Inhibition of Chikungunya Virus Replication by 1-[(2-Methylbenzimidazol-1-yl) Methyl]-2-Oxo-Indolin-3-ylidene] Amino] Thiourea(MBZM-N-IBT)

Sci Rep. 2016 Feb 4:6:20122. doi: 10.1038/srep20122.

Abstract

Chikungunya virus (CHIKV) infection is one of the most challenging human Arboviral infections with global significance and without any specific antiviral. In this investigation, 1-[(2-methylbenzimidazol-1-yl) methyl]-2-oxo-indolin-3-ylidene] amino] thiourea (MBZM-N-IBT) was synthesised as a molecular hybrid of 2-methyl benzimidazole and isatin-β-thiosemicarbazone and its anti-CHIKV property was evaluated. The release of infectious virus particles was calculated by plaque assay, expression profile of viral RNA was estimated by RT-PCR and viral protein profiles were assessed by Western blot and FACS analyses. The safety index of MBZM-N-IBT was found to be >21. The CHIKV infectious viral particle formation was abrogated around 76.02% by MBZM-N-IBT during infection in mammalian system and the viral RNA synthesis was reduced by 65.53% and 23.71% for nsP2 and E1 respectively. Surprisingly, the viral protein levels were reduced by 97% for both nsP2 and E2. In the time-of-addition experiment it abrogated viral infection at early as well as late phase of viral life cycle, which indicates about multiple mechanisms for its anti-CHIKV action. In silico analysis justified development of MBZM-N-IBT with good affinities for potential target proteins of CHIKV and related virus. With predictions of good drug-likeness property, it shows potential of a drug candidate which needs further experimental validation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology
  • Benzimidazoles / chemistry
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacology*
  • Binding Sites
  • Blotting, Western
  • Cell Survival / drug effects
  • Chikungunya virus / physiology*
  • Chlorocebus aethiops
  • Flow Cytometry
  • Isatin / analogs & derivatives*
  • Isatin / chemistry
  • Isatin / metabolism
  • Isatin / pharmacology
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Structure, Tertiary
  • RNA, Viral / genetics
  • RNA, Viral / metabolism
  • Real-Time Polymerase Chain Reaction
  • Thiourea / chemistry
  • Thiourea / metabolism
  • Thiourea / pharmacology*
  • Vero Cells
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism
  • Virus Internalization / drug effects
  • Virus Replication / drug effects*

Substances

  • 1-((2-methylbenzimidazol-1-yl)methyl)-2-oxoindolin-3-ylidene)amino)thiourea
  • Antiviral Agents
  • Benzimidazoles
  • RNA, Viral
  • Viral Nonstructural Proteins
  • Isatin
  • Thiourea