Martyn Derek C, Beletsky Galina, Cortese Joseph F, Tyndall Erin, Liu Hanlan, Fitzgerald Maria M, O'Shea Thomas J, Liang Beirong, Clardy Jon
Broad Institute Infectious Diseases Initiative, 7 Cambridge Center, Cambridge, MA 02142, USA.
Bioorg Med Chem Lett. 2009 Oct 1;19(19):5657-60. doi: 10.1016/j.bmcl.2009.08.024. Epub 2009 Aug 8.
A 43-member 1,2-dioxolane library was synthesized by coupling a 1,2-dioxolane-3-acetic acid derivative to a range of amines. Ten compounds had EC(50)s30nM against Plasmodium falciparum 3D7 and Dd2 strains, and another 15 compounds had EC(50)s50nM against both 3D7 and Dd2. The library was then subjected to a range of in vitro DMPK assays, which revealed that side chains with a heteroatom were required for favorable solubility, LogD and membrane permeability. CYP450 inhibition was isoform dependent, with 2C19 and 3A4 particularly susceptible, and the majority of compounds tested against rat and human microsomes were metabolized rapidly.
通过将1,2 - 二氧戊环 - 3 - 乙酸衍生物与一系列胺偶联，合成了一个包含43个成员的1,2 - 二氧戊环文库。十种化合物对恶性疟原虫3D7和Dd2菌株的半数有效浓度（EC50）小于30 nM，另外15种化合物对3D7和Dd2的EC50均小于50 nM。然后对该文库进行了一系列体外药物代谢动力学（DMPK）测定，结果表明，具有杂原子的侧链对于良好的溶解度、分配系数（LogD）和膜通透性是必需的。细胞色素P450（CYP450）抑制作用具有同工酶依赖性，其中2C19和3A4特别敏感，并且针对大鼠和人类微粒体测试的大多数化合物代谢迅速。
