CHARACTERIZATION OF THE ANTI-HIV-1 ACTIVITY OF 3,4-DIHYDRO-2-ALKOXY-6-BENZYL-4-OXOPYRIMIDINES (DABOS), NEW NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS

Novel 3,4-dihydro-6-benzyl-4-oxopyrimidines (DABOs): variously substit uted at both the C-2 and C-5 positions of the pyrimidine ring, proved to be specific inhibitors of the human immunodeficiency virus type 1 ( HIV-1) in vitro. Some compounds showed potency at micromolar doses, no cytotoxicity at the maximum testable doses and selectivity indexes co mparable to that of 2'-3' -dideoxyinosine (ddI). Mode of action studie s suggested that DABOs interfered with a step of the virus multiplicat ion cycle following adsorption and preceding integration. Enzyme assay s indicated that DABOs targeted HIV-1 reverse transcriptase: they inhi bited the RNA-dependent DNA polymerase activity in a template-dependen t manner and, to a lesser extent, the DNA-dependent DNA polymerase act ivity. No inhibition of the RNase-H associated activity was observed. When DABOs were assayed in combination with 3'-azido-3'-dideoxythymidi ne (AZT) or ddI against HIV-1 in cell cultures, a slightly synergistic inhibitory effect was observed. The combination of DABO 546 and AZTTP in enzyme assays showed that the two compounds were kinetically mutua lly exclusive.