Synthesis, antimicrobial activity, and preliminary mechanistic studies of phenazine sulfonamides.

The increasing emergence of antibiotic resistance highlights the urgent need for the discovery of new antimicrobial agents. Herein, we report the synthesis and antimicrobial evaluation of a series of phenazine sulfonamides (PSAs) based on 9-chloro phenazine carboxylic acid (1a) and saphenic acid (2). Our initial antimicrobial screening identified compounds with promising activity against methicillin-resistant Staphylococcus aureus (MRSA), S. epidermidis, and Neisseria gonorrhoeae. Notably, compound 7i showed activities in the low micromolar range against MRSA and S. epidermidis. In addition, compounds 7k and 7p exhibited antimicrobial effect against N. gonorrhoeae isolates. In subsequent investigations, 7i demonstrated an additive antibacterial effect against S. aureus in combination with linezolid and vancomycin. Compound 7i also improved the antimicrobial efficacy of vancomycin against vancomycin-resistant S. aureus isolates and demonstrated a powerful biofilm formation inhibition against S. aureus JE2 by suppressing key regulatory genes (agrA and saeR) and impairing virulence-associated exoprotein secretion. In addition, 7i possesses a very promising safety profile: no cytotoxicity towards mammalian cells, and lack of hemolytic and mutagenic action. The lead molecules showed promising activity in a simple in vivo model. Altogether, data from this study suggest PSA are a promising scaffold for developing antimicrobial agents.