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 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.
School of Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China.
Ban-Feng
BF
Ruan
School of Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China.
Hui-Jie
HJ
Cheng
School of Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China.
Jing
J
Ren
School of Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China.
Hong-Lin
HL
Li
School of Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China.
Lu-Lu
LL
Guo
School of Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China.
Xing-Xing
XX
Zhang
School of Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China. Electronic address: czliao@hfut.edu.cn.
Chenzhong
C
Liao
D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry*; D013329:Structure-Activity Relationship
D002867:Chromones; D008996:Monoamine Oxidase Inhibitors; D013267:Stilbenes; D008995:Monoamine Oxidase; D000077185:Resveratrol
2H-chromen-2-one; Fragment-based drug design; Isoforms selectivity; Resveratrol; hMAO