Novel 1-(4-arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazine derivatives have been investigated for their ability to inhibit selectively the activity of the human B isoform of monoamine oxidase. These compounds were obtained as racemates and (R)-enantiomers by a stereoconservative synthetic pattern in high yield and enantiomeric excess. The (S)-enantiomers of the most active derivatives have been separated by enantioselective HPLC. All compounds showed selective activity against hMAO-B with IC50 ranging between 21.90 and 0.018 ?M. A preliminary molecular modeling approach was carried out to justify the importance of this substituted aromatic ring in the interaction with both isoforms. Superim- positions of the best fully energy minimized hMAO-A and -B poses of the most selective derivative (5a) indicated that the aromatic and the thiazole moieties were located close to the FAD coenzyme, suggesting a functional role in catalysis as also demonstrated by the presence of a structural “aromatic cage” in hMAOs and in several flavin-dependent amine oxidizing enzymes described by others.21 The sum of these interactions, in particular the hydrogen bond between Tyr326 and hydrazone NH, could also explain the better hMAO-B recognition of this scaffold. The analysis of the influence of the stereochemistry on the biological behavior confirmed the results previously obtained. These findings increase our confidence in this model and stimulate us to continue investigations in designing more potent and selective analogues that may have interesting therapeutic potential as original chemical models (templates) for the design and sub- sequent development of new drugs useful for improving the pharmacological treatment of major depressive disorders and neurodegenerative diseases.

SYNTHESIS, STEREOCHEMICAL SEPARATION, AND BIOLOGICAL EVALUATION OF SELECTIVE INHIBITORS OF HUMAN MAO-B: 1-(4-ARYLTHIAZOL-2-YL)-2-(3-METHYLCYCLOHEXYLIDENE)HYDRAZINES / Chimenti, Franco; Secci, Daniela; Bolasco, Adriana; Chimenti, Paola; Granese, A; Carradori, S; Yanez, M; Orallo, F; Sanna, Ml; Gallinella, B; Cirilli, R.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 53:(2010), pp. 6516-6520. [10.1021/jm100120s]

SYNTHESIS, STEREOCHEMICAL SEPARATION, AND BIOLOGICAL EVALUATION OF SELECTIVE INHIBITORS OF HUMAN MAO-B: 1-(4-ARYLTHIAZOL-2-YL)-2-(3-METHYLCYCLOHEXYLIDENE)HYDRAZINES

CHIMENTI, Franco;SECCI, DANIELA;BOLASCO, Adriana;CHIMENTI, Paola;GRANESE A;
2010

Abstract

Novel 1-(4-arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazine derivatives have been investigated for their ability to inhibit selectively the activity of the human B isoform of monoamine oxidase. These compounds were obtained as racemates and (R)-enantiomers by a stereoconservative synthetic pattern in high yield and enantiomeric excess. The (S)-enantiomers of the most active derivatives have been separated by enantioselective HPLC. All compounds showed selective activity against hMAO-B with IC50 ranging between 21.90 and 0.018 ?M. A preliminary molecular modeling approach was carried out to justify the importance of this substituted aromatic ring in the interaction with both isoforms. Superim- positions of the best fully energy minimized hMAO-A and -B poses of the most selective derivative (5a) indicated that the aromatic and the thiazole moieties were located close to the FAD coenzyme, suggesting a functional role in catalysis as also demonstrated by the presence of a structural “aromatic cage” in hMAOs and in several flavin-dependent amine oxidizing enzymes described by others.21 The sum of these interactions, in particular the hydrogen bond between Tyr326 and hydrazone NH, could also explain the better hMAO-B recognition of this scaffold. The analysis of the influence of the stereochemistry on the biological behavior confirmed the results previously obtained. These findings increase our confidence in this model and stimulate us to continue investigations in designing more potent and selective analogues that may have interesting therapeutic potential as original chemical models (templates) for the design and sub- sequent development of new drugs useful for improving the pharmacological treatment of major depressive disorders and neurodegenerative diseases.
2010
01 Pubblicazione su rivista::01a Articolo in rivista
SYNTHESIS, STEREOCHEMICAL SEPARATION, AND BIOLOGICAL EVALUATION OF SELECTIVE INHIBITORS OF HUMAN MAO-B: 1-(4-ARYLTHIAZOL-2-YL)-2-(3-METHYLCYCLOHEXYLIDENE)HYDRAZINES / Chimenti, Franco; Secci, Daniela; Bolasco, Adriana; Chimenti, Paola; Granese, A; Carradori, S; Yanez, M; Orallo, F; Sanna, Ml; Gallinella, B; Cirilli, R.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 53:(2010), pp. 6516-6520. [10.1021/jm100120s]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/360702
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