Impact of Lipophilicity-Tuning on the Antimicrobial Activity of a Series of β-Face-Expanding Bile Acid Derivatives.

The increasing prevalence of antimicrobial resistance has stimulated the search for new molecular scaffolds with improved efficacy and selectivity. In this study, five bile acid-derived aminosteroids (AC series) and their corresponding biphenyl-functionalized derivatives (BIAC series) were synthesized and evaluated against Staphylococcus aureus and Enterococcus faecalis. Antimicrobial activity, hemolytic activity, and lipophilicity were investigated to establish structure-activity relationships. Quantum mechanics-derived lipophilicity (QM-logP) successfully captured subtle differences associated with the number, position, and orientation of hydroxyl groups on the steroid nucleus, providing a level of discrimination not achieved by conventional fragment-based methods. Introduction of the biphenyl moiety significantly increased lipophilicity and resulted in enhanced antimicrobial activity throughout the BIAC series compared with the parent AC compounds. BIAC05Q emerged as the most promising derivative, combining potent antibacterial activity with low hemolysis. The superior performance of BIAC05Q appears to be associated with the presence of an axial hydroxyl group at C7, which promotes a favorable amphiphilic balance and aggregation propensity. Collectively, the results suggest that the antimicrobial activity of these bile acid derivatives is closely linked to their supramolecular behavior and support the hypothesis that self-assembled aggregates, rather than individual molecules, may constitute the bioactive species. These findings highlight the value of QM-logP-guided molecular design as a strategy to optimize amphiphilicity, aggregation, antimicrobial activity, and selectivity in bile acid-based antimicrobial agents.