A novel series of teriflunomide derivatives as orally active inhibitors of human dihydroorotate dehydrogenase for the treatment of colorectal carcinoma

Human dihydroorotate dehydrogenase (hDHODH) is a key enzyme in the de novo synthesis pathway of pyrimidine nucleotide in cells. The moderate efficiency of teriflunomide, an approved hDHODH inhibitor for the treatment of multiple sclerosis, limited its therapeutic application of malignancy. Herein, thirty-seven novel teriflunomide derivatives with a biphenyl scaffold were designed, synthesized and evaluated. As a result, the optimal compound A37 exhibited a potent hDHODH inhibitory activity with an IC50 value of 10.2 nM, which was about 40-fold stronger than that of teriflunomide (IC50 = 407.8 nM), and showed favorable antiproliferative activities against HCT116 cells with an IC50 value of 0.3 μM. Meanwhile, A37 displayed an acceptable safety profile at an oral dosage of 400 mg/kg in the acute toxicity assay, and exhibited a promising antitumor effect with tumor growth inhibition rate of 54.4% at an oral dosage of 30 mg/kg in HCT116 xenograft model. These results indicate that A37 is an efficacious hDHODH inhibitor with potential in the treatment of colorectal carcinoma. [Display omitted] •Thirty-seven novel teriflunomide derivatives with a biphenyl scaffold were designed, synthesized and evaluated.•Compound A37 exhibited a potent hDHODH inhibitory activity, which was about 40-fold stronger than that of teriflunomide.•Compound A37 exhibited a promising antitumor effect with TGI rate of 54.4% at an oral dosage of 30 mg/kg in vivo.