5-Aminopyrazole-4-Carboxamide-Based Compounds Prevent the Growth of Cryptosporidium parvum

Antimicrob Agents Chemother. 2017 Jul 25;61(8):e00020-17. doi: 10.1128/AAC.00020-17. Print 2017 Aug.

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; Cryptosporidium parvum; bumped kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

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