期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 10, 期 10, 页码 1457-1461出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00285
关键词
Trifluoromethylthio; Sulfonimidamide; Mycobacterium tuberculosis; Mycobacterium abscessus; cytotoxicity; medicinal chemistry; drug discovery
资金
- National Research Foundation of South Africa [87706]
- Medicinal Research Council
- UKZN-School of Health Sciences
- National Institutes of Health, USA [R33AI111739]
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 mu g/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 mu g/mL; compound 15 IC50 = 65 mu g/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.
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