Discovery of novel 1,3,5-triazine-thiazolidine-2,4-diones as dipeptidyl peptidase-4 inhibitors with antibacterial activity targeting the S1 pocket for the treatment of type 2 diabetes

A novel series of 1,3,5-triazine-thiazolidine-2,4-diones was synthesized and characterized by a number of analytical and spectroscopic techniques. The molecules were screened for the in vitro inhibition of dipeptidyl peptidase-4 and compound 7a showed the most prominent inhibition with IC 50 = 6.25 μM. The other compounds showed considerable inhibition (IC 50 = 12.11-49.21 μM). Docking studies indicated that the lipophilic thiazolidine-2,4-dione fragment of ligand 7a was oriented towards the tight lipophilic cavity of the S1 pocket of the active site formed by residues such as Tyr631, Val656, Trp659, Tyr662, Tyr666 and Val711 via the formation of H-bonds with Tyr547. One of the amines present on the wings of the triazine formed a hydrogen bond with Glu205, a vital residue for the N-terminal recognition site with an efficient CDOCKER interaction energy. In a bacterial inhibition study, the entire set of compounds showed excellent activity and, in some instances, were found to be equipotent to the cefixime used as a standard. A novel series of 1,3,5-triazine-thiazolidine-2,4-diones was synthesized and characterized by a number of analytical and spectroscopic techniques.