A new class of antituberculosis agents.
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 beta-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 = C(10)) contained a single methylene spacer between the sulfone and carboxamide and exhibited an MIC of 0.75-1.5 microg/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.
Jones
P B
PB
Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, USA.
Parrish
N M
NM
Houston
T A
TA
Stapon
A
A
Bansal
N P
NP
Dick
J D
JD
Townsend
C A
CA
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C413349:3-sulfonyltridecanamide; D000577:Amides; D000995:Antitubercular Agents; D013450:Sulfones