Crystal Structure, Hirshfeld Surface Analysis, and Molecular Modeling of a Flexible Aliphatic β-Diketone with Potential Acetylcholinesterase Inhibitory Activity

Abstract

A flexible aliphatic β-diketone, 4,4′-(hexane−1,6-diylbis(azanediyl))bis(pentan-2-one) (AB), was synthesized under solvent-free conditions and isolated in 79% yield as a crystalline solid. Its molecular and supramolecular structure was established by single-crystal X-ray diffraction, which showed that AB crystallizes in the triclinic space group P-1. Hirshfeld surface analysis and associated fingerprint plots showed that the molecular conformation is stabilized by intramolecular N–H···O hydrogen bonds, whereas crystal packing is supported by intermolecular C-H···O contacts and a dominant contribution from H···H dispersive interactions. Energy-framework analysis further supported a dual stabilization regime in which localized electrostatic interactions are reinforced by a broader dispersion-driven network. To extend the structural study toward a possible biological relevance, molecular docking against human acetylcholinesterase (PDB ID: 4EY7) was carried out after protocol validation by re-docking of donepezil (RMSD = 0.305 Å). Compound AB showed a predicted binding affinity of − 7.3 kcal mol⁻¹, and 100 ns molecular dynamics simulations indicated a stable protein–ligand complex. In silico ADME and toxicity predictions suggested blood–brain barrier permeability and a more favorable predicted acute toxicity profile than donepezil. These results identify AB as a structurally well-defined aliphatic β-diketone whose solid-state organization and computed interaction properties merit further investigation.

Graphical Abstract