3-(1H-pyrrol-2-yl)-2-oxazolidinones as novel monoamine oxidase type A inhibitors.
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 microM, whilst their anti-MAO-B activity is considerably lower (Ki = >100-0.5 microM). 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 (K(iMAO-A) = 0.087-0.004 microM) and A-selective (A-selectivity ratio: >11,111-41) compounds in this series. Exceptions are represented by the N1-benzyl derivative 2d (K(iMAO-A) = 0.009 microM) and the N1-allylpyrrole 2o (K(iMAO-A) = 0.04 microM). 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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Dipartimento di Studi Farmaceutici, Università degli Studi di Roma La Sapienza, P. le A. Moro 5, 00185 Roma, Italy.
Artico
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Valente
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Sbardella
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Turini
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Befani
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Vedova
L Dalla
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Agostinelli
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D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002417:Cattle; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D008968:Molecular Conformation; D008995:Monoamine Oxidase / Q000187:drug effects*; D023303:Oxazolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D023303:Oxazolidinones; D008995:Monoamine Oxidase