Development of Piperidinols and Engelhardiones as Novel Antituberculosis Agents

描述（由申请人提供）：结核病（TB）是一种传染性空气传播疾病，由一种致命的细菌病原体结核分枝杆菌引起。结核病是世界上第二大传染病，仍然是21世纪最大的公共卫生问题之一。据世界卫生组织（世卫组织）估计，世界人口中约有三分之一潜伏感染结核细菌，每年有近200万人死于这一致命疾病，由于人类免疫缺陷病毒（艾滋病毒）合并感染、多种药物和广泛耐药结核病，感染病例数量仍在迅速上升。结核病治疗方案的共同挑战和问题包括其潜伏期、长期治疗方案、艾滋病毒合并感染和新出现的耐药性。值得注意的是，自40年前利福平问世以来，尚未发现结核病特异性药物，因此，结核病药物研究界迫切需要开发具有新的作用机制和较少交叉耐药特性的快速有效的抗结核药物。从历史上看，包括结核病药物在内的大多数抗菌药物来自天然产物，其余来自合成小分子。在本研究中，我们将采用HTS hits引导和天然产物启发的方法来开发新型抗结核药物。第一个具体目标是进一步优化和开发合成抗结核哌替啶醇衍生物，第二代系列的设计驱动力是专注于提高期望的活性，降低毒性，从而提高整体治疗指数。方法包括：(1)基于第一代哌替啶醇衍生物的SAR系统优化和检测；还将探索几个新的哌啶醇衍生物系列，以努力确定新的化学型或支架，以便进一步评价和开发。第二个具体目标是设计和合成用于抗结核筛查的天然恩格尔哈酮类似物。大环二苯基醚类半胱甘肽（Engelhardione）对结核分枝杆菌H37Rv有较强的体外抗结核活性（MIC = 0.2 <g/mL）。尽管其具有强大的活性，但文献中尚未报道恩格尔哈地酮的合成及其类似物的抗结核评价，这种发展的缺乏促使我们将药物化学的努力直接应用于这一应用。为此，我们建议首先通过调整现有的合成方案来开发一种可行的合成方法，其次是设计和合成其类似物和衍生物用于抗结核测试，以努力确定更有效和毒性更低的恩格尔哈迪酮实验候选物。

DESCRIPTION (provided by applicant): Tuberculosis (TB) is a contagious airborne disease caused by a deadly bacterium pathogen called mycobacterium tuberculosis. TB is the second leading infectious disease in the world and remains one of the biggest public health problems in the 21st century. According to the World Health Organization (WHO), it is estimated that about a third of the world's population are latently infected with TB bacteria, almost 2 million people die from this deadly disease annually, and the number of infected cases are still rising rapidly because of human immunodeficiency virus (HIV) coinfection, multi-drug and extensively drug resistant tuberculosis. The common challenges and problems regarding tuberculosis treating regimens include its latency, long treating regimen, HIV coinfection, and emerging drug resistance. Notably, no TB specific drugs have been discovered since the introduction of Rifampin 40 years ago, therefore, there is an urgent need for TB drug research community to develop fast acting and potent antituberculosis agents with new mechanism of action and less cross resistance properties. Historically, the majority of antimicrobial agents including TB drugs originate from natural products with the remaining derived from synthetic small molecules. In this proposal, we will apply HTS hits guided and natural product inspired approaches to develop novel antituberculosis agents. The first specific aim focuses on further optimization and development of synthetic antitubercular piperidinol derivatives, the design driver toward a second generation series is to focus on enhancing the desired activity, lowering the toxicity, and thus improving overall therapeutic index. The approaches include: (i) Systematic optimization and examination of SAR based on first generation piperidinol derivatives; (ii) Several new series of piperidinol derivatives will also be explored in an effort to identify new chemotypes or scaffolds for further evaluation and development. The second specific aim is to design and synthesize natural Engelhardione analogues for antituberculosis screening. Engelhardione, a macrocyclic diphenyl ether haptanoid, was reported to show potent in vitro antituberculosis activity against Mycobacterium tuberculosis strain H37Rv (MIC = 0.2 <g/mL). Despite its potent activity, there is no reported synthesis of Engelhardione and antituberculosis evaluation of its analogues in the literature, this lack of development prompts us to direct medicinal chemistry effort in this application. In this aim, we propose to first develop a feasible synthesis toward Engelhardione by adapting existing synthetic schemes, the second subaim is to design and synthesize its analogues and derivatives for antituberculosis testing in an effort to identify more potent and less toxic Engelhardione experimental candidates. PUBLIC HEALTH RELEVANCE: Due to the emergence and evolution of drug resistant mycobacterium tuberculosis, there is an urgent need to discover new chemotype TB drugs with novel mechanism of action and low toxic properties. In this application, by employing HTS hits guided and natural product inspired approaches we propose to optimize and develop synthetic piperidinol derivatives and natural Engelhardione analogues as novel antituberculosis agents. The results of the proposed research will generate significant biological data and gain important understanding regarding novel piperidinol and Engelhardione antituberculosis agents, after this study, we hope to identify promising candidates with potent in vitro activity and low toxicity for subsequent in vivo efficacy and toxicity studies. Furthermore, development of these novel antituberculosis agents has the potential to overcome the cross resistance with current clinically used TB drugs and to shorten current TB treating regimen.