Cyanethylation of two decahydroquinolone isosters and evaluation of antibacterial properties of new β-aminonitriles

Abstract

Driven by the growing threat of antimicrobial resistance, the search for novel antibacterial agents has identified decahydroquinoline derivatives as promising structural scaffolds. The aim of this work was a comparative study of the synthetic reactivity of two decahydroquinolone isomers and the subsequent antimicrobial activity of their N-cyanoethylated products. The target compounds were synthesized via an aza-Michael addition, wherein the influence of stereochemistry on reactivity was investigated, and a Cu(OAc)₂ catalyst was optimized for the sterically hindered isomer. Antimicrobial activity was assessed by the broth microdilution method, while cytotoxicity was evaluated using an MTT assay on the MDCK kidney cell line. It was established that the position of the methyl group within the decahydroquinoline core is a critical determinant of both the steric accessibility for N-cyanoethylation and the resulting biological activity. The N-(β’-cyanoethyl)-2a-methyldecahydroquinolin-4-one exhibited selective bactericidal activity against the Gram-positive strain Staphylococcus aureus (MBC = 5 mg/mL), whereas its 10-methyl substituted analogue was completely inactive. Importantly, the active compound demonstrated low cytotoxicity (CTC₅₀ > 0.8 mg/mL), indicating a favorable selectivity profile. These findings identify the 2a-methyldecahydroquinolin-4-one fragment as a promising scaffold for the rational design of new selective antibacterial agents.