Latent inhibitors. Part 6. Inhibition of dihydro-orotate dehydrogenase by substituted 5-benzylhydantoins

Abstract

A series of substituted 5-benzyl-3-(1-carboxy-2-phenylethyl)hydantoins was prepared by condensation of aromatic aldehydes with the corresponding 5-unsubstituted hydantoin followed by reduction of the intermediate benzylidene derivative. The compounds were assessed as inhibitors of dihydro-orotate dehydrogenase from Clostridium oroticum. It was found that hydrophobic and electron-donating substituents in the phenyl ring of the benzyl group favoured binding and irreversible inhibition. The results for the series were correlated with standard substituent parameters from which a mechanism of inhibition was derived. This involved rapid deprotonation of the hydantoin at C-5 followed by rate-determining removal of hydride, or its equivalent.