Design, synthesis, and in vitro evaluation of novel dipeptidyl peptidase IV inhibitors

Abstract

The current research describes the design, synthesis, and in vitro evaluate as DPPIV inhibitors for four new compounds. The design of the new compounds aimed to study the effect of replacing the 2-benzyl-piperazine ring system of a reported potent DPP IV inhibitor, IC 50 of 19 nM, with piperidine and pyrrolidine heterocyclic ring systems. The newly synthesized compounds, along with the lead compound, were studied for docking affinities and mode of interactions with the DPP active site using molecular modelling approach in an attempt to correlate between the binding parameters and the observed in vitro inhibitory activities. Compound (1), a 4-benzylpiperidine derivative, possessed a ΔG value of -8.9 Kcal/mol, and an IC 50 of 1.6 ± 0.04 µM. Compound (2), a 2-benzylpyrrolidine derivative, showed a ΔG value of -9.0 Kcal/mol, and an IC 50 of 0.3 ± 0.03 µM. Compound (3), a phenethyl-piperazine derivative, exhibited a ΔG value of -8.9 Kcal/mol, and an IC 50 of 1.2 ± 0.04 µM. Compound (4), a 4-amino-1-benzylpiperidine derivative, showed a ΔG value of -8.9 Kcal/mol, and an IC 50 of 4 ± 0.08 µM. The study revealed that compound (2), with reduced ring size into pyrrolidine in place of the lead compound piperazine ring, while retaining the benzyl substitution at the 2-position, resulted in the most active inhibitor among the four newly designed compounds; however, with less inhibitory activity in comparison to the reported 2-benzyl-piperazine