20862-91-3Relevant articles and documents
Design of inhibitors of influenza virus membrane fusion: Synthesis, structure-activity relationship and in vitro antiviral activity of a novel indole series
Brancato, Virginia,Peduto, Antonella,Wharton, Stephen,Martin, Stephen,More, Vijaykumar,Di Mola, Antonia,Massa, Antonio,Perfetto, Brunella,Donnarumma, Giovanna,Schiraldi, Chiara,Tufano, Maria Antonietta,de Rosa, Mario,Filosa, Rosanna,Hay, Alan
, p. 125 - 135 (2013)
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)-1. H-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.
Structure-based optimization and synthesis of antiviral drug Arbidol analogues with significantly improved affinity to influenza hemagglutinin
Wright, Zo? V.F.,Wu, Nicholas C.,Kadam, Rameshwar U.,Wilson, Ian A.,Wolan, Dennis W.
supporting information, p. 3744 - 3748 (2017/07/27)
Influenza is a highly contagious respiratory viral infection responsible for up to 50,000 deaths per annum in the US alone. The need for new therapeutics with novel modes of action is of paramount importance. We determined the X-ray structure of Arbidol with influenza hemagglutinin and found it was located in a distinct binding pocket. Herein, we report a structure-activity relationship study based on the co-complex combined with bio-layer interferometry to assess the binding of our compounds. Addition of a meta-hydroxy group to the thiophenol moiety of Arbidol to replace a structured water molecule in the binding pocket resulted in a dramatic increase in affinity against both H3 (1150-fold) and H1 (98-fold) hemagglutinin subtypes. Our analogues represent novel leads to yield more potent compounds against hemagglutinin that block viral entry.
Further studies on ethyl 5-hydroxy-indole-3-carboxylate scaffold: Design, synthesis and evaluation of 2-phenylthiomethyl-indole derivatives as efficient inhibitors of human 5-lipoxygenase
Peduto, Antonella,Bruno, Ferdinando,Dehm, Friedrike,Krauth, Verena,De Caprariis, Paolo,Weinigel, Christina,Barz, Dagmar,Massa, Antonio,De Rosa, Mario,Werz, Oliver,Filosa, Rosanna
, p. 492 - 498 (2014/06/10)
5-Lipoxygenase (5-LO), an enzyme that catalyzes the initial steps in the biosynthesis of pro-inflammatory leukotrienes, is an attractive drug target for the pharmacotherapy of inflammatory and allergic diseases. Here, we present the design, synthesis and
