title: Synthesis and anti-HIV-1 activity of thio analogues of dihydroalkoxybenzyloxopyrimidines.
abstract: Various thio analogues of dihydroalkoxybenzyloxopyrimidines (DABOs), a new class of non-nucleoside 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 alkyloxy 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 microM and lacked cytotoxicity at doses as high as 300 microM. 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.
authors.affiliation: Dipartimento di Studi Farmaceutici, Università di Roma La Sapienza, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Mai
authors.forename: M
authors.initials: M
authors.lastname: Artico
authors.forename: G
authors.initials: G
authors.lastname: Sbardella
authors.forename: S
authors.initials: S
authors.lastname: Massa
authors.forename: A G
authors.initials: AG
authors.lastname: Loi
authors.forename: E
authors.initials: E
authors.lastname: Tramontano
authors.forename: P
authors.initials: P
authors.lastname: Scano
authors.forename: P
authors.initials: P
authors.lastname: La Colla
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D011743:Pyrimidines