title: Characterization of the anti-HIV-1 activity of 3,4-dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs), new non-nucleoside reverse transcriptase inhibitors.
abstract: Novel 3,4-dihydro-6-benzyl-4-oxopyrimidines (DABOs), variously substituted 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 comparable to that of 2'-3'-dideoxyinosine (ddI). Mode of action studies suggested that DABOs interfered with a step of the virus multiplication cycle following adsorption and preceding integration. Enzyme assays indicated that DABOs targeted HIV-1 reverse transcriptase: they inhibited the RNA-dependent DNA polymerase activity in a template-dependent manner and, to a lesser extent, the DNA-dependent DNA polymerase activity. No inhibition of the RNase-H associated activity was observed. When DABOs were assayed in combination with 3'-azido-3'-dideoxythymidine (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 mutually exclusive.
authors.affiliation: Dipartimento di Biologia Sperimentale, Università di Cagliari, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Tramontano
authors.forename: M E
authors.initials: ME
authors.lastname: Marongiu
authors.forename: A
authors.initials: A
authors.lastname: de Montis
authors.forename: A G
authors.initials: AG
authors.lastname: Loi
authors.forename: M
authors.initials: M
authors.lastname: Artico
authors.forename: S
authors.initials: S
authors.lastname: Massa
authors.forename: A
authors.initials: A
authors.lastname: Mai
authors.forename: P
authors.initials: P
authors.lastname: la Colla
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002478:Cells, Cultured; D054306:Dideoxynucleotides; D004347:Drug Interactions; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D011743:Pyrimidines / Q000494:pharmacology* / Q000633:toxicity; D011744:Pyrimidinones / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; C092123:DABO 546; D054306:Dideoxynucleotides; D011743:Pyrimidines; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; D015215:Zidovudine; C052873:zidovudine triphosphate; D054303:HIV Reverse Transcriptase