Phenothiazine–Bile Acid Conjugates: A Novel Approach to Combat Gram-Negative Bacterial Resistance

= 79.74 ± 2.2 μM). Cytotoxicity profiling in mammalian cells revealed tunable selectivity, particularly for triazole-linked derivatives. Density functional theory calculations and global reactivity descriptor analysis established correlations between electronic softness, electrophilicity, and antibacterial performance. Complementary docking studies indicated enhanced binding affinity of the conjugates toward Gram-negative membrane-associated proteins relative to PTZ alone. Intracellular ROS assessment excluded oxidative stress-mediated cytotoxicity, supporting a membrane-associated mechanism modulated by electronic properties. Collectively, these results validate BA-PTZ conjugation as a rational design strategy to overcome Gram-negative permeability barriers and provide structure-guided principles for the optimization of membrane-targeted antimicrobial bioconjugates.