文献类型：期刊文献

英文题名：Novel Selective and Potent Inhibitors of Malaria Parasite Dihydroorotate Dehydrogenase: Discovery and Optimization of Dihydrothiophenone Derivatives

作者：Xu, Minghao[1,2];Zhu, Junsheng[1];Diao, Yanyan[1];Zhou, Hongchang[1,3];Ren, Xiaoli[1];Sun, Deheng[1];Huang, Jin[1];Han, Dongmei[4];Zhao, Zhenjiang[1];Zhu, Lili[1];Xu, Yufang[1,2];Li, Honglin[1]

机构：[1]E China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab Chem Biol, Shanghai 200237, Peoples R China;[3]Huzhou Teachers Coll, Sch Med, Dept Microbiol, Huzhou 313000, Peoples R China;[4]Shanghai Jiao Tong Univ, Instrumental Anal Ctr, Shanghai 200240, Peoples R China

年份：2013

卷号：56

期号：20

起止页码：7911

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000326259900019)】；

基金：We also thank Prof. Weibin Guan and Dr. Lei Shan of the Second Military Medical University for helpful discussions. This work was supported by the Fundamental Research Funds for the Central Universities, the Shanghai Natural Science Fund for Youth Scholars (grant 12ZR144280), the National Natural Science Foundation of China (grants 21372078, 81302697, 21173076, 81102375, 81222046 and 81230076), the Shanghai Committee of Science and Technology (grants 11DZ2260600 and 12401900801), and the 863 Hi-Tech Program of China (grant 2012AA020308). H.L. is also sponsored by Program for New Century Excellent Talents in University (grant NCET-10-0378) and Shanghai Rising-Star Tracking Program (grant 13QH1401100).

语种：英文

摘要：Taking the emergence of drug resistance and lack of effective antimalarial vaccines into consideration, it is of significant importance to develop novel antimalarial agents for the treatment of malaria. Herein, we elucidated the discovery and structure-activity relationships of a series of dihydrothiophenone derivatives as novel specific inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). The most promising compound, 50, selectively inhibited PfDHODH (IC50 = 6 nM, with >14 000-fold species-selectivity over hDHODH) and parasite growth in vitro (IC50 = 15 and 18 nM against 3D7 and Dd2 cells, respectively). Moreover, an oral bioavailability of 40% for compound 50 was determined from in vivo pharmacokinetic studies. These results further indicate that PfDHODH is an effective target for antimalarial chemotherapy, and the novel scaffolds reported in this work might lead to the discovery of new antimalarial agents.