Design, Syntheses and Studies of Novel Antituberculosis Agents

描述(申请人提供)：超过20亿人患有肺结核！该提案侧重于两种方法，这两种方法将导致开发所需的新的抗结核药物。第一，与分枝杆菌毒素相关的研究，这种化合物调节对结核分枝杆菌的生长和毒力至关重要的铁的同化，导致发现了简单、容易合成、有效、无毒、高度选择性的小分子抗结核病药物，包括咪唑并[1，2-a]吡啶，其开发将是第二个目标。本申请中描述的结果表明，至少有三种方法可以利用铁同化过程作为潜在的“阿喀琉斯之踵”来开发新的抗结核药物：(A)干扰(抑制)分枝杆菌铁的同化，(B)利用铁的同化来选择性地给药，以及(C)利用基本的Fe(+3)到Fe(+2)的还原来产生引起细胞内分枝杆菌损害的反应。此外，通过对所有目标合成化合物、中间体和成分进行高通量抗结核筛选，发现了新型有效的(亚微摩尔)简单小分子抗结核药物，最著名的是恶唑啉分枝杆菌蛋白成分和新的咪唑并[1，2-a]吡啶类似物(对多药耐药(MDR)和极端耐药(XDR)结核病具有低纳米分子抗结核活性！)。这些重大成果鼓励使用三个具体目标的进一步发展。目的1.优化高效、无毒、选择性、代谢稳定、价廉的小分子抗结核药物。利用开发的有效化学(以及描述的新合成)，我们将扩大SAR研究，测量选择性和毒性，并调节我们新型小分子先导化合物(特别是新的非常有效和代谢稳定的咪唑并[1，2-a]吡啶)的代谢，以增强抗结核病效果。该化学将有助于合成mycobactin药物结合物(目标2)。目的2.设计、合成和研究结核分枝杆菌铁同化抑制剂及其药物结合物。其目的是证明一个基本原则，即利用对分枝杆菌生长和毒力绝对必要的铁同化可以为开发抗结核病药物提供新的方法，同时评估未被探索的“特洛伊木马”方法。目的3.使用适当的体内外临床前研究评价所有先导化合物。通过我们的广泛合作，我们将评估所有样本的抗结核活性[包括结核分枝杆菌的MDR(多药耐药)和XDR(极端耐药)菌株]。我们还将进行相关研究，包括具有抗结核病活性的新化合物的总体毒性、代谢、药代动力学(PK)、最大耐受量(MTD)和作用模式研究。为了实现这些目标，已经组建了一支由高素质的同事和合作者组成的团队。

DESCRIPTION (provided by applicant): More than two billion people have tuberculosis! This proposal focuses on two approaches that will lead to the development of needed new antiTB agents. The first, studies associated with mycobactins, compounds that regulate assimilation of iron that is essential for growth and virulence of Mycobacterium tuberculosis, led to the discovery of simple, easily synthesized, potent, non-toxic, remarkably selective small molecule antiTB agents, including imidazo[1,2-a]pyridines, the development of which will be the second goal. The results described in this application indicate that at least three methods can be used to exploit the iron assimilation process as a potential "Achilles' heel" to develop novel antiTB agents: (a) interference (inhibition) of mycobacterial iron assimilation, (b) utilization of iron assimilation for TB-selective drug delivery, and (c) use of the essential Fe(+3) to Fe(+2) reduction to generate reactions that cause intracellular mycobacterial damage. Moreover, access to high throughput antiTB screening of all targeted synthetic compounds, intermediates and components led to the discovery of new types of potent (sub micromolar) simple small molecule antiTB agents, most notably, oxazolines and oxazoles derived from studies of the oxazoline mycobactin component and new imidazo[1,2-a]pyridine analogs (with low nanomolar antiTB activity against multidrug resistant (MDR) and extreme drug resistant (XDR) TB!). These significant results encourage further development using three specific aims. Aim 1. Optimize our potent, non-toxic, selective, metabolically stable and inexpensive small molecule antiTB agents. Using the effective chemistry developed (and described new syntheses) we will extend SAR studies, measure selectivity and toxicity, and modulate metabolism of our novel small molecule leads (especially the new very potent and metabolically stable imidazo[1,2-a]pyridines) for enhanced antiTB efficacy. The chemistry will facilitate syntheses of mycobactin drug conjugates (aim 2). Aim 2. Design, synthesize and study mycobactin-derived inhibitors of iron assimilation of tuberculosis and mycobactin-drug conjugates. The goal is to demonstrate the fundamental principle that exploitation of the iron assimilation that is absolutely essential for mycobacterial growth and virulence can provide new approaches to development of antiTB agents while assessing the underexplored "Trojan Horse" approach. Aim 3. Evaluate all lead compounds using appropriate in vitro and in vivo pre-clinical studies. Through our extensive collaborations, we will evaluate all samples for antiTB activity [including MDR (multi-drug resistant) and XDR (extreme drug resistant) strains of M. tuberculosis]. We will also perform related studies, including gross toxicity, metabolism, pharmacokinetics (PK), maximum tolerated dose (MTD) and mode of action studies of new compounds with antiTB activity. A highly qualified team of coworkers and collaborators has been assembled to accomplish the goals.