Selective and potent urea inhibitors of Cryptosporidium parvum inosine 5’-monophosphate dehydrogenase


Cryptosporidium parvum and related species are zoonotic intracellular parasites of the intestine. Cryptosporidium is a leading cause of diarrhea in small children around the world. Infection can cause severe pathology in children and immunocompromised patients. This waterborne parasite is resistant to common methods of water treatment and therefore a prominent threat to drinking and recreation water even in countries with strong water safety systems. The drugs currently used to combat these organisms are ineffective. Genomic analysis revealed that the parasite relies solely on inosine-5?-monophosphate dehydrogenase (IMPDH) for the biosynthesis of guanine nucleotides. Herein, we report a selective urea-based inhibitor of C. parvum IMPDH (CpIMPDH) identified by high-throughput screening. We performed a SAR study of these inhibitors with some analogues exhibiting high potency (IC50 < 2 nM) against CpIMPDH, excellent selectivity >1000-fold versus human IMPDH type 2 and good stability in mouse liver microsomes. A subset of inhibitors also displayed potent antiparasitic activity in a Toxoplasma gondii model.




Copyright 2012 Journal of Medicinal Chemistry. This is a post-print version of a published paper that is available at: Recommended citation: Gorla, Suresh Kumar, Mandapati Kavitha, Minjia Zhang, Xiaoping Liu, Lisa Sharling, Deviprasad R. Gollapalli, Boris Striepen, Lizbeth Hedstrom, and Gregory D. Cuny. "Selective and potent urea inhibitors of Cryptosporidium parvum inosine 5?-monophosphate dehydrogenase." Journal of medicinal chemistry 55, no. 17 (2012): 7759-7771.doi: 10.1021/jm3007917. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.