5-Aminopyrazole-4-carboxamide-based compounds prevent the growth of Cryptosporidium parvum

Wenlin Huang; Ryan Choi; Matthew A. Hulverson; Zhongsheng Zhang; Molly C. McCloskey; Deborah A. Schaefer; Grant R. Whitman; Lynn K. Barrett; Rama Subba Rao Vidadala; Michael W. Riggs; Dustin J. Maly; Wesley C. Van Voorhis; Kayode K. Ojo; Erkang Fan

doi:10.1128/AAC.00020-17

5-Aminopyrazole-4-carboxamide-based compounds prevent the growth of Cryptosporidium parvum

Wenlin Huang
, Ryan Choi
, Matthew A. Hulverson
, Zhongsheng Zhang
, Molly C. McCloskey
, Deborah A. Schaefer
, Grant R. Whitman
, Lynn K. Barrett
, Rama Subba Rao Vidadala
, Michael W. Riggs
, Dustin J. Maly
, Wesley C. Van Voorhis
, Kayode K. Ojo
, Erkang Fan

Animal&Biomedical Sciences-Res

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

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.

Original language	English (US)
Article number	e00020
Journal	Antimicrobial Agents and Chemotherapy
Volume	61
Issue number	8
DOIs	https://doi.org/10.1128/AAC.00020-17
State	Published - Aug 2017

Keywords

5-aminopyrazole-4-carboxamide
Bumped kinase inhibitors
Cryptosporidium parvum

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)
Infectious Diseases

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10.1128/AAC.00020-17

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Huang, W., Choi, R., Hulverson, M. A., Zhang, Z., McCloskey, M. C., Schaefer, D. A., Whitman, G. R., Barrett, L. K., Vidadala, R. S. R., Riggs, M. W., Maly, D. J., Van Voorhis, W. C., Ojo, K. K., & Fan, E. (2017). 5-Aminopyrazole-4-carboxamide-based compounds prevent the growth of Cryptosporidium parvum. Antimicrobial Agents and Chemotherapy, 61(8), Article e00020. https://doi.org/10.1128/AAC.00020-17

@article{3ae1b7414ae04f7c80331234513922da,

title = "5-Aminopyrazole-4-carboxamide-based compounds prevent the growth of Cryptosporidium parvum",

abstract = "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.",

keywords = "5-aminopyrazole-4-carboxamide, Bumped kinase inhibitors, Cryptosporidium parvum",

author = "Wenlin Huang and Ryan Choi and Hulverson, \{Matthew A.\} and Zhongsheng Zhang and McCloskey, \{Molly C.\} and Schaefer, \{Deborah A.\} and Whitman, \{Grant R.\} and Barrett, \{Lynn K.\} and Vidadala, \{Rama Subba Rao\} and Riggs, \{Michael W.\} and Maly, \{Dustin J.\} and \{Van Voorhis\}, \{Wesley C.\} and Ojo, \{Kayode K.\} and Erkang Fan",

year = "2017",

month = aug,

doi = "10.1128/AAC.00020-17",

language = "English (US)",

volume = "61",

journal = "Antimicrobial Agents and Chemotherapy",

issn = "0066-4804",

publisher = "American Society for Microbiology",

number = "8",

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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

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

UR - https://www.scopus.com/pages/publications/85026375904

UR - https://www.scopus.com/pages/publications/85026375904#tab=citedBy

U2 - 10.1128/AAC.00020-17

DO - 10.1128/AAC.00020-17

M3 - Article

C2 - 28533246

AN - SCOPUS:85026375904

SN - 0066-4804

VL - 61

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 8

M1 - e00020

ER -

5-Aminopyrazole-4-carboxamide-based compounds prevent the growth of Cryptosporidium parvum

Abstract

Keywords

ASJC Scopus subject areas

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