Abstract
AIMS: This study aimed to design, synthesize, and evaluate a novel series of pyridine-linked thiazolidinone analogues (1-15) as dual inhibitors of thymidine phosphorylase and α-glucosidase, with potential therapeutic applications in diabetes mellitus and cancer-related angiogenesis. MATERIALS & METHODS: The compounds were synthesized through a multistep reaction pathway and characterized by spectroscopic techniques. Their inhibitory activities were assessed against α-glucosidase and thymidine phosphorylase using in vitro enzyme assays. Molecular docking studies were performed to elucidate binding interactions, while ADMET analysis predicted pharmacokinetic properties. Enzyme kinetics studies were conducted to determine the mode of inhibition. RESULTS: The synthesized analogues displayed strong inhibitory activity, with IC₅₀ values ranging from 2.10 ± 0.20 to 19.10 ± 0.20 µM against α-glucosidase and 3.10 ± 0.20 to 19.80 ± 0.10 µM against thymidine phosphorylase. Several compounds demonstrated superior potency compared to standard drugs, including compound 2 (IC₅₀ = 2.10 ± 0.20 µM for α-glucosidase; 3.10 ± 0.20 µM for thymidine phosphorylase). Docking and ADMET analyses confirmed favorable drug-like properties, while kinetic studies revealed competitive inhibition at low concentrations. CONCLUSIONS: The pyridine-linked thiazolidinone analogues represent promising dual inhibitors with potential as therapeutic leads for diabetes mellitus and thymidine phosphorylase-associated disorders.