Kumar Rohitesh, Duffy Sandra, Avery Vicky M, Davis Rohan A
Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
Bioorg Med Chem Lett. 2017 Sep 1;27(17):4091-4095. doi: 10.1016/j.bmcl.2017.07.039. Epub 2017 Jul 15.
A plant-derived natural product scaffold, 3,7,8-trihydroxyserrulat-14-en-19-oic acid (1) was isolated in high yield from the aerial parts of the endemic Australian desert plant Eremophila microtheca. This scaffold (1) was subsequently used in the generation of a series of new amide analogues via a one-pot mixed anhydride amidation using pivaloyl chloride. The structures of all analogues were characterized using MS, NMR, and UV data. The major serrulatane natural products (1-3), isolated from the plant extract, and all amide analogues (6-15) together with several pivaloylated derivatives of 3,7,8-trihydroxyserrulat-14-en-19-oic acid (16-18) were evaluated for their antimalarial activity against 3D7 (chloroquine sensitive) and Dd2 (chloroquine resistant) Plasmodium falciparum strains, and preliminary cytotoxicity data were also acquired using the human embryonic kidney cell line HEK293. The natural product scaffold (1) did not display any antimalarial activity at 10µM. Replacing the carboxylic acid of 1 with various amides resulted in moderate activity against the P. falciparum 3D7 strain with IC values ranging from 1.25 to 5.65µM.
一种植物源天然产物骨架，即3,7,8 - 三羟基锯齿烷 - 14 - 烯 - 19 - 酸（1），从澳大利亚特有的沙漠植物小叶兔耳草的地上部分以高产率分离得到。随后，通过使用新戊酰氯的一锅法混合酸酐酰胺化反应，该骨架（1）被用于生成一系列新的酰胺类似物。所有类似物的结构通过质谱（MS）、核磁共振（NMR）和紫外（UV）数据进行了表征。对从植物提取物中分离出的主要锯齿烷天然产物（1 - 3）、所有酰胺类似物（6 - 15）以及3,7,8 - 三羟基锯齿烷 - 14 - 烯 - 19 - 酸的几种新戊酰化衍生物（16 - 18），针对3D7（氯喹敏感）和Dd2（氯喹耐药）恶性疟原虫菌株进行了抗疟活性评估，并使用人胚肾细胞系HEK293获得了初步的细胞毒性数据。天然产物骨架（1）在10µM时未显示出任何抗疟活性。用各种酰胺取代1的羧酸后，对恶性疟原虫3D7菌株产生了中等活性，IC值范围为1.25至5.65µM。
