Synthesis, SAR, and computational evaluation of novel thiazolidinone-based antidiabetic hybrids: insights from enzyme...

This study aims to design and synthesize novel benzothiazole based thiazolidinone derivatives as potential inhibitors of carbohydrate-hydrolyzing enzymes, addressing the urgent need for effective therapeutic agents to manage type 2 diabetes mellitus through enzymatic regulation. All the novel benzothiazole based thiazolidinone derivatives were investigated against α-amylase and α-glucosidase with significant potential for treating a common metabolic problem, diabetes mellitus. The synthesis of these derivatives was confirmed using ¹HNMR, ¹³CNMR, and HREI-MS. Biological assessment was carried out by comparing the new analogs with acarbose (IC₅₀ = 5.40 ± 0.30 µM for α-amylase and 5.70 ± 0.50 µM for α-glucosidase). The synthesized analogs exhibited a range of inhibitory activities with IC₅₀ values for α-amylase ranging from 19.30 ± 0.20 µM to 3.60 ± 0.10 µM and for α-glucosidase ranged from 20.60 ± 0.40 to 4.40 ± 0.20 µM. Notably, compound 9 with a trifluoromethyl group showed significant binding interaction, contributing to its high potency. Molecular docking studies provided insights into the binding interactions of all the potent analogs, while density functional theory (DFT) calculations explored the stability and reactivity of the active compounds. Additionally, ADMET analysis was conducted for examining drug-likeness of the potent compounds.