Supramolecular assembly mediated by hydrogen bonds and weak noncovalent interactions in two eucalyptol derivatives with potential antineoplastic activity: Crystal structure, Hirshfeld surface analysis, DFT calculations and Molecular docking analysis

Abstract

In the present article, we report on the synthesis of two eucalyptol derivatives, namely 1,3,3-trimethyl-2-oxabicycle[2.2.2] octane-5,8-diol (4) and 1,3,3-trimethyl-2-oxabicycle[2.2.2]octane-5-acetyl-8-oxo (6). The crystal structure of both compounds has been determined and analyzed in detail. The Hirshfeld surface analysis and their two-dimensional fingerprint plots provide a qualitative picture of the hydroxyl and acetoxy substituents effects on the crystal packing. This analysis showed that O-H···O hydrogen bonds are the key contributors to the intermolecular stabilization in the crystal of 4. Furthermore, the supramolecular assembly of 6 is mainly stabilized by a combination of C-H···O hydrogen bonds and weak C-H···π(C=O) contacts. Intermolecular interaction energies for dimers observed in these structures were calculated using the CrystalExplorer17.5 program and DFT calculations at B3LYP-D3-def2-TZVP level of theory being comparable between them. The strength and nature of the intermolecular interactions have been studied by using a variety of computational tools including MEP, QTAIM, and NCIplot analysis. A detailed molecular docking analysis against ten cancer targets revealed that the eucalyptol scaffold could serve as a promising scaffold for developing anticancer agents. ADMET analysis confirmed that both compounds exhibit drug-like properties.