Design, synthesis, and antidiabetic evaluation of triazolopyrimidine thioacetamides as potent and selective ?-glucosidase inhibitors

Abstract

Diabetes mellitus is a global health challenge characterized by chronic hyperglycemia. alpha-Glucosidase inhibitors, like acarbose, are pivotal in managing postprandial blood glucose levels but are often associated with gastrointestinal side effects. This study aimed to rationally design and synthesize a library of 2-((6-amino-5,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)thio)-N-arylacetamide derivatives (15a-15ae) as potent and selective alpha-glucosidase inhibitors. All 31 target compounds exhibited inhibitory activity (IC50 ranging from 7.09 mu M to 245.57 mu M) under assay conditions where the reference drug, acarbose, exhibited an IC50 value of 750.67 mu M. The most potent compound, 15o (IC50 = 7.09 +/- 0.2 mu M), demonstrated approximately 106-fold higher potency than acarbose under the identical assay conditions. Kinetic analysis indicated that 15o acted as a competitive inhibitor (Ki = 6.9 mu M). Moreover, this compound did not show alpha-amylase inhibitory activity and cytotoxicity at concentration of 100 mu M, showing preliminary indications of favorable safety and selectivity. Spectroscopic studies (CD, fluorescence) and computational analyses (model performance and augmentation, docking, and MD simulations) confirmed the strong binding affinity and stabilization of compound 15o within the enzyme's active site. In vivo evaluation in a diabetic rat model demonstrated that 15o (30 mg/kg BW) significantly reduced fasting blood glucose, improved glucose tolerance in OGTT, reduced HbA1c levels to near-normal ranges, and restored hepatic and pancreatic histology, with effects better than those observed with acarbose in this model. Compound 15o also exhibited acceptable acute toxicity profiles. These findings introduced compound 15o as a promising lead candidate for further structural development of anti-diabetic agents.