title: Biological and biochemical anti-HIV activity of the benzothiadiazine class of nonnucleoside reverse transcriptase inhibitors.
abstract: A series of benzothiadiazine derivatives were screened against the human immunodeficiency virus (HIV) and certain structure-activity relationships were defined for anti-HIV activity in this chemical class. The selected representative NSC 287474 was a highly potent inhibitor of HIV-induced cell killing and HIV replication in a variety of human cell lines, as well as in fresh human peripheral blood lymphocytes and macrophages. The compound was active against a panel of biologically diverse laboratory and clinical strains of HIV-1, including the AZT-resistant strain G910-6. However, the agent was inactive against HIV-2, and also against both nevirapine- and pyridinone-resistant strains (N119 and A17) of HIV-1, which are cross-resistant to several structurally diverse nonnucleoside reverse transcriptase inhibitors. The compound selectively inhibited HIV-1 reverse transcriptase, but not HIV-2 reverse transcriptase. Combination of NSC 287474 with AZT synergistically inhibited HIV-1-induced cell killing in vitro. The compound did not inhibit the replication of the Rauscher murine leukemia retrovirus or the simian immunodeficiency virus. The benzothiadiazine class of compounds represents a new active anti-HIV-1 chemotype within the diverse group of nonnucleoside reverse transcriptase inhibitors.
authors.affiliation: Virology Research Division, Southern Research Institute, Frederick Research Center, MD 21701.
authors.forename: R W
authors.initials: RW
authors.lastname: Buckheit
authors.forename: V
authors.initials: V
authors.lastname: Fliakas-Boltz
authors.forename: W D
authors.initials: WD
authors.lastname: Decker
authors.forename: J L
authors.initials: JL
authors.lastname: Roberson
authors.forename: C A
authors.initials: CA
authors.lastname: Pyle
authors.forename: E L
authors.initials: EL
authors.lastname: White
authors.forename: B J
authors.initials: BJ
authors.lastname: Bowdon
authors.forename: J B
authors.initials: JB
authors.lastname: McMahon
authors.forename: M R
authors.initials: MR
authors.lastname: Boyd
authors.forename: J P
authors.initials: JP
authors.lastname: Bader
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D001581:Benzothiadiazines / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004352:Drug Resistance, Microbial; D004357:Drug Synergism; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D001581:Benzothiadiazines; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D054303:HIV Reverse Transcriptase