title: Synthesis, in vitro evaluation and cocrystal structure of 4-oxo-[1]benzopyrano[4,3-c]pyrazole Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase (CpIMPDH) inhibitors.
abstract: Cryptosporidium inosine 5'-monophosphate dehydrogenase (CpIMPDH) has emerged as a therapeutic target for treating Cryptosporidium parasites because it catalyzes a critical step in guanine nucleotide biosynthesis. A 4-oxo-[1]benzopyrano[4,3-c]pyrazole derivative was identified as a moderately potent (IC50 = 1.5 μM) inhibitor of CpIMPDH. We report a SAR study for this compound series resulting in 8k (IC50 = 20 ± 4 nM). In addition, an X-ray crystal structure of CpIMPDH·IMP·8k is also presented.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston , Science and Research Building 2, Room 549A, Houston, Texas 77204, United States.
authors.forename: Zhuming
authors.initials: Z
authors.lastname: Sun
authors.forename: Jihan
authors.initials: J
authors.lastname: Khan
authors.forename: Magdalena
authors.initials: M
authors.lastname: Makowska-Grzyska
authors.forename: Minjia
authors.initials: M
authors.lastname: Zhang
authors.forename: Joon Hyung
authors.initials: JH
authors.lastname: Cho
authors.forename: Chalada
authors.initials: C
authors.lastname: Suebsuwong
authors.forename: Pascal
authors.initials: P
authors.lastname: Vo
authors.forename: Deviprasad R
authors.initials: DR
authors.lastname: Gollapalli
authors.forename: Youngchang
authors.initials: Y
authors.lastname: Kim
authors.forename: Andrzej
authors.initials: A
authors.lastname: Joachimiak
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Hedstrom
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
mesh_terms: D000083:Acetanilides / Q000138:chemical synthesis* / Q000494:pharmacology*; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology*; D016785:Cryptosporidium parvum / Q000187:drug effects / Q000201:enzymology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: C000595876:4-oxo-N-(3-methoxyphenyl)-(1)benzopyrano(4,3-c)pyrazole-1(4H)-acetamide; D000083:Acetanilides; D003374:Coumarins; D004791:Enzyme Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D007168:IMP Dehydrogenase