Carbohydrate-derived bicyclic selenazolines as new dual inhibitors (cholinesterases/OGA) against Alzheimer's disease.

Autor: Velueta-Viveros M; Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, 72570 Puebla, PUE, México., Martínez-Bailén M; Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Sevilla, Spain., Puerta A; BioLab, Instituto Universitario de Bio-Orgánica 'Antonio González' (IUBO-AG), Universidad de La Laguna, Astrofísico Francisco Sánchez 2, E-38206 La Laguna, Spain., Romero-Hernández LL; Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, 72570 Puebla, PUE, México., Křen V; Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague 4, Czech Republic., Merino-Montiel P; Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, 72570 Puebla, PUE, México. Electronic address: penelope.merino@correo.buap.mx., Montiel-Smith S; Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, 72570 Puebla, PUE, México., Fernandes MX; BioLab, Instituto Universitario de Bio-Orgánica 'Antonio González' (IUBO-AG), Universidad de La Laguna, Astrofísico Francisco Sánchez 2, E-38206 La Laguna, Spain., Moreno-Vargas AJ; Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Sevilla, Spain., Padrón JM; BioLab, Instituto Universitario de Bio-Orgánica 'Antonio González' (IUBO-AG), Universidad de La Laguna, Astrofísico Francisco Sánchez 2, E-38206 La Laguna, Spain. Electronic address: jmpadron@ull.es., López Ó; Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Sevilla, Spain. Electronic address: osc-lopez@us.es., Fernández-Bolaños JG; Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Sevilla, Spain.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2022 Oct; Vol. 127, pp. 105983. Date of Electronic Publication: 2022 Jun 25.
DOI: 10.1016/j.bioorg.2022.105983
Abstrakt: 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 (IC 50  = 0.46 µM), the most prevalent cholinesterase in advanced disease stages, with a roughly 4.8 selectivity index in connection to AChE (IC 50  = 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 (IC 50  = 0.053 µM for hOGA, >100 µM for hHexB), and, thus, with an outstanding selectivity (IC 50 (hHexB)/IC 50 (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.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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