title: Phthalazinone inhibitors of inosine-5'-monophosphate dehydrogenase from Cryptosporidium parvum.
abstract: Cryptosporidium parvum (Cp) is a potential biowarfare agent and major cause of diarrhea and malnutrition. This protozoan parasite relies on inosine 5'-monophosphate dehydrogenase (IMPDH) for the production of guanine nucleotides. A CpIMPDH-selective N-aryl-3,4-dihydro-3-methyl-4-oxo-1-phthalazineacetamide inhibitor was previously identified in a high throughput screening campaign. Herein we report a structure-activity relationship study for the phthalazinone-based series that resulted in the discovery of benzofuranamide analogs that exhibit low nanomolar inhibition of CpIMPDH. In addition, the antiparasitic activity of select analogs in a Toxoplasma gondii model of C. parvum infection is also presented.
authors: Department of Chemistry, Brandeis University, MS009, 415 South Street, Waltham, MA 02454, USA.
authors: Corey R
authors: CR
authors: Johnson
authors: Suresh Kumar
authors: SK
authors: Gorla
authors: Mandapati
authors: M
authors: Kavitha
authors: Minjia
authors: M
authors: Zhang
authors: Xiaoping
authors: X
authors: Liu
authors: Boris
authors: B
authors: Striepen
authors: Jan R
authors: JR
authors: Mead
authors: Gregory D
authors: GD
authors: Cuny
authors: Lizbeth
authors: L
authors: Hedstrom
mesh_terms: D000977:Antiparasitic Agents / Q000494:pharmacology*; D003457:Cryptosporidiosis / Q000188:drug therapy; D016785:Cryptosporidium parvum / Q000187:drug effects* / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010793:Phthalazines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000977:Antiparasitic Agents; D004791:Enzyme Inhibitors; D010793:Phthalazines; D007168:IMP Dehydrogenase