TY - JOUR
T1 - Design of multi-target compounds as AChE, BACE1, and amyloid-β1-42 oligomerization inhibitors
T2 - In silico and in vitro studies
AU - Hernández-Rodríguez, Maricarmen
AU - Correa-Basurto, José
AU - Martínez-Ramos, Federico
AU - Padilla-Martínez, Itzia Irene
AU - Benítez-Cardoza, Claudia G.
AU - Mera-Jiménez, Elvia
AU - Rosales-Hernández, Martha Cecilia
N1 - Publisher Copyright:
© 2014 - IOS Press and the authors. All rights reserved.
PY - 2014
Y1 - 2014
N2 - Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-β (Aβ) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Aβ, act as AChEIs and have antioxidant properties. Once the compounds were designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, β-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Aβ monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 μM) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit Aβ oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models.
AB - Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-β (Aβ) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Aβ, act as AChEIs and have antioxidant properties. Once the compounds were designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, β-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Aβ monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 μM) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit Aβ oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models.
KW - Acetylcholinesterase
KW - Alzheimer's disease
KW - amyloid-β
KW - inhibitor
KW - β-site AβPP cleaving enzyme 1
UR - http://www.scopus.com/inward/record.url?scp=84923652482&partnerID=8YFLogxK
U2 - 10.3233/JAD-140471
DO - 10.3233/JAD-140471
M3 - Artículo
C2 - 24762947
SN - 1387-2877
VL - 41
SP - 1073
EP - 1085
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 4
ER -