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

被引：41

作者：

Johnson, Corey R. ^{[1
]}

Gorla, Suresh Kumar ^{[2
]}

Kavitha, Mandapati ^{[2
]}

Zhang, Minjia ^{[2
]}

Liu, Xiaoping ^{[3
]}

Striepen, Boris ^{[3
,4
]}

Mead, Jan R. ^{[5
,6
]}

Cuny, Gregory D. ^{[7
,8
,9
]}

Hedstrom, Lizbeth ^{[1
,2
]}

机构：

[1] Brandeis Univ, Dept Chem, Waltham, MA 02454 USA

[2] Brandeis Univ, Dept Biol, Waltham, MA 02454 USA

[3] Univ Georgia, Ctr Trop & Emerging Global Dis, Athens, GA 30602 USA

[4] Univ Georgia, Dept Cellular Biol, Athens, GA 30602 USA

[5] Atlanta VA Med Ctr, Atlanta, GA 30322 USA

[6] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA

[7] Brigham & Womens Hosp, Lab Drug Discovery Neurodegenerat, Cambridge, MA 02139 USA

[8] Harvard Univ, Sch Med, Cambridge, MA 02139 USA

[9] Univ Houston, Coll Pharm, Dept Pharmacol & Pharmaceut Sci, Houston, TX 77204 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 04期

关键词：

IMPDH; IMP dehydrogenase; Cryptosporidiosis; Antiparasitic; IMP DEHYDROGENASE; IDENTIFICATION; APICOMPLEXAN; CYTOKINE; GENOME;

D O I：

10.1016/j.bmcl.2012.12.037

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：1004 / 1007

页数：4

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