Novel Synergistic Antimalarials with Resistance Reversal Function

尽管为根除疟疾作出了广泛努力，但疟疾对全球的影响仍然令人震惊。这个 毁灭性的局势在很大程度上是由于多药的出现和传播而加剧的-- 抗药性恶性疟原虫是最致命的疟疾形式的原因。预防和拖延 抗药性的出现是抗疟疾药物开发的一个重要目标。单一疗法和高度 可变的药物靶点每个都促进了耐药性，从长远来看，两者都是不受欢迎的 对抗多药耐药疟疾的战略。本提案中描述的新的化学类型代表一种 革命性的方法。它特别旨在通过以下方式利用其他具有理想特性的化合物的优点 使一种新的联合治疗策略成为可能。我们的创新设计解决了一种不变的寄生虫 靶标，并在单个分子中融合了固有的效力和抗阻功能。它代表着一种 扩大、加强和维持有效的抗疟疾药物组合的新战略。我们建议的工作是 这项应用寻求开发新的、有效的、安全的、廉价的和可持续的抗疟疾药物，可以联合 与其他抗疟疾药物组成协同组合治疗疟疾，从而在世界范围内支持 消灭这种疾病。该项目的具体目标是最大限度地发挥双重免疫系统的抗疟疾潜力。 通过药效、协同、药理和代谢结构优化实现吖啶酮类化合物的功能 稳定性；完成通过该计划开发的主要候选对象的临床前评估 研究；评估安全性，探讨这些协同抗疟疾药物的作用模式(S 并探索对某些吖啶酮候选药物的耐药性倾向。

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. The devastating situation is largely attributed to and aggravated by the emergence and spread of multidrug- resistant Plasmodium falciparum, the cause of the deadliest form of malaria. Preventing and delaying emergence of drug-resistance is an essential goal of antimalarial drug development. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against multi-drug resistant malaria. The novel chemotype described in this proposal represents a revolutionary approach. It specifically aims to exploit the strengths of other compounds with ideal traits by making possible a new combination therapy strategy. Our innovative design addresses an immutable parasite target and merges intrinsic potency with resistance-counteracting functions in a single molecule. It represents a novel strategy to expand, enhance, and sustain effective antimalarial drug combinations. Our proposed work in this application seeks to develop novel, potent, safe, inexpensive, and sustainable antimalarial that can be co- formulated with other antimalarials in a synergistic combination to treat malaria, thus supporting world-wide elimination of the disease. The specific goal of this project is to maximize the antimalarial potential of the dual- function acridone chemotype through structural optimization for potency, synergy, pharmacology and metabolic stability; to accomplish preclinical assessment of lead candidates that are developed through this program of research; to evaluate for safety, to investigate the mode of action(s) for these synergistic antimalarial acridones, and to explore the propensity for drug resistance to selected acridone candidates.