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. 2022 Apr 29;11(5):884.
doi: 10.3390/antiox11050884.

Study on the Neuroprotective, Radical-Scavenging and MAO-B Inhibiting Properties of New Benzimidazole Arylhydrazones as Potential Multi-Target Drugs for the Treatment of Parkinson's Disease

Neda Anastassova  1 , Denitsa Aluani  2 , Nadya Hristova-Avakumova  3 , Virginia Tzankova  2 , Magdalena Kondeva-Burdina  2 , Miroslav Rangelov  1 , Nadezhda Todorova  4 , Denitsa Yancheva  1
Affiliations

Study on the Neuroprotective, Radical-Scavenging and MAO-B Inhibiting Properties of New Benzimidazole Arylhydrazones as Potential Multi-Target Drugs for the Treatment of Parkinson's Disease

Neda Anastassova et al. Antioxidants (Basel). .

Abstract

Oxidative stress is a key contributing factor in the complex degenerating cascade in Parkinson's disease. The inhibition of MAO-B affords higher dopamine bioavailability and stops ROS formation. The incorporation of hydroxy and methoxy groups in the arylhydrazone moiety of a new series of 1,3-disubstituted benzimidazole-2-thiones could increase the neuroprotective activity. In vitro safety evaluation on SH-SY5Y cells and rat brain synaptosomes showed a strong safety profile. Antioxidant and neuroprotective effects were evaluated in H2O2-induced oxidative stress on SH-SY5Y cells and in a model of 6-OHDA-induced neurotoxicity in rat brain synaptosomes, where the dihydroxy compounds 3h and 3i demonstrated the most robust neuroprotective and antioxidant activity, more pronounced than the reference melatonin and rasagiline. Statistically significant MAO-B inhibitory effects were exerted by some of the compounds where again the catecholic compound 3h was the most potent inhibitor similar to selegiline and rasagiline. The most potent antioxidant effect in the ferrous iron induced lipid peroxidation assay was observed for the three catechols-3h and 3j, 3q. The catecholic compound 3h showed scavenging capability against superoxide radicals and antioxidant effect in the iron/deoxyribose system. The study outlines a perspective multifunctional compound with the best safety profile, neuroprotective, antioxidant and MAO-B inhibiting properties.

