Synthesis and evaluation of coumarin derivatives as potential dual-action HIV-1 protease and reverse transcriptase inhibitors

Bioorg Med Chem. 2013 Apr 1;21(7):1964-71. doi: 10.1016/j.bmc.2013.01.025. Epub 2013 Jan 22.

Abstract

Baylis-Hillman-derived 3-(benzylaminomethyl)coumarins have been treated, sequentially, with chloroacetyl chloride and propargylamine to afford alkynylated coumarins as substrates for Click Chemistry reactions with azidothymidine (AZT) in the presence of a Cu(I) catalyst. The dual-action HIV-1 protease (PR) and reverse transcriptase (RT) inhibition potential of the resulting N-benzylated cycloaddition products, and a series of non-benzylated analogues, has been explored using saturation transfer difference (STD) NMR, computer modelling and enzyme inhibition techniques.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Coumarins / chemical synthesis
  • Coumarins / chemistry*
  • Coumarins / pharmacology*
  • HIV Infections / drug therapy
  • HIV Infections / virology
  • HIV Protease / metabolism
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / chemistry*
  • HIV Protease Inhibitors / pharmacology*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Humans
  • Models, Molecular
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Zidovudine / chemical synthesis
  • Zidovudine / chemistry
  • Zidovudine / pharmacology

Substances

  • Coumarins
  • HIV Protease Inhibitors
  • Reverse Transcriptase Inhibitors
  • Zidovudine
  • HIV Reverse Transcriptase
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1