5-Alkyl-2-alkylamino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones, a new series of potent, broad-spectrum non-nucleoside reverse transcriptase inhibitors belonging to the DABO family

Bioorg Med Chem. 2005 Mar 15;13(6):2065-77. doi: 10.1016/j.bmc.2005.01.005.


2-Alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones (F(2)-NH-DABOs) 4, 5 belonging to the dihydro-alkoxy-benzyl-oxopyrimidine (DABO) family and bearing different alkyl- and arylamino side chains at the C(2)-position of the pyrimidine ring were designed as active against wild type (wt) human immunodeficiency virus type 1 (HIV-1) and some relevant HIV-1 mutants. Biological evaluation indicated the importance of the further anchor point of compounds 4, 5 into the non-nucleoside binding site (NNBS): newly synthesized compounds were highly active against both wild type and the Y181C HIV-1 strains. In anti-wt HIV-1 assay the potency of amino derivatives did not depend on the size or shape of the C(2)-amino side chain, but it associated with the presence of one or two methyl groups (one at the pyrimidine C(5)-position and the other at the benzylic carbon), being thymine, alpha-methyluracil or alpha-methylthymine derivatives almost equally active in reducing wt HIV-1-induced cytopathogenicity in MT-4 cells. Against the Y181C mutant strain, 2,6-difluorobenzyl-alpha-methylthymine derivatives 4d, 5h'-n' showed the highest potency and selectivity among tested compounds, both a properly sized C(2)-NH side chain and the presence of two methyl groups (at C(5) and benzylic positions) being crucial for high antiviral action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Amination
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / classification
  • Anti-HIV Agents / pharmacology*
  • Benzyl Compounds / chemistry*
  • Benzyl Compounds / pharmacology*
  • Cell Line
  • Fluorine / chemistry
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects
  • HIV-1 / enzymology
  • HIV-1 / genetics
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Mutation / genetics
  • Nucleosides / chemistry
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / classification*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship


  • Anti-HIV Agents
  • Benzyl Compounds
  • Ligands
  • Nucleosides
  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • Fluorine
  • HIV Reverse Transcriptase