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.

人二氢乳清酸脱氢酶（h DHODH）是细胞内嘧啶核苷酸从头合成途径中的关键酶。特立氟胺是一种获批用于治疗多发性硬化症的h DHODH 抑制剂，其中等疗效限制了其在恶性肿瘤治疗中的应用。在此，设计、合成和评估了 37 种具有联苯支架的新型特立氟胺衍生物。结果，最佳化合物A37表现出有效的h DHODH 抑制活性，IC ₅₀值为 10.2 nM，比特立氟胺强约 40 倍（IC ₅₀ = 407.8 nM)，并显示出对 HCT116 细胞的良好抗增殖活性，IC ₅₀值为 0.3 μM。同时，A37在急性毒性试验中以400 mg/kg的口服剂量表现出可接受的安全性，在HCT116异种移植模型中以30 mg/kg的口服剂量表现出良好的抗肿瘤作用，肿瘤生长抑制率为54.4% . 这些结果表明A37是一种有效的h DHODH抑制剂，具有治疗结直肠癌的潜力。