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Title: | Rivastigmine-Benzimidazole Hybrids as Promising Multitarget Metal-Modulating Compounds for Potential Treatment of Neurodegenerative Diseases | Authors: | Vicente-Zurdo, David Brunetti, Leonardo Piemontese, Luca Guedes, Beatriz Cardoso, Sandra M. Chavarria, Daniel Borges, Fernanda Madrid, Yolanda Chaves, Sílvia Santos, M. Amélia |
Keywords: | Alzheimer’s disease; Parkinson’s disease; rivastigmine hybrids; metal chelation; cholinesterases; monoamine oxidase; amyloid- aggregation | Issue Date: | 5-May-2023 | Publisher: | MDPI | Project: | UIDB/00100/2020 UIDP/00100/2020 UIDB/04539/2020 LA/P/0058/2020 info:eu-repo/grantAgreement/UIDP/04539/2020 UIDB/00081/2020 UIDP/00081/2020 LA/P/0056/2020 PID2020-114714RB-I00 S2018/BAA-4393 FPU18/00573 PD/BD/2020.06543 NORTE-01-0145-FEDER-085468 |
Serial title, monograph or event: | International Journal of Molecular Sciences | Volume: | 24 | Issue: | 9 | Abstract: | With the goal of combating the multi-faceted Alzheimer's disease (AD), a series of Rivastigmine-Benzimidazole (RIV-BIM) hybrids was recently reported by us as multitarget-directed ligands, thanks to their capacity to tackle important hallmarks of AD. In particular, they exhibited antioxidant activity, acted as cholinesterase inhibitors, and inhibited amyloid-β (Aβ) aggregation. Herein, we moved forward in this project, studying their ability to chelate redox-active biometal ions, Cu(II) and Fe(III), with widely recognized roles in the generation of oxidative reactive species and in protein misfolding and aggregation in both AD and Parkinson's disease (PD). Although Cu(II) chelation showed higher efficiency for the positional isomers of series 5 than those of series 4 of the hybrids, the Aβ-aggregation inhibition appears more dependent on their capacity for fibril intercalation than on copper chelation. Since monoamine oxidases (MAOs) are also important targets for the treatment of AD and PD, the capacity of these hybrids to inhibit MAO-A and MAO-B was evaluated, and they showed higher activity and selectivity for MAO-A. The rationalization of the experimental evaluations (metal chelation and MAO inhibition) was supported by computational molecular modeling studies. Finally, some compounds showed also neuroprotective effects in human neuroblastoma (SH-SY5Y cells) upon treatment with 1-methyl-4-phenylpyridinium (MPP+), a neurotoxic metabolite of a Parkinsonian-inducing agent. | URI: | https://hdl.handle.net/10316/113305 | ISSN: | 1422-0067 | DOI: | 10.3390/ijms24098312 | Rights: | openAccess |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais |
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