Keywords: MAO-B inhibition; MTDLs; Parkinson’s disease; benzimidazoles; catechols; lipid peroxidation; neuroprotection; superoxide scavenging; synaptosomes; synthesis.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Scheme 1
Scheme 1
Structures of well-known and newly developed MAO-B inhibitors and multifunctional compounds: I—rasagiline; II—safinamide; III—benzylideneindanone derivative; IV—thiophenylcoumarin derivative; V—benzimidazole hydrazone derivative.
Scheme 2
Scheme 2
Synthesis of N,N′-disubstituted benzimidazole-2-thione arylhydrazones. Reagents and conditions: (a) methyl acrylate, DMF, refluxing; (b) hydrazine hydrate, ethanol solution, refluxing; (c) corresponding aldehyde, ethanol, refluxing.
Figure 1
Figure 1
Protective effects of compounds 3d, 3e, 3h, 3i, 3m, 3n, and 3p and reference melatonin and rasagiline at different concentrations (1, 10 and 50 μM) in a model of H2O2-induced oxidative damage in human neuroblastoma SH-SY5Y cells: compound 3d (A), compound 3e (B), compound 3h (C), compound 3i (D), compound 3m (E), compound 3n (F), compound 3p (G), melatonin (H) and rasagiline (I). Data are presented as means from three independent experiments ± SD. * p < 0.05, ** p < 0.01, *** p < 0.001, vs. H2O2 treated cells (one-way analysis of variance with Dunnet’s post hoc test).
Figure 2
Figure 2
Effect of the new arylhydrazone derivatives on: (a) synaptosomal viability and (b) GSH levels. Synaptosomal viability was assessed after treatment with various concentrations of the new benzimidazole arylhydrazones 3e, 3h, 3i, and 3m at concentrations 1, 10, 100, and 200 μM, and after treatment with the reference compounds melatonin and rasagiline at the same concentrations. Data are presented as means from three independent experiments ± SD. * p < 0.05, ** p < 0.01, *** p < 0.001, vs. control (one-way analysis of variance with Dunnet’s post hoc test).
Figure 3
Figure 3
Effect of the tested benzimidazole aryhydrazones 3e, 3h, 3i, 3m (10 μM) on the synaptosomal viability and GSH levels in a model of 6-OHDA (150 μM) induced oxidative stress compared to the reference compounds rasagiline and melatonin. Data are represented as means from three independent experiments ± SD. *** p < 0.001, vs. untreated control (CTRL); + p < 0.05, ++ p < 0.01, +++ p < 0.001 vs. 6-OHDA (one-way analysis of variance with Dunnet’s post hoc test).
Figure 4
Figure 4
In vitro inhibiting activity of compounds 3d, 3e, 3h, 3i, 3m, 3n, 3p on human recombinant MAO-B enzyme. Data are presented as means from three independent experiments ± SD. Sample series were compared by one-way analysis of variance with Dunnet’s post hoc test. *** p < 0.001, vs. control.
Figure 5
Figure 5
Three-dimensional (3D) representation of the interactions of the ligands in the MAO-B cavity (left part) and interaction maps (right part); the following colours have been used for representing the different components: the proximity contour—depicted by a black dotted line, polar amino acids—pink, lipophilic amino acids—green, basic amino acids—blue, acidic amino acids—red; hydrogen bond interactions—depicted by blue arrows, lipophilic interactions—green dotted lines. Docked structures are represented by the balls and sticks method, while FAD is represented by sticks.
Figure 5
Figure 5
Three-dimensional (3D) representation of the interactions of the ligands in the MAO-B cavity (left part) and interaction maps (right part); the following colours have been used for representing the different components: the proximity contour—depicted by a black dotted line, polar amino acids—pink, lipophilic amino acids—green, basic amino acids—blue, acidic amino acids—red; hydrogen bond interactions—depicted by blue arrows, lipophilic interactions—green dotted lines. Docked structures are represented by the balls and sticks method, while FAD is represented by sticks.
Figure 6
Figure 6
Effect of the tested hydrazone derivatives [90 µmol/L] on the in vitro Fe(II) induced oxidative damage in the lecithin containing model system [1 mg/mL]. Melatonin, Trolox, and Quercetin (labeled with M, T, and Q, respectively) have been used as reference compounds at the same concentrations. All data are expressed as Mean ± SEM. The effect of compounds labeled with ● is considered statistically identical (p < 0.05) compared with the effect of Compound 3a (containing the residue of unsubstituted benzaldehyde). Analogically with #, we labeled the compounds with an effect statistically identical (p < 0.05) to 3d.
Figure 7
Figure 7
Scavenging abilities in model system with enzymatic (X-XO) and non-enzymatic generation of the superoxide anion radical. Results have been presented as percentage of the control sample. Data are presented as means from three independent experiments ± SD (n = 3). * p < 0.05, ** p < 0.01, *** p < 0.001, vs. control sample for each assay (one-way ANOVA with Bonferroni post hoc test).
Figure 7
Figure 7
Scavenging abilities in model system with enzymatic (X-XO) and non-enzymatic generation of the superoxide anion radical. Results have been presented as percentage of the control sample. Data are presented as means from three independent experiments ± SD (n = 3). * p < 0.05, ** p < 0.01, *** p < 0.001, vs. control sample for each assay (one-way ANOVA with Bonferroni post hoc test).
Figure 8
Figure 8
Effect of the tested hydrazone derivative 3h [80 µmol/L] on the in vitro Fe(II) induced degradation of 2-deoxyribose [0.5 mmol/L]. Melatonin, Trolox, and Quercetin at the same concentrations have been used as reference compounds. All data are expressed as Mean ± SEM. The effect of the compound labeled with ● is considered statistically identical (p < 0.05) compared with the effect of Trolox.
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