Examinando por Autor "Cardoso, Sandra M"

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Novel Rivastigmine Derivatives as Promising Multi‐Target Compounds for Potential Treatment of Alzheimer’s Disease
(MDPI, 2022-06-26) Vicente-Zurdo, David; Rosales-Conrado, Noelia; León-González, María Eugenia; Brunetti, Leonardo; Piemontese, Luca; Raquel Pereira-Santos, A; Cardoso, Sandra M; Madrid, Yolanda; Chaves, Sílvia; Santos, M. Amélia
Alzheimer’s disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti‐AD drugs has been focused on multi‐target compounds. In this work, seven novel hybrids (RIV–BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid β‐peptide (Aβ) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Aβ42 aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC50 = 32.1 μM), but compounds of series 5 are better inhibitors of BChE (IC50 = 0.9−1.7 μM) than those of series 4. Series 5 also showed good capacity to inhibit self‐ (42.1−58.7%) and Cu(II)‐induced (40.3−60.8%) Aβ aggregation and also to narrow (22.4−42.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH‐SY5Y cells by Aβ42 and oxidative stress. Therefore, RIV– BIM hybrids seem to be potential drug candidates for AD with multi‐target abilities.
Rivastigmine–Benzimidazole Hybrids as Promising Multitarget Metal-Modulating Compounds for Potential Treatment of Neurodegenerative Diseases
(MDPI, 2023-05-05) Vicente-Zurdo, David; Brunetti, Leonardo; Piemontese, Luca; Guedes, Beatriz; Cardoso, Sandra M; Chavarria, Daniel; Borges, Fernanda; Madrid, Yolanda; Chaves, Sílvia; Santos, M. Amélia
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