Lactose-conjugated 2-iminothiazolidin-4-ones: synthesis, inhibitory activity and molecular simulations as potential inhibitors against enzymes responsible for type 2 diabetes

Abstract

A series of new substituted lactose-conjugated 2-iminothiazolidin-4-ones 7a–h were synthesized and scanned for their inhibitory activity against enzymes responsible for type 2 diabetes, including α-amylase, α-glucosidase, DPP-4, and PTP1B. Three lactose-conjugated 2-iminothiazolidin-4-ones 7c, 7e, and 7f exhibited the highest inhibitory activity against the selected enzymes. Compounds 7c and 7e were the strongest inhibitors for DPP-4 and α-amylase, respectively, whereas 7f exhibited strong inhibition against α-glucosidase and PTP1B. These compounds had also high anti-glycation and antioxidant activities and were not cytotoxic to the WI-38 cell line. A molecular docking study was applied to the three most potent inhibitors 7c, 7e, and 7f in inhibition against enzymes 1OSE, 3TOP, 3W2T, and 1NNY. These ligands had active interactions with the residues in the catalytic pocket of these enzymes consistent with their inhibitory efficacy against each enzyme tested. Molecular dynamics simulations were applied for four typical complexes 7e/1OSE, 7f/3TOP, 7c/3W2T, and 7f/1NNY to validate the obtained in vitro data of these compounds. The obtained results indicated that these inhibitors had stable dynamic interactions in the catalytic pocket of the respective enzymes to promote their activity. The presence of the di-imine bridge bond helped to connect the thiazolidin-4-one ring and the aromatic ring, communicating the influence of the alternative groups on the overall activity of the target molecule. Additionally, the β-lactose portion contributes to the binding of the target molecule to the residue at the active site and increases the inhibitory activity of the target compounds.