Alkylated benzimidazoles: Design, synthesis, docking, DFT analysis, ADMET property, molecular dynamics and activity against HIV and YFV

Comput Biol Chem. 2020 Dec:89:107400. doi: 10.1016/j.compbiolchem.2020.107400. Epub 2020 Oct 6.

Abstract

A series of alkylated benzimidazole derivatives was synthesized and screened for their anti-HIV, anti-YFV, and broad-spectrum antiviral properties. The physicochemical parameters and drug-like properties of the compounds were assessed first, and then docking studies and MD simulations on HIV-RT allosteric sites were conducted to find the possible mode of their action. DFT analysis was also performed to confirm the nature of the hydrogen bonding interaction of active compounds. The in silico studies indicated that the molecules behaved like possible NNRTIs. The nature - polar or non-polar and position of the substituent present at fifth, sixth, and N-1 positions of the benzimidazole moiety played an important role in determining the antiviral properties of the compounds. Among the various compounds, 2-(5,6-dibromo-2-chloro-1H-benzimidazol-1-yl)ethan-1-ol (3a) showed anti-HIV activity with an appreciably low IC50 value as 0.386 × 10-5μM. Similarly, compound 2b, 3-(2-chloro-5-nitro-1H-benzimidazol-1-yl) propan-1-ol, showed excellent inhibitory property against the yellow fever virus (YFV) with EC50 value as 0.7824 × 10-2μM.

Keywords: Antiviral profile; DFT; Docking; HIV; Molecular dynamics; YFV.

MeSH terms

  • Animals
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology*
  • Catalytic Domain
  • Chlorocebus aethiops
  • Density Functional Theory
  • HIV / drug effects*
  • HIV / enzymology
  • HIV Reverse Transcriptase / chemistry
  • HIV Reverse Transcriptase / metabolism
  • Microbial Sensitivity Tests
  • Models, Chemical
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / pharmacokinetics
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Vero Cells
  • Yellow fever virus / drug effects*
  • Yellow fever virus / enzymology

Substances

  • Benzimidazoles
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase