Article
Carbohydrate-derived bicyclic selenazolines as new dual inhibitors (cholinesterases/OGA) against Alzheimer's disease
Author/s | Velueta Viveros, Martha
Martínez Bailén, Macarena Puerta, Adrián Romero Hernández, Laura L. Křen, Vladimír Merino Montiel, Penélope Montiel Smith, Sara Fernandes, Miguel X. Moreno Vargas, Antonio José Padrón, José M. López López, Óscar Fernández-Bolaños Guzmán, José María |
Department | Universidad de Sevilla. Departamento de Química orgánica |
Publication Date | 2022-10 |
Deposit Date | 2024-02-05 |
Published in |
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Abstract | Concerned by the urgent need to explore new approaches for the treatment of Alzheimer's disease, we herein describe the synthesis and evaluation of new multitarget molecules. In particular, we have focused our attention ... Concerned by the urgent need to explore new approaches for the treatment of Alzheimer's disease, we herein describe the synthesis and evaluation of new multitarget molecules. In particular, we have focused our attention on modulating the activity of cholinesterases (AChE, BuChE) in order to restore the levels of the neurotransmitter acetylcholine, and of O-GlcNAcase (OGA), which is associated with hyperphosphorylation of tau protein, in turn related to the formation of neurofibrillary tangles in the brain. Specifically, we considered the possibility of using carbohydrate-fused 1,3-selenazolines, decorated with a 2-alkylamino or 2-alkoxy moieties. On the one hand, the presence of a selenium atom might be useful in modulating the intrinsic oxidative stress in AD. On the other hand, such bicyclic structure might behave as a transition state analogue of OGA hydrolysis. Moreover, upon protonation, it could mimic the ammonium cation of acetylcholine. The lead compound, bearing a propylamino moiety on C-2 position of the selenazoline motif, proved to be a good candidate against AD; it turned out to be a strong inhibitor of BuChE (IC50 = 0.46 µM), the most prevalent cholinesterase in advanced disease stages, with a roughly 4.8 selectivity index in connection to AChE (IC50 = 2.2 µM). This compound exhibited a roughly 12-fold increase in activity compared to galantamine, one of the currently marketed drugs against AD, and a selective AChE inhibitor, and virtually the same activity as rivastigmine, a selective BuChE inhibitor. Furthermore, it was also endowed with a strong inhibitory activity against human OGA, within the nanomolar range (IC50 = 0.053 µM for hOGA, >100 µM for hHexB), and, thus, with an outstanding selectivity (IC50(hHexB)/IC50(hOGA) > 1887). The title compounds also exhibited an excellent selectivity against a panel of glycosidases and a negligible cytotoxicity against tumor and non-tumor cell lines. Docking simulations performed on the three target enzymes (AChE, BuChE, and OGA) revealed the key interactions to rationalize the biological data. |
Funding agencies | Ministerio de Ciencia e Innovación (MICIN). España Junta de Andalucía Comunidad Autónoma de Canarias Mexican CONACYT |
Project ID. | PID2020-116460RB-I00
FQM-134 FQM- 345 ProID2020010101 CB-2015/25746 |
Citation | Velueta Viveros, M., Martínez Bailén, M., Puerta, A., Romero Hernández, L.L., Křen, V., Merino Montiel, P.,...,Fernández-Bolaños Guzmán, J.M. (2022). Carbohydrate-derived bicyclic selenazolines as new dual inhibitors (cholinesterases/OGA) against Alzheimer's disease. Bioorganic Chemistry, 127, 105983. https://doi.org/10.1016/j.bioorg.2022.105983. |
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