An overview on medicinal perspective of thiazolidine-2,4-dione: A remarkable scaffold in the treatment of type 2 diabetes

Abstract

Diabetes or diabetes mellitus is a complex or polygenic disorder, which is characterized by increased levels of glucose (hyperglycemia) and deficiency in insulin secretion or resistance to insulin over an elongated period in the liver and peripheral tissues. Thiazolidine-2,4-dione (TZD) is a privileged scaffold and an outstanding heterocyclic moiety in the field of drug discovery, which provides various opportunities in exploring this moiety as an antidiabetic agent. In the past few years, various novel synthetic approaches had been undertaken to synthesize different derivatives to explore them as more potent antidiabetic agents with devoid of side effects (i.e., edema, weight gain, and bladder cancer) of clinically used TZD (pioglitazone and rosiglitazone). In this review, an effort has been made to summarize the up to date research work of various synthetic strategies for TZD derivatives as well as their biological significance and clinical studies of TZDs in combination with other category as antidiabetic agents. This review also highlights the structure-activity relationships and the molecular docking studies to convey the interaction of various synthesized novel derivatives with its receptor site.

Keywords: ADDP, 1,1′-(Azodicarbonyl)dipiperidine; AF, activation factor; ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; Boc, Butyloxycarbonyl; DBD, DNA-binding domain; DCM, dichloromethane; DM, diabetes mellitus; DMF, dimethylformamide; DMSO, dimethyl sulfoxide; DNA, deoxyribonucleic acid; Diabetes; E, Entgegen; ECG, electrocardiogram; FDA, food and drug administration; FFA, free fatty acid; GAL4, Galactose transporter type; GLUT4, glucose transporter type 4; GPT, glutamic pyruvic transaminase; HCl, Hydrochloric Acid; HDL, high-density lipoprotein; HEK, human embryonic kidney; HEp-2, Human epithelial type 2; HFD, high-fat diet; IDF, international diabetes federation; IL-β, interlukin-beta; INS-1, insulin-secreting cells; K2CO3, Potassium carbonate; KOH, potassium hydroxide; LBD, ligand-binding domain; LDL, low-density lipoprotein; MDA, malondialdehyde; NA, nicotinamide; NBS, N-bromosuccinimide; NFκB, nuclear factor kappa-B; NO, nitric oxide; NaH, Sodium Hydride; OGTT, oral glucose tolerance test; PDB, protein data bank; PPAR, peroxisome-proliferator activated receptor; PPAR-γ; PPRE, peroxisome proliferator response element; PTP1B, protein-tyrosine phosphatase 1B; Pd, Palladium; Pioglitazone; QSAR, quantitative structure-activity relationship; RXR, retinoid X receptor; Rosiglitazone; SAR, structure-activity relationship; STZ, streptozotocin; T2DM, type 2 diabetes mellitus; TFA, trifluoroacetic acid; TFAA, trifluoroacetic anhydride; TG, triglycerides; THF, tetrahydrofuran; TNF-α, tumor necrosis factor-alpha; TZD, thiazolidine-2,4-dione; Thiazolidine-2,4-diones; WAT, white adipose tissue; Z, Zusammen; i.m, Intramuscular; mCPBA, meta-chloroperoxybenzoic acid.

Graphical abstract

Fig. 1

The history of TZDs (modified and).

Fig. 2

Chemical structures of clinically used thiazolidine-2, 4-dione compounds (structures are original and made by using chem draw ultra 12.0).

Fig. 3A

General structure of PPAR (modified and).

Fig. 3B

Mechanistic action of TZDs (modified and).

Fig. 4

Various targets of TZDs on PAAR-γ (modified and).

Fig. 5A

SAR of ethoxy benzyl based TZD analogs (structures are original and made by using chem draw ultra 12.0).

Fig. 5B

SAR of pyrazole based TZD analogs (structures are original and made by using chem draw ultra 12.0).

Fig. 6A

SAR of N-substituted TZD analogs (structures are original and made by using chem draw ultra 12.0).

Fig. 6B

SAR of flavonyl based TZD analogs (structures are original and made by using chem draw ultra 12.0).

Fig. 6C

SAR of sulfonyl based TZD analogs (structures are original and made by using chem draw ultra 12.0).

Fig. 7A

SAR of naphthyl based TZD analogs (structures are original and made by using chem draw ultra 12.0).

Fig. 7B

SAR of phenothiazine based TZD analogs (structures are original and made by using chem draw ultra 12.0).

Fig. 8A

SAR of amide-based analogs substituted at N-position of TZD (structures are original and made by using chem draw ultra 12.0).

Fig. 8B

SAR of amide-based analogs substituted at 5th position of TZD (structures are original and made by using chem draw ultra 12.0).

Fig. 9A

SAR of imidazo-thiadiazole based TZD analogs (structures are original and made by using chem draw ultra 12.0).

Fig. 9B

SAR of dispiropyrrolidines based TZD analogs (structures are original and made by using chem draw ultra 12.0).

Fig. 10A

SAR of acid-based TZD analogs (structures are original and made by using chem draw ultra 12.0).

Fig. 10B

SAR of benzylidene based TZD analogs (structures are original and made by using chem draw ultra 12.0).

Fig. 11A

SAR of benzofused TZD analogs (structures are original and made by using chem draw ultra 12.0).

Fig. 11B

SAR of chromones based TZD analogs (structures are original and made by using chem draw ultra 12.0).