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.

• Authors: 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
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 61 Issue 8 (08 2017) ISSN: 1098-6596 [Electronic] United States
• PMID: 28533246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2017 American Society for Microbiology.

Chemical References

• 5-aminopyrazole
• Antiprotozoal Agents
• Protein Kinase Inhibitors
• Protozoan Proteins
• Pyrazoles
• Protein Kinases
• calcium-dependent protein kinase

Topics

• Animals
• Antiprotozoal Agents (chemistry, pharmacology)
• Cryptosporidiosis (drug therapy, parasitology)
• Cryptosporidium parvum (drug effects, growth & development)
• Mice
• Protein Kinase Inhibitors (pharmacology)
• Protein Kinases (metabolism)
• Protozoan Proteins (metabolism)
• Pyrazoles (chemistry, pharmacology)