N-Trifluoromethylthiolated Sulfonimidamides and Sulfoximines: Anti-microbial, Anti-mycobacterial, and Cytotoxic Activity.
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Thota N, Makam P, Rajbongshi KK, Nagiah S, Abdul NS, Chuturgoon AA, Kaushik A, Lamichhane G, Somboro AM, Kruger HG, Govender T, Naicker T, Arvidsson PI
ACS Med Chem Lett 10 (10) 1457-1461 [2019-10-10; online 2019-09-11]
Herein we demonstrate the expanded utility of a recently described N-trifluoromethylthiolation protocol to sulfonimidamide containing substances. The novel N-trifluoromethylthio sulfonimidamide derivatives thus obtained were evaluated for antibacterial activity against Mycobacterium tuberculosis (M. tb.) and Mycobacterium abscessus and Gram + Ve (Streptococcus aureus, Bacillus subtilis), and Gram - Ve (Escherichia coli, Pseudomonas aeruginosa) bacteria. Two compounds, 13 and 15 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 13 IC50 = 15 μg/mL; compound 15 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.
Drug Discovery and Development (DDD) [Technology development]
PubMed 31620233
DOI 10.1021/acsmedchemlett.9b00285
Crossref 10.1021/acsmedchemlett.9b00285