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Article

Novel C7-Substituted Coumarins as Selective Monoamine Oxidase Inhibitors: Discovery, Synthesis and Theoretical Simulation

by 1,2,†, 3,†, 2, 2, 2, 4,* and 1,2,*
1
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
2
Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China
3
Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Ji’nan 250012, Shandong, China
4
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, No 18877, Jingshi Road, Ji’nan 250002, Shandong, China
*
Authors to whom correspondence should be addressed.
The first two authors contributed equally.
Academic Editor: Orazio Nicolotti
Received: 8 October 2019 / Revised: 27 October 2019 / Accepted: 31 October 2019 / Published: 5 November 2019
(This article belongs to the Special Issue Design, Synthesis, and Biological Evaluation of Enzyme Inhibitors)
There is a continued need to develop new selective human monoamine oxidase (hMAO) inhibitors that could be beneficial for the treatment of neurological diseases. However, hMAOs are closely related with high sequence identity and structural similarity, which hinders the development of selective MAO inhibitors. “Three-Dimensional Biologically Relevant Spectrum (BRS-3D)” method developed by our group has demonstrated its effectiveness in subtype selectivity studies of receptor and enzyme ligands. Here, we report a series of novel C7-substituted coumarins, either synthesized or commercially purchased, which were identified as selective hMAO inhibitors. Most of the compounds demonstrated strong activities with IC50 values (half-inhibitory concentration) ranging from sub-micromolar to nanomolar. Compounds, FR1 and SP1, were identified as the most selective hMAO-A inhibitors, with IC50 values of 1.5 nM (selectivity index (SI) < −2.82) and 19 nM (SI < −2.42), respectively. FR4 and FR5 showed the most potent hMAO-B inhibitory activity, with IC50 of 18 nM and 15 nM (SI > 2.74 and SI > 2.82). Docking calculations and molecular dynamic simulations were performed to elucidate the selectivity preference and SAR profiles. View Full-Text
Keywords: monoamine oxidase (MAO) inhibitors; BRS-3D; subtype selectivity; molecular dynamic simulations; in silico pharmacokinetic predictions monoamine oxidase (MAO) inhibitors; BRS-3D; subtype selectivity; molecular dynamic simulations; in silico pharmacokinetic predictions
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MDPI and ACS Style

Wang, D.; Hong, R.-Y.; Guo, M.; Liu, Y.; Chen, N.; Li, X.; Kong, D.-X. Novel C7-Substituted Coumarins as Selective Monoamine Oxidase Inhibitors: Discovery, Synthesis and Theoretical Simulation. Molecules 2019, 24, 4003. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24214003

AMA Style

Wang D, Hong R-Y, Guo M, Liu Y, Chen N, Li X, Kong D-X. Novel C7-Substituted Coumarins as Selective Monoamine Oxidase Inhibitors: Discovery, Synthesis and Theoretical Simulation. Molecules. 2019; 24(21):4003. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24214003

Chicago/Turabian Style

Wang, Dong, Ren-Yuan Hong, Mengyao Guo, Yi Liu, Nianhang Chen, Xun Li, and De-Xin Kong. 2019. "Novel C7-Substituted Coumarins as Selective Monoamine Oxidase Inhibitors: Discovery, Synthesis and Theoretical Simulation" Molecules 24, no. 21: 4003. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24214003

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