理肺散中抗结核活性生物碱的定向发现及作用机制初步研究

结核病是全球近年来由单一病原微生物感染导致死亡的头号杀手，而现有药物多具有毒副作用、且耐药性不断增强，因此从中药中定向发现新颖抗结核活性成分用于开发新型高效低毒抗结核药物具有重要意义。理肺散是一味对肺结核具有特色疗效的药食两用中药，但其抗结核活性成分尚不清楚，前期申请人通过“活性追踪、液质指认”的研究策略初步发现其抗结核有效部位主要为单萜吲哚生物碱类成分，且UPLC-HRMS分析表明有效部位中可能存在一系列该类微量新颖活性成分。因此，本项目拟在活性与UPLC-HRMS相结合的研究策略指导下，设计特异性的富集纯化方法，快速获得富含单萜吲哚生物碱的有效部位及单体化合物，进一步通过抗结核活性筛选优选出活性显著、结构新颖的先导化合物，并对其作用机制展开初步研究。本项目不仅能够为开发新型高效低毒抗结核药物奠定基础，同时为阐明理肺散抗结核药效物质基础及充分开发与利用提供科学依据。

Tuberculosis is the leading cause of death attributable to a single infectious pathogen in recent years but the existing drugs mostly have side effects and the growing problem of antibiotic resistance. Therefore, the search for new antituberculosis drugs with high efficacy and low toxicity had become an urgent need for patients. Hedyotis scandens is an edible Chinese herbal, which has been recorded as a therapeutic agent for tuberculosis but its active ingredient is not yet clear. Our resent study showed that its ethanol extracts exhibited significant antituberculosis activity and the monoterpene indole alkaloids could be the main active components. Moreover, it was proved that some novel active compounds might be contained based on bioactivity-guided and UPLC-HRMS analysis, which indicated the presence of novel antituberculosis compounds in Hedyotis scandens. Thus, a specific enrichment and purification method will be optimized to fast and directionally isolate novel antituberculosis compounds under the bioactivity-guided and UPLC-HRMS analysis. Their structure elucidation, antituberculosis activity, and active mechanism will be further researched to found antituberculosis lead compounds. In this project, the result will be provide molecular templates for development of new antituberculosis drugs, and provide scientific basis for the exploitation of Hedyotis scandens.