Structure-activity relationship study of selective benzimidazole-based inhibitors of Cryptosporidium parvum IMPDH

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Kirubakaran, Sivapriya³  Gorla, Suresh Kumar³  Sharling, Lisa⁴  Zhang, Minjia³  Liu, Xiaoping⁴  Ray, Soumya S.^6,2  MacPherson, Iain S.³  Striepen, Boris^4,5  Hedstrom, Lizbeth^3,7  Cuny, Gregory D.¹ 

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

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

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

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

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

[6] Brigham Womens Hosp, Ctr Neurol Dis, Dept Neurol, Cambridge, MA 02139 USA

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

关键词: Cryptosporidium;    Parasite;    Protozoan;    Inosine 5 '-monophosphate dehydrogenase (IMPDH);    Inhibitor;    Benzimidazole;    Structure-activity relationship;   

DOI  :  10.1016/j.bmcl.2012.01.029

来源: Elsevier

【 摘 要 】

Cryptosporidium parasites are important waterborne pathogens of both humans and animals. The Cryptosporidium parvum and Cryptosporidium hominis genomes indicate that the only route to guanine nucleotides is via inosine 5 '-monophosphate dehydrogenase (IMPDH). Thus the inhibition of the parasite IMPDH presents a potential strategy for treating Cryptosporidium infections. A selective benzimidazole-based inhibitor of C. parvum IMPDH (CpIMPDH) was previously identified in a high throughput screen. Here we report a structure-activity relationship study of benzimidazole-based compounds that resulted in potent and selective inhibitors of CpIMPDH. Several compounds display potent antiparasitic activity in vitro. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

Free