Design and synthesis of tetrahedral intermediate analogs as potential dihydroorotase inhibitors

Abstract

Three new heterocyclic analogues (4-6) of dihydroorotic acid were designed, synthesized, and tested as inhibitors of dihydroorotase. Each compound possessed a tetrahedral sulfur atom at the position equivalent to carbon 4 in the dihydroorotate ring in an attempt to mimic the presumed tetrahedral transition state in the course of the enzymatic reaction. Additionally, N-carbamyl-3-phosphonoalanine was prepared and evaluated as a dihydroorotase inhibitor. Compounds 4 and 6 were modest inhibitors (I50's of 0.52 and 0.18 mM, respectively), but the other candidate inhibitors showed little inhibition at 1 mM.