Synthesis, in vitro evaluation and cocrystal structure of 4-oxo-[1]benzopyrano[4,3-c]pyrazole Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase (CpIMPDH) inhibitors

J Med Chem. 2014 Dec 26;57(24):10544-50. doi: 10.1021/jm501527z. Epub 2014 Dec 4.

Abstract

Cryptosporidium inosine 5'-monophosphate dehydrogenase (CpIMPDH) has emerged as a therapeutic target for treating Cryptosporidium parasites because it catalyzes a critical step in guanine nucleotide biosynthesis. A 4-oxo-[1]benzopyrano[4,3-c]pyrazole derivative was identified as a moderately potent (IC50 = 1.5 μM) inhibitor of CpIMPDH. We report a SAR study for this compound series resulting in 8k (IC50 = 20 ± 4 nM). In addition, an X-ray crystal structure of CpIMPDH·IMP·8k is also presented.

Publication types

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

MeSH terms

  • Acetanilides / chemical synthesis*
  • Acetanilides / pharmacology*
  • Coumarins / chemical synthesis*
  • Coumarins / pharmacology*
  • Cryptosporidium parvum / drug effects
  • Cryptosporidium parvum / enzymology*
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • IMP Dehydrogenase / antagonists & inhibitors*
  • In Vitro Techniques
  • Models, Molecular
  • Molecular Structure
  • Pyrazoles / chemistry*
  • Structure-Activity Relationship

Substances

  • 4-oxo-N-(3-methoxyphenyl)-(1)benzopyrano(4,3-c)pyrazole-1(4H)-acetamide
  • Acetanilides
  • Coumarins
  • Enzyme Inhibitors
  • Pyrazoles
  • pyrazole
  • IMP Dehydrogenase