Design, synthesis, and enzyme kinetics of novel benzimidazole and quinoxaline derivatives as methionine synthase inhibitors

Bioorg Med Chem. 2014 Jan 1;22(1):550-8. doi: 10.1016/j.bmc.2013.10.052. Epub 2013 Nov 8.


Methionine synthase catalyzes the transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine, producing methionine and tetrahydrofolate. Benzimidazole and deazatetrahydrofolates derivatives have been shown to inhibit methionine synthase by competing with the substrate 5-methyltetrahydrofolate. In this study, a novel series of substituted benzimidazoles and quinoxalines were designed and assessed for inhibitory activity against purified rat liver methionine synthase using a radiometric enzyme assay. Compounds 3g, 3j, and 5c showed the highest activity against methionine synthase (IC₅₀: 20 μM, 18 μM, 9 μM, respectively). Kinetic analysis of these compounds using Lineweaver-Burk plots revealed characteristics of mixed inhibition for 3g and 5c; and uncompetitive inhibition for 3j. Docking study into a homology model of the rat methionine synthase gave insights into the molecular determinants of the activity of this class of compounds. The identification of these drug-like inhibitors could lead the design of the next generation modulators of methionine synthase.

Keywords: 5-Methyltetrahydrofolate; Benzimidazole; Cancer; Methionine synthase; Quinoxaline.

MeSH terms

  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / chemistry*
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / genetics
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / metabolism
  • Animals
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Fungal Proteins / chemistry*
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism
  • Methionine / metabolism
  • Models, Molecular
  • Quinoxalines / chemical synthesis*
  • Quinoxalines / chemistry


  • Benzimidazoles
  • Fungal Proteins
  • Quinoxalines
  • Methionine
  • benzimidazole
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase