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Human dihydroorotate dehydrogenase ( h DHODH) is an attractive therapeutic target for the treatment of rheumatoid arthritis, transplant rejection and other autoimmune diseases. Based on the X-ray structure of  h DHODH in complex with lead compound  7 , a series of benzylidenehydrazinyl-substituted thiazole derivatives as potent inhibitors of  h DHODH were designed and synthesized, of which  19  and  30  were the most potent with IC 50  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  h DHODH and the 2-(2-methylenehydrazinyl)thiazole scaffold. This work not only elucidates promising scaffolds targeting  h DHODH 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.

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