title: 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 alpha-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.
authors.affiliation: Department of Biology, Brandeis University, MS009, 415 South Street, Waltham, Massachusetts 02454, USA.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Maurya
authors.forename: Deviprasad R
authors.initials: DR
authors.lastname: Gollapalli
authors.forename: Shivapriya
authors.initials: S
authors.lastname: Kirubakaran
authors.forename: Minjia
authors.initials: M
authors.lastname: Zhang
authors.forename: Corey R
authors.initials: CR
authors.lastname: Johnson
authors.forename: Nicole N
authors.initials: NN
authors.lastname: Benjamin
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Hedstrom
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003457:Cryptosporidiosis / Q000188:drug therapy; D016785:Cryptosporidium parvum / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D014230:Triazoles; D007168:IMP Dehydrogenase