Potent and selective inhibition of human monoamine oxidase-B by 4-dimethylaminochalcone and selected chalcone derivatives
2019
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 IC 50 values of 0.029, 0.061, and 0.075 μM, respectively. 4-Nitrochalcone ( 4 ) and 4-chlorochalcone ( 3 ) also potently inhibited hMAO-B with IC 50 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 (IC 50 = 3.28 μM). Compounds 1 and 2,2′-dihydroxy-4′,6′-dimethoxychalcone ( 12 ) potently inhibited hMAO-A with IC 50 values of 0.18 and 0.39 μM, respectively. In addition, compounds 4 and 2 also effectively inhibited AChE with IC 50 values of 1.25 and 6.07 μM, respectively, and thus, exhibited dual-targeting. Compound 2 reversibly and competitively inhibited hMAO-B with a K i 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.
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