TY - JOUR
T1 - Inhibition of siderophore biosynthesis by 2-triazole substituted analogues of 5′-O-[N-(salicyl)sulfamoyl]adenosine
T2 - Antibacterial nucleosides effective against Mycobacterium tuberculosis
AU - Gupte, Amol
AU - Boshoff, Helena I.
AU - Wilson, Daniel J.
AU - Neres, João
AU - Labello, Nicholas P.
AU - Somu, Ravindranadh V.
AU - Xing, Chengguo
AU - Barry, Clifton E.
AU - Aldrich, Courtney C.
PY - 2008/12/11
Y1 - 2008/12/11
N2 - 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.
AB - 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.
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U2 - 10.1021/jm8008037
DO - 10.1021/jm8008037
M3 - Article
C2 - 19053762
AN - SCOPUS:57349154252
SN - 0022-2623
VL - 51
SP - 7495
EP - 7507
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 23
ER -