Design, synthesis, optimization and antiviral activity of a class of hybrid dengue virus E protein inhibitors (original) (raw)

2015, Bioorganic & Medicinal Chemistry Letters

The β-OG pocket is a cavity in the flavivirus envelope (E) protein that was identified by Modis et al. (2003) as a promising site for the design of antiviral agents that interfere with virus entry into the host cell. The availability of the X-ray crystal structure of the dengue virus (DENV) E protein provided an opportunity for in silico drug design efforts to identify candidate inhibitors. The present study was set up to explore whether it is possible to generate a novel class of molecules that are hybrids between two hit compounds that have been reported previously by Zhou et al. (2008) following an in silico screening effort against the DENV E protein. First, a library of twenty hybrid molecules were designed and synthesized to explore the feasibility of this strategy. Antiviral evaluation in a virus-cellbased assay for DENV proved this approach to be successful, after which another twenty-four molecules were produced to further explore and optimize the potency of this novel class of hybrid inhibitors. In the end, a molecule was obtained with an EC 50 against dengue virus serotype 2 in the low micromolar range (23, 1.32 ± 0.41 µM).

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