title: Rationally designed dual inhibitors of HIV reverse transcriptase and integrase.
abstract: Bifunctional inhibitors were designed and synthesized based on 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)a1 non-nucleoside reverse transcriptase (RT) inhibitors and diketoacid (DKA) integrase (IN) inhibitors. Biochemical studies revealed activity against RT and IN at low nanomolar and low micromolar concentrations, respectively. Exceptionally low IC50 values from a cell-based assay were achieved along with remarkably high therapeutic indices. Compound 7 was identified as the best compound of the series (IC50: 24 nM against RT, 4.4 microM against IN, and 10 nM against HIV-1).
authors.forename: Zhengqiang
authors.initials: Z
authors.lastname: Wang
authors.forename: Eric M
authors.initials: EM
authors.lastname: Bennett
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.forename: Christine
authors.initials: C
authors.lastname: Salomon
authors.forename: Robert
authors.initials: R
authors.lastname: Vince
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D066298:In Vitro Techniques; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013941:Thymine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D007659:Ketones; C061818:1-((2-hydroxyethoxy)methyl)-6-(phenylthio)thymine; D054303:HIV Reverse Transcriptase; D013941:Thymine