Synthetic and therapeutic potential of 4-thiazolidinone and its analogs

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Introduction
The chemistry of five-membered rings containing two heteroatoms has been an interesting field of study for decades. Among which 4-thiazolidinone ring system 1 has been studied extensively as it is a core structure in various synthetic compounds and an important scaffold known to be associated with several biological activities. The literature survey revealed that the 4-thiazolidinone moiety can be substituted at positions 2, 3 and 5, but substitution at 2-position specifically results in structurally diverse and potent derivatives.
The 4-thiazolidinone scaffold is not only synthetically important but also possesses diverse therapeutic activities which include antidiabetic, 1 antimicrobial, 2 anticonvulsant, 3 antitubercular, 4 antitumour, 5 antiviral, 6 antiparkinsonian, 7 anti-arthritic, 8 analgesic and anti-inflammatory 9,10 activities. Some thiazolidinone derivatives have better activity than standard drugs and could become a new drug for the market in the future. The successful introduction of Ralitoline as a potent anticonvulsant, 11 Etozoline as an antihypertensive 12 and Epalrestat as an aldose reductase inhibitor for the treatment of diabetic neuropathy 13 has been demonstrated the therapeutic potential of 4-thiazolidinone derivatives (Fig. 1). With the development of faster new 4-thiazolidinone based therapeutic agents, it is essential to compile the latest information with previously available information in order to understand the status of this chemical moiety in medicinal chemistry research.
Inspired by these observations, this review summarizes the various synthetic methods available for the synthesis of the 4-thiazolidinone core structure and the therapeutic journey of this nucleus to give a flying bird eye-catch view of the 4-thiazolidinone nucleus. Although several reviews have been published earlier on 4-thiazolidinones, [14][15][16][17][18] the focus was either synthetic routes or chemical reactions of the nucleus or the several biological activities of the thiazolidinone derivatives or published a few years ago. Our effort is an exhaustive and systematic compilation of synthetic, as well as the therapeutic voyage of 4-thiazolidinone and its derivatives in the recent past.

Syntheses of 4-thiazolidinones
The reaction of acid hydrazide 2 with aromatic aldehydes yielded corresponding hydrazones 3 which on further reaction with thioglycolic acid in methanol give 2-substituted 4-thiazolidinones -4. 19 Thiazolidinones 5 can be synthesized by taking three components i.e. an amine, a carbonyl compound and a mercapto acid in two steps. The reactions proceed by initial formation of an imine (the nitrogen of amine attacks the carbonyl of aldehyde or ketone), which undergoes attack by sulfur nucleophile followed by intramolecular cyclization on the elimination of water. 20 Hydrazine carbothioamide 7 was prepared by condensation of an aromatic ester (6) with thiosemicarbazide, which underwent ready heterocyclization upon its reaction with chloroacetic acid in presence of sodium acetate to afford thiazolidin-4-one (8). 21 Reacting the appropriate amine with chloroacetyl chloride in DMF at room temperature and then cyclization of resulting acetamide in the presence of ammonium thiocyanate affords substituted thiazolidin-4-ones (9). 22

Biological activities
In the literature survey, our main objective was to search the potent compounds for various pharmacological activities with lesser adverse effects. Thiazolidinone is well established in the literature as an important biologically active heterocyclic compound and thus is the subject of many research studies.

Antitumor/Anticancer activity
Gawronska-Grzywacz et al., 2019 synthesized a series of 2,3-disubstituted 1,3-thiazolidin-4-one and subjected to in vitro study of cytotoxicity towards human cancer cell lines. The compounds 37a (IC50= 2.67 mM) and 37b (IC50= 2.93 mM) were most active against human renal adenocarcinoma 769-P cells. The detailed analysis of the antiproliferative potential of these compounds revealed that these compounds carried out G1 cell cycle arrest in 769-P cells. displayed the highest cytotoxicity which was even higher than the reference drug cisplatin. Moreover, these compounds were found to be non-toxic on human erythrocytes even at high concentrations. 43 Kulabaş et al., 2017 synthesized 2-imino-1,3-thiazolidin-4-ones and evaluated them for antiviral and anticancer activities. None of the compounds showed significant antiviral activity. The cytotoxic property was evaluated against NIH3T3 cell line and the anticancer activity was evaluated against K562, MCF-7, HT-29, SJSA1, A549, PC-3, HeLa cell lines. The compound 41 was found to be nontoxic and displayed 35.82% cell growth inhibition against HeLa cell line at 10 µM dose. 44 Appalanaidu et al., 2016 synthesized a series of 2-imino-4-thiazolidinone derivatives and screened for cytotoxicity against three cancer cell lines i.e., B16F10, A549 and PANC-1 and normal cell line (CHO). The compounds bearing the thiophene ring were more effective than the compounds bearing the furan ring. Three compounds 42a, 42b, 42c were found to be effective against the tested cancer cell lines in the order B16F10 > A549 > PANC-1. Compounds 42a and 42c are nontoxic to noncancerous CHO cell line whereas the 42b compound exhibits cytotoxicity at high concentration (50-100 µM). 45 Wang et al., 2011, synthesized a series of novel 4-thiazolidinone and indolin-2-one hybrid derivatives and evaluated their cytotoxic activities against four human cancer cell lines by MTT assay. Most of the prepared compounds showed moderate to excellent cytotoxic activities against one or more cancer cell lines. Compound 43 showed potent antitumor activity against all four human cancer cell lines. 46 Havrylyuk et al., 2010, synthesized 3-or 2-substituted 4-thiazolidinones with benzothiazole moiety and screened in vitro for anticancer activity. Among tested compounds, compound 44 was found to be the most active compound. 47 Lv et al., 2010, prepared two series of thiazolidinone derivatives for potential EGFR and HER-2 kinase inhibitory activity. In particular, compound 45 has demonstrated significant EGFR and HER-2 kinase inhibitory activity and inhibitory activity in tumor growth inhibition as a potential anticancer agent. 48 Zhou

