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. 2018 Sep 27;61(18):8390-8401.
doi: 10.1021/acs.jmedchem.8b00913. Epub 2018 Sep 12.

Discovery of Indole Derivatives as Novel and Potent Dengue Virus Inhibitors

Dorothée Bardiot  1 , Mohamed Koukni  1 , Wim Smets  1 , Gunter Carlens  1 , Michael McNaughton  1 , Suzanne Kaptein  2 , Kai Dallmeier  2 , Patrick Chaltin  1   3 , Johan Neyts  2 , Arnaud Marchand  1
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Discovery of Indole Derivatives as Novel and Potent Dengue Virus Inhibitors

Dorothée Bardiot et al. J Med Chem. .

Abstract

3-Acyl-indole derivative 1 was identified as a novel dengue virus (DENV) inhibitor from a DENV serotype 2 (DENV-2) phenotypic antiviral screen. Extensive SAR studies led to the discovery of new derivatives with improved DENV-2 potency as well as activity in nanomolar to micromolar range against the other DENV serotypes. In addition to the potency, physicochemical properties and metabolic stability in rat and human microsomes were improved during the optimization process. Chiral separation of the racemic mixtures showed a clear preference for one of the two enantiomers. Furthermore, rat pharmacokinetics of two compounds will be discussed in more detail, demonstrating the potential of this new series of pan-serotype-DENV inhibitors.

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