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

• Type of Material: Article
• Authors: Corey R. Johnson, Brandeis University; Suresh Kumar Gorla, Brandeis University; Mandapati Kavitha, Brandeis University; Minjia Zhang, Brandeis University; Xiaoping Liu, University of Georgia; Boris Striepen, University of Georgia; Jan R Mead, Emory University; Gregory D. Cuny, Brigham and Women's Hospital; Lizbeth Hedstrom, Brandeis University
• Language: English
• Date: 2013-02-15
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmcl.2012.12.037
• Title of Journal or Parent Work: Bioorganic and Medicinal Chemistry Letters
• ISSN: 0960-894X
• Volume: 23
• Issue: 4
• Start Page: 1004
• End Page: 1007
• Grant/Funding Information: This work was supported by funding from the National Institute of Allergy and Infectious Diseases (U01 AI075466 and U01 AI075466S1) to LH.
• Keywords: Chemistry, Medicinal; IMP dehydrogenase; Antiparasitic; GENOME; Science & Technology; IMP DEHYDROGENASE; CYTOKINE; APICOMPLEXAN; Life Sciences & Biomedicine; Physical Sciences; Cryptosporidiosis; Chemistry, Organic; IDENTIFICATION; IMPDH; Chemistry; Pharmacology & Pharmacy
• Research Categories: Biology, Cell; Health Sciences, Pharmacology; Chemistry, Biochemistry

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.