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Synthesis and evaluation of small molecules bearing a benzyloxy substituent as novel and potent monoamine oxidase inhibitors.


ABSTRACT: A new series of small molecules bearing a benzyloxy substituent have been designed, synthesized and evaluated for hMAO inhibitory activity in vitro. Most of the compounds were potent and selective MAO-B inhibitors, and were weak inhibitors of MAO-A. In particular, compounds 9e (IC50 = 0.35 ?M) and 10e (IC50 = 0.19 ?M) were the most potent MAO-B inhibitors, and exhibited the highest selectivity for MAO-B (9e, SI > 285.7-fold and 10e, SI = 146.8-fold). In addition, the structure-activity relationships for MAO-B inhibition indicated that electron-withdrawing groups in the open small molecules were more suitable for MAO-B inhibition, and substitutions at the benzyloxy of the open small molecules, particularly with the halogen substituted benzyloxy, were more favorable for MAO-B inhibition. Molecular docking studies have been done to explain the potent MAO-B inhibition of the open small molecules. Furthermore, the representative compounds 9e and 10e showed low neurotoxicity in SH-SY5Y cells in vitro. So the small molecules bearing the benzyloxy substituent could be used to develop promising drug candidates for the therapy of neurodegenerative diseases.

SUBMITTER: Lan JS 

PROVIDER: S-EPMC6072412 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Synthesis and evaluation of small molecules bearing a benzyloxy substituent as novel and potent monoamine oxidase inhibitors.

Lan Jin-Shuai JS   Zhang Tong T   Liu Yun Y   Zhang Yong Y   Hou Jian-Wei JW   Xie Sai-Sai SS   Yang Jing J   Ding Yue Y   Cai Zhen-Zhen ZZ  

MedChemComm 20170105 2


A new series of small molecules bearing a benzyloxy substituent have been designed, synthesized and evaluated for hMAO inhibitory activity <i>in vitro</i>. Most of the compounds were potent and selective MAO-B inhibitors, and were weak inhibitors of MAO-A. In particular, compounds <b>9e</b> (IC<sub>50</sub> = 0.35 μM) and <b>10e</b> (IC<sub>50</sub> = 0.19 μM) were the most potent MAO-B inhibitors, and exhibited the highest selectivity for MAO-B (<b>9e</b>, SI > 285.7-fold and <b>10e</b>, SI = 1  ...[more]

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