Design, synthesis, optimization and antiviral activity of a class of hybrid dengue virus E protein inhibitors
DOI: 10.1016/j.bmcl.2015.02.059
Title: Design, synthesis, optimization and antiviral activity of a class of hybrid dengue virus E protein inhibitors
Journal Title: Bioorganic & Medicinal Chemistry Letters
Volume: 25
Issue: 8
Publication Date: 15 April 2015
Start Page: 1747
End Page: 1752
Published online: online 2 March 2015
ISSN: 0960-894X
Affiliations:

  • a Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra 835 215 (JH), India

  • b Laboratory for Virology and Experimental Chemotherapy, Rega Institute for Medical Research, University of Leuven (KU Leuven), B-3000 Leuven, Belgium
  • Abstract: pocket is a cavity in the flavivirus envelope (E) protein that was identified by Proc. Natl. Acad. Sci. U.S.A.2003, 100, 6986 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 ACS. Chem. Biol.2008, 3, 765 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-cell-based 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 EC50 against dengue virus serotype 2 in the low micromolar range (23, 1.32 ± 0.41 μM).
    Accepted: 24 February 2015
    Received: 29 August 2014
    Revised: 28 January 2015
    Tel: +32 16 337353 (J.N.), +91 9470137264 (V.J.).?Both
    Email: Johan.Neyts@rega.kuleuven.be venkatesanj@bitmesra.ac.in

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