Pyrimidine Type Enzyme Inhibitors: I. Design of Active Pyrimidines of Virostatic Value

Abstract

Alkenyl groups were attached to heterocyclic nitrogens of uracil ring assuming that the adjacent carbonyl groups might potentiate their (Nitrogen atoms) inductive effect to an extent enough to polarise the unsaturated double bond. The resulting N-alkenyl uracil derivatives react at room temperature with mercapto ethanol in an anti- Markownikoff’s manner yielding abnormal thioethers. The increased reactivity of the alkenyl group of the uracil compounds towards the SH group of mercapto ethanol led to the examination of their effect on the SH enzyme alcohol-dehydrogenase activity. Results with the virostatic l-allyl-3,5-di-ethyl-6-chlorouracil (Acluracil®) have now shown that it inhibits the enzyme activity to ∼70% at concentration of 2.98 ×10-3 mol/l; the 50% inhibition being achieved at 1.14×10-3 mol/l of the inhibitor concentration. Despite the fact that in vitro the alkenyluracils react with SH groups and the enzyme alcohol-dehydrogenase being an SH enzyme, the present studies do not afford evidence for the involvement of the prosthetic or other sulfhydryl groups of the enzyme protein in inhibition of the enzyme activity.