Synthesis and Anti-HIV-1 Activity of Thio Analogues of Dihydroalkoxybenzyloxopyrimidines

Article abstract of DOI:10.1021/jm00017a010

Various thio analogues of dihydroalkoxybenzyloxopyrimidines (DABOs), a new class of nonnucleoside reverse transcriptase inhibitors, were found to selectively inhibit the HIV-1 multiplication in vitro.Among the C-5 H-substituted 6-benzyl-3,4-dihydro-4-oxopyrimidines, the introduction of alkylthio or cycloalkylthio substituents at C-2 of the pyrimidine ring led to derivatives (S-DABOs) which were up to 10-fold more potent than the alkoxy or cycloalkyloxy counterparts.The further introduction of a methyl group at the 3'-position of the benzyl portion of 2-(alkylthio)-6-benzyluracils reduced the cytotoxicity leading to more selective compounds.Among C-5 methyl-substituted S-DABOs, numerous derivatives showed EC50 values as low as 0.6 μM and lacked cytotoxicity at doses as high as 300 μM.In the C-5 double methyl-substituted series, a more pronounced cytotoxicity was observed and the further introduction of a methyl at the 3'-position in the benzylidene group resulted in total loss of antiviral activity.S-DABOs, namely 2-(alkylthio)-6-benzyl-3,4-dihydro-4-oxopyrimidines, were synthesized by reacting proper methyl (phenylacetyl)acetates or their 2-methyl compounds with thiourea to afford 6-benzyl-4-oxo-1,2,3,4-tetrahydro-2-thiaoxopyrimidines or the related 5-methyl derivatives.Treatment of the latter derivatives with alkyl or cycloalkyl halides in alkaline medium gave the required title compounds.