Dihydroorotate dehydrogenase (DHODH) catalyzes the de novo biosynthesis of pyrimidine, which is a a precursor to form the base elements in DNA and RNA. Over-activity of DHODH is related to cancer and rheumatoid diseases. Inhibitors of DHODH, such as brequinar and leflunomide, are benefits of immunosuppressive and antiproliferative effects in RA; however, cumulative toxicities have been reported. Researches investigated that brequinar and leflunomide differentially and distinctly act on active site of DHODH. In search of beneficial disease-modifying antirheumatic drugs (DMARDs), a series of hybrid of brequinar-leflunomide compounds have been synthesized in moderate yields in our laboratories. Those target compounds are under pharmacological evaluations, using brequinar and leflunomide as controls, by both the in vitro suppressing the production of nitric oxide (NO) in LPS-elicited macrophage Raw 264.7 cells and the in-vivo ;arrageenan-induced paw edema assay for further a SAR study.