Martyn Derek C, Ramirez Armando P, Beattie Meaghan J, Cortese Joseph F, Patel Vishal, Rush Margaret A, Woerpel K A, Clardy Jon
Broad Institute Infectious Diseases Initiative, 7 Cambridge Center, Cambridge, MA 02142, USA.
Bioorg Med Chem Lett. 2008 Dec 15;18(24):6521-4. doi: 10.1016/j.bmcl.2008.10.083. Epub 2008 Nov 1.
Artemisinin-derived compounds play an integral role in current malaria chemotherapy. Given the virtual certainty of emerging resistance, we have investigated spiro-1,2-dioxolanes as an alternative scaffold. The endoperoxide functionality was generated by the SnCl(4)-mediated annulation of a bis-silylperoxide and an alkene. The first set of eight analogs gave EC(50) values of 50-150 nM against Plasmodium falciparum 3D7 and Dd2 strains, except for the carboxylic acid analog. A second series, synthesized by coupling a spiro-1,2-dioxolane carboxylic acid to four separate amines, afforded the most potent compound (EC(50) approximately 5 nM).
青蒿素衍生化合物在当前疟疾化疗中发挥着不可或缺的作用。鉴于出现耐药性几乎是必然的，我们研究了螺环-1,2-二氧戊环作为一种替代骨架。内过氧化物官能团是通过二硅基过氧化物与烯烃在四氯化锡介导下的环化反应生成的。第一组八个类似物对恶性疟原虫3D7和Dd2菌株的半数有效浓度（EC50）值为50 - 150 nM，但羧酸类似物除外。通过将螺环-1,2-二氧戊环羧酸与四种不同的胺偶联合成的第二系列化合物中，得到了最有效的化合物（EC50约为5 nM）。
