Isostructurality and energetics of competitive C–H⋯π interactions in adamantane-benzoate hybrids: a computational ADME study

Abstract

A comprehensive investigation of the supramolecular architecture in nine 2-(adamantan-1-yl)-2-oxoethyl benzoates is reported, integrating experimental X-ray data with advanced theoretical analysis. Beyond expanding on previously reported structural aspects, this work quantifies isostructural relationships using the dissimilarity index (X) and packing similarity (PS_ab), providing a rigorous numerical basis for observed packing motifs. Crystal stability is governed by a complex interplay of C–H⋯O hydrogen bonds and “edge-to-face” C–H⋯π contacts, further supported by C–H⋯Cl interactions and π-stacking in specific derivatives. Lattice and interaction energies were partitioned using the PIXEL method. Visualization and quantification of the intermolecular contacts were performed by Hirshfeld surface analysis. The electronic nature and cooperativity of the adamantane–benzoate C–H⋯π contacts were elucidated through MEP, QTAIM-NCI and NBO calculations. Finally, the pharmacological potential of the series was evaluated via in silico ADME predictions. The compounds exhibited high gastrointestinal absorption and optimal drug-likeness parameters, although their high lipophilicity suggests potential limitations in aqueous solubility. These results characterize the adamantane-benzoate scaffold as a viable candidate for future drug design.