Design, synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitors

Bioorg Med Chem. 2014 Jun 15;22(12):3180-6. doi: 10.1016/j.bmc.2014.04.003. Epub 2014 Apr 24.

Abstract

By targeting the ThDP binding site of Escherichia coli PDHc-E1, two new 'open-chain' classes of E. coli PDHc-E1 inhibitors, amide and urea derivatives, were designed, synthesized, and evaluated. The amide derivatives of compound 6d, with 4-NO2 in the benzene ring, showed the most potent inhibition of E. coli PDHc-E1. The urea derivatives displayed more potent inhibitory activity than the corresponding amide derivatives with the same substituent. Molecular docking studies confirmed that the urea derivatives have more potency due to the two hydrogen bonds formed by two NH of urea with Glu522. The docking results also indicate it might help us to design more efficient PDHc-E1 inhibitors that could interact with Glu522.

Keywords: Amide and urea derivatives; Molecular docking; PDHc-E1 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry*
  • Binding Sites
  • Catalytic Domain
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / drug effects*
  • Escherichia coli / enzymology
  • Hydrogen Bonding
  • Models, Molecular
  • Molecular Docking Simulation*
  • Molecular Structure
  • Pyruvate Dehydrogenase (Lipoamide) / antagonists & inhibitors*
  • Urea / chemistry*

Substances

  • Amides
  • Enzyme Inhibitors
  • Urea
  • Pyruvate Dehydrogenase (Lipoamide)