Dual Function Acridones as A New Antimalarial Chemotype

描述(申请人提供)：疟疾仍然是世界上最致命的疾病之一，它摧毁了数百万人的生命，给家庭、社区甚至国家带来了粉碎希望的负担。这种疾病使人士气低落的影响不仅限于每年的死亡人数，还包括对家庭和社会结构的影响，对流行地区的持续贫困的影响，以及给世界40%的人口造成难以形容的痛苦。这种毁灭性的局势在很大程度上归因于耐多药恶性疟原虫的出现和传播，并因此而加剧，恶性疟原虫是最致命的疟疾形式的原因。单一疗法和高度可变的药物靶点都促进了耐药性，这两者都不是有效的抗多药疟疾长期战略的可取之处。由于目前或在不久的将来没有可用的疫苗，迫切需要新的、低成本、有效、安全和可持续的疟疾治疗方法。 如果根除疟疾的全球努力要取得成功，这一努力的化疗和化学预防部分都必须解决现有治疗方法的空白和弱点。可负担性、对最脆弱人群的安全性以及对耐药适应的低敏感性都代表着未得到满足的需求。与其他药物类别(如呼吸抑制剂和抗叶酸)相比，对喹啉类抗疟药的抗药性发展缓慢(如氯喹)或低级(如奎宁)。对于这类较老的药物，成本非常低，在儿童和怀孕期间使用它们有丰富的经验，而且很长的药物消除时间促进了短程治疗。 矛盾的是，尽管氯喹的失败是全球抗药性危机的核心，但这些药物实际上是目前治疗和间歇性预防的新型抗疟疾药物所追求的理想。 这项提案和我们最近在《自然》杂志上发表的文章中描述的新型化学类型代表了一种革命性的方法。它的具体目标是通过开发一种新的联合治疗策略来利用其他具有理想特性的化合物的优势。我们创新的吖啶酮设计解决了一个不变的寄生虫靶标，并在单个分子中融合了固有的效力和抗药性功能，这是第一个也是唯一报道这样做的化学类型。它代表了一种新的战略，以扩大、加强和维持有效的抗疟疾药物组合。 提高新药(如哌喹)药效和恢复旧药(如氯喹)药效的能力是一种独特而强大的工具，非常适合随着新一轮根除疟疾努力的进行而获得尽可能广泛的好处。鉴于疟疾对全球的影响之大，这些努力取得成功的意义不亚于改善数百万人的生活和改变整个国家面貌的机会。 与公共卫生的相关性：这项题为“作为一种新的抗疟疾化学型的双功能生物碱类化合物”的申请涉及广泛的挑战领域(15)翻译科学和具体挑战主题15-AI-103：开发治疗被忽视的热带病的药物，特别强调疟疾。 我们已经发现并寻求改进治疗疟疾的双功能抗疟疾吖啶酮类药物。 每年有数百万人死于疟疾，迫切需要新的抗疟疾药物，这些药物对儿童和怀孕期间安全的多药耐药感染有效。如果这些药物被证明足够安全和有效，可以投入实际使用，潜在的好处不亚于拯救数百万人的生命。

DESCRIPTION (provided by applicant): Malaria remains one of the world's deadliest diseases, destroying lives by the millions and staggering families, communities and even nations with a burden that crushes hope. The demoralizing impact of the disease extends beyond the annual body count to effects on family and social structure, on sustained poverty in endemic areas, and in creating untold suffering for 40% of the world's population. The devastating situation is largely attributed to and aggravated by the emergence and spread of multi-drug resistant Plasmodium falciparum, the cause of the most deadly form of malaria. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against MDR malaria. With no available vaccine currently or in the near future, there is a dire need for novel, low cost, effective, safe, and sustainable malaria treatment. If a global effort to eradicate malaria is to be successful, both chemotherapeutic and chemoprophylactic components of that effort must address the gaps and weaknesses in the armamentarium of currently available therapies. Affordability, safety in the most vulnerable, and low susceptibility to drug resistance adaptations each represent unmet needs. In contrast to other drug classes (e.g., respiratory inhibitors and anti-folates), development of drug resistance to quinoline antimalarials has been slow (e.g., chloroquine) or of low order (e.g.,quinine). For older drugs in this class, cost is very low, there is extensive experience with their use in children and during pregnancy, and short-course therapy is facilitated by very long drug elimination times. Paradoxically then, although the failure of chloroquine is at the core of the global drug-resistance crisis, these drugs actually characterize the ideals now sought in new antimalarial drugs for both treatment and intermittent prophylaxis. The novel chemotype described in this proposal and in our recent publication featured in Nature 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 acridone design addresses an immutable parasite target and merges intrinsic potency with resistance-counteracting functions in a single molecule, and is the first and only chemotype reported to do so. It represents a novel strategy to expand, enhance, and sustain effective antimalarial drug combinations. The ability to enhance the efficacy of newer drugs (e.g., piperaquine) and to restore the efficacy of older drugs (e.g., chloroquine) represents a uniquely powerful tool, and one ideally suited to achieve the broadest possible benefit as a renewed malaria eradication effort proceeds. Given the scope of the global impact of malaria, the significance of success in these efforts would be nothing less than improving the lives of millions of individuals and the chance to change the face of entire nations. PUBLIC HEALTH RELEVANCE: This application entitled "Dual Function Acridones As A New Antimalarial Chemotype" addresses broad Challenge Area (15) Translational Science and specific Challenge Topic 15-AI-103: Develop drugs for neglected tropical diseases, with a special emphasis on malaria. We have discovered and seek to improve dual function antimalarial acridones for treatment of malaria. Millions die each year from malaria, and there is a great need for new antimalarial drugs that are effective against multi-drug resistant infection, safe in children and during pregnancy. If these drugs prove to be safe and effective enough to go into actual use, the potential benefit is nothing less than saving millions of lives.