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抗氯喹疟疾传播所带来的全球健康问题。一种被称为“逆转氯喹”(RCQs)的口服廉价替代药物被提出，预计将对氯喹耐药性和氯喹敏感疟疾起作用。具体地说，本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。这将通过生产一组不同的RCQ结构，然后测试它们对抗氯喹敏感和抗氯喹疟疾，以及溶解性、中枢神经系统受体活性和细胞毒性来实现。然后，将对最有希望的候选药物进行评估，作为治疗疟疾的口服药物在小鼠身上使用。目标2.评估RCQ的行动模式(S)。这将通过对RCQ结构进行战略性改变的RCQ变体的设计和测试来实现，通过对其抗疟疾作用的具体方面进行探索，通过光谱分析血红素和RCQ之间的相互作用，通过抑制血球蛋白的形成，以及通过测量联合使用CQ对CQ积累/外流的影响。在确定了RCQ分子设计的可行性，以及对RCQ分子特征和RCQ抗疟疾疗效之间的相关性提供了基本了解后，RCQ结构将进行“调整”，以优化其在人类中的实际使用方面。虽然我们是专门针对恶性疟原虫进行这项研究的，但RCQS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，死亡人数在100万到300万之间，其中大多数不是儿童，就是孕妇。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好药物产生抗药性的菌株。这项为该项目概述的工作是生产和测试旨在规避这种耐药性的新药，并阐明这些新药的作用方式(S)。

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.