Design, Synthesis, X‑ray Crystallographic Analysis, and Biological Evaluation of Thiazole Derivatives as Potent and Selective Inhibitors of Human Dihydroorotate Dehydrogenase

Human dihydroorotate dehydrogenase (<i>Hs</i>DHODH) 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 <b>4</b>, which was previously identified as potential <i>Hs</i>DHODH inhibitor, a novel series of thiazole derivatives were designed and synthesized. The X-ray complex structures of the promising analogues <b>12</b> and <b>33</b> confirmed that these inhibitors bind at the putative ubiquinone binding tunnel and guided us to explore more potent inhibitors, such as compounds <b>44</b>, <b>46</b>, and <b>47</b> which showed double digit nanomolar activities of 26, 18, and 29 nM, respectively. Moreover, <b>44</b> 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 <i>Hs</i>DHODH