title: Derivatives of imidazotriazine and pyrrolotriazine C-nucleosides as potential new anti-HCV agents.
abstract: Previous investigations identified 2'-C-Me-branched ribo-C-nucleoside adenosine analogues, 1, which contains a pyrrolo[2,1-f][1,2,4]triazin-4-amine heterocyclic base, and 2, which contains an imidazo[2,1-f][1,2,4]triazin-4-amine heterocyclic base as two compounds with promising anti-HCV in vitro activity. This Letter describes the synthesis and evaluation of a series of novel analogues of these compounds substituted at the 2-, 7-, and 8-positions of the heterocyclic bases. A number of active new HCV inhibitors were identified but most compounds also demonstrated unacceptable cytotoxicity. However, the 7-fluoro analogue of 1 displayed good potency with a promising cytotherapeutic margin.
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Draffan
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Frey
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Fraser
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Brett
authors.initials: B
authors.lastname: Pool
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Carlie
authors.initials: C
authors.lastname: Gannon
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Tyndall
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Julia
authors.initials: J
authors.lastname: Cianci
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Harding
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Lilly
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Hufton
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Rosliana
authors.initials: R
authors.lastname: Halim
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Saba
authors.initials: S
authors.lastname: Jahangiri
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Silas
authors.initials: S
authors.lastname: Bond
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Tyrone P
authors.initials: TP
authors.lastname: Jeynes
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Van T T
authors.initials: VT
authors.lastname: Nguyen
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Veronika
authors.initials: V
authors.lastname: Wirth
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Luttick
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Danielle
authors.initials: D
authors.lastname: Tilmanis
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Melinda
authors.initials: M
authors.lastname: Pryor
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Porter
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Morton
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Bo
authors.initials: B
authors.lastname: Lin
authors.affiliation: Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 rue Cunard, Laval, Québec H7S 2G5, Canada.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
authors.affiliation: Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 rue Cunard, Laval, Québec H7S 2G5, Canada.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Bethell
authors.affiliation: Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 rue Cunard, Laval, Québec H7S 2G5, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
authors.affiliation: Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 rue Cunard, Laval, Québec H7S 2G5, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Simoneau
authors.affiliation: Biota Scientific Management Pty. Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Tucker
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation / Q000187:drug effects*; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry*; D012367:RNA, Viral / Q000235:genetics; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry*; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D007093:Imidazoles; D009705:Nucleosides; D011758:Pyrroles; D012367:RNA, Viral; D014227:Triazines
keywords: Antiviral; C-nucleoside; Hepatitis C; NS5B polymerase