基于天然产物优势结构的新型抗结核化合物的设计合成及生物学评价

结核杆菌分枝菌酸生物合成途径一直是非常重要的抗结核药物靶标，负责催化分枝菌酸合成最后一步的Pks13是近年来被证实的潜在新靶点。本项目采取基于天然产物的优势结构开展的合理抗结核药物设计合成为策略，发现和发展靶向Pks13的类天然产物抗结核杆菌活性化合物(coumestan衍生物)，并评估化合物的抗结核效果及初步的药代动力学、毒理学性质，阐述相关分子作用机制，深入探索具有全新作用机制的小分子化合物在结核病领域的潜在应用价值，获得具有全新作用机制和优异的体内、外活性的抗结核药物先导化合物，为寻找治疗MDR、XDR甚至是TDR的临床候选药物打下基础。同时关注化合物对血脑屏障通透性，发展可以透过血脑屏障的活性化合物，用于开发高死亡率的中枢神经系统感染结核病例的治疗药物。

Disrupting the mycolic acid biosynthetic pathway is a well proven and effective therapeutic target for chemical intervention for TB. Pks13 is responsible for the last step of mycolic acid biosynthesis and is validated as a viable target for future antitubercular research. The current proposed project aimed at developing novel anti-TB compounds targeting Pks13 with privileged structures from natural products (coumestan derivatives). We propose to extend these studies to explore the potential use in anti-TB therapeutics. The newly synthesized coumestan and benzofuran derivatives will be tested against drug susceptible H37Rv strain of M.tb. in tandem with preliminary measurements of some key ADME-tox properties including the permeability to the BBB. Our innovative approach aim to development of novel entities with potential to move into clinical trials as anti-TB medications, especially in the case of MDR, XDR, or the deathly CNS-TB.