5′-O-[(N-acyl)sulfamoyl]adenosines as antitubercular agents that inhibit MbtA: An adenylation enzyme required for siderophore biosynthesis of the mycobactins

Chunhua Qiao, Amol Gupte, Helena I. Boshoff, Daniel J. Wilson, Eric M. Bennett, Ravindranadh V. Somu, Clifton E. Barry, Courtney C. Aldrich

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

A study of the structure - activity relationships of 5′-O-[N- (salicyl)sulfamoyl]adenosine (6), a potent inhibitor of the bifunctional enzyme salicyl-AMP ligase (MbtA, encoded by the gene Rv2384) in Mycobacterium tuberculosis, is described, targeting the salicyl moiety. A systematic series of analogues was prepared exploring the importance of substitution at the C-2 position revealing that a hydroxy group is required for optimal activity. Examination of a series of substituted salicyl derivatives indicated that substitution at C-4 was tolerated. Consequently, a series of analogues at this position provided 4-fluoro derivative, which displayed an impressive MIC 99 of 0.098 μM against whole-cell M. tuberculosis under iron-limiting conditions. Examination of other heterocyclic, cycloalkyl, alkyl, and aminoacyl replacements of the salicyl moiety demonstrated that these nonconserative modifications were poorly tolerated, a result consistent with the fairly strict substrate specificities of related non-ribosomal peptide synthetase adenylation enzymes.

Original languageEnglish (US)
Pages (from-to)6080-6094
Number of pages15
JournalJournal of medicinal chemistry
Volume50
Issue number24
DOIs
StatePublished - Nov 29 2007

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