Discovery of Oxaboroles as New Antimalarial Agents

描述(申请人提供)：非常需要治疗疟疾的新药。该计划旨在开发新的含硼小分子作为抗疟疾药物。我们的初步结果表明，新的含硼小分子(恶唑醇)具有强大的抗疟疾活性，重要的是，很可能满足新药的标准药代动力学和安全性标准，以及对抗疟疾药物的独特要求。我们假设，系统的药物发现计划将确定相对容易生产并满足新抗疟疾药物的既定标准的优化的恶硼内酯。此外，我们将使用系统的方法来确定特定的抗疟疾药物 恶臭杂环化合物的作用机理。对作用机制的认识将有助于药物的优化和对耐药性的理解。具体地说，我们将检验这个假设 抗疟药氧硼化合物抑制疟原虫亮氨酰tRNA合成酶(LEUR)。这一假说是基于其他恶臭类化合物对真菌或细菌的特定活性。此外，我们还将评估抵抗机制。我们的计划将需要Anacor和加州大学旧金山分校的一个疟疾研究小组继续合作，Anacor是硼化学领域的世界领先者，在抗疟疾药物开发方面拥有近20年的经验。我们计划的具体目标将是1)点击-领先发现奥博洛尔抗疟疾药物，2)领先优化奥博罗尔抗疟疾药物，以及3)表征奥博罗尔的作用机制和耐药性。我们预计，在该项目的时间框架内，我们将确定用于开发抗疟疾的恶唑醇候选药物，我们将对这些化合物的抗疟疾作用机制获得重要的见解。

DESCRIPTION (provided by applicant): New drugs for malaria are greatly needed. This program is directed toward the development of new boron-containing small molecules as antimalarial drugs. Our preliminary results suggest that novel boron-containing small molecules (oxaboroles) have potent antimalarial activity and, importantly, are likely to meet standard pharmacokinetic and safety criteria for new drugs and also the unique requirements for antimalarials. We hypothesize that a systematic drug discovery program will identify optimized oxaboroles that are relatively simple to produce and meet established criteria for new antimalarial agents. Further, we will use a systematic approach to identify a specific antimalarial mechanism of action for oxaboroles. Appreciation of the mechanism of action will aid in drug optimization and in the understanding of drug resistance. Specifically, we will test the hypothesis that antimalarial oxaboroles inhibit a plasmodial leucyl tRNA synthetase (LeuRS). This hypothesis is based on specific activity of other oxaboroles against fungal or bacterial LeuRS. In addition, we will assess mechanisms of resistance. Our program will entail continued collaboration between Anacor, the world leader in boron chemistry and a malaria research group at the University of California, San Francisco with nearly two decades experience in antimalarial drug discovery. Specific aims of our program will be 1) hit-to-lead discovery of oxaborole antimalarials, 2) lead optimization of oxaborole antimalarials, and 3) characterization of the mechanisms of action and resistance for lead oxaboroles. We anticipate that, within the time-frame of this project, we will identify a candidate oxaborole antimalarial for development and that we will gain important insights into the antimalarial mechanisms of action of these compounds.