Abstract
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.
Highlights
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Using green chemistry principles, six phthalimides were synthesized in good yields.
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Dioxoisoindolines D and F were potent inhibitors of BuChE and AChE, respectively.
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The improved Bonting and Featherstone method proved useful for evaluating BuChE activity.
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Acknowledgements
This work was supported by SIP (M1930, 20194934, 20196847, and 20201031) from the Instituto Politécnico Nacional, and by Consejo Nacional de Ciencia y Tecnología (CONACYT-Mexico). EA-J is a postdoctoral fellow from CONACYT.
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Ruiz-Maciel, O., Padilla-Martínez, I.I., Sánchez-Labastida, L.A. et al. Inhibitory activity on cholinesterases produced by aryl-phthalimide derivatives: green synthesis, in silico and in vitro evaluation. Med Chem Res 29, 1030–1040 (2020). https://doi.org/10.1007/s00044-020-02543-2
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DOI: https://doi.org/10.1007/s00044-020-02543-2