TY - JOUR
T1 - Inhibition of siderophore biosynthesis in Mycobacterium tuberculosis with nucleoside bisubstrate analogues
T2 - Structure-activity relationships of the nucleobase domain of 5′-O-[N-(salicyl)sulfamoyl]adenosine
AU - Neres, João
AU - Labello, Nicholas P.
AU - Somu, Ravindranadh V.
AU - Boshoff, Helena I.
AU - Wilson, Daniel J.
AU - Vannada, Jagadeshwar
AU - Chen, Liqiang
AU - Barry, Clifton E.
AU - Bennett, Eric M.
AU - Aldrich, Courtney C.
PY - 2008/9/11
Y1 - 2008/9/11
N2 - 5′-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is a prototype for a new class of antitubercular agents that inhibit the aryl acid adenylating enzyme (AAAE) known as MbtA involved in biosynthesis of the mycobactins. Herein, we report the structure-based design, synthesis, biochemical, and biological evaluation of a comprehensive and systematic series of analogues, exploring the structure-activity relationship of the purine nucleobase domain of Sal-AMS. Significantly, 2-phenyl-Sal-AMS derivative 26 exhibited exceptionally potent antitubercular activity with an MIC99 under iron-deficient conditions of 0.049 μM while the N-6-cyclopropyl-Sal-AMS 16 led to improved potency and to a 64-enhancement in activity under iron-deficient conditions relative to iron-replete conditions, a phenotype concordant with the designed mechanism of action. The most potent MbtA inhibitors disclosed here display in vitro antitubercular activity superior to most current first line TB drugs, and these compounds are also expected to be useful against a wide range of pathogens that require aryl-capped siderphores for virulence.
AB - 5′-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is a prototype for a new class of antitubercular agents that inhibit the aryl acid adenylating enzyme (AAAE) known as MbtA involved in biosynthesis of the mycobactins. Herein, we report the structure-based design, synthesis, biochemical, and biological evaluation of a comprehensive and systematic series of analogues, exploring the structure-activity relationship of the purine nucleobase domain of Sal-AMS. Significantly, 2-phenyl-Sal-AMS derivative 26 exhibited exceptionally potent antitubercular activity with an MIC99 under iron-deficient conditions of 0.049 μM while the N-6-cyclopropyl-Sal-AMS 16 led to improved potency and to a 64-enhancement in activity under iron-deficient conditions relative to iron-replete conditions, a phenotype concordant with the designed mechanism of action. The most potent MbtA inhibitors disclosed here display in vitro antitubercular activity superior to most current first line TB drugs, and these compounds are also expected to be useful against a wide range of pathogens that require aryl-capped siderphores for virulence.
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U2 - 10.1021/jm800567v
DO - 10.1021/jm800567v
M3 - Article
C2 - 18690677
AN - SCOPUS:51849155973
SN - 0022-2623
VL - 51
SP - 5349
EP - 5370
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 17
ER -