NDLI: Selective and potent urea inhibitors of Cryptosporidium parvum inosine 5′ monophosphate dehydrogenase

Content Provider	PubMed Central
Author	Gorla, Suresh Kumar Kavitha, Mandapati Zhang, Minjia Liu, Xiaoping Lisa, Sharling Gollapalli, Deviprasad R. Boris, Striepen Hedstrom, Lizbeth Cuny, Gregory D.
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 (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.
Related Links	http://dx.doi.org/10.1021/jm3007917
Ending Page	7771
Page Count	13
Starting Page	7759
File Format	PDF
ISSN	00222623
e-ISSN	15204804
Journal	Journal of medicinal chemistry
Issue Number	17
Volume Number	55
Language	English
Publisher Date	2012-09-13
Access Restriction	Open
Subject Keyword	Molecular Medicine Drug Discovery Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Molecular Medicine

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