title: Design of inhibitors of influenza virus membrane fusion: synthesis, structure-activity relationship and in vitro antiviral activity of a novel indole series.
abstract: The fusion of virus and endosome membranes is an essential early stage in influenza virus infection. The low pH-induced conformational change which promotes the fusogenic activity of the haemagglutinin (HA) is thus an attractive target as an antiviral strategy. The anti-influenza drug Arbidol is representative of a class of antivirals which inhibits HA-mediated membrane fusion by increasing the acid stability of the HA. In this study two series of indole derivatives structurally related to Arbidol were designed and synthesized to further probe the foundation of its antiviral activity and develop the basis for a structure-activity relationship (SAR). Ethyl 5-(hydroxymethyl)-1-methyl-2-(phenysulphanylmethyl)-1H-indole-3-carboxylate (15) was identified as one of the most potent inhibitors and more potent than Arbidol against certain subtypes of influenza A viruses. In particular, 15 exhibited a much greater affinity and preference for binding group 2 than group 1 HAs, and exerted a greater stabilising effect, in contrast to Arbidol. The results provide the basis for more detailed SAR studies of Arbidol binding to HA; however, the greater affinity for binding HA was not reflected in a comparable increase in antiviral activity of 15, apparently reflecting the complex nature of the antiviral activity of Arbidol and its derivatives.
authors.affiliation: MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Virginia
authors.initials: V
authors.lastname: Brancato
authors.forename: Antonella
authors.initials: A
authors.lastname: Peduto
authors.forename: Stephen
authors.initials: S
authors.lastname: Wharton
authors.forename: Stephen
authors.initials: S
authors.lastname: Martin
authors.forename: Vijaykumar
authors.initials: V
authors.lastname: More
authors.forename: Antonia
authors.initials: A
authors.lastname: Di Mola
authors.forename: Antonio
authors.initials: A
authors.lastname: Massa
authors.forename: Brunella
authors.initials: B
authors.lastname: Perfetto
authors.forename: Giovanna
authors.initials: G
authors.lastname: Donnarumma
authors.forename: Chiara
authors.initials: C
authors.lastname: Schiraldi
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Tufano
authors.forename: Mario
authors.initials: M
authors.lastname: de Rosa
authors.forename: Rosanna
authors.initials: R
authors.lastname: Filosa
authors.forename: Alan
authors.initials: A
authors.lastname: Hay
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D015195:Drug Design; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D009980:Influenza A virus / Q000187:drug effects* / Q000378:metabolism; D007251:Influenza, Human / Q000188:drug therapy / Q000517:prevention & control; D061985:Madin Darby Canine Kidney Cells; D008561:Membrane Fusion; D013329:Structure-Activity Relationship; D053586:Virus Internalization / Q000187:drug effects*; D013440:Sulfides
chemical_list: D000998:Antiviral Agents; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007211:Indoles; C585351:ethyl 5-(hydroxymethyl)-1-methyl-2-(phenysulfanylmethyl)-1H-indole-3-carboxylate; C086979:umifenovir; D013440:Sulfides
keywords: Antiviral action; Arbidol derivatives; Differential binding to haemagglutinin; Fluorescence binding assay; Influenza haemagglutinin; pH stabilization