(E)-3-Heteroarylidenechroman-4-ones as potent and selective monoamine oxidase-B inhibitors

被引：32

作者：

Desideri, Nicoletta ^{[1
]}

Monaco, Luca Proietti ^{[1
]}

Fioravanti, Rossella ^{[1
]}

Biava, Mariangela ^{[1
]}

Yanez, Matilde ^{[2
]}

Alcaro, Stefano ^{[3
]}

Ortuso, Francesco ^{[3
]}

机构：

[1] Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, Ple Aldo Moro 5, I-00185 Rome, Italy

[2] Univ Santiago de Compostela, Fac Farm, Dept Farmacol, Campus Univ Sur, E-15782 Santiago De Compostela, La Coruna, Spain

[3] Magna Graecia Univ Catanzaro, Dipartimento Sci Salute, Campus Univ S Venuta,Viale Europa, I-88100 Catanzaro, Italy

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 117卷

关键词：

Monoamine oxidases; Selective hMAO-B inhibitors; Chroman-4-ones; Homoisoflavonoids; Docking studies; EXOCYCLIC ALPHA; BETA-UNSATURATED KETONES; HOMOISOFLAVONOIDS; SCAFFOLD;

D O I：

10.1016/j.ejmech.2016.03.081

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of (E)-3-heteroarylidenechroman-4-ones (1a-r) was designed, synthesized and investigated in vitro for their ability to inhibit the enzymatic activity of both human monoamine oxidase (hMAO) isoforms, hMAO-A and hMAO-B. All the compounds were found to be selective hMAO-B inhibitors showing IC50 values in the nanomolar or micromolar range. (E)-5,7-Dichloro-3-{[(2-(dimethylamino) pyrimidin-5-yl]methylene}chroman-4-one (1c) was the most interesting compound identified in this study, endowed with higher hMAO-B potency (IC50 = 10.58 nM) and selectivity (SI > 9452) with respect to the reference selective inhibitor selegiline (IC50 = 19.60 nM, IC50 > 3431). Molecular modelling studies were performed for rationalizing at molecular level the target selective inhibition of our compounds, revealing a remarkable contribution of hydrogen bond network and water solvent. (C) 2016 Elsevier Masson SAS. All rights reserved.

引用

页码：292 / 300

页数：9

共 33 条

[21] Structure-cytotoxic activity relationship of 3-arylideneflavanone and chromanone (E,Z isomers) and 3-arylflavones [J].

Kupcewicz, Bogumila ;

Balcerowska-Czerniak, Grazyna ;

Malecka, Magdalena ;

Paneth, Piotr ;

Krajewska, Urszula ;

Rozalski, Marek .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (14) :4102-4106

[22] Synthesis of exocyclic α,β-unsaturated ketones [J].

Lévai, A .

ARKIVOC, 2004, :15-33

[23]

Lévai A, 1999, HETEROCYCL COMMUN, V5, P441

[24]

LEVAI A, 1992, PHARMAZIE, V47, P56

[25] Selected furanochalcones as inhibitors of monoamine oxidase [J].

Robinson, Sarel J. ;

Petzer, Jacobus P. ;

Petzer, Anel ;

Bergh, Jacobus J. ;

Lourens, Anna C. U. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (17) :4985-4989

[26]

Schrodinger N.Y., 2017, Schrodinger

[27] Synthesis, stereochemical assignments, and biological activities of homoisoflavonoids [J].

Siddalah, V ;

Rao, CV ;

Venkateswarlu, S ;

Krishnaraju, AV ;

Subbaraju, GV .

BIOORGANIC & MEDICINAL CHEMISTRY, 2006, 14 (08) :2545-2551

[28] Structure of human monoamine oxidase A at 2.2-Å resolution:: The control of opening the entry for substrates/inhibitors [J].

Son, Se-Young ;

Ma, Achun ;

Kondou, Youhei ;

Yoshimura, Masato ;

Yamashita, Eiki ;

Tsukihara, Tomitake .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (15) :5739-5744

[29]

Tapas K.M., 2011, E-J CHEM, V8, P863

[30] Synthesis of 2,4-diaryl chromenopyridines and evaluation of their topoisomerase I and II inhibitory activity, cytotoxicity, and structure-activity relationship [J].

Thapa, Uttam ;

Thapa, Pritam ;

Karki, Radha ;

Yun, Minho ;

Choi, Jae Hun ;

Jahng, Yurngdong ;

Lee, Eunyoung ;

Jeon, Kyung-Hwa ;

Na, Younghwa ;

Ha, Eun-Mi ;

Cho, Won-Jea ;

Kwon, Youngjoo ;

Lee, Eung-Seok .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2011, 46 (08) :3201-3209

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