文献类型：期刊文献

英文题名：Rational Design of Benzylidenehydrazinyl-Substituted Thiazole Derivatives as Potent Inhibitors of Human Dihydroorotate Dehydrogenase with in Vivo Anti-arthritic Activity

作者：Li, Shiliang[1];Luan, Guoqin[1];Ren, Xiaoli[1];Song, Wenlin[1];Xu, Liuxin[1];Xu, Minghao[1];Zhu, Junsheng[1];Dong, Dong[1];Diao, Yanyan[1];Liu, Xiaofeng[1];Zhu, Lili[1];Wang, Rui[1];Zhao, Zhenjiang[1];Xu, Yufang[1];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

年份：2015

卷号：5

外文期刊名：SCIENTIFIC REPORTS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000362334900001)】；

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, the National Natural Science Foundation of China (grants 81102375, 21372078, 81302697, 81222046 and 81230076) (X.L., Z.Z., L.Z. and 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.). Lili Zhu is also sponsored by the Shanghai Natural Science Fund for Youth Scholars (grant 12ZR1442800). Honglin Li 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 (141035).

语种：英文

摘要：Human dihydroorotate dehydrogenase (hDHODH) is an attractive therapeutic target for the treatment of rheumatoid arthritis, transplant rejection and other autoimmune diseases. Based on the X-ray structure of hDHODH in complex with lead compound 7, a series of benzylidenehydrazinyl-substituted thiazole derivatives as potent inhibitors of hDHODH were designed and synthesized, of which 19 and 30 were the most potent with IC50 values in the double-digit nanomolar range. Moreover, compound 19 displayed significant anti-arthritic effects and favorable pharmacokinetic profiles in vivo. Further X-ray structure and SAR analyses revealed that the potencies of the designed inhibitors were partly attributable to additional water-mediated hydrogen bond networks formed by an unexpected buried water between hDHODH and the 2-(2-methylenehydrazinyl) thiazole scaffold. This work not only elucidates promising scaffolds targeting hDHODH for the treatment of rheumatoid arthritis, but also demonstrates that the water-mediated hydrogen bond interaction is an important factor in molecular design and optimization.