Interrogating imidazo[2,1-b]thiazole-4-thiazolidinone hybrids as antidiabetic leads: molecular cartography, pharmacokinetic profiling and rodent therapeutic response.

Abstract

Diabetes mellitus remains a major global health challenge, necessitating the development of new therapeutic agents targeting key enzymes involved in carbohydrate metabolism. In this study, ten novel imidazo-thiazole-thiazolidinone hybrids were designed, synthesized and their structural integrity was confirmed through 1H NMR and 13C NMR along with mass determination by HREI-MS. After characterization, each derivative was subjected to in-vitro evaluation using acarbose (reference) to assess their anti-diabetic potential through the inhibition of key enzymes. Compound 3 and 6 with IC50 values 3.20 ± 0.20 μM, 2.10 ± 0.30 μM for α-amylase and 3.70 ± 0.30 μM, 2.60 ± 0.20 μM for α-glucosidase acted as the excellent inhibitors, markedly affecting rate of enzymatic reactions, with kinetic studies revealing their mode of inhibition. The SAR analysis revealed key substituents enhanced ligand-enzyme affinity, supported by molecular docking showing their specific binding. Furthermore, in-vivo cytotoxic assessment in rat models was performed to examine toxicological aspects and biocompatibility of synthesized compounds. Pharmacophore modeling, DFT calculations and MD simulations were also conducted to provide mechanistic insights. Comprehensive ADMET analysis including bioavailability, toxicity prediction, oral suitability and drug-likeness together with in-vivo safety evaluation complemented the in-vitro and computational findings, demonstrating these imidazo-thiazole based thiazolidinone derivatives hold promise as effective therapeutics against diabetes mellitus.