Phthalazinone inhibitors of inosine-5'-monophosphate dehydrogenase from Cryptosporidium parvum.

Abstract

Cryptosporidium parvum (Cp) is a potential biowarfare agent and major cause of diarrhea and malnutrition. This protozoan parasite relies on inosine 5'-monophosphate dehydrogenase (IMPDH) for the production of guanine nucleotides. A CpIMPDH-selective N-aryl-3,4-dihydro-3-methyl-4-oxo-1-phthalazineacetamide inhibitor was previously identified in a high throughput screening campaign. Herein we report a structure-activity relationship study for the phthalazinone-based series that resulted in the discovery of benzofuranamide analogs that exhibit low nanomolar inhibition of CpIMPDH. In addition, the antiparasitic activity of select analogs in a Toxoplasma gondii model of C. parvum infection is also presented.

• Authors: Corey R Johnson, Suresh Kumar Gorla, Mandapati Kavitha, Minjia Zhang, Xiaoping Liu, Boris Striepen, Jan R Mead, Gregory D Cuny, Lizbeth Hedstrom
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 23 Issue 4 Pg. 1004-7 (Feb 15 2013) ISSN: 1464-3405 [Electronic] England
• PMID: 23324406 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Antiparasitic Agents
• Enzyme Inhibitors
• Phthalazines
• IMP Dehydrogenase

Topics

• Antiparasitic Agents (pharmacology)
• Cryptosporidiosis (drug therapy)
• Cryptosporidium parvum (drug effects, enzymology)
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• IMP Dehydrogenase (antagonists & inhibitors, metabolism)
• Phthalazines (chemistry, pharmacology)
• Structure-Activity Relationship