Developing triazolopyrimidines as novel anti-tubercular agents

开发三唑并嘧啶作为新型抗结核药物

• 批准号: 10672660
• 负责人: Tanya Parish
• 金额: $ 49.23万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-17 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10672660
• 关键词: Animal Model; Anti-Bacterial Agents; Antibiotics; Antimicrobial Resistance; Antitubercular Agents; Bacteria; Biological; Cell Wall; Cessation of life; Chronic; Clinical; Data; Development; Drug Kinetics; Drug Targeting; Drug resistance; Electron Transport; Future; Genetic Transcription; Goals; Health; In Vitro; Infection; Lead; Metabolic; Modeling; Monitor; Mycobacterium tuberculosis; New Agents; Organism; Outcome; Pathway interactions; Penetration; Persons; Pharmaceutical Preparations; Phase II Clinical Trials; Population; Property; Quantitative Structure-Activity Relationship; Regimen; Reporting; Resistance; Respiration; Series; Structure; Testing; Translations; Tuberculosis; Work; World Health Organization; analog; combat; cytotoxicity; design; drug candidate; drug development; drug discovery; drug-sensitive; global health; improved; in vivo; inhibitor; mouse model; multiple drug use; mutant; mycobacterial; novel; novel therapeutics; resistant strain; respiratory; targeted treatment; therapeutically effective; tuberculosis drugs; tuberculosis treatment

Project Summary Mycobacterium tuberculosis, the causative agent of tuberculosis, is a major health problem globally. The World Health Organization reports that billions of people are latently infected with the organism, the number of new cases continues to rise (>10 million in 2019) and >1 million died from tuberculosis in 2019. Current anti-tubercular drugs are mainly effective against metabolically active and replicating bacteria. In addition to the need for new antibiotics that are effective against both drug sensitive and drug resistant strains, there is an urgent need for new therapeutics that can shorten therapy. We have identified the triazolopyrimidines as anti-tubercular agents. The series has attractive biological properties with potent anti-tubercular activity, activity against non-replicating (persistent/tolerant) bacteria, a narrow spectrum of activity, and low cytotoxicity. Our preliminary data suggests that these molecules target a key step in bacterial respiration. We have made analogs of the series which show potential for further development. Our long-term goal is to develop the triazolopyrimidines series as new anti-tubercular agents with excellent physicochemical and biological properties. In this 3-year proposal we will complete sufficient exploration of the series to generate proof of concept that the molecules work in an animal model of infection. We will also conduct studies to identify the target and/or mode of action and to determine which other drugs (or drug candidates) would be the best partners for a novel combination regimen. The outcomes of this project would be (i) confirmation that the triazolopyrimidine series is a tractable series for further development as a novel anti-tubercular drug; (ii) confirmation of the mode of action; and (iii) identification of the best combination partners. Demonstration of in vivo activity and tractability of the series would lead to a full drug discovery and development project in the future.

项目摘要 结核分枝杆菌（Mycobacterium tuberculosis）是结核病的病原体，是全球主要的健康问题。世界 卫生组织报告说，数十亿人潜伏感染了这种生物， 病例继续增加（2019年超过1000万），2019年死于结核病的人数超过100万。当前抗结核药物 药物主要对代谢活性和复制细菌有效。除了需要新的 对于既能有效对抗药物敏感菌株又能有效对抗药物抗性菌株的抗生素， 可以缩短治疗时间的新疗法。 我们已经确定了三唑并嘧啶类抗结核药物。该系列具有吸引人的生物 具有强效抗结核活性、抗非复制性（持久性/耐受性）细菌活性、 活性谱窄，细胞毒性低。我们的初步数据表明，这些分子的目标是 细菌呼吸的关键步骤。我们已经做了系列的类似物，这些类似物显示出进一步开发的潜力。 发展 我们的长期目标是开发三唑并嘧啶系列作为新的抗结核药物， 物理化学和生物学特性。在这3年的计划中，我们将完成对 系列，以产生概念证明，这些分子在感染的动物模型中起作用。我们还将进行 研究，以确定目标和/或作用模式，并确定哪些其他药物（或候选药物） 将是新的联合疗法的最佳搭档。 该项目的结果将是（i）确认三唑并嘧啶系列是一个易于处理的系列， 进一步开发为新型抗结核药物;（ii）确认作用方式;（iii）鉴定 最佳组合伙伴。该系列的体内活性和易处理性的证明将导致 未来的药物发现和开发项目。