. that, in general, the enzymatic inhibitory activity coincided with the results of the rat paw edema assay.

Figure 26. Chemical structures of pyrazolyl benzenesulfonamide derivatives 24a, 24b. Figure 26. Chemical structures of pyrazolyl benzenesulfonamide derivatives 24a, 24b. Figure 26. Chemical structures of pyrazolyl benzenesulfonamide derivatives 24a, 24b. Fourteen 2-imino-4-thiazolidinone derivatives have been synthesized and evaluated by Ali et al. Fourteen 2-imino-4-thiazolidinone derivatives have been synthesized and evaluated by [99] forFourteen their in 2-imino-4-thiazolidinone vivo anti-inflammatory activity. derivatives In order have to been elucidate synthesized the mechanism and evaluated of action, by Ali docking et al. Ali et al. [99] for their in vivo anti-inﬂammatory activity. In order to elucidate the mechanism of [99]on thefor theirCOX-2 in vivoenzyme anti-inflammatory has been performed activity. forIn orderall compounds. to elucidate theBased mechanism on docking of action, results, docking three action,oncompounds, the docking COX-2 25a onenzyme, the25b COX-2and has 25c been enzyme (Figure performed has27) beenwere for performedchosenall compounds. for testing for allBased compounds.their on COX-1/COX-2 docking Based results, inhibitory on dockingthree results,compounds,activity. three The compounds, evaluation25a, 25b and revealed25a 25c, 25b (Figure thatand compound 25c27) (Figurewere 25c chosen ,27 with) were forthe chosentestinghighest theiranti-inflammatory for testing COX-1/COX-2 their COX-1/COX-2 activity inhibitory and inhibitoryactivity.best glide activity.The energy evaluation among The evaluation revealed these three, that revealed appeared compound that to 25calso compound, withbe the the strongest25c highest, with COX-2anti-inflammatory the highest inhibitor anti-inﬂammatory with activity IC50 = 3.29and μΜ and SI = 29.00. activitybest glide and energy best glide among energy these among three, appeared these three, to also appeared be the strongest to also beCOX-2 the strongestinhibitor with COX-2 IC50 inhibitor= 3.29 withμΜ IC and50 = SI 3.29 = 29.00.µM and SI = 29.00.

Figure 27. Chemical structures of 2-imino-4-thiazolidinone derivatives 25a– c. Figure 27. Chemical structures of 2-imino-4-thiazolidinone derivatives 25a–c. GeronikakiFigure et al. 27. [100]Chemical used structures docking ofanalysis 2-imino-4-thiazolidinone to predict the effectiveness derivatives 25a of– cnew. designed compoundsGeronikaki (26a –et26k al., Figure[100] used28) by docking insertion analysis of adamantany to predictl moiety the effectiveness to previously of synthesized new designed and compoundstested as COX/LOX (26a–26k inhibitors, Figure 28) 2-thiazolylimino-5-arylidene-4-thiazolidinones by insertion of adamantanyl moiety to previously [89]. It synthesized was found andthat testedcompound as COX/LOX 26c had inhibitorsthe best estimated 2-thiazolylimino-5-arylidene-4-thiazolidinones binding energies to LOX and COX-2 [89]. (−12.57 It was kcal/mol found thatand compound−12.54 kcal/mol), 26c had while the the best best estimated estimated bindin binding genergies energy toto COX-1LOX and was COX-2 observed (−12.57 for compound kcal/mol and26d −(−12.5412.13 kcal/mol), kcal/mol). while It should the best be mentioned estimated bindinthat, ing allenergy seven to pairs COX-1 of waspreviously observed synthesized for compound and new 26d

(−12.13 kcal/mol). It should be mentioned that, in all seven pairs of previously synthesized and new

Molecules 2018, 23, 685 15 of 21

Geronikaki et al. [100] used docking analysis to predict the effectiveness of new designed compounds (26a–26k, Figure 28) by insertion of adamantanyl moiety to previously synthesized and tested as COX/LOX inhibitors 2-thiazolylimino-5-arylidene-4-thiazolidinones [89]. It was found that compound 26c had the best estimated binding energies to LOX and COX-2 (−12.57 kcal/mol and −12.54 kcal/mol), while the best estimated binding energy to COX-1 was observed for compound Molecules 2018, 23, x 15 of 22 26d (−12.13 kcal/mol). It should be mentioned that, in all seven pairs of previously synthesized and newadamantanyl adamantanyl derivatives derivatives (26a (26a–26f– 26fandand 26i26i), the), the estimated estimated binding binding energy energy of ofthe the adamantanyl adamantanyl derivativesderivatives was was lower lower than than that that of of the the non-substitutednon-substituted analogues analogues for for all all three three enzymes, enzymes, showing showing a a betterbetter predicted predicted activity activity for for the the adamantanyl adamantanyl compounds.compounds.

