title: Structure-based design of novel dihydroalkoxybenzyloxopyrimidine derivatives as potent nonnucleoside inhibitors of the human immunodeficiency virus reverse transcriptase.
abstract: Two highly potent dihydroalkoxybenzyloxopyrimidine (DABO) derivatives targeting the nonnucleoside inhibitor (NNI) binding site of human immunodeficiency virus (HIV) reverse transcriptase (RT) have been designed based on the structure of the NNI binding pocket and tested for anti-HIV activity. Our lead DABO derivative, 5-isopropyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-on e, elicited potent inhibitory activity against purified recombinant HIV RT and abrogated HIV replication in peripheral blood mononuclear cells at nanomolar concentrations (50% inhibitory concentration, <1 nM) but showed no detectable cytotoxicity at concentrations as high as 100 microM.
authors.affiliation: Drug Discovery Program, Hughes Institute, St. Paul, Minnesota 55113, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Sudbeck
authors.forename: C
authors.initials: C
authors.lastname: Mao
authors.forename: R
authors.initials: R
authors.lastname: Vig
authors.forename: T K
authors.initials: TK
authors.lastname: Venkatachalam
authors.forename: L
authors.initials: L
authors.lastname: Tuel-Ahlgren
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C116724:5-isopropyl-2-((methylthiomethyl)thio)-6-(benzyl)pyrimidin-4(1H)-one; D011744:Pyrimidinones; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D013440:Sulfides; D054303:HIV Reverse Transcriptase