TY - JOUR
T1 - Inhibitory activity on cholinesterases produced by aryl-phthalimide derivatives
T2 - green synthesis, in silico and in vitro evaluation
AU - Ruiz-Maciel, Omar
AU - Padilla-Martínez, Itzia I.
AU - Sánchez-Labastida, Luis A.
AU - Soriano-Ursúa, Marvin A.
AU - Andrade-Jorge, Erik
AU - Trujillo-Ferrara, José G.
N1 - Publisher Copyright:
© 2020, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Background: Alzheimer’s disease (AD) is characterized by cognitive impairment and loss of immediate memory resulting from neuronal death in different brain areas, mainly those producing acetylcholine. Acetylcholinesterase inhibitors improve cognitive function, delay mental deterioration, and reduce other symptoms. Despite being the cornerstone for treating mild–moderate AD, these compounds are only palliative agents and often have severe adverse effects. Recently, butyrylcholinesterase (BuChE) has been found to be involved in AD. The aim of this study was to synthesize a series of six phthalimides with structural relationship with monoamines and evaluate them in vitro and in silico as AChE and BuChE inhibitors. In addition, a modified version of the Bonting and Featherstone method for determining AChE activity was adapted for the assessment of BuChE activity. Results: Six molecules (dioxoisoindolines A–F) were synthesized in good yields using a green chemistry approach. Dioxoisoindolines E and F were more active for AChE, with a Ki of 232 and 193 µM, respectively. Contrarily, dioxoisoindolines C and D showed up to fivefold greater selectivity for BuChE than AchE, with a Ki of 200 and 100 µM, respectively. The competitive inhibitory activity of the latter two molecules was similar to that of the reference compounds. Molecular docking demonstrated the participation of carbonyl carbons and aromatic rings in the high affinity of dioxoisoindoles for cholinesterases. Conclusion: The modified version of the Bonting and Featherstone method was successfully adapted to quantify BuChE activity. Dioxoisoindolines C and D displayed greater inhibition of BuChE versus AChE, with good inhibition of both enzymes. Thus, they are promising lead compounds for developing new BuChE/AChE inhibitors. [Figure not available: see fulltext.]
AB - Background: Alzheimer’s disease (AD) is characterized by cognitive impairment and loss of immediate memory resulting from neuronal death in different brain areas, mainly those producing acetylcholine. Acetylcholinesterase inhibitors improve cognitive function, delay mental deterioration, and reduce other symptoms. Despite being the cornerstone for treating mild–moderate AD, these compounds are only palliative agents and often have severe adverse effects. Recently, butyrylcholinesterase (BuChE) has been found to be involved in AD. The aim of this study was to synthesize a series of six phthalimides with structural relationship with monoamines and evaluate them in vitro and in silico as AChE and BuChE inhibitors. In addition, a modified version of the Bonting and Featherstone method for determining AChE activity was adapted for the assessment of BuChE activity. Results: Six molecules (dioxoisoindolines A–F) were synthesized in good yields using a green chemistry approach. Dioxoisoindolines E and F were more active for AChE, with a Ki of 232 and 193 µM, respectively. Contrarily, dioxoisoindolines C and D showed up to fivefold greater selectivity for BuChE than AchE, with a Ki of 200 and 100 µM, respectively. The competitive inhibitory activity of the latter two molecules was similar to that of the reference compounds. Molecular docking demonstrated the participation of carbonyl carbons and aromatic rings in the high affinity of dioxoisoindoles for cholinesterases. Conclusion: The modified version of the Bonting and Featherstone method was successfully adapted to quantify BuChE activity. Dioxoisoindolines C and D displayed greater inhibition of BuChE versus AChE, with good inhibition of both enzymes. Thus, they are promising lead compounds for developing new BuChE/AChE inhibitors. [Figure not available: see fulltext.]
KW - Acetylcholinesterase
KW - Alzheimer
KW - Butyrylcholinesterase
KW - Dioxoisoindolines
KW - Inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85084219722&partnerID=8YFLogxK
U2 - 10.1007/s00044-020-02543-2
DO - 10.1007/s00044-020-02543-2
M3 - Artículo
SN - 1054-2523
VL - 29
SP - 1030
EP - 1040
JO - Medicinal Chemistry Research
JF - Medicinal Chemistry Research
IS - 6
ER -