No abstract

Although respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and young children, attempts to develop an effective therapy have so far proved unsuccessful. Here we report the preclinical profiles of PC786, a potent nonnucleoside RSV L protein polymerase inhibitor, designed for inhalation treatment of RSV infection. PC786 demonstrated a potent and selective antiviral activity against laboratory-adapted or clinical isolates of RSV-A (50% inhibitory concentration [IC50], <0.09 to 0.71 nM) and RSV-B (IC50, 1.3 to 50.6 nM), which were determined by inhibition of cytopathic effects in HEp-2 cells without causing detectable cytotoxicity. The underlying inhibition of virus replication was confirmed by PCR analysis. The effects of PC786 were largely unaffected by the multiplicity of infection (MOI) and were retained in the face of established RSV replication in a time-of-addition study. Persistent anti-RSV effects of PC786 were also demonstrated in human bronchial epithelial cells. In vivo intranasal once daily dosing with PC786 was able to reduce the virus load to undetectable levels in lung homogenates from RSV-infected mice and cotton rats. Treatment with escalating concentrations identified a dominant mutation in the L protein (Y1631H) in vitro. In addition, PC786 potently inhibited RSV RNA-dependent RNA polymerase (RdRp) activity in a cell-free enzyme assay and minigenome assay in HEp-2 cells (IC50, 2.1 and 0.5 nM, respectively). Thus, PC786 was shown to be a potent anti-RSV agent via inhibition of RdRp activity, making topical treatment with this compound a novel potential therapy for the treatment of human RSV infections.

No abstract

In this paper we try to convince you that the usual prejudices against photochemistry are not always well founded, supported by examples from the literature and from our own work. In fact, photochemistry can be a very powerful tool, for example in some elegant total syntheses which use key photochemical steps. Furthermore, the exploitation of chromatic orthogonality which allows wavelength-selective reactions, and recent strategies opening the possibility of enantioselective catalysis in photochemical reactions, expand the scope of this versatile synthetic tool. Finally, state-of-art LED-technology has allowed the development of small and easy-to-use photoreactors.

Kurz und bündig: Mit einer kupferkatalysierten Umsetzung vom Friedel‐Crafts‐Typ ließ sich die Titelreaktion verwirklichen. Eine iterative C‐H‐Arylierungsstrategie konnte auch zur Arylierung von Anilinen durch sequenzielles Anbinden unterschiedlicher aromatischer Gruppen an die para‐, ortho‐ und meta‐Positionen genutzt werden (siehe Schema, Bn=Benzyl, Piv=Pivaloyl).