Synthesis, stereochemical identification, and selective inhibitory activity against human monoamine oxidase-B of 2-methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones

被引：91

作者：

Chimenti, Franco ^{[1
]}

Maccioni, Elias ^{[2
]}

Secci, Daniela ^{[1
]}

Bolasco, Adriana ^{[1
]}

Chimenti, Paola ^{[1
]}

Granese, Arianna ^{[1
]}

Carradori, Simone ^{[1
]}

Alcaro, Stefano ^{[3
]}

Ortuso, Francesco ^{[3
]}

Yanez, Matilde ^{[4
]}

Orallo, Francisco ^{[4
]}

Cirilli, Roberto ^{[5
]}

Ferretti, Rosella ^{[5
]}

La Torre, Francesco ^{[5
]}

机构：

[1] Univ Roma La Sapienza, Dipartimento Chim & Tecnol Sostanze Biol Camente, I-00185 Rome, Italy

[2] Univ Cagliari, Dipartimento Farmaco Chim Tecnol, I-09124 Cagliari, Italy

[3] Univ Catanzaro Magna Graecia, Dipartimento Sci Farmaco Biol Complesso Nini Barb, I-88021 Roccelletta Di Borgia, CZ, Italy

[4] Univ Santiago Compostela, Fac Farm, Dept Farmacol, E-15782 La Coruna, Spain

[5] Ist Super Sanita, Dipartimento Farmaco, I-00161 Rome, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 16期

关键词：

D O I：

10.1021/jm800132g

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 2-methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones have been investigated for their ability to inhibit selectively the activity of the human A and B isoforms of monoamine oxidase (MAO). The target compounds, which present a stereogenic center on the cyclohexane ring, were obtained as pure (R) and (S) enantiomers by enantioselective HPLC. The absolute configuration of homochiral forms isolated on a semipreparative scale was obtained by a combined strategy based on chemical correlation and single-crystal X-ray diffraction. All compounds showed higher activity against the human MAO-B isoform with IC(50) values ranging between 26.81 +/- 2.74 mu M and 14.20 +/- 0.26 nM, and the assays carried out on the pure enantiomers showed higher activity for the (R) form. A computational study was performed by molecular mechanics, DFT-based quantomechanics, and docking techniques on the most active and human MAO-B selective inhibitor 8.

引用

页码：4874 / 4880

页数：7

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