Department of Chemistry, Brandeis University, MS009, 415 South Street, Waltham, MA 02454, USA.
Bioorg Med Chem Lett. 2013 Feb 15;23(4):1004-7. doi: 10.1016/j.bmcl.2012.12.037. Epub 2012 Dec 27.
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.
微小隐孢子虫（Cp）是一种潜在的生物战剂，也是腹泻和营养不良的主要原因。这种原生动物寄生虫依赖肌苷 5'-单磷酸脱氢酶（IMPDH）来产生鸟嘌呤核苷酸。在高通量筛选活动中，先前已经鉴定出一种对 CpIMPDH 具有选择性的 N-芳基-3,4-二氢-3-甲基-4-氧-1-酞嗪乙酰胺抑制剂。本文报道了基于酞嗪酮系列的构效关系研究，发现了苯并呋喃酰胺类似物，对 CpIMPDH 的抑制作用达到纳摩尔级。此外，还介绍了在微小隐孢子虫感染弓形虫模型中选择类似物的抗寄生虫活性。
