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


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.



IMPDH, IMP dehydrogenase, cryptosporidiosis, Antiparasitic


Copyright 2013 Bioorganic and Medicinal Chemistry Letters. This is a post-print version of a published paper that is available at: Recommended citation: Johnson, Corey R., Suresh Kumar Gorla, Mandapati Kavitha, Minjia Zhang, Xiaoping Liu, Boris Striepen, Jan R. Mead, Gregory D. Cuny, and Lizbeth Hedstrom. "Phthalazinone inhibitors of inosine-5?-monophosphate dehydrogenase from Cryptosporidium parvum." Bioorganic & medicinal chemistry letters 23, no. 4 (2013): 1004-1007. doi: 10.1016/j.bmcl.2012.12.037. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.