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Synthesis and molecular modelling studies of novel sulphonamide derivatives as dengue virus 2 protease inhibitors.

Abstract
Development of antivirals for dengue is now based on rational approach targeting the enzymes involved in its life cycle. Among the targets available for inhibition of dengue virus, non-structural protein NS2B-NS3 protease is considered as a promising target for the development of anti-dengue agents. In the current study we have synthesized a series of 4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)benzene-1-sulphonamide derivatives and screened for DENV2 protease activity. Compounds 16 and 19 showed IC50 of DENV2 Protease activity with 48.2 and 121.9μM respectively. Molecular docking and molecular dynamic simulation studies were carried out to know the binding mode responsible for the activity. MD simulations revealed that, NS2B/NS3 protease was more stable when it binds with the active compound. Structure optimization of the lead compounds 16 and 19 and their co-crystallization studies are underway.
AuthorsAjay Kumar Timiri, Subasri Selvarasu, Manish Kesherwani, Vishwanathan Vijayan, Barij Nayan Sinha, Velmurugan Devadasan, Venkatesan Jayaprakash
JournalBioorganic chemistry (Bioorg Chem) Vol. 62 Pg. 74-82 (Oct 2015) ISSN: 1090-2120 [Electronic] United States
PMID26247308 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Inc. All rights reserved.
Chemical References
  • 4-(1,3-dioxoisoindolin-2-yl)-N-(4-ethylphenyl)benzenesulphonamide
  • 4-(1,3-dioxoisoindolin-2-yl)-N-(naphthalen-1-yl)benzenesulphonamide
  • Indoles
  • Naphthalenes
  • Phthalimides
  • Protease Inhibitors
  • Sulfonamides
  • NS3 protease, dengue virus
  • Serine Endopeptidases
Topics
  • Dengue Virus
  • Enzyme Assays
  • High-Throughput Screening Assays
  • Indoles (chemical synthesis, chemistry, pharmacology)
  • Models, Molecular
  • Molecular Docking Simulation
  • Naphthalenes (chemistry, pharmacology)
  • Phthalimides
  • Protease Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Serine Endopeptidases (drug effects)
  • Sulfonamides (chemical synthesis, chemistry, pharmacology)

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