Design, Synthesis, and Biological Evaluation of β-Ketosulfonamide Adenylation Inhibitors as Potential Antitubercular Agents

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...

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Bibliographic Details
Published in:Organic letters 2006-10, Vol.8 (21), p.4707-4710
Main Authors: Vannada, Jagadeshwar, Bennett, Eric M, Wilson, Daniel J, Boshoff, Helena I, Barry, Clifton E, Aldrich, Courtney C
Format: Article
Language:English
Subjects:
Adenosine - analogs & derivatives
Adenosine - chemical synthesis
Adenosine - chemistry
Adenosine - pharmacology
Antitubercular Agents - chemical synthesis
Antitubercular Agents - chemistry
Antitubercular Agents - pharmacology
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis - drug effects
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
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Summary: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 β-ketosulfonamide linkage of 3 and 4.
ISSN:1523-7060
1523-7052
DOI:10.1021/ol0617289