Synthesis and Biological Evaluation of Imidazo-Thiadiazole-Linked Benzisoxazole Hybrids as Dual <i>α</i>-Glucosidase and <i>α</i>-Amylase Inhibitors With Antioxidant Potential
CHEMISTRYSELECT, cilt.11, sa.35, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 11 Sayı: 35
- Basım Tarihi: 2026
- Doi Numarası: 10.1002/slct.74449
- Dergi Adı: CHEMISTRYSELECT
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Academic Search Ultimate (EBSCO)
- Recep Tayyip Erdoğan Üniversitesi Adresli: Evet
Özet
Type 2 diabetes mellitus (T2DM) remains a major global health challenge, necessitating the discovery of novel therapeutics with improved safety and efficacy. In this study, a series of imidazo-thiadiazole-linked benzisoxazoles (1-20) was synthesized and evaluated for dual inhibitory activity against alpha-glucosidase and alpha-amylase enzymes. Most compounds showed potent enzyme inhibition, with compounds 3 and 4 exhibiting superior activity against alpha-glucosidase and alpha-amylase (IC50 = 1.56 and 3.01 & micro;M for compound 3; IC50 = 3.24 and 5.82 & micro;M for compound 4) compared to the standard drug acarbose (IC50 = 14.85 and 15.25 & micro;M). Enzyme kinetic studies revealed both competitive and uncompetitive modes of inhibition. Structure-activity relationship (SAR) analysis highlighted that para-substituted electron-withdrawing groups significantly enhanced inhibitory potential. Antioxidant activity was assessed using cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays, with compound 2 displaying the strongest effect. Molecular docking supported the in vitro results, revealing favorable interactions with key catalytic residues of target enzymes. ADME/T profiling confirmed desirable pharmacokinetic properties and drug-likeness. Overall, these findings suggest that the synthesized hybrids represent promising multifunctional candidates for T2DM therapy, combining potent enzyme inhibition, antioxidant activity, and favorable drug-like profiles.