Macfarlane Burnet Institute for Medical Research and Public Health , Melbourne, 3004, Australia.
Monash University , Clayton, Victoria 3800, Australia.
J Med Chem. 2017 Feb 9;60(3):1171-1188. doi: 10.1021/acs.jmedchem.6b01673. Epub 2017 Jan 26.
Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.
新型抗疟治疗药物，需要针对寄生虫生命周期的多个阶段，以应对当前药物抗药性的出现问题。在这里，我们描述了 2-苯胺喹唑啉类作为抗疟药物的优化。该类别从公开的抗疟筛选数据中确定，经过优化，生成了具有与已知抗疟药氯喹和甲氟喹相当的抗疟原虫活性的先导化合物。在优化过程中，我们确定了活性所必需的功能，并提高了体外代谢和溶解度。所得的先导化合物对多重耐药株疟原虫具有很强的活性，并在无性阶段的环期和配子体发生期阻止寄生虫。最后，我们证明在 4 天的疟疾疾病负担的小鼠模型中，先导化合物具有口服疗效。
