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 结核分枝杆菌是结核病的病因，是全球主要的健康问题。世界 卫生组织报告说，数十亿人被潜在的有机体感染，新的人数 病例持续增长（2019年> 1000万），2019年因结核病而死于100万。 药物主要针对代谢活性和复制细菌有效。除了需要新的 抗药敏感和耐药菌株有效的抗生素，迫切需要 可以缩短疗法的新治疗剂。 我们已经将三唑吡啶胺鉴定为抗结核药。该系列具有吸引人的生物学 具有有效抗结核活性的特性，对非复制（持续/耐受性）细菌的活性，A 活性范围狭窄，细胞毒性低。我们的初步数据表明，这些分子针对 细菌呼吸的关键步骤。我们制作了该系列的类似物，该系列有可能进一步 发展。 我们的长期目标是开发三唑吡咪定系列，为新的抗结核剂，具有出色的 物理化学和生物学特性。在这个为期三年的建议中，我们将完成对 序列是为了产生分子在动物感染模型中起作用的概念证明。我们还将进行 研究识别目标和/或作用方式的研究，并确定哪些其他药物（或候选药物） 将是一种新型组合方案的最佳合作伙伴。 该项目的结果将是（i）确认三唑吡啶定系列是一个可易处理的系列 作为一种新型的抗结核药物进一步发展； （ii）确认作用方式； （iii）识别 最好的组合伙伴。该系列的体内活性和易处理性的演示将导致 将来的全面药物发现与开发项目。