Synthesis of pyridin-3-yl-1,3,4-oxadiazole and 5-p-tolyl-1,3,4-oxadiazole derivatives and their evaluation as antihyperglycemic agents, AChE and BuChE inhibitors, and antioxidants

Abstract

Thirty oxadiazole derivatives 1–30 were synthesized via nucleophilic substitution reactions between 1,3,4-oxadiazole-2-thiol and benzyl/phenacyl halides. The structural elucidation of compounds was done by EI-MS, HREI-MS, ^1HNMR , and ^13CNMR . The compounds were divided into three categories based on their substitution patterns. Among thirty synthetic compounds, four compounds, 13, 14, 15, and 19, were found to be new. The inhibitory activities of compounds were evaluated against α-amylase, α-glucosidase, AChE, and BuChE in vitro. Compound 8 (IC₅₀ = 20.71 ± 0.16; 19.04 ± 0.52 µM), possessing a 2-chloro-4-fluoro benzyl ring, demonstrated the highest antihyperglycemic activity among these oxadiazoles. Despite showing slightly lower activity than the standard acarbose (IC₅₀ = 13.19 ± 0.26; 16.28 ± 0.24 µM), it can be a potential candidate for further exploration as an antihyperglycemic agent. Compound 16 (IC₅₀ = 7.33 ± 0.02; 9.5 ± 0.16 µM) containing an unsubstituted phenacyl group demonstrated the highest inhibitory potential against AChE and BChE enzymes as compared to the standard donepezil with IC₅₀ values of 2.05 ± 0.12 µM and 4.02 ± 0.06 µM. Molecular docking analysis revealed favorable interactions, including hydrogen bonding, hydrophobic, and π-π stacking interactions between the compounds and the target proteins. Additionally, the antioxidant potential of the compounds was assessed using DPPH and ABTS radical scavenging assays, and compounds revealed significant activities. The study provides valuable insights into the structure-activity relationship of these compounds, which could guide future drug design efforts for more potent enzyme inhibitors.