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
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acetanilides / chemical synthesis*
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Acetanilides / pharmacology*
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Coumarins / chemical synthesis*
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Coumarins / pharmacology*
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Cryptosporidium parvum / drug effects
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Cryptosporidium parvum / enzymology*
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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IMP Dehydrogenase / antagonists & inhibitors*
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In Vitro Techniques
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Models, Molecular
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Molecular Structure
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Pyrazoles / chemistry*
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Structure-Activity Relationship
Substances
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4-oxo-N-(3-methoxyphenyl)-(1)benzopyrano(4,3-c)pyrazole-1(4H)-acetamide
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Acetanilides
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Coumarins
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Enzyme Inhibitors
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Pyrazoles
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pyrazole
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IMP Dehydrogenase