Developing triazolopyrimidines as novel anti-tubercular agents

项目摘要 结核分枝杆菌是结核病的病原体，是全球主要的健康问题。世界 卫生组织报告称，数十亿人潜伏感染这种微生物，新增人数 病例继续上升(2019年为1000万例)，2019年有100万例死于结核病。当前抗结核药物 药物主要对代谢活跃和复制细菌有效。除了需要新的 对于对药物敏感和耐药菌株都有效的抗生素，迫切需要 可以缩短治疗时间的新疗法。 我们已确定三唑并嘧啶类化合物为抗结核药物。该系列具有诱人的生物学特性 具有强大的抗结核活性的特性，对非复制(持久性/耐受性)细菌的活性， 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 细菌呼吸的关键一步。我们已经对这一系列进行了类比，显示出进一步发展的潜力 发展。 我们的长期目标是开发三唑并嘧啶类化合物作为新的抗结核药物，具有良好的 理化和生物学特性。在这份为期3年的计划中，我们将完成对 系列以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) 将是一种新的联合疗法的最佳合作伙伴。 这一项目的成果将是：(一)确认三唑并嘧啶系列是一种易于处理的系列 作为一种新的抗结核药物的进一步开发；(2)作用模式的确认；以及(3)鉴定 最好的组合合伙人。该系列在体内的活性和易操纵性的展示将导致 未来将全面开展药物发现和开发项目。

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.