title: Potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) by 5-ethyl-6-phenylthiouracil derivatives through their interaction with the HIV-1 reverse transcriptase.
abstract: In the search for 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT) derivatives, we have found several 5-ethyl-6-(phenylthio)uracil analogues to be highly potent and selective inhibitors of human immunodeficiency virus (HIV) type 1. 1-Benzyloxymethyl-5-ethyl-6-phenylthiouracil, the most potent congener of the series, inhibits HIV-1 replication in a variety of cell systems, including peripheral blood lymphocytes, at a concentration of 1.5-7.0 nM, which is lower by a factor of 10(3) than the 50% antivirally effective concentration of the parent compound HEPT. The 5-ethyl-6-(phenylthio)uracil analogues, like HEPT itself, do not inhibit HIV-2 replication but do inhibit replication of 3'-azido-3'-deoxythymidine-resistant mutants of HIV-1. 1-Benzyloxy-methyl-5-ethyl-6-phenylthiouracil and its congeners are targeted at the HIV-1 reverse transcriptase (RT). They do not inhibit HIV-2 RT. They do not need to be metabolized to exert their inhibitory effect on HIV-1 RT. Yet this inhibitory effect is competitive with the natural substrate dTTP. The HEPT derivatives represent a group of RT inhibitors with a unique mode of interaction with HIV-1 RT.
authors.affiliation: Department of Bacteriology, Fukushima Medical College, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Ubasawa
authors.forename: H
authors.initials: H
authors.lastname: Takashima
authors.forename: K
authors.initials: K
authors.lastname: Sekiya
authors.forename: I
authors.initials: I
authors.lastname: Nitta
authors.forename: K
authors.initials: K
authors.lastname: Umezu
authors.forename: H
authors.initials: H
authors.lastname: Nakashima
authors.forename: S
authors.initials: S
authors.lastname: Mori
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship; D013941:Thymine / Q000031:analogs & derivatives*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; C025677:4-(hydroxy-3-piperidylpropyl)-5-methyl-2-phenyltriazole; D013941:Thymine