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: Junsheng Zhu, Le Han, Yanyan Diao, Xiaoli Ren, Minghao Xu, Liuxin Xu, Shiliang Li, Qiang Li, Dong Dong, Jin Huang, Xiaofeng Liu, Zhenjiang Zhao, Rui Wang, Lili Zhu, Yufang Xu, Xuhong Qian, Honglin Li
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 3 Pg. 1123-39 (Feb 12 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 25580811 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Dihydroorotate Dehydrogenase
• Thiazoles
• Oxidoreductases Acting on CH-CH Group Donors

Topics

• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, pharmacology)
• Crystallography, X-Ray
• Dihydroorotate Dehydrogenase
• Dose-Response Relationship, Drug
• Drug Design
• Humans
• Models, Molecular
• Molecular Structure
• Oxidoreductases Acting on CH-CH Group Donors (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Thiazoles (chemical synthesis, chemistry, pharmacology)