Dihydroxynitrobenzaldehydes and hydroxymethoxynitrobenzaldehydes: synthesis and biological activity as catechol-O-methyltransferase inhibitors.

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.