靶向恶性疟原虫DHODH的新型小分子抑制剂的设计、合成和抗疟活性评价

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) has been regarded as an attractive target for the treatment of malaria. In our upfront work, a promising hit compound (AM04) with a novel 3,5-disubstituted-1,2,4-triazole scaffold was identified by a ligand- and structure-based virtual screening. Here in, rational drug design、virtual ADME evaluation and molecular docking are utilized for structural optimization and modification of AM04 focusing on core, 3-easter group and 5-aryl. A series of 3,5-disubstituted-1,2,4-triazole derivatives and analogues will be synthesized. Target compounds will be tested and evaluated for their PfDHODH inhibitory activity, species-specificity over human DHODH and in vitro antimalarial activity against FCC-1 strain. 3D-QSAR models (CoMFA and CoMSIA) will be built and structure-activity relationships will be discussed carefully. Potential leads will be evaluated by in vivo murine P. berghei efficacy model. This project is trying to identify one or two promising lead compounds, which provide theoretic and experimental basis for developing antimalarial drugs with high potency, low toxicity, good specificity and independent intellectual property rights.

恶性疟原虫二氢乳清酸脱氢酶（PfDHODH）是抗疟药物研究中的重要靶点之一，本项目拟以前期计算机虚拟筛选发现的结构新颖、活性较好的3,5-二取代-1,2,4-三氮唑类苗头化合物AM04为起点，结合理性药物设计思想、类药性虚拟筛选和分子对接对苗头化合物的母核、5-芳环和3-酯基进行结构优化改造，合成相应目标分子，评价其对PfDHODH的抑制活性、对人DHODH的种属选择性及对恶性疟原虫FCC-1虫株的抗疟活性，分析构效关系，建立定量构效关系（3D-QSAR）模型，确定影响活性的主要结构参数；在动物体内抗疟活性评价的基础上力争发现1~2个具开发前景的优良先导分子，为进一步研发高效低毒、选择性佳并具自主知识产权的抗疟新药提供理论与实验依据。

恶性疟原虫二氢乳清酸脱氢酶（PfDHODH）是抗疟药物研究中的重要靶点之一，本项目以前期计算机虚拟筛选发现的苗头化合物AM04为起点，对其进行结构优化改造，合成了一类全新结构3,5-二取代-1,2,4-三氮唑类PfDHODH抑制剂。通过系统的体外抗疟活性评价，获得了较全面的构效关系，其中4个化合物的PfDHODH抑制活性在纳摩尔级。代表性化合物27表现优异，具有很好的PfDHODH抑制活性（IC50 =0.018μM）和体外抗疟原虫活性，对氯喹抗性和非抗性虫株均敏感（Pf3D7: IC50 = 0.045 μM，PfDd2: IC50 = 0.041 μM）；体内实验表明，化合物27口服4天能够显著抑制伯氏鼠疟的生长（ED50 = 5.86 mg/kg/day）。此外，本项目还发现了一类全新结构3,6-二氯咔唑氨基醇类抗疟化合物，具有较好的体外抗疟原虫活性，但PfDHODH抑制活性很弱，对该类化合物的抗疟作用机制进行了探索，通过实验验证了该类化合物可能作用于虐色素的合成。本项目通过三年的实施，获得了1个口服体内有效、抗疟活性好、与氯喹无交叉抗性的PfDHODH抑制剂优良先导分子，为进一步发展具有自主知识产权的抗疟药物奠定基础。