Recent Pharmacological Developments on Rhodanines and 2,4-Thiazolidinediones

Thiazolidines are five-member heterocyclic having sulfur, nitrogen, and oxygen atoms in their ring structure and exhibiting potent as well as wide range of pharmacological activities. In this minireview, recent updates on synthesis and pharmacological evaluations of molecules based on 2,4-thiazolidine and rhodanine are discussed.


Introduction
Five-membered heterocyclic molecules containing thiazole nucleus with carbonyl group on fourth carbon such as rhodanine and 2,4-thiazolidinedione derivatives have broad spectrum of pharmacological activities. In past two decades, rhodanines and 2,4-thiazolidinediones have emerged as potent antidiabetic agents. Some of them are clinically used such as ciglitazone, englitazone, pioglitazone, glitazones, epalrestat, and troglitazone for the treatment of type 2 diabetes mellitus and related complications. This is the reason why investigation/molecular modification and pharmacological evaluation of these molecules have attracted special attention of synthetic chemists and pharmacologists, respectively. In recent years, a number of synthetic/pharmacological protocols based on these molecules have been emerged extensively and in witness available in the literature. These multifaceted molecules exhibit varied type of biological activities. Some recent developments in synthesis and pharmacology of these molecules are discussed in this section.
Trypanocidal activity of substituted rhodanine-3-acetic acids has been reported recently [26]. The only rhodanine acetic acid derivative that has been used clinically is the aldose reductase inhibitor epalrestat 4. It was marketed in Japan and used to slow eye damage associated with diabetes and to prevent diabetic peripheral neuropathy [1,22,[27][28][29]. Aldose reductase is not the only enzyme inhibited by rhodanine carboxylic acids. It was found that many other enzymes are also inhibited by the derivatives of this structural class and may be responsible for their various biological effects [30]. Other rhodanine-based molecules have also been popular as small molecule inhibitors of numerous targets such as hepatitis C viral (HCV) NS3 protease [31], antidiabetic mechanism [32], aldose reductase [33], -lactamase [34,35], histidine decarboxylase [36], and JNK Stimulatory Phosphatase-1 (JSP-1) [37]. This section is a brief account on synthesis and biological effects and recent developments of newly prepared potential drugs based on nitrogen-sulphur containing heterocycles having rhodanine nucleus.

Rhodanine as Antiapoptotic Agent.
Xing and his coworker synthesized, a series of BH3I-1 based dimeric modulators of 6. The overexpression of antiapoptotic Bcl-2 proteins which protects cells from apoptosis is one mechanism for tumours to acquire drug resistance. In this study they found dimeric modulators 7-8 have enhanced binding activity against antiapoptotic Bcl-2 proteins and proved dimerization of monomeric modulators is one practical approach to enhance the bioactivity of Bcl-2 antagonists [39]. Moorthy and his group [40] designed and synthesized 5-isopropylidiene derivatives of 5-benzilidene-3-ethyl rhodanine (BTR-1) 9, 3-dimethyl-2-thio-hydantoin (ITH-1) 10, and 3-ethyl-2-thio-2,4-oxazolidinedione (ITO-1) 11 and tested their chemotherapeutic properties. They found all the compounds induced cytotoxicity in a time-and concentrationdependent manner on leukemic cell line, CEM. Among these compounds, BTR-1 9 was found to be manifold more potent in inducing cytotoxicity than ITH-1 10 and ITO-1 11 with an IC50 value of <10 M and affected cell division by inducing a block at S phase, which finally led to the activation of apoptosis.
The same research group reported [41] the synthesis of 5-isopropylidene-3-ethyl rhodanine 12 by conventional and microwave-assisted method, and they found that rhodanine ITR 12 treatment led to cytotoxicity in leukemic cell line, CEM, by inducing apoptosis.  [42] thiazolo [4,5-dlpyrimidines with rhodanines and investigated the obtained products (7 compounds with 60-80% yields) 13 for antimicrobial screening and they found antifungal activity against Aspergillus niger and Penicillium sp. with IZ 20-38 mm and MIC <50-<25 g/mL. They claimed compound 14 is the most active against Aspergillus niger while compound 15 is the most active against Penicillium sp.; and 5-fold less active than the standard antibiotic clotrimazole. They concluded that the presence of an alkyl group at position 3 of the thiazolopyrimidine ring 14 is superior to that of other aromatic substituents; also the introduction of an arylideneamino group at position 6 of 15 enhanced the antifungal activity.  Opperman and his group disclosed [43] that aryl rhodanines 16-19 did not exhibit antibacterial activity against any of the bacterial strains tested and are not cytotoxic against HeLa cells. Their study revealed that the aryl rhodanines 16-19 specifically inhibit the early stages of biofilm development by preventing attachment of the bacteria (specifically inhibit biofilm formation of S. aureus, S. epidermidis, Enterococcus faecalis, E. faecium, and E. gallinarum but not the Gramnegative species Pseudomonas aeruginosa or Escherichia coli.) to surfaces.

