Biological evaluation of some novel 1,3-bis substituted-2-isopropylamidines by in silico molecular dynamics and simulation studies

Abstract

A tandem one-pot synthesis of some novel 1,3-bis substituted-2-isopropylamidines is reported. The conversion involves the base-mediated tandem acylation of benzylamines with isobutyryl chloride in DCM, and the subsequent amidation of the amide intermediate generated in situ in POCl₃ in a nitrogen atmosphere. In-silico ADME and drug-likeness prediction showed good pharmacokinetic properties. Molecular docking was performed to assess the binding affinities of the purified 1,3-bis substituted-2-isopropylamidines with a wide range of protein targets of pathological significance. Among the synthesized molecules, compound 5b showed the highest binding affinity (−10.5 kcal mol⁻¹) with the cdk2 receptor, an important cancer progression receptor. The best pose of the 5b-cdk2 complex was further used in simulation studies of the molecular dynamics. The stability of the protein–ligand complex was theoretically assessed in the simulations of the molecular dynamics using RMSD, RMSF, and analysis of hydrogen bonds.