Latent inhibitors. Part 7. Inhibition of dihydro-orotate dehydrogenase by spirocyclopropanobarbiturates

Abstract

A series of 5-spirocyclopropanobarbiturates bearing alkyl and aryl substituents on the cyclopropane ring has been synthesized. Dihydro-orotate dehydrogenase from Clostridium oroticum was shown to be inhibited by these compounds. A related series of 5-membered-ring compounds (hydantoins and pyrazoles) was prepared but all the compounds were found to be inactive. In order to correlate these observations with previous results concerning 5-arylmethylhydantoins and 5-arylidene-hydantoins as inhibitors, 5-arylidenebarbiturates were also assessed as inhibitors and found to be the most active of the compounds investigated. The results are interpreted in the context of molecular recognition by this enzyme and the possibility of using substrate surrogates as templates for constructing latent inhibitors of enzymes.