Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

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• 作者：Kathryn M. Nelson ; Kishore Viswanathan ; Surendra Dawadi ; Benjamin P. Duckworth ; Helena I. Boshoff ; Clifton E. Barry ; III ; Courtney C. Aldrich
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：July 23, 2015
• 年：2015
• 卷：58
• 期：14
• 页码：5459-5475
• 全文大小：604K
• ISSN：1520-4804

文摘

MbtA catalyzes the first committed biosynthetic step of the mycobactins, which are important virulence factors associated with iron acquisition in <i>Mycobacterium tuberculosis.i> MbtA is a validated therapeutic target for antitubercular drug development. 5鈥?<i>Oi>-[<i>Ni>-(Salicyl)sulfamoyl]adenosine (1) is a bisubstrate inhibitor of MbtA and exhibits exceptionally potent biochemical and antitubercular activity. However, 1 suffers from suboptimal drug disposition properties resulting in a short half-life (<i>ti>_1/2), low exposure (AUC), and low bioavailability (<i>Fi>). Four strategies were pursued to address these liabilities including the synthesis of prodrugs, increasing the p<i>Ki>_a of the acyl-sulfonyl moiety, modulation of the lipophilicity, and strategic introduction of fluorine into 1. Complete pharmacokinetic (PK) analysis of all compounds was performed. The most successful modifications involved fluorination of the nucleoside that provided substantial improvements in <i>ti>_1/2 and AUC. Increasing the p<i>Ki>_a of the acyl-sulfonyl linker yielded incremental enhancements, while modulation of the lipophilicity and prodrug approaches led to substantially poorer PK parameters.