Triazole Inhibitors of Cryptosporidium parvum Inosine 5?-Monophosphate Dehydrogenase

Abstract

Cryptosporidium parvum is an important human pathogen and potential bioterrorism agent. This protozoan parasite cannot salvage guanine or guanosine and therefore relies on inosine 5?-monophosphate dehydrogenase (IMPDH) for biosynthesis of guanine nucleotides and hence for survival. Because C. parvum IMPDH is highly divergent from the host counterpart, selective inhibitors could potentially be used to treat cryptosporidiosis with minimal effects on its mammalian host. A series of 1,2,3-triazole containing ether CpIMPDH inhibitors are described. A structure?activity relationship study revealed that a small alkyl group on the ?-position of the ether was required, with the (R)-enantiomer significantly more active than the (S)-enantiomer. Electron-withdrawing groups in the 3- and/or 4-positions of the pendent phenyl ring were best, and conversion of the quinoline containing inhibitors to quinoline-N-oxides retained inhibitory activity both in the presence and absence of bovine serum albumin. The 1,2,3-triazole CpIMPDH inhibitors provide new tools for elucidating the role of IMPDH in C. parvum and may serve as potential therapeutics for treating cryptosporidiosis.

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Citation

Copyright 2009 Journal of Medicinal Chemistry. This is a post-print version of a published paper that is avaiable at: https://pubs.acs.org/doi/abs/10.1021/jm900410u. Recommended citation: Maurya, Sushil K., Deviprasad R. Gollapalli, Shivapriya Kirubakaran, Minjia Zhang, Corey R. Johnson, Nicole N. Benjamin, Lizbeth Hedstrom, and Gregory D. Cuny. "Triazole inhibitors of Cryptosporidium parvum inosine 5?-monophosphate dehydrogenase." Journal of medicinal chemistry 52, no. 15 (2009): 4623-4630. doi: 10.1021/jm900410u. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.