HOOC
Chen and his group synthesized [46] several hybrid compounds (19 compounds with 31-58% yields) 25 having International Journal of Medicinal Chemistry 5 chalcone and rhodanine-3-acetic acid units and tested these compounds for their antibacterial activity. They found some compounds presented great antimicrobial activities against Gram-positive bacteria (including the multidrug-resistant clinical isolates) as active as the standard drug (norfloxacin) and less active than oxacillin.

Pharmacological Developments in 2,4-Thiazolidinediones
The most commonly used antidiabetic agents have been sulfonylureas, metformin, and certain alphaglucosidase inhibitors and meglitinides. These agents increase insulin secretion from pancreatic -cells but sometimes induce severe hypoglycemia and weight gain [56], and hyperinsulinemia is known to be a risk factor for ischemic heart disease [57]. In addition, high rates of both primary and secondary failure have been observed with these drugs [58][59][60][61]. Therefore, drugs that ameliorate the insulin resistance without stimulating insulin release from -cells have been developed for the treatment of type 2 diabetes. Type 2 diabetes is a multifactorial disease defined by a high plasma glucose level and is characterized by both insulin resistance and impaired insulin secretion by pancreatic -cells [62]. The prototypical 2,4-thiazolidinedione, ciglitazone 47 was discovered [63] by Takeda Chemical Industries, Ltd., Japan, and has antihyperglycemic activity in insulin-resistant animal models, KKAy mice [64], and Wistar fatty rats [65] but no effect in insulin-deficient animal models of diabetes [66,67]. During structure-activity relationship studies on 2,4-thiazolidinediones and related compounds, they discovered highly potent compounds, such as pioglitazone 48 [68] and AD-5061 49 [69]. Since the discovery of ciglitazone 47, a number of pharmaceutical companies have been evaluating new 2,4-thiazolidinedione analogs as agents for improving insulin resistance. Troglitazone 50 [70] was launched first in the market but had been withdrawn because of liver toxicity and related deaths associated with the drug. Nowadays, two 2,4-thiazolidinedione class agents, pioglitazone 48 and rosiglitazone 51 [71], have been clinically used. Furthermore, many companies are still endeavoring to find a new glucose-lowering agent [72][73][74][75][76][77][78][79][80][81][82][83][84]. Although the precise mechanism of action of these drugs remains unknown, a recent study suggests that antidiabetic thiazolidinediones interact with a family of nuclear receptors known as peroxisome proliferator-activated receptor (PPAR)- [85]. PPAR is one of a subfamily of PPARs encoded by independent genes. Three human PPARs, designated PPAR , PPAR , and PPAR , have been identified to date [86][87][88]. It was also observed that the potency for the activation of PPAR in vitro mirrored the in vivo glucose-lowering activity in diabetic ob/ob mice [89]. This would indicate that the major mechanisms of action of 2,4-thiazolidinediones involve PPAR . In case of those 2,4thiazolidinediones already on the market, several side effects, such as anaemia, edema, and body weight gain, have been reported [90]. Therefore, search for new compounds with fewer side effects and a more advanced profile than existing drug molecules is the main focus of attention for chemists as well as for pharmacologists. Recent developments in the synthesis and evaluations of thiazolidinedione-based compounds for a variety of biological activities along with antidiabetes is discussed in the ongoing pages.

Thiazolidinedione as Antidiabetic Agent. Rakowitz et al.
synthesised [91] and tested several 5-benzyl-2,4-thiazolidinediones 52-53 as in vitro aldose reductase inhibitors (ARIs). Their evaluation shows N-unsubstituted 5-benzyl-2,4-thiazolidinediones 52 and (5-benzyl-2,4-dioxothiazolidin-3-yl)acetic acids 53 displayed moderate-to-high inhibitory activity levels. The insertion of an acetic chain on N-3 significantly enhanced AR inhibitory potency, leading to acids 53 which proved to be the most effective among the tested compounds. In addition, in N-unsubstituted derivatives 52 the presence of an additional aromatic ring on the 5-benzyl moiety was generally beneficial. Madhavan et al. synthesized [92] and evaluated 2,4thiazolidinedione derivatives of 1,3-benzoxazinone for their PPAR-and -dual activation. They obtained that a compound DRF-2519 (54), through SAR of TZD derivatives of benzoxazinone, has shown potent dual PPAR activation. In ob/ob mice, it showed better efficacy than the comparator molecules. In fat fed rat model, it showed significant improvement in lipid parameters, which was better than fibrates.