FigureFigure 28. 28.Chemical Chemical structures structures of of 4-adamantanyl-2-thiazolylimino-5-arylidene-4-thiazolidinones. 4-adamantanyl-2-thiazolylimino-5-arylidene-4-thiazolidinones.

Moreover, new adamantanyl derivatives, 26g and 26h were designed and evaluated using dockingMoreover, analysis. new These adamantanyl two compounds derivatives, did not26g haveand pairs26h withwere previous designed synthesized and evaluated compounds. using dockingIt was analysis.found that These their predicted two compounds binding didenergies not have to COX pairs and with LOX previous enzymes synthesizedwas low, especially compounds. for It wascompound found that26g their (−12.22 predicted kcal/mol). binding The energies evaluation to COX of LOX and LOXinhibitory enzymes activity was low, revealed especially that for compoundcompounds26g 26c(−–12.2226e, 26g kcal/mol)., 26h and The 26kevaluation exhibited good of LOX activity inhibitory with IC activity50s 38, 98, revealed 45, 34, 60 that and compounds 56 μM, 26crespectively.–26e, 26g, 26h Asand far26k as exhibitedCOX-1 inhibition good activity is conc witherned, IC50 thes 38, best 98, 45,activity 34, 60 was and found 56 µM, to respectively. possess Ascompounds far as COX-1 26d inhibition and 26b is (IC concerned,50s 39 μM theand best 50 μ activityM respectively). was found Thus, to possess experimental compounds results26d coincideand 26b (ICwith50s 39 docking,µM and confirming 50 µM respectively). the rational Thus,design experimental of these thiazolidinone results coincide derivatives. with docking, conﬁrming the rational design of these thiazolidinone derivatives. 4. SAR 4. SAR The analysis of the structure–activity relationship of thiazole derivatives used in this review revealedThe analysis that thiazole of the based structure–activity thiazolidinones relationship were moderate of thiazole to good derivatives COX-1/LOX used inhibitors. in this reviewThe revealedmost favorable that thiazole substituents based thiazolidinones in benzene ring were appeared moderate to be 4-NO to good2, 3-NO COX-1/LOX2 and 3-Cl. inhibitors. Introduction The of most a methyl group in positions 4 and 5 of thiazole rings led to compounds with only COX-1 inhibitory favorable substituents in benzene ring appeared to be 4-NO2, 3-NO2 and 3-Cl. Introduction of a methyl groupactivity. in positions LOX activity 4 and was 5 oflost. thiazole The introduction rings led toof compoundsadamantanyl withsubstituent only COX-1 in position inhibitory 4 of thiazole activity. LOXring activity showed was good lost. LOX The inhibitory introduction activity. of Furthermore, adamantanyl the substituent presence of in2-NO position2, 4-NO 42, 3-Cl, of thiazole 4-Cl and ring 4-OH-3,5-OMe substituents in benzene rings increased LOX inhibition compared to unsubstituted showed good LOX inhibitory activity. Furthermore, the presence of 2-NO2, 4-NO2, 3-Cl, 4-Cl and rings. Introduction of 2 phenyl rings in positions 4,5 of thiazole rings led to COX-1/COX-2 inhibitors 4-OH-3,5-OMe substituents in benzene rings increased LOX inhibition compared to unsubstituted with the prevalence of COX-2 inhibition. The best activity against COX-2 was observed for rings. Introduction of 2 phenyl rings in positions 4,5 of thiazole rings led to COX-1/COX-2 compounds with bulky naphthalene group. Thiazolidinone derivatives with hydrazinocarbonyl inhibitorspyrazolo with benzensulfonamide the prevalence ofgroup COX-2 led inhibition.to compounds The bestwith activitygood COX-2 against and COX-2 moderate was observedCOX-1 forpotency. compounds Introduction with bulky of naphthalenephenylin position group. 4 of Thiazolidinone thiazolidin-4-one derivatives as well as with benzensulfonamide hydrazinocarbonyl pyrazologroup benzensulfonamidelinked to nitrogen of groupthe ring led resulted to compounds in compounds with good with COX-2good COX-2 and moderate and moderate COX-1 COX-1 potency. Introductionactivity. Linkage of phenylin of two position 3,4-dimethoxyphenylthi 4 of thiazolidin-4-oneazolidine-4-one as well as benzensulfonamidemolecules together groupthrough linked the to nitrogenethane of link the resulted ring resulted in good in COX-2 compounds inhibitors with with good a high COX-2 COX-1/COX-2 and moderate selectivity COX-1 index. activity. Linkage of two 3,4-dimethoxyphenylthiazolidine-4-oneThe benzothiazole based thiazolidinones moleculeswere much together better as through COX-1 theinhibitors ethane compared link resulted to in goodthiazole-based COX-2 inhibitors thiazolidinones with a high as well COX-1/COX-2 as better LOX selectivity inhibitors. index. The most favorable substituents on theThe benzene benzothiazole ring for COX-1 based inhibition thiazolidinones were 2-Cl, were 4-Cl much and 4-NO better2,, aswhile, COX-1 for LOX, inhibitors the substituents compared to thiazole-basedthat improved thiazolidinones activity were as 2-NO well as2, 3-OH, better LOX4-OH, inhibitors. 4-OMe, 4-OH, The most 3-OMe favorable and 4-OH, substituents 3,5-OMe. on the Replacement of the benzothiazole ring with benzoisothiazole resulted in less active compounds as benzene ring for COX-1 inhibition were 2-Cl, 4-Cl and 4-NO2,, while, for LOX, the substituents that COX-1 inhibitors, but substituents 2-NO2, 4-NO2, 4-Cl, 4-OH and 4-OH-3-OMe substantially improved activity were 2-NO2, 3-OH, 4-OH, 4-OMe, 4-OH, 3-OMe and 4-OH, 3,5-OMe. Replacement of theincreased benzothiazole the LOX ringactivity. with benzoisothiazole resulted in less active compounds as COX-1 inhibitors, It was observed that, in general, the hybride molecules with thiazole and other heterocycles but substituents 2-NO2, 4-NO2, 4-Cl, 4-OH and 4-OH-3-OMe substantially increased the LOX activity. with bulky and lipophilic substituents expressed good COX-2 inhibitory potency. The same good activity resulted from a combination of thiazole with celecoxib, as well as phenyl substituted fused thiazole derivatives.

