Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

MbtA catalyzes the first committed
biosynthetic step of the mycobactins,
which are important virulence factors associated with iron acquisition
in Mycobacterium tuberculosis. MbtA
is a validated therapeutic target for antitubercular drug development.
5′-O-[N-(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 (t1/2), low exposure
(AUC), and low bioavailability (F). Four strategies
were pursued to address these liabilities including the synthesis
of prodrugs, increasing the pKa 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 t1/2 and AUC.
Increasing the pKa of the acyl-sulfonyl
linker yielded incremental enhancements, while modulation of the lipophilicity
and prodrug approaches led to substantially poorer PK parameters.

MbtA催化分枝杆菌素（mycobactins）生物合成的首个关键限速步骤，而分枝杆菌素是结核分枝杆菌（Mycobacterium tuberculosis）中铁离子获取相关的重要毒力因子。MbtA是抗结核药物开发领域已验证的治疗靶点。5′-O-[N-(水杨酰)磺酰基]腺苷（1）属于MbtA的双底物抑制剂，展现出极强的生化活性与抗结核活性。但化合物1存在药物处置特性欠佳的缺陷，具体表现为半衰期（t1/2）较短、体内暴露量（AUC）较低以及生物利用度（F）不佳。为改善这些缺陷，研究团队采用了四种策略：合成前药、提高酰基-磺酰基基团的pKa值、调节亲脂性，以及向化合物1中精准引入氟原子。所有合成化合物均完成了完整的药代动力学（PK）分析。其中最成功的修饰为核苷部分的氟化改造，该改造使半衰期与AUC得到显著提升；提高酰基-磺酰基连接子的pKa值仅带来小幅增益，而调节亲脂性与前药策略则导致药代动力学参数出现明显恶化。