1,3,4-thiadiazole derivatives as antidiabetic agents: Design, synthesis, biological evaluation, and in silico studies

Abstract

The present work reports the design, synthesis, and evaluation of twelve 1,3,4-thiadiazole derivatives (9a–9l) as potential antidiabetic agents. The compounds were screened for α-amylase and α-glucosidase inhibition, with several showing moderate to strong activity. Notably, compounds 9e, 9f, and 9i exhibited the most potent effects with IC₅₀ values of 19.25 ± 0.183 μM, 18.71 ± 0.015 μM, and 18.78 ± 0.136 μM, respectively, comparable to standard inhibitors. Molecular docking studies supported the experimental findings by highlighting stabilizing hydrogen bonding and hydrophobic interactions with key catalytic residues of α-glucosidase and α-amylase. Structure–activity relationship (SAR) analysis suggested the role of halogen and alkyl substitutions in enhance potency. While the results indicate that thiadiazole scaffolds hold promise as anti-hyperglycemic leads, further optimization, ADMET profiling, and in vivo validation will be essential advance these derivatives toward therapeutic development.