The search for selective and low-toxicity α-amylase inhibitors remains a key challenge in developing safer antidiabetic therapeutics. In this study, a new series of benzodioxole–acrylamide hybrids were designed and synthesized through a structure-guided approach aimed at enhancing α-amylase inhibition and metabolic safety. The synthesized derivatives were comprehensively characterized HRMS, and multinuclear NMR (¹H, ¹³C, HETCOR) spectroscopy, and their molecular structures were further resolved at atomic resolution using Microcrystal Electron Diffraction (MicroED). Among the tested compounds, the N-4-(2-thienyl)phenyl-bearing analog IHBY56 demonstrated the highest α-amylase inhibitory potency (IC₅₀ = 0.99 µM), surpassing the reference inhibitor acarbose (IC₅₀ = 1.53 µM). Importantly, IHBY56 displayed negligible cytotoxicity across six cancer cell lines (HeLa, MCF-7, HepG2, Hep3B, B16F1, and CaCo-2) and two normal cell lines (LX-2 and HEK-293T), supporting its favorable therapeutic window. Molecular docking simulations using AutoDock Vina and UCSF Chimera revealed that IHBY56 exhibited a strong binding affinity (−8.20 kcal mol⁻¹) toward α-amylase, engaging in key hydrogen bonds with THR163 and GLN63, and forming hydrophobic contacts with VAL107 and ALA106. The integration of MicroED structural analysis and in-silico docking provided complementary insights into the conformational stability and binding behavior of the benzodioxole–acrylamide scaffold, establishing a clear structure–activity relationship. Collectively, these findings identify IHBY56 as a potent and safe α-amylase inhibitor and highlight MicroED-guided structural elucidation as a promising strategy for future rational design of enzyme-targeted antidiabetic agents.

العنوان

Journal of Molecular Structure

الناشر

Elsevier

بلد الناشر

هولندا

Indexing

Thomson Reuters

معامل التأثير

4,7

نوع المنشور

مطبوع فقط

المجلد

146300

السنة

2026

الصفحات

1-20