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

0559646 - MBÚ 2023 RIV US eng J - Journal Article
Velueta-Viveros, M. - Martinez-Bailen, M. - Puerta, A. - Romero-Hernandez, L. L. - Křen, Vladimír - Merino-Montiel, P. - Montiel-Smith, S. - Fernandes, Miguel X. - Moreno-Vargas, Antonio J. - Padron, Jose M. - Lopez, O. - Fernandez-Bolanos, J. G.
Carbohydrate-derived bicyclic selenazolines as new dual inhibitors (cholinesterases/OGA) against Alzheimer's disease.
Bioorganic Chemistry. Roč. 127, OCT 2022 (2022), č. článku 105983. ISSN 0045-2068. E-ISSN 1090-2120
R&D Projects: GA ČR(CZ) GF21-01948L
Institutional support: RVO:61388971
Keywords : Selenazolines * AChE * BuChE * oga * Docking simulations
OECD category: Biochemistry and molecular biology
Impact factor: 5.1, year: 2022
Method of publishing: Limited access
https://www.sciencedirect.com/science/article/pii/S0045206822003881?via%3Dihub

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 2alkylamino 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 mu M), the most prevalent cholinesterase in advanced disease stages, with a roughly 4.8 selectivity index in connection to AChE (IC50 = 2.2 mu M). 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 mu M for hOGA, >100 mu M 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.
Permanent Link: https://hdl.handle.net/11104/0333195