title: Selective and potent urea inhibitors of cryptosporidium parvum inosine 5'-monophosphate dehydrogenase.
abstract: 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 (IC(50) < 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.
authors.affiliation: Department of Biology, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, USA.
authors.forename: Suresh Kumar
authors.initials: SK
authors.lastname: Gorla
authors.forename: Mandapati
authors.initials: M
authors.lastname: Kavitha
authors.forename: Minjia
authors.initials: M
authors.lastname: Zhang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Liu
authors.forename: Lisa
authors.initials: L
authors.lastname: Sharling
authors.forename: Deviprasad R
authors.initials: DR
authors.lastname: Gollapalli
authors.forename: Boris
authors.initials: B
authors.lastname: Striepen
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Hedstrom
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
mesh_terms: D016785:Cryptosporidium parvum / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014508:Urea / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014508:Urea; D007168:IMP Dehydrogenase