Synthesis and biological evaluation of 3-alkyloxazolidin-2-ones as reversible MAO inhibitors

The discovery of the two forms of MAO had led to significant advances in the understanding of the physiological and biochemical roles that these enzymes play in normal processes and in disease states. The recent development of a new generation of highly selective reversible MAO inhibitors (MAOIs) have led to a renewed interest in the therapeutic potential of these new compounds with respect to early irreversible MAOIs. In fact, reversible MAOIs offer new hopes for generating superior anti-depressant and anti-parkinsonian agents by virtue of the selective inhibition of MAO-A and MAO-B, respectively. Aryloxazolidinones are one of the relatively new classes of MAOIs. Their “lead compound” is Toloxatone (Humoryl), the first reversible and selective MAO-A inhibitor introduced in clinical practice as an anti-depressant. In order to investigate the importance and hence the biological role played by the anisyl (p-methoxyphenyl) group linked to N3 atom of Toloxatone oxazolidinone ring or more in general of an aromatic group, some new N3-alkyloxazolidinones were synthesized and their ability to inhibit MAO-A and MAO-B enzymes was evaluated by a fluorimetric method that uses the kynuramine as substrate. Also modifications at C5 of the 2-oxazolidinone ring were considered. The set of N3-alkyl substituted and at C5 modified compounds showed ability to inhibit MAO-A and MAO-B but with lower extent than Toloxatone used as reference drug. Such biological results provide insights into structure-activity relationships, confirming that is necessary the presence of N3-aryl moiety to act as a potent reversible MAO inhibitor, not possible in the same extent when the aryl is replaced by an alkyl group (Ki≈ 10-7 M versus 10-3–10-4 M).