Synthesis, Computational Chemical Study, Molecular Docking, Dynamics Simulations, and Anti-Diabetic Potential of the Perfluorophenyl Acetamide Derivative

Abstract—: The aim of this study is to demonstrate the further synthetic capabilities of the reaction of N‑substituted phenylhydrazones with haloalkanes under modified catalytic olefination conditions. Studies of molecular geometry, electronic properties and intramolecular interactions of (Z)-N,N-dimethyl-2-(perfluorophenyl)-2-(2-phenylhydrazinylidene) acetamide (PFPA), which determine its stability, are presented. The structural and energy parameters, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies, energy gap (∆E), molecular electrostatic potential (MEP), atomic charges, dipole moment, chemical reactivity descriptors, and NBO analysis were investigated using DFT at the B3LYP/6-31+G(d,p) level. The effects of hydrogen bonding on the geometry of molecule were observed. It was found the hydrazone and acetamide groups via the N30H37⋅⋅⋅N28 and N30H3⋅⋅⋅O31 hydrogen bonds form two pseudo-six-membered rings that look like a half chair. Molecular docking and dynamics studies of the title molecule to 5-HT1BR specific receptor were performed to understand the mechanism of its action nature. The received results indicate this acetamide behaves as a competitive inverse agonist of 5-HT1B subtype receptor. The pharmacophore model of PFPA for interaction with 5-HT1BR was proposed. Additionally, the effect of the compound on α-glycosidase enzyme was examined and IC50 and Ki values were calculated.