文献类型：期刊文献

英文题名：Design, Synthesis, X-ray Crystallographic Analysis, and Biological Evaluation of Thiazole Derivatives as Potent and Selective Inhibitors of Human Dihydroorotate Dehydrogenase

作者：Zhu, Junsheng[1];Han, Le[1,2];Diao, Yanyan[1];Ren, Xiaoli[1];Xu, Minghao[1];Xu, Liuxin[1];Li, Shiliang[1];Li, Qiang[1];Dong, Dong[1];Huang, Jin[1];Liu, Xiaofeng[1];Zhao, Zhenjiang[1];Wang, Rui[1];Zhu, Lili[1];Xu, Yufang[1];Qian, Xuhong[2];Li, Honglin[1]

机构：[1]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab Chem Biol, Shanghai 200237, Peoples R China

年份：2015

卷号：58

期号：3

起止页码：1123

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000349573800009)】；

基金：We thank the staff at Shanghai Synchrotron Radiation Facility for assistances with data collection. This work was supported by the Fundamental Research Funds for the Central Universities to Y.X, the National Natural Science Foundation of China (Grants 81102375, 21372078, 81302697, 81222046, and 81230076) (X.L., Z.Z, L.Z, H.L.), the Shanghai Committee of Science and Technology (Grant 14431902400) (H.L.), and the 863 Hi-Tech Program of China (Grant 2012AA020308) (H.L.). L.Z. is also sponsored by the Shanghai Natural Science Fund for Youth Scholars (Grant 12ZR144280). H.L. is also sponsored by Shanghai Rising-Star Tracking Program (Grant 13QH1401100), the Innovation Program of Shanghai Municipal Education Commission (Grant 13SG32), and Fok Ying Tung Education Foundation (Grant 141035).

语种：英文

摘要：Human dihydroorotate dehydrogenase (HsDHODH) is a flavin-dependent mitochondrial enzyme that has been certified as a potential therapeutic target for the treatment of rheumatoid arthritis and other autoimmune diseases. On the basis of lead compound 4, which was previously identified as potential HsDHODH inhibitor, a novel series of thiazole derivatives were designed and synthesized. The X-ray complex structures of the promising analogues 12 and 33 confirmed that these inhibitors bind at the putative ubiquinone binding tunnel and guided us to explore more potent inhibitors, such as compounds 44, 46, and 47 which showed double digit nanomolar activities of 26, 18, and 29 nM, respectively. Moreover, 44 presented considerable anti-inflammation effect in vivo and significantly alleviated foot swelling in a dose-dependent manner, which disclosed that thiazole-scaffold analogues can be developed into the drug candidates for the treatment of rheumatoid arthritis by suppressing the bioactivity of HsDHODH.