title: Design, synthesis, X-ray crystallographic analysis, and biological evaluation of thiazole derivatives as potent and selective inhibitors of human dihydroorotate dehydrogenase.
abstract: 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.
authors.affiliation: State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Junsheng
authors.initials: J
authors.lastname: Zhu
authors.forename: Le
authors.initials: L
authors.lastname: Han
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Diao
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Ren
authors.forename: Minghao
authors.initials: M
authors.lastname: Xu
authors.forename: Liuxin
authors.initials: L
authors.lastname: Xu
authors.forename: Shiliang
authors.initials: S
authors.lastname: Li
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Dong
authors.initials: D
authors.lastname: Dong
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Liu
authors.forename: Zhenjiang
authors.initials: Z
authors.lastname: Zhao
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Lili
authors.initials: L
authors.lastname: Zhu
authors.forename: Yufang
authors.initials: Y
authors.lastname: Xu
authors.forename: Xuhong
authors.initials: X
authors.lastname: Qian
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D000090722:Dihydroorotate Dehydrogenase; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000090722:Dihydroorotate Dehydrogenase; D013844:Thiazoles; D044925:Oxidoreductases Acting on CH-CH Group Donors