Design, Syntheses and Studies of Novel Antituberculosis Agents

描述（申请人提供）：超过20亿人患有结核病！该提案侧重于两种方法，这将导致所需的新的抗结核药物的发展。第一个是与分枝杆菌素（mycobactins）相关的研究，这种化合物调节铁的同化，而铁的同化对于结核分枝杆菌的生长和毒力是必不可少的，导致发现了简单、容易合成、有效、无毒、显著选择性的小分子抗结核药物，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，至少三种方法可用于开发铁同化过程作为潜在的“阿喀琉斯之踵”，以开发新的抗TB剂：（a）干扰（抑制）分枝杆菌铁同化，（B）利用铁同化进行TB-选择性药物递送，和（c）使用必需的Fe（+3）到Fe（+2）还原以产生引起细胞内分枝杆菌损伤的反应。此外，获得所有靶向合成化合物、中间体和组分的高通量抗TB筛选导致发现了新类型的有效的抗结核药物。（亚微摩尔）简单的小分子抗TB剂，最值得注意的是，恶唑啉和恶唑衍生自恶唑啉分枝杆菌素组分的研究和新的咪唑并[1，2-a]吡啶类似物（具有针对多药耐药（MDR）和极端耐药（XDR）TB的低纳摩尔抗TB活性）。这些重大成果鼓励进一步发展，使用三个具体目标。目标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。使用开发的有效化学（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TB疗效。该化学将促进分枝杆菌素药物偶联物的合成（目的2）。目标2.设计、合成及研究结核分枝杆菌衍生之铁同化抑制剂及分枝杆菌-药物偶联物。我们的目标是证明的基本原则，铁同化，是绝对必要的分枝杆菌的生长和毒力的开发可以提供新的方法来开发抗结核药物，同时评估未充分开发的“特洛伊木马”的方法。目标3：使用适当的体外和体内临床前研究评价所有先导化合物。通过我们广泛的合作，我们将评估所有样品的抗结核活性[包括耐多药和极端耐药的M.结核病]。我们还将进行相关研究，包括具有抗结核活性的新化合物的总体毒性、代谢、药代动力学（PK）、最大耐受剂量（MTD）和作用方式研究。一个高素质的团队的同事和合作者已经组装完成的目标。 公共卫生相关性：超过20亿人患有结核病！本提案中描述的新型抗结核药物的设计、合成和研究是基于对基本分枝杆菌铁螯合过程研究的发现。除了表明这些重点研究可以产生新的抗结核化合物外，上一个资助期的进展还产生了新的、易于合成的、代谢稳定的、具有有效抗结核活性的小分子，值得进一步研究和开发。

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. PUBLIC HEALTH RELEVANCE: More than two billion people have tuberculosis! Design, syntheses and studies of novel antiTB agents described in this proposal are based on discoveries made from studies of the essential mycobacterial iron sequestration processes. In addition to indicating that such focused studies can produce novel antiTB compounds, progress from the last grant period produced novel, easily synthesized, metabolically stable, small molecules with potent antiTB activity that merit further study and development.