Inhibition of siderophore biosynthesis by 2-triazole substituted analogues of 5'-O-[N-(salicyl)sulfamoyl]adenosine: antibacterial nucleosides effective against Mycobacterium tuberculosis.
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.
Gupte
Amol
A
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Boshoff
Helena I
HI
Wilson
Daniel J
DJ
Neres
João
J
Labello
Nicholas P
NP
Somu
Ravindranadh V
RV
Xing
Chengguo
C
Barry
Clifton E
CE
Aldrich
Courtney C
CC
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D017262:Siderophores / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*; D014709:Vero Cells
C526816:5'-O-(N-(salicyl)sulfamoyl)adenosine; D000995:Antitubercular Agents; D017262:Siderophores; D014230:Triazoles; D000241:Adenosine