Inhibitory evaluation of sulfonamide chalcones on &#946;-secretase and acylcholinesterase.
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 IC(50)s against BACE1. Potency was enhanced 10-fold or more by introducing benzenesulfonyl derivatives to the amino group: 1 (IC(50) = 48.2 μM) versus 4a (IC(50) = 1.44 μM) and 2 (IC(50) = 17.7 μM) versus 5a (IC(50) = 0.21 μM). The activity was significantly influenced by position and number of hydroxyl groups on the chalcone B-ring: 3,4-dihydroxy 5a (IC(50) = 0.21 μM) > 4-hydroxy 4a (IC(50) = 1.44 μM) > 2,4-dihydroxy 6 (IC(50) = 3.60 μM) > 2,5-dihydroxy 7 (IC(50) = 16.87 μM) > des hydroxy 4b (IC(50) = 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 IC(50)s ranging between 56.1 ~ 95.8 μM and 19.5 ~ 79.0 μM, respectively.
Division of Applied Life Science (BK21 Program), IALS, Gyeongsang National University, Jinju, Korea.
Jae Eun
JE
Kang
Jung Keun
JK
Cho
Marcus J
MJ
Curtis-Long
Hyung Won
HW
Ryu
Jin Hyo
JH
Kim
Hye Jin
HJ
Kim
Heung Joo
HJ
Yuk
Dae Wook
DW
Kim
Ki Hun
KH
Park
D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D047188:Chalcones / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology*
D047188:Chalcones; D002800:Cholinesterase Inhibitors; D013449:Sulfonamides; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human