直接作用在亮氨酰-tRNA合成酶抑制剂的设计、合成与抗结核活性评价

目前，结核病的死亡率已超过艾滋病成为全球第一大传染性疾病，全球抗结核药物研究进展较为缓慢。研究发现化合物GSK-3036656能够通过作用于结核分枝杆菌的LeuRS而发挥抗结核活性。然而该化合物并非直接作用于LeuRS，而是在体内首先与AMP形成共价加合物，然后再与LeuRS作用。鉴于目前没有发现对LeuRS具有直接作用的抗结核药物。本研究拟以GSK-3036656/AMP共价加合物为先导，基于其构效关系，通过药物化学理论和计算机辅助药物设计，获得能够直接作用于LeuRS的小分子抑制剂。利用构建的以LeuRS为靶点的筛选模型进行活性筛选，以证明药物设计的合理性。并对该类抑制剂的抗结核活性机理及药代动力学性质等进行研究，优选出具有临床前研究价值的候选化合物。本课题的设计思想先进、合理，药物作用靶点新颖，具有较扎实的理论研究和实践研究基础，可为开发直接作用于LeuRS的抗结核药物研究奠定基础。

At present, the death rate of tuberculosis has surpassed that of AIDS and has become the world's largest infectious disease, and the global research progress on anti-TB drugs has been slow. Studies have found that compound GSK-3036656 can exert anti-tuberculosis activity by acting on LeuRS of Mycobacterium tuberculosis. Given that no anti-tuberculosis drugs that have a direct effect on LeuRS are currently found. This study intends to use GSK-3036656 / AMP covalent adduct as the lead compound, based on its structure-activity relationship, through medicinal chemistry theory and computer-aided drug design, to obtain small molecule inhibitors that can directly act on LeuRS. The constructed screening model targeting LeuRS was used for active screening to prove the rationality of drug design. And the anti-tuberculosis activity mechanism and pharmacokinetic properties of the inhibitors were studied, and candidate compounds with preclinical research value were selected. The design idea of this subject is advanced and reasonable, and the target of the drug is novel. It has a solid theoretical and practical research foundation, which can lay the foundation for the development of anti-tuberculosis drugs that directly affect LeuRS.