Synthesis, Structure, Density Functional Theory Study and <i>In Silico</i> Investigation of the Biological Activity of a Newly Synthesized Hexahydroquinoline Derivative

Hexahydroquinoline is a favored scaffold in medicinal chemistry. However, the precise structural and electronic properties of its derivatives remain underexplored. Herein, we synthesized a novel hexahydroquinoline derivative, methyl 2,7,7-trimethyl-4-(4-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (I), characterized its structural and electronic properties and assessed its potential biological activity. Compound I was formed via the multicomponent reaction of 4-nitrobenzaldehyde, dimedone, methyl acetoacetate and ammonium acetate and its structure was unambiguously confirmed by X-ray crystallography and density functional theory (DFT) calculations. Hirshfeld surface, energy framework and quantum theory of atoms in molecules (QTAIM) analyses revealed dominant polarization effects in crystal packing, with intramolecular C−H[Formula: see text]O interactions (strength: −2.6 to −4.9 kJ/mol) playing a crucial role in stabilizing the structure. Crystal void analysis indicated the presence of complex or irregular void shapes, which may reduce the mechanical strength of the molecular crystal. Molecular docking predicted a strong binding affinity for cytochrome P450 2J2 (−8.0 kcal/mol), suggesting the potential of I as a molecular probe for steroidogenesis regulation. In silico investigation of the drug-likeness and pharmacokinetic properties of I demonstrated its excellent absorption, moderate lipophilicity and low risk of cytochrome P450 polymorphism. This study provides a comprehensive strategy from synthesis to computational validation for the development of hexahydroquinoline-based therapeutics.