Antimicrobial activity
Cheddie et al., 2020 synthesized a series of 2-trifluoromethyl benzimidazole-thiazolidinone derivatives and evaluated for antibacterial activity against four Gram-negative bacteria, Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli, and Salmonella typhimurium, and two Grampositive bacteria, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus. In general, all the compounds displayed excellent activity when compared to ciprofloxacin and levofloxacin. Among them, compounds 50a, 50b and 50c having bromo or nitro group displayed a broad spectrum of activity. 2 Deep et al., 2014, synthesized novel derivatives of 4-thiazolidinone from biphenyl-4-carboxylic acid and evaluated for their antimicrobial activities. Compound 51a with its electron-withdrawing group substitutions (bromo and nitro group) on aromatic rings was found to be the most active compound against the bacterial strains. Compound 51b with their bromo substitution on both the aromatic rings was the most active compound against the fungal strains. 52 Desai et al., 2013, synthesized a series of 2-(2-chloroquinolin-3-yl)-5-((aryl)benzylidene)-3-(4oxo-2-phenylquinazolin-3(4H)-yl)thiazolidin-4-ones 52. Some of the newly synthesized compounds exhibited promising antibacterial activities against E. coli, S. aureus, P. aeruginosa, and S. pyogenus. Some exhibited very good antifungal activity against C. albicans, A. niger, and A. clavatus. Compounds 52a and 52b possessed very good activity against both bacterial and fungal species. It seemed that methyl group at the para position and hydroxyl group at the second position are very significant for activity against both bacterial and fungal strains. 53 Shukla et al., 2011, synthesized a series of thiazolidinone derivatives and screened them for antiinflammatory activity. Among them, compound 53 showed the highest anti-inflammatory activity. 54 Vats et al., 2010, synthesized a new series of 2-ketophenyl-3-substituted aryl-1-thiazolidin-4-ones 54 by cyclo condensation of ketoazomethines and thioglycolic acid and screened for antifungal activity against hazardous fungi namely Fusarium oxysporum, Alternaria brassicola, Pythium and Sclerotium by paper disc method. Compounds 54a and 54b showed the highest inhibition against Fusarium oxysporum, Alternaria brassicola, Sclerotium, and Pythium. compound 54c showed the highest inhibition against Sclerotium, compound 54d was effective against Alternaria brassicola and Sclerotium. Therefore, from the results, it was evident that compounds having electronegative groups are responsible for antifungal activity 55 Liesen et al., 2010, reported 4-thiazolidinone derivatives obtained from ethyl(5-methyl-1-Himidazole-4-carboxylate). The whole synthesized compounds were evaluated against a variety of pathogens for their antibacterial and antifungal activities. The results showed that the tested compounds possessed weak antibacterial and antifungal activities compared to standard drugs. Compounds 55 showed MIC of 270 µg/L against B. subtilis. 56 Patel and Shaikh 2010, synthesized Schiff's bases and 4-thiazolidinones from 2-chloro pyridine-3-carboxylic acid and 2-amino-6-methoxy-benzothiazole and screened for their antimicrobial activity. The compounds 56 containing Cl, NO2 group, and furan nucleus were found to be more active than the remaining synthesized compounds. 57 Palekar et al., 2009, synthesized a novel series of 4-bis(substituted phenyl)-4-thiazolidinone derivatives from terephthalic acid dihydrazide through multistep reaction sequences. Most of the compounds 57 showed moderate antibacterial activity. 58 Vicini et al., 2008, synthesized 2-heteroarylimino-5-benzylidene-4-thiazolidinones, unsubstituted or carrying hydroxyl, methoxy, nitro, and chloro groups on the benzene ring 58 and screened in vitro for their antimicrobial activity against Gram +ve and Gram -ve bacteria, yeasts, and mould. They reported that the activities depend on the substituents at the 5-benzylidene moiety. 22 Bondock

