Targeting the HIV integrase (HIV IN)

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.

No abstract

In the absence of any approved dengue-specific treatment, the discovery and development of a novel small-molecule antiviral for the prevention or treatment of dengue are critical. We previously reported the identification of a novel series of 3-acyl-indole derivatives as potent and pan-serotype dengue virus inhibitors. We herein describe our optimization efforts toward preclinical candidates 24a and 28a with improved pan-serotype coverage (EC 50 's against the four DENV serotypes ranging from 0.0011 to 0.24 μM for 24a and from 0.00060 to 0.084 μM for 28a), chiral stability, and oral bioavailability in preclinical species, as well as showing a doseproportional increase in efficacy against DENV-2 infection in vivo in mice.

Diels–Alder reactions of ethene with 2(1H)‐pyrazinones bearing a homochiral auxiliary group are presented. The cycloaddition products form with diasteromeric excesses of up to 50 %. To the best of our knowledge, these are the firstDiels–Alder reactions with ethene showing some degree of diastereoselectivity. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)