Design, synthesis, and biological evaluation of beta-ketosulfonamide adenylation inhibitors as potential antitubercular agents.
[reaction: see text] The antitubercular nucleoside antibiotics 1 and 2 were recently described that inhibit the adenylate-forming enzyme MbtA and disrupt biosynthesis of the virulence-conferring siderophore known as mycobactin in Mycobacterium tuberculosis. Herein, we report efforts to refine this inhibitor scaffold by replacing the labile acylsulfamate linkage (highlighted) with the more chemically robust beta-ketosulfonamide linkage of 3 and 4.
Vannada
Jagadeshwar
J
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Bennett
Eric M
EM
Wilson
Daniel J
DJ
Boshoff
Helena I
HI
Barry
Clifton E
CE
Aldrich
Courtney C
CC
D000241:Adenosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000995:Antitubercular Agents; D013449:Sulfonamides; D000241:Adenosine