title: Specific targeting highly conserved residues in the HIV-1 reverse transcriptase primer grip region. Design, synthesis, and biological evaluation of novel, potent, and broad spectrum NNRTIs with antiviral activity.
abstract: Pyrrolobenzoxazepinones (PBOs) represent a new class of human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) whose prototype is 5. Molecular modeling studies based on the X-ray structures of HIV-1 RT prompted the synthesis of novel analogues which were tested as anti-HIV agents. The PBO derivatives specifically designed to target the highly conserved amino acid residues within the beta12-beta13 hairpin, namely primer grip, proved to be very potent against the most common mutant enzymes, including the highly resistant K103N mutant strain. Structure-activity relationships (SARs) are discussed in terms of a possible interaction with the RT binding site, depending on the nature of the substituents at C-6. Among the pyrrolobenzoxazepines investigated, 15c appeared to be the most promising NNRTI of the series characterized by potent antiviral activity, broad spectrum, and low cytotoxicity. 15c showed synergistic antiviral activity with AZT.
authors.affiliation: Dipartimento di Chimica delle Sostanze Naturali, Universita' di Napoli Federico II, via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Paul
authors.initials: P
authors.lastname: Huleatt
authors.forename: Bruno
authors.initials: B
authors.lastname: Catalanotti
authors.forename: Marco
authors.initials: M
authors.lastname: Persico
authors.forename: Meri
authors.initials: M
authors.lastname: De Angelis
authors.forename: Isabella
authors.initials: I
authors.lastname: Fiorini
authors.forename: Vito
authors.initials: V
authors.lastname: Nacci
authors.forename: Anna
authors.initials: A
authors.lastname: Ramunno
authors.forename: Manuela
authors.initials: M
authors.lastname: Rodriquez
authors.forename: Giovanni
authors.initials: G
authors.lastname: Greco
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Alberto
authors.initials: A
authors.lastname: Bergamini
authors.forename: Stefano
authors.initials: S
authors.lastname: Marini
authors.forename: Massimo
authors.initials: M
authors.lastname: Coletta
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Silvio
authors.initials: S
authors.lastname: Spadari
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002478:Cells, Cultured; D017124:Conserved Sequence; D015195:Drug Design; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D054303:HIV Reverse Transcriptase / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D010077:Oxazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D010077:Oxazepines; D011758:Pyrroles; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D054303:HIV Reverse Transcriptase