Department of Medicinal Chemistry, ‡Department of Biosciences, and §Drug Metabolism and Pharmacokinetics (DMPK) and Animal Sciences, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
J Med Chem. 2014 Jul 10;57(13):5702-13. doi: 10.1021/jm500535j. Epub 2014 Jun 24.
Whole-cell high-throughput screening of the AstraZeneca compound library against the asexual blood stage of Plasmodium falciparum (Pf) led to the identification of amino imidazoles, a robust starting point for initiating a hit-to-lead medicinal chemistry effort. Structure-activity relationship studies followed by pharmacokinetics optimization resulted in the identification of 23 as an attractive lead with good oral bioavailability. Compound 23 was found to be efficacious (ED90 of 28.6 mg·kg(-1)) in the humanized P. falciparum mouse model of malaria (Pf/SCID model). Representative compounds displayed a moderate to fast killing profile that is comparable to that of chloroquine. This series demonstrates no cross-resistance against a panel of Pf strains with mutations to known antimalarial drugs, thereby suggesting a novel mechanism of action for this chemical class.
对阿斯利康化合物库进行全细胞高通量筛选以对抗恶性疟原虫（Pf）的无性血阶段，发现了氨基咪唑类化合物，这是启动命中到先导的药物化学工作的一个很好的起点。通过构效关系研究和药代动力学优化，确定 23 是一种具有良好口服生物利用度的有吸引力的先导化合物。化合物 23 在人源化恶性疟原虫小鼠模型（Pf/SCID 模型）中具有疗效（ED90 为 28.6mg·kg(-1)）。代表性化合物显示出中度至快速的杀伤特征，与氯喹相当。该系列化合物对一组具有已知抗疟药物突变的 Pf 株没有交叉耐药性，这表明该类化合物具有新的作用机制。
