Novel diaryl ureas with efficacy in a mouse model of malaria

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• 作者：John W. Anderson^a ; Dimitri Sarantakis^a ; Jacek Terpinski^a ; T.R. Santha Kumar^b ; Han-Chun Tsai^c ; Mack Kuo^c ; Arba L. Ager^d ; William R. Jacobs Jr. Jr.^e ; ^f ; Guy A. Schiehser^a ; Sean Ekins^g ; James C. Sacchettini^c ; David P. Jacobus^a ; David A. Fidock^b ; Joel S. Freundlich^h ; ⁱ ; ^{freundjs@umdnj.edu}
• 关键词：Plasmodium falciparum ; Malaria ; Drug discovery ; Diaryl urea
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：15 February, 2013
• 年：2013
• 卷：23
• 期：4
• 页码：1022-1025
• 全文大小：422 K

文摘

Exploration of triclosan analogs has led to novel diaryl ureas with significant potency against in vitro cultures of drug-resistant and drug-sensitive strains of the human malaria parasite Plasmodium falciparum. Compound 18 demonstrated EC₅₀ values of 37 and 55 nM versus in vitro cultured parasite strains and promising in vivo efficacy in a Plasmodium berghei antimalarial mouse model, with >50 % survival at day 31 post-treatment when administered subcutaneously at 256 mg/kg. This series of compounds provides a chemical scaffold of novel architecture, as validated by cheminformatics analysis, to pursue antimalarial drug discovery efforts.