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

Abstract

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.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

“…1 A) against ~280,000 compounds library towards the ubiquinone-binding site of DHODH (Diao et al, 2012 ). We finally obtained two highly potent DHODHi S312 and S416 with IC 50 of 29.2 nmol/L and 7.5 nmol/L through structural optimization (Li et al, 2015 ; Zhu et al, 2015a ), which are >10-folds potent than the FDA approved DHODHi Teriflunomide (IC 50 of 307.1 nmol/L). By using these two potent inhibitors, we could fully evaluate DHODH as a valuable host target both in infected cells and in vivo in infected animals.…”

Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme inde novopyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2

“…1A) against ~280,000 compounds library towards the ubiquinone-binding site of DHODH 26 . We finally obtained two highly potent DHODHi S312 and S416 with IC50s of 29.2 nM and 7.5 nM through structural optimization 27,28 , which are > 10-folds potent than the FDA approved DHODHi Teriflunomide (IC50 of 307.1 nM). By using these two potent inhibitors, we could fully evaluate DHODH as a valuable host target both in infected cells and in vivo in infected animals.…”

Synthesis, structure–activity relationship and binding mode analysis of 4-thiazolidinone derivatives as novel inhibitors of human dihydroorotate dehydrogenase

“…1,2 The significance of DHODH in rapidly proliferating cells such as tumor cells and active T and B lymphocytes makes it an ideal target for pharmacological intervention. 3 Some inhibitors of DHODH have proven efficacy for the treatment of malaria, 4,5 autoimmune diseases, [6][7][8] cancer, 9 psoriasis, 10 virus proliferation [11][12][13] and acute myeloid leukemia. 14 Leflunomide (1) and brequinar (3) are two representative examples of such DHODH inhibitors ( Fig.…”