Structure-guided design of Benzodioxole-acrylamide hybrids as potent and low-toxicity α-amylase inhibitors: Integration of MicroED and molecular docking analyses
JOURNAL OF MOLECULAR STRUCTURE, cilt.1368, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 1368
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.molstruc.2026.146300
- Dergi Adı: JOURNAL OF MOLECULAR STRUCTURE
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Chimica, Compendex, INSPEC, Academic Search Ultimate (EBSCO), Engineering Source (EBSCO)
- Anahtar Kelimeler: Antidiabetic lead, Benzodioxole–acrylamide hybrids, MicroED, Molecular docking, Structure–activity relationship, α-Amylase inhibition
- Gazi Üniversitesi Adresli: Evet
Özet
The search for selective and low-toxicity alpha-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 alpha-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 alpha-amylase inhibitory potency (IC50 = 0.99 & micro;M), surpassing the reference inhibitor acarbose (IC50 = 1.53 & micro;M). 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 alpha-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 alpha-amylase inhibitor and highlight MicroED-guided structural elucidation as a promising strategy for future rational design of enzyme-targeted antidiabetic agents.