Design, synthesis and biological evaluation of thiazole- and indole-based derivatives for the treatment of type II diabetes

Present studies have shown that the lipid carrier has a significant role in several aspects of metabolic syndrome in A-FABP/ap2-deficient mice, including type 2 diabetes and atherosclerosis. 38 Thiazole- and indole-based derivatives were synthesized and investigated for their inhibitory effects on the production of LPS-stimulated TNF-α. Among them, 12b exhibited an excellent inhibitory efficiency compared to BMS309403 (95% vs. 85%) at the concentration of 10 μM and a binding affinity for ap2 with the apparent Ki values 33 nM. Oral administration of 12b at a dosage of 50 mg/kg effectively reduced the levels of plasma blood glucose, triglycerides, insulin, total cholesterol and alanine aminotransferase in high-fat/diet-induced obesity model. The results highlighted that 12b was a potent anti-diabetic agent.

The docking 12b to the protein of ap2 showed that it specifically binds to endogenous fatty acids include Tyr 19 and Arg 78.Figure optionsDownload as PowerPoint slideHighlights
► Sixteen Thiazole-based derivatives and twenty-two indole-based derivatives were designed and synthesized.
► All synthesized compounds were evaluated for their ability to inhibit the production of LPS-induced TNF-α.
► The most active compound 12b was docked to the protein of ap2 and for further in vivo studies in DIO rats.