Inhibition of Siderophore Biosynthesis in Mycobacterium tuberculosis with Nucleoside Bisubstrate Analogues: Structure−Activity Relationships of the Nucleobase Domain of 5′-O-

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• 作者：Joã ; o Neres ; Nicholas P. Labello ; Ravindranadh V. Somu ; Helena I. Boshoff ; Daniel J. Wilson ; Jagadeshwar Vannada ; Liqiang Chen ; Clifton E. Barry ; ; Eric M. Bennett ; Courtney C. Aldrich
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：September 11, 2008
• 年：2008
• 卷：51
• 期：17
• 页码：5349-5370
• 全文大小：450K
• 年卷期：v.51,no.17(September 11, 2008)
• ISSN：1520-4804

文摘

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.