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

  • Int J Biol Macromol. 2019 Sep 15:137:426-432. doi: 10.1016/j.ijbiomac.2019.06.167.
Jong Min Oh  1 ,  Myung-Gyun Kang  2 ,  Ahreum Hong  3 ,  Ji-Eun Park  4 ,  Soo Hyun Kim  4 ,  Jae Pil Lee  1 ,  Seung Cheol Baek  1 ,  Daeui Park  2 ,  Sang-Jip Nam  5 ,  Myoung-Lae Cho  4 ,  Hoon Kim  6
Affiliations
  • 1. Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea.
  • 2. Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114, Republic of Korea.
  • 3. Graduate School of Industrial Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
  • 4. National Development Institute of Korean Medicine, Gyeongsan 38540, Republic of Korea.
  • 5. Graduate School of Industrial Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea; Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Republic of Korea.
  • 6. Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea. Electronic address: [email protected].
PMID: 31271801 DOI: 10.1016/j.ijbiomac.2019.06.167
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.

Keywords
4-Dimethylaminochalcone; Acetylcholinesterase; Docking simulation; Dual-targeting function; Human monoamine oxidase.
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