结核病仍然是我国面临的重大健康难题，针对缺乏理想抗结核药物的现状，本课题目标是针对新型的结核菌毒力蛋白（mPTPB）靶点，筛选高效、特异、低毒的抗结核菌的活性先导物。项目前期研究中，从一株海洋真菌Diaporthe sp. SYSU-HQ3中，发现两种新的具有强抑制mPTPB活性的化合物diaporisoindole A和tenellone C， IC50值分别为4.2和5.2μM。本项目在此基础上，以mPTPB为筛选靶点，对海洋真菌Diaporthe sp. SYSU-HQ3进行深入研究，从该菌中发现更多的、新的、mPTPB抑制剂；并通过优化培养条件，规模化制备diaporisoindole A和tenellone C；对两种活性化合物进行结构修饰和构构效关系研究，并进行抗结核活性和初步急性毒性研究，获得高效低毒的抗结核活性先导化合物，为其临床前实验打下基础。

Tuberculosis (TB) is a devastating infectious disease around the China, there is an urgent need for new programmes and strategies to improve the effectiveness against TB. For the lack of the efficient and less toxic agents to cure and eradication of TB, the Mtb protein tyrosine phosphatase B(mPTPB) as an important target, was used to screen more potent, specific, and less toxic inhibitors.In our previous investigations, diaporisoindole A and diaporisoindole C, two novel mPTPB inhibitors with IC50 values of 4.2 and 5.2 μM, respectively, were isolated and identified from the mangrove endophytic fungus Diaporthe sp. SYSU-HQ3. On the basis of this findings, it is worthy for us to further investigation of this fungus so as to find more potency and new mPTPB inhibitors.The strategies including optimization the cultivation medium to improve the production of diaporisoindole A and tenellone C, and the structure modification toward the active compounds diaporisoindole A and tenellone C were carried out. The obtained compounds from this proposal were evaluated for their mPTPB inhibitory activity, and the acute toxicity to animals to discover efficient and less toxic lead compounds, which can provide a foundation for clinical research.