α-glucosidase inhibitors Compound 8d(Kasetsart University)

This study aimed to design and synthesize a series of 1,2,3‐triazole‐quinazolinone derivatives ( 8a – 8q ) as potential α‐glucosidase inhibitors. Our initial model compound 8a exhibited higher in vitro α‐glucosidase inhibitory activity (IC 50  = 10.16 ± 0.358 µM) compared to acarbose (IC 50  = 51.23 ± 10.21 µM). This promising result was supported by molecular docking studies, which revealed favorable binding interactions with human α‐glucosidase, with an estimated binding free energy of –6.93 kcal/mol and a predicted inhibition constant ( K ᵢ) of 8.27 µM. Based on the promising in vitro and in silico results of 8a , the other sixteen 1,2,3‐triazole‐quinazolinone derivatives ( 8b – 8q ) were subsequently synthesized. Screening identified nine compounds with over 70% inhibition, with compound 8d emerging as the most potent (IC 50 of 1.72 ± 0.046 µM). Docking studies of 8d with both Saccharomyces cerevisiae and human α‐glucosidase showed strong interactions, consistent with experimental findings. Structure‐activity relationship (SAR) analysis analysis suggested that the quinazolinone core, 1,2,3‐triazole ring, amino sulfide moiety, and a benzyl group with an ortho or meta halogen (Br or I) are crucial for optimal activity. Furthermore, 8d passed ADMET predictions, suggesting it could be a promising orally bioavailable inhibitor. These findings provide valuable insights for developing new α‐glucosidase inhibitors.