Synthesis and biological evaluations of 1,3,4-thiadiazole derivatives as dual acting enzyme inhibitors to target inflammation and diabetes

Inflammation and metabolic disorders like diabetes mellitus share complex pathways that drive disease progression, emphasizing the urgent need for multi-target therapeutics for effective management. In the present study, a series of 1,3,4-thiadiazole derivatives (14–26) bearing phenyl and benzyl substitutions at fifth position of thiadiazole core were synthesized and characterized with spectroscopic techniques like FT-IR,¹H NMR,¹³C NMR and EI-MS. The biological evaluation revealed promising inhibition of the key inflammatory enzymes (COX-2 and 5-LOX), and metabolic enzymes (α-glucosidase and α-amylase) linked to type 2 diabetes. Among the tested derivatives, compound 16 exhibited the most potent dual action, with IC₅₀ values of 8.78 μg/ml (COX-2), 4.51 μg/ml (5-LOX), 69.41 μg/ml (α-glucosidase), and 50.50 μg/ml (α-amylase), demonstrated moderated activity as compared to the standard inhibitors. Compound 26 also exhibited significant anti-inflammatory, with IC50 values of 2.03 μg/ml (COX-2), 6.03 μg/ml (5-LOX). Molecular docking studies further supported the biological findings, revealing binding interactions of these derivatives with the active sights of targeted enzymes, reinforcing their potential as lead candidates for dual acting anti-inflammatory and anti-diabetic agents. These findings suggest that 1,3,4-thiadiazole derivatives have the potential to develop as multi-functional therapeutics to target inflammation and metabolic dysregulations.