Dihydro(alkylthio)(naphthylmethyl)oxopyrimidines: Novel non-nucleoside reverse transcriptase inhibitors of the S-DABO series

Article abstract of DOI:10.1021/jm960802y

Novel compounds related to 2-(cyclohexylthio)-3,4-dihydro-5-methyl-6- (3-methylbenzyl)-4-oxopyrimidine (3c, MC 639) have been synthesized and tested as inhibitors of human immunodeficiency virus type-1 (HIV-1). Reaction of thiourea with ethyl arylmethylacetoacetates furnished 5-alkyl-6- (arylmethyl)-3,4-dihydro-2-mercapto-4-oxopyrimidines which were then alkylated at the sulfur atom to afford the required 2-alkylthio or 2- cycloalkylthio derivatives (S-DABOs). Chemical modifications at N-3, C-4, and C-6 of the pyrimidine ring were attempted with the aim of improving antiretroviral activity. In particular, replacement of the benzyl group with the 1-naphthylmethyl moiety enhanced the activity of S-DABOs, whereas N-3 alkylation and C=O transformation into C=S at position 4 of the pyrimidine ring led to compounds devoid of anti-HIV-1 activity. Lower activity was generally observed when 1-naphthylmethyl was replaced by the isomeric 2- naphthylmethyl moiety. The most active compounds showed activity in the low micromolar range with EC₅₀ values comparable to that of nevirapine.