Synthesis, semipreparative HPLC separation, biological evaluation, and 3D-QSAR of hydrazothiazole derivatives as human monoamine oxidase B inhibitors.

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Chimenti F, Secci D, Bolasco A, Chimenti P, Granese A, Carradori S, Maccioni E, Cardia MC, Yanez M, Orallo F, Alcaro S, Ortuso F, Cirilli R, Ferretti R, Distinto S, Kirchmair J, Langer T

Synthesis, semipreparative HPLC separation, biological evaluation, and 3D-QSAR of hydrazothiazole derivatives as human monoamine oxidase B inhibitors.

Bioorg Med Chem. 2010 Jul 15;18(14):5063-70. doi: 10.1016/j.bmc.2010.05.070. Epub 2010 Jun 1.

PubMed ID
20579890 [ View in PubMed
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Abstract

The present study reports on synthesis in high yields (70-99%), HPLC enantioseparation, inhibitory activity against human monoamino oxidases, and molecular modeling including 3D-QSAR studies, of a large series of (4-aryl-thiazol-2-yl)hydrazones (1-45). Most of the synthesized compounds proved to be potent and selective inhibitors of hMAO-B isoform in the micromolar or nanomolar range, thus demonstrating that hydrazothiazole could be considered a good pharmacophore to design new hMAO-B inhibitors. Due to the presence in some derivatives of a chiral center, we also performed a semipreparative chromatographic enantioseparation of these compounds obtained by a stereoconservative pattern. The separated enantiomers were submitted to in vitro biological evaluation to point out the stereorecognition of the active site of the enzyme towards these structures. Finally, a 3D-QSAR study was carried out using Comparative Molecular Field Analysis (CoMFA), aiming to deduce rational guidelines for the further structural modification of these lead compounds.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
ClorgilineAmine oxidase [flavin-containing] AIC 50 (nM)5N/AN/ADetails
IproniazidAmine oxidase [flavin-containing] BIC 50 (nM)7547N/AN/ADetails
IsatinAmine oxidase [flavin-containing] BIC 50 (nM)18754N/AN/ADetails
MoclobemideAmine oxidase [flavin-containing] AIC 50 (nM)361382N/AN/ADetails
SelegilineAmine oxidase [flavin-containing] AIC 50 (nM)67250N/AN/ADetails
SelegilineAmine oxidase [flavin-containing] BIC 50 (nM)20N/AN/ADetails