A combined experimental and theoretical analysis of the solid-state supramolecular self-assembly of N-(2,4-dichlorophenyl)-1-naphthamide: Synthesis, anticholinesterase potential and molecular docking analysis

Abstract In the present report, we describe the synthesis of the amide derivative, N -(2,4-dichlorophenyl)-1-naphthamide, 3 , via a facile chemical route. The title compound was isolated in 86% yield. The structure of compound 3 was established using spectroscopic methods and X-ray crystallography. In the crystal structure of 3 , supramolecular assembly is dominated by classical N–H⋯O hydrogen bonding and C–Cl … π halogen bonding interactions which were examined in detail using several theoretical methods and DFT calculations. The optimized geometric parameters of compound 3 were calculated using density functional theory (DFT/B3LYP and DFT/M06-2X) quantum chemical methods with the 6-311++G(d,p) basis set using the crystallographic coordinates. Additionally, fragments contributing to the HOMO and LUMO molecular orbitals were investigated at the same level of theory. The nature and various types of intermolecular interactions in the crystal structure were also realized by Hirshfeld surface analysis. The biological properties such as anti-Alzheimer's potential were also assessed which reveals strong acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory effects. Compound 3 was 16-fold more active inhibitor of acetylcholinesterase compared to neostigmine with an IC 50 value of 1.044 ± 0.76  μ M in addition to 21-fold strong inhibition against butyrylcholinesterase. The in vitro bioactivity results were further strengthened by the molecular docking analysis revealing the presence of several important interactions with the active site residues from cholinesterase (AChE & BChE) enzymes.