Dual Function Acridones as A New Antimalarial Chemotype

描述（由申请人提供）：疟疾仍然是世界上最致命的疾病之一，摧毁了数百万人的生命，并使家庭、社区甚至国家陷入困境，其负担粉碎了希望。这种疾病的破坏性影响超出了每年的死亡人数，影响到家庭和社会结构，影响到流行地区的持续贫困，并给世界40%的人口造成了难以形容的痛苦。造成这一灾难性局势的主要原因是，造成最致命疟疾的原因是具有多重抗药性的恶性疟原虫的出现和蔓延，并因这种疟原虫的出现和蔓延而加剧。单一疗法和高度可变的药物靶标都促进了耐药性，并且在对抗MDR疟疾的有效长期策略中两者都是不可取的。由于目前或在不久的将来没有可用的疫苗，迫切需要新型、低成本、有效、安全和可持续的疟疾治疗。 如果根除疟疾的全球努力要取得成功，该努力的化学治疗和化学预防组成部分都必须解决现有治疗手段中的差距和弱点。负担能力、最脆弱人群的安全性和耐药性适应的低敏感性都是未满足的需求。与其他药物类别（例如，呼吸抑制剂和抗叶酸剂），对喹啉类抗疟药的耐药性发展缓慢（例如，氯喹）或低级（例如，奎宁）。对于这类较老的药物，成本非常低，在儿童和妊娠期间使用它们有广泛的经验，并且由于药物消除时间很长，因此便于短期治疗。 奇怪的是，虽然氯喹的失败是全球耐药性危机的核心，但这些药物实际上是目前寻求用于治疗和间歇性预防的抗疟新药的理想特征。 在这项提案中以及我们最近在《自然》杂志上发表的文章中描述的新型化学型代表了一种革命性的方法。它的具体目标是通过使新的联合治疗策略成为可能来利用具有理想性状的其他化合物的优势。我们的创新吖啶酮设计解决了一个不可变的寄生虫目标，并在单个分子中融合了内在效力与抵抗力抵消功能，并且是第一个也是唯一一个报告这样做的化学型。它代表了一种扩大、增强和维持有效抗疟药物组合的新策略。 增强新药疗效的能力（例如，哌喹）和恢复旧药物的功效（例如，氯喹）是一种独特的强有力的工具，非常适合在新的消灭疟疾努力中实现尽可能广泛的惠益。鉴于疟疾的全球影响范围，这些努力取得成功的意义不亚于改善数百万人的生活，并有机会改变整个国家的面貌。 公共卫生相关性：本申请题为“双功能吖啶酮作为一种新的抗疟疾化学型”，涉及广泛的挑战领域（15）转化科学和具体的挑战主题15-AI-103：开发被忽视的热带疾病的药物，特别强调疟疾。 我们已经发现并寻求改进用于治疗疟疾的双功能抗疟吖啶酮。 每年有数百万人死于疟疾，因此迫切需要新的抗疟药物，这些药物应能有效对抗耐多药感染，对儿童和孕妇安全。如果这些药物被证明是安全和有效的，足以投入实际使用，其潜在的好处不亚于挽救数百万人的生命。

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.