Potent and selective inhibition of human monoamine oxidase-B by 4-dimethylaminochalcone and selected chalcone derivatives

Jong Min Oh, Myung Gyun Kang, Ahreum Hong, Ji Eun Park, Soo Hyun Kim, Jae Pil Lee, Seung Cheol Baek, D. Park, Sang Jip Nam, Myoung Lae Cho, Hoon Kim

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12 Scopus citations

Abstract

Six synthetic (1–6) and six natural (7–12) chalcones were tested for human monoamine oxidases (hMAOs) and acetylcholinesterase (AChE) inhibitory activities. Compounds 4-dimethylaminochalcone (2), 4′-chloro-4-dimethylaminochalcone (5), and 2,4′-dichloro-4-dimethylaminochalcone (1) potently inhibited hMAO-B with IC50 values of 0.029, 0.061, and 0.075 μM, respectively. 4-Nitrochalcone (4) and 4-chlorochalcone (3) also potently inhibited hMAO-B with IC50 values of 0.066 and 0.082 μM, respectively (2.3- and 2.6-fold less than compound 2). Compound 2 had a high selectivity index (113.1) for hMAO-B over hMAO-A (IC50 = 3.28 μM). Compounds 1 and 2,2′-dihydroxy-4′,6′-dimethoxychalcone (12) potently inhibited hMAO-A with IC50 values of 0.18 and 0.39 μM, respectively. In addition, compounds 4 and 2 also effectively inhibited AChE with IC50 values of 1.25 and 6.07 μM, respectively, and thus, exhibited dual-targeting. Compound 2 reversibly and competitively inhibited hMAO-B with a Ki value of 0.0066 μM. Docking simulations showed binding affinities of compounds 1 to 5 for hMAO-B were higher than those for hMAO-A or AChE and suggested these five chalcones form hydrogen bonds with MAO-B at Cys172 but that they do not form hydrogen bonds with hMAO-A or AChE. These findings suggest compound 2 be considered a promising and dual-targeting lead compound for the treatment of Alzheimer's disease.

Original languageEnglish
Pages (from-to)426-432
Number of pages7
JournalInternational Journal of Biological Macromolecules
Volume137
DOIs
StatePublished - 15 Sep 2019

Keywords

  • 4-Dimethylaminochalcone
  • Acetylcholinesterase
  • Docking simulation
  • Dual-targeting function
  • Human monoamine oxidase

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