Antiviral and Anti-HIV activities
Güzeldemirci et al., 2018 synthesized a series of 4-thiazolidinones bearing an imidazo[2,1b]thiazole moiety and evaluated them against a broad and diverse panel of RNA-and DNA viruses using cytopathic effect (CPE) reduction assays in an appropriate cell culture models. Some of the compounds displayed moderate antiviral activity. Among them, the compound 66 displayed moderate but consistent activity against three strains of influenza A virus, including the 2009 pandemic virus A/H1N1 Virginia/ATCC3/2009 (cytotoxicity >100 µM). 6 Ravichandran et al., 2011, synthesized a series of 1,3-thiazolidin-4-ones and tested against representative members of the virus including Herpes simplex virus-1 (KOS), Herpes simplex virus-2 (G), Influenza A H3N2 subtype, Influenza B, and their cytotoxic concentration was evaluated. None of the synthesized compounds are active against Herpes simplex virus-1 (KOS) and Herpes simplex virus-2 (G). The compound 67 showed better anti-viral activity against Influenza A H3N2 subtype and Influenza B at the concentration of 249-263 µM, whereas cytotoxicity was found to be >283 µM. 64 Ravichandran et al., 2009, used the 3D-QSAR approach to explore the structural requirements of thiazolidinone derivatives for anti-HIV activity and concluded that that 3ʹʹ, 2ʹʹ, 6ʹʹ substituted aromatic rings of thiazolidinones 68 are important for anti-HIV activity. 65 Balzarini et al, 2007, synthesized a series of novel thiazolidin-4-ones bearing a lipophilic adamantyl substituent at position 2, and versatile substituents on the nitrogen atom of the thiazolidine ring, were synthesized. Whereas several compounds exhibited a modest anti-HIV-1 activity, (±)-2adamantan-1-yl-3-(4,6-dimethyl-pyridin-2-yl)-thiazolidin-4-one 69 was endowed with remarkable antiviral potency. 66 In fact, 1-(4-bromophenyl) substituted 5-methyl-4-thiazolidinone derivative 70 showed the most favorable antiviral activity against BVDV. 67 Rawal et al., 2005, synthesized a series of 2-(aryl)-3-furan-2-ylmethyl-thiazolidin-4-ones as selective HIV-RT Inhibitors. Compound 71 was found to be most active. 68 Barreca et al., 2001, synthesized a series of 2,3-diaryl-1,3-thiazolidin-4-ones 72 and screened for their anti-HIV activity. The anti-HIV activity was strongly enhanced by introducing a 2-pyridinyl substituent at the N-3 atom of the thiazolidinone ring and in particular by introducing two chlorine atoms at 2ʹ and 6ʹ positions of the phenyl ring. In fact, 6-methylpyridin-2-yl derivatives 72a and 72b possessed the most promising activity. 69   showed MIC values equivalent to the standard drug isoniazid. The substitution with the chloro group in phenyl ring of thiazolidinone nucleus was highly active which suggested that electron-withdrawing groups enhance the activity. 71 Srivastava et al., 2005, synthesized a series of 4-thiazolidinone derivatives and screened them for antimycobacterial activity. Compound 76 was found to be most active. 72 Trivedi et al., 2004, synthesized some new potential 4-oxothiazolidinones in which they added 4quinazolinone to enhance the medicinal value of the 4-thiazolidinone moiety and screened for antitubercular activity. Significant activity was observed in compounds 77 bearing substituents 2hydroxy-5-bromophenyl, 4-hydroxyphenyl, 2-chlorophenyl, 4-chlorophenyl, 4-methoxy phenyl, 3nitrophenyl. 73

Miscellaneous activities
Matrix metalloproteinases (MMPs) are involved in inflammatory processes and thus induce tissue damage. Thus, Incerti et al., 2018 synthesized a series of 2-(1,2-benzothiazol-3-yl)-N-(4-oxo-2-phenyl-1,3-thiazolidin-3-yl)propanamides combining a benzisothiazole and 4-thiazolidinone and evaluated for their inhibitory activity against MMP-9. 11 Compound 78, bearing a 4-carboxyphenyl substituent at C2 of the 4-thiazolidinone ring, exhibited the most promising profile, being able to inhibit MMP-9 at nanomolar level (IC50 = 40 nM). Docking studies revealed that the carboxylate group of 78 has a monodentate interaction with the Zn atom and H bonds with three of the active site residues (Gly186, Tyr423, and His401). This compound can therefore be considered as a lead compound for the development of new therapeutic agents to prevent tissue damage.

Conclusion
The ease of the synthesis of 4-thiazolidinone derivatives allows for structure-activity studies of various substitutions at different positions of this versatile chemical moiety and their application in medicinal chemistry and research as illustrated in Table 1. Further studies on this privileged scaffold are going on to explore its potential for the treatment of various diseases. This article is an endeavor to find potential future directions in the design of novel potent analogs of 4-thiazolidinone based compounds for different biological targets.