Ruthenium-based antimalarial agents

钌基抗疟剂

• 批准号: 8126351
• 负责人: ROBERTO A SANCHEZ-DELGADO
• 金额: $ 31.09万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8126351
• 关键词: 5 year old; Alkylation; Aminoquinolines; Amodiaquine; Antimalarials; Area; Artemisinins; Biological; Biological Assay; Biological Factors; Characteristics; Chemicals; Chemistry; Child; Chloroquine; Chloroquine resistance; Clinical Trials; Combined Modality Therapy; Communicable Diseases; Complex; Data; Development; Drug Kinetics; Drug resistance; Drug usage; Evaluation; Funding; Goals; Health; Heme; Human; Hybrids; Individual; Inorganic Chemistry; Lead; Link; Literature; Malaria; Medicine; Mefloquine; Metals; Modification; Molecular Structure; Parasite resistance; Parasites; Pathway interactions; Pharmaceutical Preparations; Plasma; Preparation; Property; Recrudescences; Reporting; Research; Research Personnel; Resistance; Ruthenium; Scheme; Scientist; Side; Solubility; Structure; Students; Techniques; Testing; Toxic effect; Training; Trypanosoma cruzi; United States National Institutes of Health; Work; World Health Organization; artemisinine; base; benflumetol; chemotherapeutic agent; chemotherapy; drug development; experience; global health; human disease; innovation; metal complex; novel; pharmacophore; prevent; programs; public health relevance; quinoline; single molecule

DESCRIPTION (provided by applicant): Malaria is one of the most prevalent infectious diseases worldwide and it represents a major global health issue for which new effective chemotherapies are urgently needed. The most successful antimalarial drug for decades was chloroquine, but the widespread emergence of resistant parasites in most endemic areas severely limits its efficacy. First- line antimalarial treatments today are based on artemisinin and related 1, 2, 4-trioxanes; these drugs are highly active and fast acting against chloroquine-resistant malaria, but they are limited by their short plasma half-lives, which results in parasite recrudescence when used as a monotherapy. The World Health Organization currently recommends combination therapies composed of artemisinin and amodiaquine, lumefantrine or mefloquine. Nevertheless, such combinations suffer from problems related to differences in solubility and pharmacokinetics of the individual components, which may compromise the ability of the trioxanes to prevent emergence of drug resistance; therefore new effective antimalarial therapies are needed. Our long-term goal is to discover and develop novel metal-based antimalarial chemotherapeutic agents for the treatment of human disease. Our objective in this proposal is to identify new lead compounds toward ruthenium-derived drugs for the treatment of malaria and to elucidate their mechanisms of action. Our central hypothesis is that combining ruthenium with chloroquine, a trioxane, or chloroquine and a trioxane in a single molecule will lead to new multifunctional compounds effective for specific targets in resistant malaria parasites, as a result of the physicochemical characteristics of the organometallic structure. This research is based upon our previous work and data from other researchers, strongly indicating that metal-based approach is a promising alternative for the development of non-toxic chemotherapeutic agents against resistant malaria. The specific aims of the project are: 1. to synthesize and evaluate the antimalarial potential and toxicity of covalently linked Ru-chloroquine complexes targeting heme aggregation. 2. To synthesize and evaluate Ru-trioxane and Ru-(bis) trioxane complexes as potential non-toxic antimalarial agents acting by radical alkylation mechanisms. 3. To synthesize and evaluate hybrid Ru-chloroquine-trioxane complexes as potential non-toxic antimalarial agents acting by dual mechanisms. PUBLIC HEALTH RELEVANCE: Malaria is one of the most prevalent infectious diseases worldwide; 300-500 million people become infected and close to a million die of malaria each year, mostly children under 5 years of age. The most important issue in the treatment of malaria today is the widespread emergence of resistance to commonly used drugs. This proposal presents a promising alternative toward the development of novel and effective metal-based antimalarial therapies and it opens important avenues of research for understanding their mechanisms of action.

描述（由申请人提供）：疟疾是全球最普遍的传染病之一，它代表了迫切需要新的有效化学疗法的一个主要全球健康问题。几十年来，最成功的抗疟药是氯喹，但在大多数地方性地区，抗性寄生虫的广泛出现严重限制了其功效。当今的一线抗疟疾治疗基于青蒿素和相关的1、2、4-三氧烷；这些药物具有高度活跃和快速对抗氯喹的疟疾作用，但它们受到短血浆半衰期的限制，这在用作单一疗法时会导致寄生虫复发。世界卫生组织目前建议组合疗法，由阿耳马素和阿莫迪亚喹，lumefantrine或甲氟喹组成。然而，这种组合遭受了与各个成分溶解性和药代动力学差异有关的问题，这可能会损害三人X烷在防止耐药性中出现的能力；因此，需要新的有效抗疟疾疗法。 我们的长期目标是发现和开发新型的基于金属的抗疟药化学治疗剂来治疗人类疾病。我们在这项提案中的目标是确定新的铅化合物，用于芬太尼衍生的药物治疗疟疾，并阐明其作用机理。我们的中心假设是，将ruthenium与单个分子中的氯喹，三人烷或氯喹和三人烷结合在一起，将导致有效的抗性疟疾寄生虫特异性靶标的新的多功能化合物，这是有机化结构的物理学特征的结果。这项研究基于我们以前的工作和其他研究人员的数据，强烈表明基于金属的方法是开发抗抗性疟疾的无毒化学治疗剂的有希望的替代方法。该项目的具体目的是：1。综合和评估靶向血红素聚集的共价连接的Ru-Choroquine复合物的抗疟疾潜力和毒性。 2。综合和评估Ru-Trioxane和Ru-（Bis）三反X烷复合物作为通过自由基烷基化机制作用的潜在无毒抗性剂。 3。综合和评估杂交ru-氯喹硫代烷络合物作为通过双重机制作用的潜在无毒抗性剂。 公共卫生相关性：疟疾是全球最普遍的传染病之一；每年有300-50万人被感染，接近一百万的疟疾死亡，主要是5岁以下的儿童。当今疟疾治疗的最重要问题是对常用药物的抗药性的广泛出现。该提案为开发新型和有效的金属抗疟疾疗法提供了一种有希望的替代方法，并为理解其作用机理开辟了重要的研究途径。