Novel 2H-chromen-2-one derivatives of resveratrol: Design, synthesis, modeling and use as human monoamine oxidase inhibitors

Using a fragment-based drug design strategy, two biomedical interesting fragments, resveratrol and coumarin were linked to design a series of novel human monoamine oxidase (hMAO) inhibitors with a scaffold of 3-((E)-3-(2-((E)-styryl)phenyl)acryloyl)-2H-chromen-2-one, which demonstrated a very intere...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2015-10, Vol.103, p.185-190
Main Authors: Ruan, Ban-Feng, Cheng, Hui-Jie, Ren, Jing, Li, Hong-Lin, Guo, Lu-Lu, Zhang, Xing-Xing, Liao, Chenzhong
Format: Article
Language:English
Subjects:
2H-chromen-2-one
Chromones - chemical synthesis
Chromones - chemistry
Chromones - pharmacology
Dose-Response Relationship, Drug
Drug Design
Fragment-based drug design
hMAO
Humans
Isoforms selectivity
Models, Molecular
Molecular Structure
Monoamine Oxidase - metabolism
Monoamine Oxidase Inhibitors - chemical synthesis
Monoamine Oxidase Inhibitors - chemistry
Monoamine Oxidase Inhibitors - pharmacology
Resveratrol
Stilbenes - chemistry
Structure-Activity Relationship
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Summary:Using a fragment-based drug design strategy, two biomedical interesting fragments, resveratrol and coumarin were linked to design a series of novel human monoamine oxidase (hMAO) inhibitors with a scaffold of 3-((E)-3-(2-((E)-styryl)phenyl)acryloyl)-2H-chromen-2-one, which demonstrated a very interesting selectivity profile against hMAO-A and hMAO-B: some compounds with this scaffold are selective hMAO-A inhibitors, whereas some are selective hMAO-B inhibitors. The small changes in the substituents of the coumarin moiety led to this interesting selectivity profile. The most potent selective hMAO-B inhibitor D7 has a selectivity ratio of 20.93, with an IC50 value of 2.78 μM, similar or better than selegiline (IC50 = 2.89 μM), a selective hMAO-B inhibitor currently in the market for the treatment of Parkinson's disease. Our modeling study indicates that Tyr 326 of hMAO-B (or corresponded Ile 335 of hMAO-A) may be the determinant for the specificity of these compounds. The selectivity profile of compounds reported herein suggests that we can further develop both selective hMAO-A and hMAO-B inhibitors based on this novel scaffold. [Display omitted] •Two biomedical interesting fragments, resveratrol and coumarin, were linked to design a series of novel hMAO inhibitors.•The inhibitors demonstrated a very interesting selectivity profile against hMAO-A and hMAO-B.•The selectivity is strongly influenced by the nature of the substituents in the coumarin moiety.•Tyr 326 of hMAO-B may be the determinant for the specificity of these compounds.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2015.08.055