Chromone, a Privileged Scaffold for the Development of Monoamine Oxidase Inhibitors

Abstract

Two series of novel chromone derivatives were synthesized and investigated for their ability to inhibit the activity of monoamine oxidase. The SAR data indicate that chromone derivatives with substituents in position 3 of γ-pyrone nucleus act preferably as MAO-B inhibitors, with IC(50) values in the nanomolar to micromolar range. Almost all chromone 3-carboxamides display selectivity toward MAO-B. Identical substitutions on position 2 of γ-pyrone nucleus result in complete loss of activity in both isoforms (chromones 2-12 except 3 and 5). Notably, chromone (19) exhibits an MAO-B IC(50) of 63 nM, greater than 1000-fold selectivity over MAO-A, and behaves as a quasi-reversible inhibitor. Docking experiments onto the MAO binding of the most active compound highlight different interaction patterns among the isoforms A and B. The differential analysis of the solvation effects among the chromone isomers gave additional insight about the superior outline of the 3-substituted chromone derivatives.

Monoamine oxidase inhibitory activities of heterocyclic chalcones

“…Potential tight-binding of inhibitors to the MAOs has been previously reported for a variety of different classes of compounds. [44][45][46][47] Since the inhibition of MAO-B by compound 4h may not to be readily reversible and 4h therefore may exhibit a degree of tight-binding to the MAO-B active site, the reversibility of MAO-B inhibition by 4h was further examined by dialysis. For this purpose MAO-B and 4h, at a concentration of 4 Â IC 50 , were preincubated for a period of 15 min and subsequently dialysed for 24 h. The residual enzyme activity was measured and compared to similar dialysis experiments performed in the absence of inhibitor and presence of the irreversible inhibitor, (R)-deprenyl.…”

Parkinson's Disease Management. Part II- Discovery of MAO-B Inhibitors Based on Nitrogen Heterocycles and Analogues

“…MAOs-catalyzed reaction involves the oxidation of the amine function, via the formation of an imine intermediate with a simultaneous reduction of the flavin cofactor that is reoxidized subsequently by molecular oxygen, with hydrogen peroxide release. The imine intermediate is then hydrolyzed, yielding ammonia and the corresponding aldehyde (Scheme 1) [38]. In mammals two isoforms of MAOs are present: MAO-A and MAO-B, which are distinguished based on their preference for the substrate and the sensitivity of their interaction with specific inhibitors [37].…”

Synthesis and Transformation of Halochromones

“…Chromone-type compounds are well-known for their variety of biological properties, that include antitumor [4][5][6][7][8][9][10][11][12][13][14][15], hepatoprotective [16], antioxidant [17][18][19][20][21], anti-inflammatory [22][23][24][25], cardioprotective [26], antimicrobial [27,28] and antiviral activities [29,30]. The vast range of biological effects associated with these structural skeletons has led to substantial research devoted to the isolation from natural resources, synthesis and transformation of chromone derivatives and also to biological evaluation with emphasis on their potential medicinal applications.…”