Biological potential of thiazolidinedione derivatives of synthetic origin

Thiazolidinediones are sulfur containing pentacyclic compounds that are widely found throughout nature in various forms. Thiazolidinedione nucleus is present in numerous biological compounds, e.g., anti-malarial, antimicrobial, anti-mycobacterium, anticonvulsant, antiviral, anticancer, anti-inflammatory, antioxidant, anti-HIV (human immunodeficiency virus) and antitubercular agent. However, owing to the swift development of new molecules containing this nucleus, many research reports have been generated in a brief span of time. Therefore seems to be a requirement to collect recent information in order to understand the current status of the thiazolidinedione nucleus in medicinal chemistry research, focusing in particular on the numerous attempts to synthesize and investigate new structural prototypes with more effective antidiabetic, antimicrobial, antioxidant, anti-inflammatory, anticancer and antitubercular activity.


Introduction
The number of antimicrobial drugs available in the market is vast, but there is a need to discover novel antimicrobial agents with better pharmacodynamic and pharmacokinetic properties with lesser or no side effects. Most of thiazolidinediones exhibit good bactericidal activity against various Gram-positive and Gram-negative bacteria. The bactericidal activity of thiazolidinediones derivatives depends on the substitution on the heterocyclic thiazolidine ring rather than the aromatic moiety.
Thiazolidinedione (Scheme 1) along with their derivatives draw attention as they have diverse biological as well as clinical use. Researchers focus on this moiety because it is involved in the control of various physiological activities. Heterocyclic moieties having Nitrogen and Sulfur are involved in a broad range of pharmacological processes. This created interest among researchers who have synthesized variety of thiazolidinediones derivatives and screened them for their various biological activities. In the present study, we have made an attempt to collect biological properties of thiazolidinediones and its derivatives of synthetic origin.

Thiazolidinedione derivatives as antidiabetic agents
Diabetes mellitus (DM), also known as diabetes, is represented by the high blood sugar level over a period of prolonged time. There are three types of diabetes: (i) type 1 DM in which pancreas fails to produce insulin. Previously, it was referred as "insulin-dependent diabetes mellitus" or "juvenile diabetes", (ii) type-2 DM a condition in which cells does not respond to insulin. Previously, it was referred as "non insulin-dependent diabetes mellitus", (iii) gestational diabetes is the third main type and arises in pregnant women with no prior record of diabetes with high blood sugar levels [1].
The fundamental reasons of diabetes are a low production of insulin, the inability of the body to use it, or a combination of both (hormone which regulate carbohydrate, fat and protein metabolism). Normally it is a long-standing syndrome having different clinical revelation, with a number of problems such as cardiovascular, hypertension, renal, neurological. It is a disease in which pancreas does not secrete sufficient insulin or cells prevent reacting toward secreted insulin, that's why cells cannot absorb blood glucose. Its symptoms are recurrent urination, tiredness, too much dehydration and hunger. It is cured by change in food habits, by regulation of proper diet; oral prescription and few situations include insulin injection [2,3]. The thiazole moiety is a significant heterocyclic unit in drug invention. Literature survey shows that the wide-spread studies have been carried out on the production of thiazolidinediones. Thiazolidiones compounds shows a number of pharmacological activities such as antimicrobial, antitubercular, anti-tumor, anti-viral, anti-HIV, anti-inflammatory and anti-diabetic effects [4][5][6].
Datar et al. [7] synthesized a new series of thiazolidinediones by the reaction of thiazolidenedione with several benzaldehyde derivatives using Scheme 2. In vitro anti-diabetic activity of synthesized compound was performed by SLM model. In this series compounds 1 and 2 found to be most active [5-(3,4-dimethoxy)benzylidine-2,4-thiazolidinedione,5-(3,4,5 trimethoxy)benzylidine-2,4-thiazolidenedione] due to presence of methoxy group and comparable to standard drug pioglitazone studies. The results of the most active compound are indicated Tables 1 and 2 (Datar et al. [7]).
Swapna et al. [8] synthesized novel thiazolidinediones by using Scheme 3. In vitro antidiabetic activity performed by alloxan induced tail tipping method. From this series compound 3, 4, 5 showed highest activity as comparable to standard drug metformin because of presence of electron donating group. The results of most active derivatives showed in Table 3 (Swapna et al. [8]).
Badiger et al. [9] synthesized novel thiazolidinediones derived from 4-fluorophenylacetic acid and thiosemicarbazide in phosphorous oxychloride using Scheme 5    position as compared to standard drug pioglitazone. The results of synthesized compounds presented in Table 5 (Badiger et al. [9]). Patil et al. [10] synthesized a new series of thiazolidinedione derivatives derived from thiourea and chloroacetic acid in ethanol/DMF as presented in Scheme 6. The In vitro antidiabetic activity of synthesized compounds was performed by alloxan induced tail tipping method. From these series compounds 11, 12 and 13 showed better activities compared to pioglitazone and metformin as standard drug. The results of most active derivatives showed in Table 6 (Patil et al. [10]).
Srikanth et al. [11] synthesized an innovative sequence of thiazolidinediones using 4-fluoroaniline, methyl acrylate and thiourea using proper solvent as showed in Scheme 7. The In vitro antidiabetic activities of synthesized compounds were confirmed by tail vein method and ANOVA method. In this series compounds 14, 15, 16 and 17 showed significant activity as compared to standard drug rosiglitazone. The results of synthesized compounds presented in Table 7 (Srikanth et al. [11]  Nikalje et al. [12] designed few thiazolidinediones derivatives from thiazolidindione via 4-hydroxy, 3-ethoxy benzaldehyde in ethanol, benzoic acid and piperidine using Scheme 8. The In vitro antidiabetic activity of synthesized compounds was confirmed by ANOVA, alloxan induced diabetic rat model and dunnet' t test. From this series compounds 18, 19, 20, 21, and 22 showed better activity as compared to standard drug rosiglitazone. The results of synthesized compounds presented in Table 8 (Nikalje et al. [12]).
Jawale et al. [16] synthesized innovative chain of thiazolidinediones derived from maleic anhydride and thiourea was treated with water using Scheme 12. The In vitro antidiabetic activity of synthesized compounds was performed by alloxan induced tail tipping method using wister rat, dunnet' t test and SLM model. Among them compounds 37, 38, 39 and 40 found to be significant activity metformin using as standard drug. The     results of most active derivatives showed in Table 12 (Jawale et al. [16]).

