Synthesis, semipreparative HPLC separation, biological evaluation, and 3D-QSAR of hydrazothiazole derivatives as human monoamine oxidase B inhibitors
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- 作者：Franco Chimenti ; Daniela Secci ; Adriana Bolasco ; Paola Chimenti ; Arianna Granese ; Simone Carradori ; Elias Maccioni ; M. Cristina Cardia ; Matilde Yá ; ñ ; ez ; Francisco Orallo ; Stefano Alcaro ; Franc
- 关键词：Hydrazothiazole derivatives ; 3D-QSAR ; Human monoamine oxidase B inhibitors
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2010
- 出版时间：15 July 2010
- 年：2010
- 卷：18
- 期：14
- 页码：5063-5070
- 全文大小：528 K
文摘
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.