Ruthenium-based antimalarial agents

钌基抗疟剂

• 批准号: 7939393
• 负责人: ROBERTO A SANCHEZ-DELGADO
• 金额: $ 31.4万
• 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/7939393
• 关键词: 5 year old; Alkylation; Aminoquinolines; Amodiaquine; Antimalarials; Area; Artemisinins; Arts; Biological; Biological Assay; Biological Factors; Chagas Disease; 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; Half-Life; 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; Poison; 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; analog; artemisinine; base; benflumetol; chemotherapeutic agent; chemotherapy; drug development; experience; global health; human disease; innovation; metal complex; novel; pharmacophore; prevent; programs; public health relevance; quinoline; s-trioxane; 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）：疟疾是世界范围内最流行的传染病之一，它是一个重大的全球健康问题，迫切需要新的有效化疗方法。几十年来最成功的抗疟药物是氯喹，但大多数流行地区广泛出现的耐药寄生虫严重限制了其疗效。当今的一线抗疟治疗基于青蒿素和相关的 1,2,4-三恶烷；这些药物对氯喹耐药性疟疾具有高活性和快速作用，但其血浆半衰期短，当用作单一疗法时会导致寄生虫复发。世界卫生组织目前推荐由青蒿素和阿莫地喹、本芴醇或甲氟喹组成的联合疗法。然而，此类组合存在与各个组分的溶解度和药代动力学差异相关的问题，这可能会损害三恶烷防止出现耐药性的能力；因此，需要新的有效的抗疟疗法。 我们的长期目标是发现和开发新型金属基抗疟化疗药物来治疗人类疾病。我们在此提案中的目标是确定用于治疗疟疾的钌衍生药物的新先导化合物并阐明其作用机制。我们的中心假设是，由于有机金属结构的物理化学特性，将钌与氯喹、三恶烷或氯喹和三恶烷结合在一个分子中将产生新的多功能化合物，对耐药性疟疾寄生虫的特定目标有效。这项研究基于我们之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针对耐药性疟疾的无毒化疗药物的有前途的替代方案。该项目的具体目标是： 1. 合成并评估针对血红素聚集的共价连接的 Ru-氯喹复合物的抗疟潜力和毒性。 2. 合成并评价Ru-三恶烷和Ru-(双)三恶烷配合物作为通过自由基烷基化机制发挥作用的潜在无毒抗疟剂。 3. 合成并评估Ru-氯喹-三恶烷杂化复合物作为潜在的无毒抗疟药物，通过双重机制发挥作用。 公共卫生相关性：疟疾是全世界最流行的传染病之一；每年有 300-5 亿人被感染，近一百万人死于疟疾，其中大多数是 5 岁以下的儿童。当今疟疾治疗中最重要的问题是普遍出现对常用药物的耐药性。该提案为开发新型有效的金属抗疟疗法提供了一种有前景的替代方案，并为了解其作用机制开辟了重要的研究途径。