Thiazolidinedione derivatives as antimicrobial agents
Long-ago, contagious diseases caused by multidrugresistant microorganisms have become a serious issue, representing a growing threat to human health and being a major problem in many countries worldwide. There has been a significant increase in clinical drug resistance over the past few decades, owing to exploitation of antimicrobial agents, thus many infectious disease can no longer be treated successfully with general anti-infective agents [17]. Modern therapies and management technique such as bone marrow or solid-organ transplants, and newer much aggressive chemotherapy have resulted in a rapidly inflating number of immune-suppressed patient. So, in order to meet above mentioned challenges, there is an urgent need for the development of novel antimicrobial agents [18].
In this study, Nawale et al. [19] synthesized a new series of 5-Substituted 2,4-thiazolidinedione derivatives (Scheme 13) and evaluated for in vitro antimicrobial showed good activity against all microorganism. The results of synthesized compounds presented in Table 15 (Moorthy et al. [5]).
Alagawadi et al. [21] designed some novel derivatives of imidazole fused with thiazolidine-2,4-dione and evaluated them for their antibacterial activity against

Thiazolidine-2,4-dione derivatives as anti-inflammatory agents
The future of anti-inflammatory compound lies in the development of orally active drugs that decreases production or activities of pro-inflammatory cytokines. Anti-inflammatory compounds are normally used for curing of different infectious conditions. Therefore, the rate of incidence of disease limits its clinical use. Thus here is requirement of designing advance drugs with improved activity and long term relieve from chronic inflammatory condition [26]. The complete knowledge and understanding of the pivotal role of inflammation in seemingly untreated diseases has resulted in development of novel anti-inflammatory agents [27].  Youssef et al. [26] synthesized some novel active pyrazolyl-2,4-thiazolidinedione derivatives (Scheme 22) followed by their in vitro anti-inflammatory evaluation. Among them, compounds 71 and 72 [(Z)-3-allyl-5-((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl(methylene) thiazolidine-2,4-dione] showed moderate to good antiinflammatory activity using celecoxib as standard and turpentine oil as control. The results of potent derivatives presented in Tables 21, 22 Table 24 (Ma et al. [28]).

Thiazolidinedione derivatives as anticancer agents
Cancer is a genetic disorder that has always been a major threat all over the world and has been characterized by proliferation of abnormal cells and exhibiting an increasing mortality rate globally and being characterized by  rapid formation of abnormal cells and spreading through metastasis to different organs [29,30]. Currently available treatment (chemotherapy and radiotherapy) for most types of cancer only provide temporary therapeutic benefits as well as being limited by a narrow therapeutic index, remarkable toxicity and acquired resistance [31]. In recent times, advance in clinical researches for anticancer agents have been increased and as neoplastic cells are the anomalous proliferation of cells in the body which cause cancer, various effective compounds derived    from natural products have been isolated and developed as anticancer agents. These chemical compounds are formulated with a view to create effective action with minimum side effects against cancer [32].
Anh et al. [34] designed a chain of novel chromony thiazolidinediones derived from knoevenagel condensation reaction between 3-formyl-7-methoxy chromone with   Kumar et al. [35] synthesized a series of novel 3-(substituted aryl)-1-phenyl-1H-pyrazolyl-2,4-thiazolidinedione derivatives using Scheme 26. These synthesized derivatives were screened for their cytotoxic activity against lung and breast cancer cell lines using standard doxil. In this series 83 and 84 showed highest cytotoxic activity against cancer cell lines. The results of potent compounds are presented in Table 27 (Kumar et al. [35]).

