title: Pyrrolobenzothiazepinones and pyrrolobenzoxazepinones: novel and specific non-nucleoside HIV-1 reverse transcriptase inhibitors with antiviral activity.
abstract: Two novel classes of pyrrolobenzothiazepinones and pyrrolobenzoxazepinones were investigated as potential anti-AIDS drugs. These compounds were found to inhibit HIV-1 reverse transcriptase (RT) enzyme in vitro and to prevent HIV-1 cytopathogenicity in T4 lymphocytes, without appreciable activity on HIV-2 cytopathic effects, and against HBV as well as calfthymus DNA alpha-polymerase. Their potency is influenced by substituents at position 6 and on the fused aromatic ring. Specifically, small lipophilic substituents at C-6 were preferred, whereas substitutions on the benzo-fused ring were found to be detrimental to activity, with respect to the unsubstituted compounds. Modification of the pie-system at C-6 is well tolerated, although the replacement of the benzo-fused with a [2,3]naphtho-fused ring leads to a less active compound. Maximum potency and specificity is achieved with a phenyl and an ethyl group at position 6 of the pyrrolobenzoxazepinone system. In the enzymatic assay the oxazepinone derivative (+/-)-6-ethyl-6-phenylpyrrolo[2,1-d][1,5] benzoxazepin-7(6H)-one 16e (IC50 = 0.25 microM) was found to be more potent than nevirapine (IC50 = 0.5 microM), tested in the same experimental conditions using rC.dG as a template-primer. In cell culture assay benzoxazepine 16e was active against HIV-1, both wild type and AZT-sensitive, and HIV-1 (IIIB) strains, but not against HIV-2. In enzyme assay although 16e inhibited HIV-1 RT, it was inactive against the nevirapine-resistant recombinant RT Y181C at 50 microM. Molecular modeling studies suggest that these derivatives present a 3D pharmacophoric arrangement similar to that of other non-nucleoside inhibitors such as nevirapine.
authors.affiliation: Dipartimento Farmaco Chimico Technologico, Universitá di Siena, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Campiani
authors.forename: V
authors.initials: V
authors.lastname: Nacci
authors.forename: I
authors.initials: I
authors.lastname: Fiorini
authors.forename: M P
authors.initials: MP
authors.lastname: De Filippis
authors.forename: A
authors.initials: A
authors.lastname: Garofalo
authors.forename: G
authors.initials: G
authors.lastname: Greco
authors.forename: E
authors.initials: E
authors.lastname: Novellino
authors.forename: S
authors.initials: S
authors.lastname: Altamura
authors.forename: L
authors.initials: L
authors.lastname: Di Renzo
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010077:Oxazepines / Q000138:chemical synthesis / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000187:drug effects* / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D010077:Oxazepines; D018894:Reverse Transcriptase Inhibitors; D013841:Thiazepines; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase