SYNTHESIS AND ANTI-HIV-1 ACTIVITY OF THIO ANALOGS OF DIHYDROALKOXYBENZYLOXOPYRIMIDINES

Various thio analogues of dihydroalkoxybenzyloxopyrimidines (DABOs), a new class of nonnucleoside reverse transcriptase inhibitors, were fou nd to selectively inhibit the HIV-1 multiplication in vitro. Among the C-5 H-substituted 6-benzyl-3,4-dihydro-4-oxopyrimidines, the introduc tion of alkylthio or cycloalkylthio substituents at C-2 of the pyrimid ine ring led to derivatives (S-DABOs) which were up to 10-fold more po tent than the alkyloxy or cycloalkyloxy counterparts. The further intr oduction of a methyl group at the 3'-position of the benzyl portion of 2-(alkylthio)-6-benzyluracils reduced the cytotoxicity leading to mor e selective compounds. Among C-5 methyl-substituted S-DABOs, numerous derivatives showed EC(50) values as low as 0.6 mu M and lacked cytotox icity at doses as high as 300 mu M. In the C-5 double methyl-substitut ed 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-(alkyl thio)-6-benzyl-3,4-dihydro-4-oxo were synthesized by reacting proper m ethyl (phenylacetyl)acetates or their 2-methyl compounds with thiourea to afford nzyl-4-oxo-1,2,3,4-tetrahydro-2-thiaoxopyrimidines or the r elated 5-methyl derivatives. Treatment of the latter derivatives with alkyl or cycloalkyl halides in alkaline medium gave the required title compounds.