TY - JOUR
T1 - 5-Aminopyrazole-4-carboxamide-based compounds prevent the growth of Cryptosporidium parvum
AU - Huang, Wenlin
AU - Choi, Ryan
AU - Hulverson, Matthew A.
AU - Zhang, Zhongsheng
AU - McCloskey, Molly C.
AU - Schaefer, Deborah A.
AU - Whitman, Grant R.
AU - Barrett, Lynn K.
AU - Vidadala, Rama Subba Rao
AU - Riggs, Michael W.
AU - Maly, Dustin J.
AU - Van Voorhis, Wesley C.
AU - Ojo, Kayode K.
AU - Fan, Erkang
N1 - Funding Information:
Research described was supported by the National Institute of Allergy and Infectious Diseases and the National Institute of Child Health and Human Development of the National Institutes of Health under award numbers R01AI089441, R01AI111341, and R01HD080670. The work was also supported by awards 2014-06183 and 2014-67015-22106 from the U.S. Department of Agriculture National Institute of Food and Agriculture and PATH Drug Solutions, South San Francisco, California (grant DFI 1850-02-405099).
Publisher Copyright:
© 2017 American Society for Microbiology. All Rights Reserved.
PY - 2017/8
Y1 - 2017/8
N2 - Cryptosporidium parvum calcium-dependent protein kinase 1 (CpCDPK1) is a promising target for drug development against cryptosporidiosis. We report a series of low-nanomolar CpCDPK1 5-aminopyrazole-4-carboxamide (AC) scaffold inhibitors that also potently inhibit C. parvum growth in vitro. Correlation between anti-CpCDPK1 and C. parvum 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.
AB - Cryptosporidium parvum calcium-dependent protein kinase 1 (CpCDPK1) is a promising target for drug development against cryptosporidiosis. We report a series of low-nanomolar CpCDPK1 5-aminopyrazole-4-carboxamide (AC) scaffold inhibitors that also potently inhibit C. parvum growth in vitro. Correlation between anti-CpCDPK1 and C. parvum 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.
KW - 5-aminopyrazole-4-carboxamide
KW - Bumped kinase inhibitors
KW - Cryptosporidium parvum
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U2 - 10.1128/AAC.00020-17
DO - 10.1128/AAC.00020-17
M3 - Article
C2 - 28533246
AN - SCOPUS:85026375904
VL - 61
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 8
M1 - e00020
ER -