Designed Antimalarial Agents Overcoming Chloroquine-Resistance

描述（由申请人提供）：本提案中提出的工作意图是应对抗氯喹疟疾传播带来的全球健康问题。为了满足对可口服且价格低廉的替代药物的需求，我们开发了一种称为“反向氯喹”（RCQs）的新型分子，它既可治疗氯喹耐药疟疾，也可治疗氯喹敏感疟疾。在此，我们描述了一个新的RCQ分子亚类，我们称之为分枝RCQ （bRCQ）分子。这些bRCQ分子甚至可能比“简单”的rcq更好。该项目的目标是了解如何优化bRCQ分子的结构特征，以产生最佳的口服抗疟疾药物。这将通过生产一组不同的bRCQ结构来完成，然后在红细胞培养（体外测试）中测试它们对氯喹敏感和氯喹抗性疟疾的抗性，以及溶解度、中枢神经系统受体活性和细胞毒性。然后，最有希望的候选药物将作为口服的抗疟疾药物在小鼠中进行评估。一旦这些实验证明了bRCQ分子设计的可行性，并对bRCQ分子特征与抗疟疾功效之间的相关性提供了基本的理解，bRCQ结构将被“调整”，以优化它们在人类中的实际应用。虽然我们的研究是专门针对恶性疟原虫（最有问题的人类疟疾变体），但bRCQs也应该对其他人类疟疾有效。虽然某些“地方性市场”的利润率可能非常微薄，但在印度和中国等国家，支付药品的能力正在增强，而且军事和旅游市场有望实现合理的商业化。

DESCRIPTION (provided by applicant): The intent of the work presented in this proposal is to counter the worldwide health problem brought on by the spread of chloroquine-resistant malaria. To address the need for an orally available and inexpensive replacement drug, we have developed a novel class of molecules called "reversed chloroquines" (RCQs) which act against both chloroquine-resistant and chloroquine-sensitive malaria. Herein we describe a new sub-class of RCQ molecules, which we term branched RCQ (bRCQ) molecules. These bRCQ molecules may be even better than the 'simple' RCQs. The goal of the described project is to understand how to optimize structural features in the bRCQ molecules to yield the best possible, orally available drug against malaria. This will be accomplished by producing a panel of varied bRCQ structures, and then testing them against chloroquine-sensitive and chloroquine-resistant malaria in red cell culture (an in vitro test), 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. Once these experiments demonstrate the feasibility of the bRCQ molecular design, as well as provide fundamental understanding of correlations between molecular features and efficacy of bRCQs against malaria, the bRCQ structures will be "tuned" in order to optimize practical aspects of their use in humans. Although we are directing this study specifically against P. falciparum, the most problematic human malaria variant, bRCQs should also be effective against the other human malarias. Although there may be a very thin profit margin to be had some 'endemic markets', there is an increasing ability to pay for drugs in countries such as India and China and the military and traveler markets have promise for reasonable commercialization.