Synthesis, SwissADME prediction, and biological evaluation of 2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitriles

This study describes the synthesis, in silico evaluation, and biological evaluation of 2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitriles bearing diverse substituents at positions 1 and 4. Compounds 1–8 were previously reported and were included here as reference members of the series, whereas compounds 9–24 were prepared and characterized in the present study. N-Nitroso (9–12), N-formyl (13–16), and N-alkyl (17–24) derivatives were investigated to examine how changes in N-substitution alter physicochemical properties and biological activity. Structural characterization was performed using IR, 1H NMR, and 13C NMR spectroscopy. SwissADME was employed to predict physicochemical, pharmacokinetic, and drug-likeness descriptors. All compounds complied with the principal rule-based drug-likeness filters evaluated; these findings are interpreted as computational indications of favorable physicochemical space rather than evidence of drug candidacy or oral bioavailability. In vitro MTT assays identified compounds 6 and 18 as the most active members of the tested cytotoxicity set, with IC50 values of 89.35–160.0 μM across Hep-G2, MCF7, and HT29 cells. Compounds 19, 21, and 24 showed the most pronounced antibacterial activity, with compound 19 giving MIC values of 16–128 μM against several bacterial strains. The observed structure-activity trends indicate that N-alkylation, aryl substituent electronics, and hydrophobicity influence activity. The computational findings are presented as supportive hypotheses for these experimental observations, and additional target-based and mechanistic studies will be required to establish the underlying mechanisms.