Synthesis and α‐Glucosidase Inhibitory Potential of 1,3,4‐Oxadiazoles: SAR Studies, Molecular Docking, and DFT Analysis

作者：Hammad Khan, Faheem Jan, Ali Raza Ayub, Abdul Shakoor, Ajmal Khan, Ahmed Al‐Harrasi, Momin Khan, Shaukat Ali · 发表于：ChemistrySelect · 年份：2025 · DOI：10.1002/slct.202503551 · 被引用次数：2 · 研究领域：Natural Antidiabetic Agents Studies、Synthesis and biological activity、Nonlinear Optical Materials Research

Abstract A series of 1,3,4‐oxadiazole derivatives (1e‐10e) was successfully synthesized starting from 3,4‐dihydroxyphenylacetic acid. The synthesized compounds demonstrated significant α‐glucosidase inhibitory potential, with IC 50 values ranging from 18.16 ± 0.48 µM to 46.11 ± 2.37 µM, superior than standard acarbose (IC 50 = 873.34 ± 1.67 µM). Notably, compounds 2e (IC 50 = 18.16 ± 0.48 µM), 3e (IC 50 = 18.60 ± 0.97 µM), and 6e (IC 50 = 19.38 ± 0.74 µM) were identified as the most potent inhibitors. Molecular docking studies revealed strong binding affinities for most active compounds, ranging from −8.9 to −9.3 kcal/mol within the active site of α‐glucosidase. A strong correlation between inhibitory potency and binding affinity was observed, exemplified by compound 3e , which displayed the highest binding score (−9.3 kcal/mol) and one of the lowest IC 50 values. To evaluate structural stability, density functional theory (DFT) calculations were performed at the B3LYP/6–311++G(d,p) level. Intramolecular interactions were analyzed using reduced density gradient (RDG) and DFT‐D3 methods. Additionally, the electronic properties and chemical behavior of the compounds were investigated using time‐dependent density functional theory (TD‐DFT) at the CAM‐B3LYP/6–311++G(d,p) level. Significantly, our study provided detailed insights into charge delocalization, orbital contributions, and efficient donor–acceptor interactions, supporting the electronic rationale.