Experimental and theoretical studies of methyl 1-(2-chloroacetyl)-4-hydroxy-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate: Insights from synthesis, spectroscopic, crystal structure, Hirshfeld surface, DFT, ELF, RDG, IRI, ADMET and docking studies

Abstract

Methyl 1-(2-chloroacetyl)-4‑hydroxy-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate (compound 2) was synthesized by the condensation of 3-carboxymethyl-2,6-diphenylpiperidine-4-one with chloroacetylchloride, and characterized by FT-IR spectroscopy. Further confirmation of the molecular structure was obtained by the single crystal X-ray diffraction (SC-XRD) technique. The study revealed that the piperidine ring adopts boat conformation with equatorial orientation of two phenyl rings at C-2 and C-6. Intermolecular contacts and hydrogen bonding interactions were explored by Hirshfeld surface and 2D fingerprint analyses, showing that the major contact were H∙∙∙H (57.7 %), C∙∙∙H/H∙∙∙C (14.2 %), O∙∙∙H/H∙∙∙O (15.3), Cl∙∙∙H/H∙∙∙Cl (7.1 %) and C∙∙∙Cl/Cl∙∙∙C (12.7 %). Intramolecular interaction was examined through the Radiant density gradient (RDG), Interaction region indicator (IRI), Electron localization function (ELF), and localized orbital locator (LOL) to understand hyperconjugration and π-electrons delocalization in the molecule. DFT studies such as structure optimization, HOMO-LUMO orbital analysis and molecular electrostatic potential were conducted for the title compound. The topology of the molecular arrangement and intermolecular interaction energies were determined through 3D energy framework analysis. Subsequently, the compound 2 was subjected to ADMET analysis to extend its scope of bioavailability. Molecular docking studies were then employed using the tyrosine kinase inhibitor, epidermal growth factor receptor (EGFR) enzymes (PDB ID: 4WKQ and 6JOL). The study revealed significant interactions between the title ligand structure and active sites of selected proteins complex.