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4-Aminoquinoline Antimalarials Containing a Benzylmethylpyridylmethylamine Group Are Active against Drug Resistant Plasmodium falciparum and Exhibit Oral Activity in Mice
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-12-07 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01537
Mukesh C. Joshi 1 , John Okombo 1 , Samkele Nsumiwa 1 , Jeffrey Ndove 2 , Dale Taylor 2 , Lubbe Wiesner 2 , Roger Hunter 1 , Kelly Chibale 1, 3 , Timothy J. Egan 1
Affiliation  

Emergence of drug resistant Plasmodium falciparum including artemisinin-tolerant parasites highlights the need for new antimalarials. We have previously shown that dibemequines, 4-amino-7-chloroquinolines with dibenzylmethylamine (dibemethin) side chains, are efficacious. In this study, analogues in which the terminal phenyl group of the dibemethin was replaced with a 2-pyridyl group and in which the 4-amino-7-chloroquinoline was either maintained or replaced with a 4-aminoquinoline-7-carbonitrile were synthesized in an effort to improve druglikeness. These compounds exhibited significantly improved solubility and decreased lipophilicity and were potent against chloroquine-sensitive (NF54) and -resistant (Dd2 and 7G8) P. falciparum strains with 5/6 having IC50 < 100 nM against the NF54 strain. All inhibited both β-hematin (synthetic hemozoin) formation and hemozoin formation in the parasite. Parasitemia was reduced by over 90% in P. berghei infected mice in 3/6 derivatives following oral dosing at 4 × 30 mg/kg, with microsomal metabolic stability data suggesting that this could be attributed to highly active metabolites.

中文翻译:

包含苄基甲基吡啶基甲基胺基团的4-氨基喹啉抗疟药具有抗药性恶性疟原虫的活性,并具有小鼠口服活性

耐药性恶性疟原虫(包括青蒿素耐受性寄生虫)的出现凸显了对新型抗疟药的需求。先前我们已经表明,双苯甲喹,具有二苄基甲胺(dibemethin)侧链的4-氨基-7-氯喹啉是有效的。在这项研究中,合成了如下类似物:其中,将地贝米星的末端苯基替换为2-吡啶基,并维持4-氨基-7-氯喹啉或替换为4-氨基喹啉-7-腈。努力改善药物相似性。这些化合物显示出显着改善的溶解度和降低的亲脂性,并且对氯喹敏感性(NF54)和抗性(Dd2和7G8)恶性疟原虫菌株具有IC 50为5/6的作用对于NF54株,<100 nM。所有这些都抑制了寄生虫中的β-血凝素(合成的血zo素)的形成和血zo素的形成。口服剂量为4×30 mg / kg的3/6衍生物后,感染伯氏疟原虫的小鼠的3/6衍生物中的寄生虫血症降低了90%以上,微粒体代谢稳定性数据表明,这可能归因于高活性代谢物。
更新日期:2017-12-07
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