Synthesis and evaluation of bifunctional nitrocatechol inhibitors of pig liver catechol-O-methyltransferase.
Bifunctional compounds were tested in vitro as potential inhibitors of pig liver catechol-O-methyltransferase (COMT) with respect to the catechol substrate 4-[(3,4-dihydroxyphenyl)azo]benzenesulfonate. The bifunctional compounds were a composite of either two nitrocatechols or one nitrocatechol and one phenol, linked by amide bonds to a spacer unit comprising two to five methylene groups. The unsymmetrical compounds N-[2-(4-hydroxybenzoylamine)ethyl]-3,4-dihydroxy-5-nitrobenzamide], N-[3-(4-hydroxybenzoyl-amine)propyl]-3,4-dihydroxy-5-nitrobenzamide] and N-[5-(4-hydroxybenzoylamine)pentyl]-3,4-dihydroxy-5-nitrobenzamide] demonstrated strong inhibitory action against COMT with K(i) values in the 100 nM range. In comparison, the monofunctional nitrocatechol analogues of these compounds had K(i) values that were significantly higher.
Department of Chemistry, University of Otago, PO Box 56, Dunedin, New Zealand.
Karl
K
Bailey
Eng Wui
EW
Tan
D000818:Animals; D002396:Catechols / Q000138:chemical synthesis* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D013552:Swine
D002396:Catechols; D004791:Enzyme Inhibitors; D009574:Nitro Compounds; C506350:nitrocatechol