Abstract
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.
Highlights
As life expectancy grows, rendering elderly people more common in society, age related diseases have become increasingly prevalent, so it is no surprise that incidences of dementia are consequentially growing yearly
Aβ peptides are derived from a sequential proteolytic cleavage of amyloid precursor protein (APP) by the aspartate proteases, β and γ-secretase. β-Secretase (BACE1) was discovered by the four independent groups [5,6,7,8]
We have previously reported the synthesis of a series of sulfonamide chalcones and their biological applications
Summary
As life expectancy grows, rendering elderly people more common in society, age related diseases have become increasingly prevalent, so it is no surprise that incidences of dementia are consequentially growing yearly. Alzheimer’s disease (AD) is the major cause of dementia (1 in 8 of people over 65 has AD in the USA) [1]. This disease involves a progressive loss of neurons in the hippocampus and cortex which leads to serious loss of global cognitive ability. There is a heightened presence of extra neuronal aggregation of plaques composed of β-amyloid (Aβ) peptide [3] and neurofibrillary tangles [4]. Aβ peptides are derived from a sequential proteolytic cleavage of amyloid precursor protein (APP) by the aspartate proteases, β and γ-secretase. BACE1 is uniquely able to process APP and form Aβ-peptides, because BACE1 knock-out mice are unable to form
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