Phthalazinone inhibitors of inosine-5′-monophosphate dehydrogenase from Cryptosporidium parvum

Bioorganic and Medicinal Chemistry Letters

Volumn 23, Issue 4, 2013, Pages 1004-1007

  Johnson, Corey R ^a,f   Gorla, Suresh Kumar ^a   Kavitha, Mandapati ^a   Zhang, Minjia ^a   Liu, Xiaoping ^b   Striepen, Boris ^b   Mead, Jan R ^c   Cuny, Gregory D ^d,e   Hedstrom, Lizbeth ^a  

^a BRANDEIS UNIVERSITY   (United States)

^b UNIVERSITY OF GEORGIA   (United States)

^c EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d BRIGHAM AND WOMEN S HOSPITAL   (United States)

^e UNIVERSITY OF HOUSTON   (United States)

^f UNIVERSITY OF THE SCIENCES   (United States)

Author keywords

Antiparasitic; Cryptosporidiosis; IMP dehydrogenase; IMPDH

Indexed keywords

ANTIPARASITIC AGENT; INOSINATE DEHYDROGENASE; INOSINATE DEHYDROGENASE INHIBITOR;

ARTICLE; CRYPTOSPORIDIOSIS; CRYPTOSPORIDIUM PARVUM; NONHUMAN; STRUCTURE ACTIVITY RELATION; TOXOPLASMA GONDII;

ANTIPARASITIC AGENTS; CRYPTOSPORIDIOSIS; CRYPTOSPORIDIUM PARVUM; ENZYME INHIBITORS; HUMANS; IMP DEHYDROGENASE; PHTHALAZINES; STRUCTURE-ACTIVITY RELATIONSHIP;

CRYPTOSPORIDIUM PARVUM; PROTOZOA; TOXOPLASMA GONDII;

EID: 84872979660     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2012.12.037     Document Type: Article

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19. The anticryptosporidial activity of 27 was assessed in the IL-12 knockout mouse model, which resembles the acute human disease. Mice were inoculated with 1000 oocysts and treated by gavage with vehicle (10%DMSO/corn oil), vehicle plus 250 mg/kg 27, or 2000 mg/kg paromomycin starting 4 h post infection. Treatment was given once daily for 7 days and mice sacrificed on day 8 (peak infection). Parasite load was quantified by FACS assays by the presence of the oocysts in the feces at days 0, 4 and 7. Fecal pellets from the mice were collected and homogenized in adjusted volumes of 2.5% potassium dichromate. Aliquots (200 μl) of vortexed samples were processed over micro-scale sucrose gradients. The oocyst-containing fraction was collected and washed. Purified oocysts were incubated with a fluorescein-labeled oocyst-specific monoclonal antibody (OW5O-FITC) for 20 min. Samples were adjusted to 600 μl and assayed assayed with a 102-s sampling interval (100 μl) using logical gating of forward/side scatter and OW5O-FITC fluorescence signal on a Becton Dickinson FACScan flow cytometer. Flow cytometry data were evaluated by analysis of variance (Microsoft Excel; Microsoft Corporation, Redmond, WA).