2. Academic Validation
  3. Design, synthesis, optimization and antiviral activity of a class of hybrid dengue virus E protein inhibitors

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

  • Bioorg Med Chem Lett. 2015 Apr 15;25(8):1747-1752. doi: 10.1016/j.bmcl.2015.02.059.
Surender Singh Jadav 1,  Suzanne Kaptein 2,  Ajaykumar Timiri 1,  Tine De Burghgraeve 2,  Vishnu Nayak Badavath 1,  Ramesh Ganesan 1,  Barij Nayan Sinha 1,  Johan Neyts 3,  Pieter Leyssen 2,  Venkatesan Jayaprakash 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra 835 215 (JH), India.
  • 2 Laboratory for Virology and Experimental Chemotherapy, Rega Institute for Medical Research, University of Leuven (KU Leuven), B-3000 Leuven, Belgium.
  • 3 Laboratory for Virology and Experimental Chemotherapy, Rega Institute for Medical Research, University of Leuven (KU Leuven), B-3000 Leuven, Belgium. Electronic address: [email protected].
  • 4 Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra 835 215 (JH), India. Electronic address: [email protected].
PMID: 25791449 DOI: 10.1016/j.bmcl.2015.02.059
Abstract

The β-OG 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±0.41μM).

Keywords

Dengue virus; E protein; Pyrazolines; Schiff’s bases; Thiazoles.

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