无供体双氢青蒿素衍生物作为治疗脑型疟疾的多靶点药物

Bertinaria Massimo, Orjuela-Sanchez Pamela, Marini Elisabetta, Guglielmo Stefano, Hofer Anthony, Martins Yuri C, Zanini Graziela M, Frangos John A, Gasco Alberto, Fruttero Roberta, Carvalho Leonardo J M

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino , Via P. Giuria 9, 10125 Torino, Italy.

La Jolla Bioengineering Institute , 505 Coast Boulevard South, Suite 411, La Jolla, California 92037, United States.

J Med Chem. 2015 Oct 8;58(19):7895-9. doi: 10.1021/acs.jmedchem.5b01036. Epub 2015 Sep 24.

Hybrid products in which the dihydroartemisinin scaffold is combined with NO-donor furoxan and NONOate moieties have been synthesized and studied as potential tools for the treatment of cerebral malaria (CM). The designed products were able to dilate rat aorta strips precontracted with phenylephrine with a NO-dependent mechanism. All hybrid compounds showed preserved antiplasmodial activity in vitro and in vivo against Plasmodium berghei ANKA, comparable to artesunate and artemether. Hybrid 10, selected for additional studies, was capable of increasing survival of mice with late-stage CM from 27.5% to 51.6% compared with artemether. Artemisinin-NO-donor hybrid compounds show promise as potential new drugs for treating cerebral malaria.

已合成并研究了二氢青蒿素骨架与一氧化氮供体呋咱和NONOate部分相结合的杂合产物，作为治疗脑型疟疾（CM）的潜在工具。所设计的产物能够通过一氧化氮依赖性机制使预先用去氧肾上腺素收缩的大鼠主动脉条舒张。所有杂合化合物在体外和体内均对伯氏疟原虫ANKA显示出保留的抗疟活性，与青蒿琥酯和蒿甲醚相当。被选作进一步研究的杂合体10，与蒿甲醚相比，能够将晚期脑型疟疾小鼠的存活率从（使用蒿甲醚时的）27.5%提高到51.6%。青蒿素-一氧化氮供体杂合化合物有望成为治疗脑型疟疾的潜在新药。