Substituted D-Galactose-Conjugated Thiazole-Thioureas Derivatives as Promising Antidiabetic Agents: Synthesis, In Vitro Inhibition, and Molecular Simulation for α-Amylase, α-Glucosidase, Protein Glycation, and Oxidative Stress.

A thiourea series (7a-l) containing 4-arylthiazoles and the d-galactose moiety were synthesized and explored for their multi-target inhibition against α-amylase from porcine pancreas and α-glucosidase from Saccharomyces cerevisiae. Among these thioureas, 7h was the most potent inhibitor for α-amylase (IC50 of 7.84 ± 0.14 μM) and 7c was the most potent inhibitor for α-glucosidase (IC50 of 7.15 ± 0.12 μM). These thioureas also exhibited anti-glycation and antioxidant activity. They were noncytotoxic for NIH-3T3 cells. Induced-fit molecular docking study was applied to the two most potential inhibitors 7c and 7h. Their active interactions with residues in the catalytic pockets of the corresponding studied enzymes, 1OSE and 3TOP, were suitable to their inhibitory potentials against each tested enzyme. The molecular dynamics simulations validated the in vitro data for these compounds whereas the pharmacokinetics profile (ADMET) revealed the druglike properties of potent inhibitors.