Dihydroxynitrobenzaldehydes and Hydroxymethoxynitrobenzaldehydes: Synthesis and Biological Activity as catechol-O-methyltransferase Inhibitors

J Med Chem. 1992 Nov 27;35(24):4584-8. doi: 10.1021/jm00102a011.

Abstract

A series of nitro derivatives of dihydroxy- and hydroxymethoxybenzaldehyde was synthesized and tested as potential inhibitors of partially purified pig liver catechol-O-methyltransferase (COMT). All the dihydroxynitrobenzaldehydes prepared were potent inhibitors of COMT, but only one hydroxymethoxynitrobenzaldehyde (3-hydroxy-4-methoxy-5-nitrobenzaldehyde) showed activity as a COMT inhibitor. Although previously reported data showed that the presence of electron-withdrawing substituents at position 5 seemed to be very important for activity as COMT inhibitor, our results suggest that the requirement necessary to enhance the activity of the dihydroxyni-trobenzaldehyde derivatives toward COMT is the presence of the nitro group in a position ortho with respect to one hydroxyl group. The assayed compounds showed a reversible inhibition of COMT, which was mixed for all the dihydroxynitro derivatives but noncompetitive for 3-hydroxy-4-methoxy-5-nitrobenzaldehyde when pyrocatechol was the variable substrate and uncompetitive in all the inhibitors with respect to S-adenosyl-L-methionine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzaldehydes / chemical synthesis*
  • Benzaldehydes / pharmacology*
  • Catechol O-Methyltransferase / metabolism
  • Catechol O-Methyltransferase Inhibitors*
  • Catechols / metabolism
  • Kinetics
  • Liver / enzymology
  • Molecular Structure
  • S-Adenosylmethionine / metabolism
  • Structure-Activity Relationship
  • Swine

Substances

  • Benzaldehydes
  • Catechol O-Methyltransferase Inhibitors
  • Catechols
  • S-Adenosylmethionine
  • 3-hydroxy-4-methoxy-5-nitrobenzaldehyde
  • Catechol O-Methyltransferase
  • catechol