Thiazolidinedione derivatives as antioxidant agent
Free radicals produced in several biochemical reactions, cellular metabolism are negotiator for several infections  and diseases like atherosclerosis, tumor as well as heart disease. Free radicals are not only formed by normal cellular processes but also produced by exposure of numerous chemical substances (polycyclic aromatic hydrocarbon, cadmium, lead, etc.), radiations, cigarette, smoke, and higher obese food. Usually free radical development is stopped by beneficial compounds known as antioxidant. Antioxidants deactivate free radicals before they attack the cell. Natural antioxidants are body detoxifiers and natural cleansers. They convert toxins of body to harmless waste products. They protect body from many diseases like cancer, heart attack and absorb bad cholesterol. Synthetic antioxidants such as BHT (butylated hydroxytoluene) and BHA (butylated hydroxyanisole), are effective as a antioxidants are also present and are used in several industries but there use has been limited because they can cause cancer as well as other side effects. So there use is decreased in food, cosmetic and pharmaceutical products. Thus, in present there is need for the oxidation inhibitor compounds [18,36,37].
Hossain et al. [37] synthesized a series of novel O-prenylated and O-geranylated derivatives of 5-benzylidene2,4-thiazolidinedione by knoevengeal condensation as showed in Scheme 27 and evaluated for their antioxidant activity. Among the synthesized derivatives, compounds 85, 86, 87, 88 and 89 were found to be most active antioxidant agent. The significant results of potent compounds are given in Table 28 (Hossain et al. [37]).

Thiazolidinedione derivatives as anti-tubercular agents
In present day, treatment of tuberculosis diseases (TB) is chief and challenging problem because of resistance to present regimen and also appearance of drug-resistance strains in tuberculosis like mycobacterium tuberculosis, is transmitted by air and can affected all organ of the body, especially the lungs [38]. The association of tuberculosis with HIV infection is so dramatic that in some cases, nearly two-third of the patients diagnosed with the tuberculosis is also HIV-1 seropositive [39]. The current drug therapy for TB is long and complex, involving multidrug combinations (usually isoniazid, rifampin, ethambutol, and pyrazinamide for the initial 2 months and rifampin and isoniazid for an additional 4 months) [40]. There is also an alarming increase in cases of TB caused by multidrug-resistant strains of M. tuberculosis. Thus,   [3-tert-butyl-5-(4-methoxybenzylidene)-1,3-thiazolidine-2,4-dione] and 97 showed the maximum antitubercular activity against Mycobacterium tuberculosis H37Rv strain. The results of synthesized compounds presented in Table 30 (Chliamakuru et al. [42]). Pattan et al. [43] integrating a series of novel substituted thiazolidinediones via knoevenageal condensation reaction as presented in Scheme 30 and evaluated for their antitubercular activites by middle book 7H9 agar medium assay with streptomycin as the standard drug. Among all the synthesized derivatives, compounds 98 [(Z)-N-(3-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-2-oxopropyl)pyrazin-2-carboxamide] and 99 [(Z)-5-(4-methoxybenzylidene)-3-(2-oxo-2-(pyrazin-2-yl)ethyl)thiazolidine-2,4-dione] showed the maximum antitubercular activity against Mycobacterium tuberculosis H37Rv strain. The results of synthesized compounds presented in Table 31 (Pattan et al. [43]).

Conclusion
Appraisal of literature reports reveals that thiazolidinediones and its derivatives represent an important class of compound in the medicinal field with various therapeutic potentials, i.e., antidiabetic, antimicrobial,  anti-inflammatory, anticancer, antioxidant and antitubercular, antiviral, anti-malarial, anti-HIV and anti-convulsant activities etc. which created immense interest among researchers to synthesized variety of thiazolidinediones. This review focuses especially on synthesized active compounds of thiazolidinediones having different pharmacological activities playing an important role in the medicinal field. These most active thiazolidinediones derivatives may be taken as leads to discover novel agents with therapeutic potential in the future.
Authors' contributions PKV designed and finalized the scheme; SA performed review work and ST wrote the paper. All authors read and approved the final manuscript.