5. Conclusions

Molecules 2018, 23, 685 16 of 21

It was observed that, in general, the hybride molecules with thiazole and other heterocycles with bulky and lipophilic substituents expressed good COX-2 inhibitory potency. The same good activity resulted from a combination of thiazole with celecoxib, as well as phenyl substituted fused thiazole derivatives.

5. Conclusions Over recent decades, much effort was dedicated to the development of new COX/LOX inhibitors. Specifically, there is a significant amount of publications concerning the synthesis and evaluation of thiazoles and thiazolidinones with potential COX/LOX inhibitory activity. Nevertheless, although a great amount of synthesized compounds were found to be potent as COX/LOX inhibitors, only a portion of them revealed a safer pharmacological profile, compared to marketed anti-inflammatory drugs. However, from the above-mentioned studies, it is clear that thiazole and thiazolidinone derivatives can be promising targets for future research in the field of COX/LOX inhibitors in order to discover new, more effective and safer anti-inflammatory drugs.

Author Contributions: K.L. and M.F. reviewed the articles and analyzed data. K.L. and A.G. designed the review procedure. K.L. wrote the introduction and designed the chemical structures in all figures. K.L., M.F. and A.G. drafted the main part of the manuscript. K.L. and A.G. wrote the conclusions. A.G. provided general oversight and mentorship, including data interpretation and suggested revisions. M.F. had the overall care of references editing. Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are not available from the authors.

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