Inhibitory Evaluation of Sulfonamide Chalcones on β-Secretase and Acylcholinesterase

Molecules

Jae Eun Kang¹  Jung Keun Cho¹  Marcus J. Curtis-Long¹  Hyung Won Ryu¹  Jin Hyo Kim¹  Hye Jin Kim¹  Heung Joo Yuk¹  Dae Wook Kim¹ 

[1] ¹Division of Applied Life Science (BK21 Program), IALS, Gyeongsang National University, Jinju 660-701, Korea

关键词: sulfonamide chalcone;    Alzheimer’s disease (AD);    β-secretase;    acetylcholinesterase (AChE);    butyrylcholinesterase (BChE);    mixed inhibition;   

DOI  :  10.3390/molecules18010140

来源: mdpi

【 摘 要 】

The action of β-secretase (BACE1) is strongly correlated with the onset of Alzheimer’s disease (AD). Aminochalcone derivatives were examined for their ability to inhibit BACE1. Parent aminochalcones showed two digit micromolar IC₅₀s against BACE1. Potency was enhanced 10-fold or more by introducing benzenesulfonyl derivatives to the amino group: 1 (IC₅₀ = 48.2 μM) versus 4a (IC₅₀ = 1.44 μM) and 2 (IC₅₀ = 17.7 μM) versus 5a (IC₅₀ = 0.21 μM). The activity was significantly influenced by position and number of hydroxyl groups on the chalcone B-ring: 3,4-dihydroxy 5a (IC₅₀ = 0.21 μM) > 4-hydroxy 4a (IC₅₀ = 1.44 μM) > 2,4-dihydroxy 6 (IC₅₀ = 3.60 μM) > 2,5-dihydroxy 7 (IC₅₀ = 16.87 μM) > des hydroxy 4b (IC₅₀ = 168.7 μM). Lineweaver-Burk and Dixon plots and their secondary replots indicate that compound 5a was a mixed inhibitor with reversible and time-dependent behavior. Potent BACE1 inhibitors 4a,c,f, 5a–c showed moderate inhibition against two other enzymes implicated in AD pathogenesis, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC₅₀s ranging between 56.1 ~ 95.8 μM and 19.5 ~ 79.0 μM, respectively.

【 授权许可】

CC BY   
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.