Reversed Chloroquines as Antimalarial Agents

描述（由申请人提供）：本提案中提出的工作的目的是解决由氯喹耐药疟疾传播带来的全球健康问题。提出了一种称为“逆转氯喹”（RCQ）的口服可获得的且廉价的替代药物，其预期对氯喹抗性和氯喹敏感的疟疾都起作用。具体而言，为这项研究提出了以下目标：目标1。了解如何优化下一代RCQ分子的结构特征。这将通过产生一组不同的RCQ结构来实现，然后测试它们对氯喹敏感和氯喹抗性疟疾的影响，以及溶解度，中枢神经系统受体活性和细胞毒性。最有希望的候选药物将作为口服药物在小鼠中进行评估。 目标2.评估RCQ的作用方式。这将通过设计和测试对RCQ结构具有战略改变的RCQ变体以探测其抗疟疾作用的特定方面、通过血红素和RCQ之间相互作用的光谱研究、通过抑制疟原虫色素形成以及通过测量共同施用的CQ对CQ积累/流出的影响来实现。在确定了RCQ分子设计的可行性，以及提供了对RCQ抗疟疾的分子特征和功效之间的相关性的基本理解之后，将对RCQ结构进行“调整”，以优化其在人类中使用的实际方面。虽然我们正在指导这项研究专门针对恶性疟原虫，最有问题的人类疟疾变种，RCQ也应该对其他人类疟疾的红细胞阶段有效。疟疾是一种每年感染近5亿人的疾病，造成100万至300万人死亡，其中大多数是儿童或孕妇。疟疾的影响正在增加，部分原因是导致疟疾的寄生虫已经进化成对我们治疗这种疾病的最佳药物具有抗药性的菌株。本项目概述的这项工作是生产和测试旨在规避这种耐药性的新药，以及阐明这些新药的工作方式。

DESCRIPTION (provided by applicant): The intent of the work presented in this proposal is to address the worldwide health problem brought on by the spread of chloroquine-resistant malaria. An orally available and inexpensive class of replacement drugs termed "reversed chloroquines" (RCQs) is proposed which are expected to act against both chloroquine- resistant and chloroquine-sensitive malaria. Specifically, the following goals are proposed for this research: Goal 1. To understand how to optimize structural features in the next-generation set of RCQ molecules. This will be accomplished by producing a panel of varied RCQ structures, and then testing them against chloroquine-sensitive and chloroquine-resistant malaria, as well as for solubility, central nervous system receptor activity, and cytotoxicity. The most promising candidates will then be evaluated as orally available drugs against malaria in mice. Goal 2. To assess the RCQ mode(s) of action. This will be accomplished by design and testing of RCQ variants which have strategic alterations to the RCQ structures to probe for specific aspects of their action against malaria, by spectroscopic investigations of interactions between heme and RCQs, by inhibition of hemozoin formation, and by measuring the effects on CQ accumulation/efflux of co-administered CQ. After having established the feasibility of the RCQ molecular design, as well providing fundamental understanding of correlations between molecular features and efficacy of RCQs against malaria, the RCQ structures will be "tuned" in order to optimize practical aspects of their use in humans. Although we are directing this study specifically against Plasmodium falciparum, the most problematic human malaria variant, RCQs should also be effective against red blood cell stages of the other human malarias. Malaria is a disease that infects almost half a billion people annually, and kills between one and three million, most of whom are either children or pregnant women. The impact of malaria is increasing, partly because the parasite that causes malaria has evolved into strains that are resistant to our best drugs for treating the disease. This work outlined for this project is to produce and test novel drugs that are designed to circumvent this resistance, as well as to elucidate the way(s) in which these novel drugs work.