Leflunomideʹs Bioactive Metabolite Has the Minimal Structural Requirements for the Efficient Inhibition of Human Dihydroorotate Dehydrogenase

The α-cyano-β-hydroxy enamide1is an inhibitor of human dihydroorotate dehydrogenase (IC50= 0.26 μM), the rate-limiting enzyme in thede novopyrimidine biosynthesis. A structure–activity analysis based on selected derivatives of1demonstrates that both its structural characteristics and its physicochemical properties are mandatory for the efficient inhibition of the enzyme.