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

作者：Ruan, Ban Feng; Cheng, Hui Jie; Ren, Jing; Li, Hong Lin; Guo, Lu Lu; Zhang, Xing Xing; Liao, Chenzhong^*

来源：European Journal of Medicinal Chemistry, 2015, 103: 185-190.

DOI：10.1016/j.ejmech.2015.08.055

• hMAO
• Isoforms selectivity
• Fragment-based drug design
• Resveratrol
• 2H-chromen-2-one

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)acryloy1)-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 mu M, similar or better than selegiline (IC50 = 2.89 mu M), 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.

• 出版日期2015-10-20
• 单位合肥工业大学