Abstract
Long-chain lipid envelopes are characteristic of mycobacteria such as those that cause tuberculosis and leprosy. Inhibition of fatty acid synthesis or elongation is a strategy demonstrated to be clinically effective against M. tuberculosis. A new class of compounds designed to inhibit the β-ketoacyl synthase reaction of fatty acid synthesis has been developed. Of >30 compounds described, the most active were acetamides containing alkylsulfonyl substituents. Inhibitory activities were acutely sensitive to net charge, chain length, and degree of unsaturation. The most active compound 5 (alkyl = C10) contained a single methylene spacer between the sulfone and carboxamide and exhibited an MIC of 0.75-1.5 μg/mL, comparable to first-line antituberculosis drugs. These compounds are species-specific, exhibiting no significant activity against bacterial species other than M. tuberculosis and closely related strains. The synthesis, biological activity, and specificity of these compounds are described.
Original language | English (US) |
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Pages (from-to) | 3304-3314 |
Number of pages | 11 |
Journal | Journal of medicinal chemistry |
Volume | 43 |
Issue number | 17 |
DOIs | |
State | Published - Aug 24 2000 |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery