<i>N</i>-Trifluoromethylthiolated Sulfonimidamides and Sulfoximines: Anti-microbial, Anti-mycobacterial, and Cytotoxic Activity

Abstract

Herein we demonstrate the expanded utility of a recently described <i>N</i>-trifluoromethylthiolation protocol to sulfonimidamide containing substances. The novel <i>N</i>-trifluoromethylthio sulfonimidamide derivatives thus obtained were evaluated for antibacterial activity against <i>Mycobacterium tuberculosis</i> (<i>M. tb</i>.) and <i>Mycobacterium abscessus</i> and Gram + Ve (<i>Streptococcus aureus</i>, <i>Bacillus subtilis</i>), and Gram - Ve (<i>Escherichia coli</i>, <i>Pseudomonas aeruginosa</i>) bacteria. Two compounds, <b>13</b> and <b>15</b> showed high antimycobacterial activity with MIC value of 4-8 μg/mL; i.e. comparable to WHO recommended first line antibiotic for TB infection ethambutol. The same compounds were also found to be cytotoxic in HepG2 cells (compound <b>13</b> IC₅₀ = 15 μg/mL; compound <b>15</b> IC₅₀ = 65 μg/mL). A structure activity relationship, using matched pair analysis, gave the unexpected conclusion that the trifluoromethylthio moiety was responsible for the cellular and bacterial toxicity. Given the increasing use of the trifluoromethylthio group in contemporary medicinal chemistry, this observation calls for considerations before implementation of the functionality in drug design.