Design, synthesis, and biological evaluation of steroidal indole derivatives as membrane-targeting antibacterial candidates.

Rational modification of natural products plays a key role in drug discovery. Herein, a series of steroidal indole derivatives containing various substituents and steroidal skeletons were designed and synthesized with classical Fischer indole synthesis as a key step in an efficient synthetic route for the first time. The in vitro antibacterial activity of all the synthesized derivatives was evaluated against four Gram-positive strains including three Methicillin-Resistant Staphylococcus aureus. Compound 11e displayed the most potent antibacterial activity (MIC = 1-2 μg/mL) with low cytotoxicity and hemolytic activity. Derivative 11e displayed more rapid bactericidal kinetic than vancomycin in the time-kill study and was less likely to induce bacterial resistance. Moreover, the preliminary antibacterial mechanism explorations indicated that compound 11e could effectively inhibit biofilm formation, promote the accumulation of reactive oxygen species, decrease bacterial metabolism, and destroy bacterial cell membranes to exert its antibacterial effects. The study of in vivo antibacterial activity suggested that compound 11e could significantly reduce the bacteria counts in a mouse subcutaneous infection model. These findings provided a bright hope for steroidal indole derivatives as promising antibacterial candidates to settle drug resistance.