Designed Antimalarial Agents Overcoming Chloroquine-Resistance

描述（由申请人提供）：本提案中提出的工作的目的是应对由氯喹耐药性疟疾传播带来的全球健康问题。为了满足对口服和廉价替代药物的需求，我们开发了一类称为“逆转氯喹”（RCQ）的新型分子，其对氯喹耐药性和氯喹敏感性疟疾均起作用。本文中，我们描述了一个新的RCQ分子的子类，我们称之为支化RCQ（bRCQ）分子。这些bRCQ分子甚至可能比“简单”RCQ更好。该项目的目标是了解如何优化bRCQ分子的结构特征，以产生最好的口服抗疟疾药物。这将通过产生一组不同的bRCQ结构来实现，然后在红细胞培养物中测试它们对氯喹敏感和氯喹抗性疟疾的影响（体外测试），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。一旦这些实验证明了bRCQ分子设计的可行性，以及提供对bRCQ抗疟疾的分子特征和功效之间的相关性的基本理解，bRCQ结构将被“调整”，以优化其在人类中使用的实际方面。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种，bRCQ也应该对其他人类疟疾有效。虽然在一些“地方性市场”可能存在非常微薄的利润空间，但在印度和中国等国家，支付药物的能力越来越强，军事和旅行者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.