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.
Pérez
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RA
Instituto de Química Orgánica General (CSIC), Madrid, Spain.
Fernández-Alvarez
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Nieto
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Piedrafita
F J
FJ
D000818:Animals; D001547:Benzaldehydes / Q000138:chemical synthesis* / Q000494:pharmacology*; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D012436:S-Adenosylmethionine / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine
D001547:Benzaldehydes; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D012436:S-Adenosylmethionine; C078820:3-hydroxy-4-methoxy-5-nitrobenzaldehyde; D002394:Catechol O-Methyltransferase; C034221:catechol