Design, Syntheses and Studies of Novel Antituberculosis Agents

描述（由申请人提供）：全球有超过20亿人患有肺结核！本建议侧重于两种方法，这两种方法将导致开发所需的新型抗结核药物。首先，与分枝杆菌素相关的研究导致发现了简单、易于合成、有效、无毒、具有显著选择性的小分子抗结核药物，包括咪唑[1,2-a]吡啶，其开发将是第二个目标。分枝杆菌素是一种调节铁同化的化合物，对结核分枝杆菌的生长和毒力至关重要。本申请中描述的结果表明，至少有三种方法可用于利用铁同化过程作为潜在的“阿喀琉斯之脚跟”来开发新型抗结核药物：(a)干扰（抑制）分枝杆菌铁同化，(b)利用铁同化进行结核选择性药物递送，以及(c)使用必需的铁（+3）到铁（+2）还原来产生引起细胞内分枝杆菌损伤的反应。此外，对所有靶向合成化合物、中间体和成分的高通量抗结核筛选导致发现了新型有效的（亚微摩尔）简单小分子抗结核药物，最值得注意的是恶唑啉和恶唑唑，这些药物是从恶唑啉菌素成分和新的咪唑[1,2-a]吡啶类似物研究中衍生出来的（对多药耐药（MDR）和极端耐药（XDR）结核病具有低纳摩尔抗结核活性）。这些重要的结果鼓励进一步发展，使用三个具体目标。目的1。优化我们的强效、无毒、选择性、代谢稳定和廉价的小分子抗结核药物。利用开发的有效化学（和描述的新合成），我们将扩展SAR研究，测量选择性和毒性，并调节我们的新型小分子先导物（特别是新的非常有效和代谢稳定的咪唑[1,2-a]吡啶）的代谢，以增强抗结核疗效。该化学反应将促进mycoactin药物偶联物的合成（目的2）。目标2。设计、合成和研究结核分枝杆菌素衍生的铁同化抑制剂和分枝杆菌素-药物偶联物。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，可以为开发抗结核药物提供新方法，同时评估尚未开发的“特洛伊木马”方法。目标3。通过适当的体外和体内临床前研究评估所有先导化合物。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MDR（多重耐药）和XDR（极端耐药）结核分枝杆菌菌株]。我们还将开展相关研究，包括具有抗结核活性的新化合物的总毒性、代谢、药代动力学（PK）、最大耐受剂量（MTD）和作用方式研究。一个由同事和合作者组成的高素质团队已经被召集起来完成这些目标。

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.