Sirichai T.Uipanit S.Borwornpinyo S.Jaitham K.Nititrirongkul P.Songoen W.Kongkathip B.Pluempanupat W.Ngernmeesri P.Chuanopparat N.Mahidol University2025-10-212025-10-212025-01-01Chemistry an Asian Journal (2025)18614728https://repository.li.mahidol.ac.th/handle/123456789/112687This 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<inf>50</inf> = 10.16 ± 0.358 µM) compared to acarbose (IC<inf>50</inf> = 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 (Kᵢ) 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<inf>50</inf> 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.ChemistryBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1002/asia.703652-s2.0-1050187545741861471X