Inhibition of siderophore biosynthesis by 2-triazole substituted analogues of 5′-O-[N-(salicyl)sulfamoyl]adenosine: Antibacterial nucleosides effective against Mycobacterium tuberculosis

Amol Gupte, Helena I. Boshoff, Daniel J. Wilson, João Neres, Nicholas P. Labello, Ravindranadh V. Somu, Chengguo Xing, Clifton E. Barry, Courtney C. Aldrich

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Abstract

The synthesis, biochemical, and biological evaluation of a systematic series of 2-triazole derivatives of 5′-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) are described as inhibitors of aryl acid adenylating enzymes (AAAE) involved in siderophore biosynthesis by Mycobacterium tuberculosis. Structure-activity relationships revealed a remarkable ability to tolerate a wide range of substituents at the 4-position of the triazole moiety, and a majority of the compounds possessed subnanomolar apparent inhibition constants. However, the in vitro potency did not always translate into whole cell biological activity against M. tuberculosis, suggesting that intrinsic resistance plays an important role in the observed activities. Additionally, the well-known valence tautomerism between 2-azidopurines and their fused tetrazole counterparts led to an unexpected facile acylation of the purine N-6 amino group.

Original languageEnglish (US)
Pages (from-to)7495-7507
Number of pages13
JournalJournal of medicinal chemistry
Volume51
Issue number23
DOIs
StatePublished - Dec 11 2008

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