基于5-氨基吡唑-4-甲酰胺的化合物可抑制微小隐孢子虫的生长。
5-Aminopyrazole-4-Carboxamide-Based Compounds Prevent the Growth of Cryptosporidium parvum.
作者信息
Huang Wenlin, Choi Ryan, Hulverson Matthew A, Zhang Zhongsheng, McCloskey Molly C, Schaefer Deborah A, Whitman Grant R, Barrett Lynn K, Vidadala Rama Subba Rao, Riggs Michael W, Maly Dustin J, Van Voorhis Wesley C, Ojo Kayode K, Fan Erkang
机构信息
Department of Biochemistry, University of Washington, Seattle, Washington, USA.
Division of Allergy & Infectious Diseases, Center for Emerging & Reemerging Infectious Diseases (CERID), University of Washington, Seattle, Washington, USA.
出版信息
Antimicrob Agents Chemother. 2017 Jul 25;61(8). doi: 10.1128/AAC.00020-17. Print 2017 Aug.
Abstract
calcium-dependent protein kinase 1 (CDPK1) is a promising target for drug development against cryptosporidiosis. We report a series of low-nanomolar CDPK1 5-aminopyrazole-4-carboxamide (AC) scaffold inhibitors that also potently inhibit growth Correlation between anti-CDPK1 and growth inhibition, as previously reported for pyrazolopyrimidines, was not apparent. Nonetheless, lead AC compounds exhibited a substantial reduction of parasite burden in the neonatal mouse cryptosporidiosis model when dosed at 25 mg/kg.
摘要
钙依赖性蛋白激酶1（CDPK1）是抗隐孢子虫病药物开发的一个有前景的靶点。我们报告了一系列低纳摩尔浓度的CDPK1 5-氨基吡唑-4-甲酰胺（AC）支架抑制剂，它们也能有效抑制生长。与之前报道的吡唑并嘧啶不同，抗CDPK1作用与生长抑制之间的相关性并不明显。尽管如此，先导AC化合物在新生小鼠隐孢子虫病模型中以25 mg/kg给药时，寄生虫负荷显著降低。
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