Thiazolidinedione as Anti-Inflammatory Agent.
Barros et al. synthesized [96] 5-arylidene-3-benzyl-thiazolidine-2,4-diones 61 with halide groups on their benzyl rings (8 compounds) and assayed in vivo to investigate their anti-inflammatory activities, and 3-(2-bromo-benzyl)-5-(4methanesulfonyl-benzylidene)-thiazolidine-2,4-dione, compound 62, showed higher anti-inflammatory activity than the rosiglitazone reference drug as it bound PPAR with 200-fold lower affinity than the reference ligand.  [99] multisubstituted benzylidenethiazolidine-2,4-diones 68 by Knoevenagel condensation of di-or trisubstituted 4-hydroxybenzaldehydes with thiazolidine-2,4-dione and evaluated the antioxidant activities of Cu 2+ -induced oxidation of human low-density lipoproteins (LDLs). Among compounds, 69 was found to be superior to probucol in LDLantioxidant activities and found to be 9-fold more active than probucol. Hossain and Bhattacharya synthesized [100] a series of 5-arylidene-2,4-thiazolidinediones and its geranyloxy or prenyloxy derivative and studied their radical scavenging activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. They expressed comparable scavenging activities as IC50 value. Compounds 70-72 showed appreciable radical scavenging activities. The vanillin-based thiazolidinedione compound 70 displayed the highest activity comparable to that of -tocopherol. But in vivo, compound 72 showed better results in inducing phase II detoxifying/antioxidative enzyme. The compounds 70-72 found to be effective in enhancing the host antioxidant defence system such as superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), and reduced Glutathione (GSH) and at the same time lowering the serum ALT and AST level at the preliminary screening dose of 3 mg/kg in normal Swiss albino mice given orally for 20 days as compared to the control animals. The hepatic lipidperoxidation level (LPO) remained unchanged. 3.5. Thiazolidinedione as Antiobesity. Hu et al. disclosed [102] synthesis of methylsulfonamide-substituted 2,4-thiazolidinedione (6 compounds) 75 and found 76 to be a potent (EC50 = 0.01 mM, IA = 1.19) and selective (more than 110-fold over 1 and 2 agonist activity) 3 agonist. This compound has also been proven to be active and selective in an in vivo mode.  [103] benzylidene-2,4-thiazolidinedione derivatives (9 compounds) with substitutions on the phenyl ring at the ortho or para positions of the thiazolidinedione group 77 as protein tyrosine phosphatase (PTP1B) inhibitors with IC50 values in a low-micromolar range. Compound 78, the lowest, bores an IC50 of 5.0 M. In vivo efficacy of 78 as an antiobesity and hypoglycemic agent evaluated in a mouse model system. This compound also significantly suppressed weight gain and significantly improved blood parameters such as TG, total cholesterol, and NEFA. Compound 78 also was found to activate peroxisome proliferator-activated receptors (PPARs) indicating multiple mechanisms of action. Same research group [104] synthesized benzylidene-2,4thiazolidinedione derivatives (12 compounds) 79 as PTP1B inhibitors with IC50 values in a low-micromolar range. Compound 80, the lowest, bores an IC50 of 1.3 M. In a peroxisome proliferator-activated receptor-(PPAR-) promoter reporter gene assay, 80 was found to activate the transcription of the reporter gene with potencies comparable to those of troglitazone, rosiglitazone, and pioglitazone. In vivo efficacy of 80 as an antiobesity and hypoglycemic agent was evaluated in a mouse model system. Compound 80 significantly suppressed weight gain and significantly improved blood parameters such as TG, total cholesterol, and NEFA without overt toxic effects.

Conclusion
In recent past, a variety of molecules based on rhodanine and thiazolidinedione have been synthesized and evaluated with improved pharmacological activities. Due to wide range of pharmacological activities and clinically used 2,4thiazolidines, these molecules have attracted much attention and encouraged the chemists and biologists to be extensive investigations or molecular manipulations, and as a result further improved protocol with better observation is still under progress.