Abstract
Alzheimer’s disease (AD), the most common form of dementia, is characterized by a progressive degeneration of the brain that leads to loss of memory and deterioration of others cognitive functions. The only drugs currently approved for treating AD are AChE inhibitors (AChEIs). We previously tested a novel isoindoline-1,3-dione, finding potent inhibition of AChE, in part because the two carbonyl groups of phthalimide facilitate hydrogen bonds with the enzyme. The aims of the present study were: (A) To achieve a faster and cheaper technique with a reduced quantity of reactive, without significant difference in the validation of the results, by modifying the version of the method described by Bonting and Featherstone. (B) To test new isoindolines and dioxoisoindolines as AChEIs and see if the carbonyl group is really important for affinity. Both families of compounds (isoindolines and dioxoisoindolines) had an inhibitory effect. The enzymatic inhibitions produced by isoindolines were uncompetitive, whereas that evoked by dioxoisoindolines were competitive. One of the isoindoline derivatives (IsoB with a Ki of 88–160µM) showed about 5-fold greater inhibition of AChE than its corresponding dioxoisoindoline. According to molecular docking performed, dioxoisoindolines apparently interact with the catalytic active site, the peripheral anionic site, and the aromatic patch, which can explain the kind of inhibition observed. Due to the uncompetitive inhibition of isoindolines, their inhibitory behavior could not be explored in silico. We afforded a faster and more efficient method, while yielding similar results than Bonting and Featherstone method. Additionally, we demonstrated that carbonyl group affects the kind of inhibition and the affinity.
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This work was supported by SIP (m1930), Instituto Politécnico Nacional, and by CONACYT-Mexico.
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Andrade-Jorge, E., Sánchez-Labastida, L.A., Soriano-Ursúa, M.A. et al. Isoindolines/isoindoline-1,3-diones as AChE inhibitors against Alzheimer’s disease, evaluated by an improved ultra-micro assay. Med Chem Res 27, 2187–2198 (2018). https://doi.org/10.1007/s00044-018-2226-5
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DOI: https://doi.org/10.1007/s00044-018-2226-5