Inhibition of Siderophore Biosynthesis in Mycobacterium tuberculosis with Nucleoside Bisubstrate Analogues: Structure-Activity Relationships of the Nucleobase Domain of 5'-O-[N-(Salicyl)sulfamoyl]adenosine.

[摘要]：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, biochem., and biol. evaluation of a comprehensive and systematic series of analogs, exploring the structure-activity relationship of the purine nucleobase domain of Sal-AMS. Significantly, 2-phenyl-Sal-AMS deriv. 26 exhibited exceptionally potent antitubercular activity with an MIC99 under iron-deficient conditions of 0.049 mM 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 compds. are also expected to be useful against a wide range of pathogens that require aryl-capped siderophores for virulence.

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