Abstract
A novel series of 5-substituted-3-(1H-pyrrol-2-yl)-2-oxazolidinones 2a-s has been described as pyrrole analogues of toloxatone and befloxatone, two phenyl-oxazolidinones active as anti-MAO agents and used in antidepressant therapy. Tested against MAO-A and MAO-B enzymes, the majority of 2a-s show highly potent inhibitory effect against the A isoform of the enzyme, with Ki values in the range 0.52-0.004 μM, whilst their anti-MAO-B activity is considerably lower (Ki = > 100-0.5 μM). Structurally, 2a-s differs for the substituent inserted at the C5 position of the 2- oxazolidinone ring (hydroxymethyl (2a-d), methoxymethyl (2e-h), azidomethyl (2i-l), methylaminomethyl (2m-p), and aminomethyl (2q-s)), and the size of the alkyl chain at the pyrrole N1 position (methyl, ethyl, allyl, or benzyl). As a rule, apart from the C5 substitution, the bulkier is the alkyl group at the pyrrole-N1, the lower is the anti-MAO-A activity of the compounds, being the N1-methyl derivatives 2a, 2e, 2i, and 2q among the most potent (KiMAO-A = 0.087-0.004 μM) and A-selective (A-selectivity ratio: > 11,111-41) compounds in this series. Exceptions are represented by the N1-benzyl derivative 2d (KiMAO-A = 0.009 μM) and the N1-allylpyrrole 2o (KiMAO-A = 0.04 μM). In comparison with the reference drugs, these highly active derivatives are more potent than toloxatone, slightly less potent than befloxatone, and several times more A-selective than both the references. Such results indicate that 2a-s may represent a new promising series of antidepressant agents.
Keywords: mao-a, mao inhibitors, 2-oxazolidinones, 3-(1h-pyrrol-2-yl)-2-oxazolidinones, antidepressant agents
Medicinal Chemistry
Title: 3-(1H-Pyrrol-2-yl)-2-oxazolidinones as Novel Monoamine Oxidase Type A Inhibitors
Volume: 1 Issue: 2
Author(s): A. Mai, M. Artico, S. Valente, G. Sbardella, P. Turini, O. Befani, L. Dalla Vedova and E. Agostinelli
Affiliation:
Keywords: mao-a, mao inhibitors, 2-oxazolidinones, 3-(1h-pyrrol-2-yl)-2-oxazolidinones, antidepressant agents
Abstract: A novel series of 5-substituted-3-(1H-pyrrol-2-yl)-2-oxazolidinones 2a-s has been described as pyrrole analogues of toloxatone and befloxatone, two phenyl-oxazolidinones active as anti-MAO agents and used in antidepressant therapy. Tested against MAO-A and MAO-B enzymes, the majority of 2a-s show highly potent inhibitory effect against the A isoform of the enzyme, with Ki values in the range 0.52-0.004 μM, whilst their anti-MAO-B activity is considerably lower (Ki = > 100-0.5 μM). Structurally, 2a-s differs for the substituent inserted at the C5 position of the 2- oxazolidinone ring (hydroxymethyl (2a-d), methoxymethyl (2e-h), azidomethyl (2i-l), methylaminomethyl (2m-p), and aminomethyl (2q-s)), and the size of the alkyl chain at the pyrrole N1 position (methyl, ethyl, allyl, or benzyl). As a rule, apart from the C5 substitution, the bulkier is the alkyl group at the pyrrole-N1, the lower is the anti-MAO-A activity of the compounds, being the N1-methyl derivatives 2a, 2e, 2i, and 2q among the most potent (KiMAO-A = 0.087-0.004 μM) and A-selective (A-selectivity ratio: > 11,111-41) compounds in this series. Exceptions are represented by the N1-benzyl derivative 2d (KiMAO-A = 0.009 μM) and the N1-allylpyrrole 2o (KiMAO-A = 0.04 μM). In comparison with the reference drugs, these highly active derivatives are more potent than toloxatone, slightly less potent than befloxatone, and several times more A-selective than both the references. Such results indicate that 2a-s may represent a new promising series of antidepressant agents.
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Mai A., Artico M., Valente S., Sbardella G., Turini P., Befani O., Vedova Dalla L. and Agostinelli E., 3-(1H-Pyrrol-2-yl)-2-oxazolidinones as Novel Monoamine Oxidase Type A Inhibitors, Medicinal Chemistry 2005; 1 (2) . https://dx.doi.org/10.2174/1573406053175247
DOI https://dx.doi.org/10.2174/1573406053175247 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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