Enzyme kinetics-guided evaluation of thiazine hybrids targeting α-amylase and α-glucosidase with in vivo validation.

A series of novel thiazine-thiazolidinone hybrids was synthesized and evaluated for antidiabetic potential. In vitro α-amylase and α-glucosidase inhibition was performed using standard colorimetric assays. Compounds 6 and 8 showed the highest activity, with IC50 values of 3.10 ± 0.10 and 2.70 ± 0.20 μM against α-amylase, and 3.60 ± 0.20 and 3.10 ± 0.20 μM against α-glucosidase, respectively, outperforming acarbose. Preliminary safety assessment, including in vitro cytotoxicity and short-term in vivo evaluation in Wistar rats, indicated no significant toxicity based on hematological and biochemical parameters. Molecular docking revealed favorable binding interactions within enzyme active sites, while molecular dynamics simulations confirmed stable protein-ligand complexes. Pharmacophore modeling identified key structural features contributing to activity, and density functional theory (DFT) analysis provided insights into electronic properties and reactivity. ADMET predictions suggested acceptable pharmacokinetic profiles. Overall, compound 8 emerged as the most promising lead for further optimization as an antidiabetic agent.