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. 2023 May 5;24(9):8312.
doi: 10.3390/ijms24098312.

Rivastigmine-Benzimidazole Hybrids as Promising Multitarget Metal-Modulating Compounds for Potential Treatment of Neurodegenerative Diseases

David Vicente-Zurdo  1   2 , Leonardo Brunetti  1   3 , Luca Piemontese  3 , Beatriz Guedes  4 , Sandra M Cardoso  4   5 , Daniel Chavarria  6 , Fernanda Borges  6 , Yolanda Madrid  2 , Sílvia Chaves  1 , M Amélia Santos  1
Affiliations

Rivastigmine-Benzimidazole Hybrids as Promising Multitarget Metal-Modulating Compounds for Potential Treatment of Neurodegenerative Diseases

David Vicente-Zurdo et al. Int J Mol Sci. .

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.

Keywords: Alzheimer’s disease; Parkinson’s disease; amyloid-β aggregation; cholinesterases; metal chelation; monoamine oxidase; rivastigmine hybrids.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of the RIV–BIM hybrids.
Figure 2
Figure 2
Representative 1H NMR titration curves of 4c in 75% d6-DMSO/D2O medium (CL = 4.5 mM) for 6.6 < δ (ppm) < 8.2; pH* value = reading value of the pH meter previously calibrated with standard aqueous buffers pH 4 and 7. Each color and number represent a specific proton of the reported molecule.
Figure 3
Figure 3
Absorbance spectra of 4c (2.75 < pH < 11.3, CL = 4 × 10−5 M) in 50% (w/w) DMSO/H2O and outset with individual calculated spectra by Psequad [30]. The arrows indicate the evolution of the spectra when pH increases. Each line corresponds to an absorbance spectrum obtained at a specific pH.
Figure 4
Figure 4
Absorbance spectra for the Cu(II)/5a 1:2 system (2.82 < pH < 9.43) in 50% (w/w) DMSO/H2O (CL = 4 × 10−5 M) and outset with individual calculated spectra by Psequad [31]. The arrows indicate the evolution of the spectra when pH increases. Each line corresponds to an absorbance spectrum obtained at a specific pH.
Figure 5
Figure 5
Species distribution curves for the systems: Cu(II)/5a 1:2 (a) and Fe(III)/5a 1:3 (b); CL = 4 × 10−5 M).
Figure 6
Figure 6
DFT-minimized structures of 1:1 Cu/L complexes with 4a (a) and 5a (b). Color of atoms: Cu (light blue), N (blue), O (red), C (grey), and H (white).
Figure 7
Figure 7
DFT-minimized structures of Cu/L (1:2) complexes with (a) 4a and (b) 5a. Color of atoms: Cu (light blue), N (blue), O (red), C (grey), and H (white).
Figure 8
Figure 8
Superimposition of original ligand (clorgyline, green carbon chain) (PDB code: 2BXR) with (a) 4a (pink) and (b) 4d (magenta), inside the hMAO-A active site. Superimposition of original ligand (safinamide, green carbon chain) (PDB code: 2V5Z) with (c) 4d (magenta) and (d) 5a (yellow), inside the hMAOB active site. FAD and residues near this cofactor with light blue carbon chains.
Figure 8
Figure 8
Superimposition of original ligand (clorgyline, green carbon chain) (PDB code: 2BXR) with (a) 4a (pink) and (b) 4d (magenta), inside the hMAO-A active site. Superimposition of original ligand (safinamide, green carbon chain) (PDB code: 2V5Z) with (c) 4d (magenta) and (d) 5a (yellow), inside the hMAOB active site. FAD and residues near this cofactor with light blue carbon chains.
Figure 9
Figure 9
Neuroprotective effects of RIV–BIM compounds against MPP+-induced toxicity in SH-SY5Y cells. Cells were treated with the compounds for 1 h and then MPP+ was added to the medium for 24 h. MTT reduction assay was performed to assess cell viability, and the results are expressed relative to those for SH-SY5Y untreated cells. *** p < 0.001, significantly different when compared with SH-SY5Y untreated cells; ## p < 0.01, significantly different when compared with MPP+-treated SH-SY5Y cells; # p < 0.05, significantly different when compared with MPP+-treated SH-SY5Y cells. Statistical differences were analyzed using one-way ANOVA followed by Tukey’s post hoc test or using Student’s t-test.
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Grants and funding

This work was supported by the Portuguese Fundação para a Ciência e Tecnologia (FCT), through project grants: UIDB/00100/2020, UIDP/00100/2020 (CQE) UIDB/04539/2020, UIDP/04539/2020 (CNC), LA/P/0058/2020 (IMS), UIDB/00081/2020, UIDP/00081/2020 (CIQUP), LA/P/0056/2020 (IMS), PT-OPENSCREEN–NORTE-01-0145-FEDER-085468; the Spanish Ministry of Science and Innovation (PID2020-114714RB-I00), and the Community of Madrid and European funding from FSE and FEDER programs for financial support (S2018/BAA-4393, AVANSECAL-II-CM). D.V.-Z. acknowledges the Spanish Ministry of Science, Innovation, and Universities for funding through a pre-doctoral grant (FPU18/00573) and the Erasmus+ program for an international fellowship. L.B. was supported by a PD/BD/2020.06543.BD PhD fellowship.