Discovery of Indole Derivatives as Novel and Potent Dengue Virus Inhibitors

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.