Quinoline Antimalarials Containing a Dibemethin Group Are Active against Chloroquinone-Resistant Plasmodium falciparum and Inhibit Chloroquine Transport via the P. falciparum Chloroquine

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• 作者：Vincent K. Zishiri ; Mukesh C. Joshi ; Roger Hunter ; Kelly Chibale ; Peter J. Smith ; Robert L. Summers ; Rowena E. Martin ; Timothy J. Egan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 13, 2011
• 年：2011
• 卷：54
• 期：19
• 页码：6956-6968
• 全文大小：1039K
• 年卷期：v.54,no.19(October 13, 2011)
• ISSN：1520-4804

文摘

A series of 4-amino-7-chloroquinolines with dibenzylmethylamine (dibemethin) side chains were shown to inhibit synthetic hemozoin formation. These compounds were equally active against cultures of chloroquine-sensitive (D10) and chloroquine-resistant (K1) Plasmodium falciparum. The most active compound had an IC₅₀ value comparable to that of chloroquine, and its potency was undiminished when tested in three additional chloroquine-resistant strains. The three most active compounds exhibited little or no cytotoxicity in a mammalian cell line. When tested in vivo against mouse malaria via oral administration, two of the dibemethin derivatives reduced parasitemia by over 99%, with mice treated at 100 mg/kg surviving the full length of the experiment. Three of the compounds were also shown to inhibit chloroquine transport via the parasite始s chloroquine-resistance transporter (PfCRT) in a Xenopus oocyte expression system. This constitutes the first example of a dual-function antimalarial for which the ability to inhibit both hemozoin formation and PfCRT has been demonstrated directly.