Browsing by Author "Kondeva-Burdina M."
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Item Evaluation of the combined activity of benzimidazole arylhydrazones as new anti-Parkinsonian agents: Monoamine oxidase-B inhibition, neuroprotection and oxidative stress modulation(2021-11-01) Anastassova N.; Aluani D.; Kostadinov A.; Rangelov M.; Todorova N.; Hristova-Avakumova N.; Argirova M.; Lumov N.; Kondeva-Burdina M.; Tzankova V.; Yancheva D.Neuroprotective drugs and selective monoamine oxidase inhibitors can slow down the progression and improve symptoms of Parkinson's disease (PD). Since there is an implication of oxidative stress in the pathophysiological mechanisms of the disease, the compounds possessing an ability to reduce the oxidative stress are prime candidates for neuroprotection. Thereby our current study is focused on the development of new multi-target PD drugs capable of inhibiting the activity of monoamine oxidase-B while exerting neuroprotective and antioxidant properties. A small series of benzimidazole derivatives containing hydroxy and methoxy arylhydrazone fragments has been synthesized and the neurotoxicity of the compounds has been evaluated in vitro on neuroblastoma SH-SY5Y cells and on isolated rat brain synaptosomes by measuring the cell viability and the levels of reduced glutathione and a good safety profile has been shown. The 2-hydroxy-4-methoxy substituted arylhydrazone 7 was the least toxic on neuronal SH-SY5Y cells and showed the lowest neurotoxicity in rat brain synaptosomes. The neuroprotective properties of the test compounds were further assessed using two models: H2O2-induced oxidative stress on SH-SY5Y cells and 6-hydroxydopamine-induced neurotoxicity in rat brain synaptosomes. Compound 7 showed more pronounced neuroprotective activity on SH-SY5Y cells, compared to the referent melatonin and rasagiline. It also preserved the synaptosomal viability and the reduced glutathione levels; the effects were stronger than those of rasagiline and comparable to melatonin. All the tested compounds were capable to inhibit human monoamine oxidase-B enzyme to a significant extent, however, compound 7 exerted the most prominent inhibitory activity, similar to selegiline and rasagiline. The carried out molecular docking studies revealed that the activity is related to the appropriate molecular structure enabling the ligand to enter deeper in the narrow and highly lipophylic active site pocket of the human monoamine oxidase-B and has a favoring interaction with the key amino acid residues Tyr326 and Cys172. Since much scientific evidence points out the implication of iron dyshomeostasis in PD, the compounds were tested to reduce the ferrous iron induced oxidative molecular damage on biologically important molecules in an in vitro lecithin containing model system. All the investigated compounds denoted protection effect, stronger than the one of the referent melatonin. In order to support the assignments of the significant neuroprotective and antioxidant pharmacological activities, the radical-scavenging mechanisms of the most promising compound 7 were evaluated using DFT methods. It was found that the most probable free radicals scavenging mechanism in nonpolar phase is the hydrogen atom transfer from the amide group of compound 7, while in polar medium the process is expected to occur by a proton transfer. The current study outlines a perspective leading structure, bearing the potential for a new anti-PD drug. All performed procedures were approved by the Institutional Animal Care Committee of the Medical University of Sofia (Bulgarian Agency for Food Safety with Permission № 190, approved on February 6, 2020).Item Evaluation of the combined activity of benzimidazole arylhydrazones as new anti-Parkinsonian agents: Monoamine oxidase-B inhibition, neuroprotection and oxidative stress modulation(2021-11-01) Anastassova N.; Aluani D.; Kostadinov A.; Rangelov M.; Todorova N.; Hristova-Avakumova N.; Argirova M.; Lumov N.; Kondeva-Burdina M.; Tzankova V.; Yancheva D.Neuroprotective drugs and selective monoamine oxidase inhibitors can slow down the progression and improve symptoms of Parkinson's disease (PD). Since there is an implication of oxidative stress in the pathophysiological mechanisms of the disease, the compounds possessing an ability to reduce the oxidative stress are prime candidates for neuroprotection. Thereby our current study is focused on the development of new multi-target PD drugs capable of inhibiting the activity of monoamine oxidase-B while exerting neuroprotective and antioxidant properties. A small series of benzimidazole derivatives containing hydroxy and methoxy arylhydrazone fragments has been synthesized and the neurotoxicity of the compounds has been evaluated in vitro on neuroblastoma SH-SY5Y cells and on isolated rat brain synaptosomes by measuring the cell viability and the levels of reduced glutathione and a good safety profile has been shown. The 2-hydroxy-4-methoxy substituted arylhydrazone 7 was the least toxic on neuronal SH-SY5Y cells and showed the lowest neurotoxicity in rat brain synaptosomes. The neuroprotective properties of the test compounds were further assessed using two models: H2O2-induced oxidative stress on SH-SY5Y cells and 6-hydroxydopamine-induced neurotoxicity in rat brain synaptosomes. Compound 7 showed more pronounced neuroprotective activity on SH-SY5Y cells, compared to the referent melatonin and rasagiline. It also preserved the synaptosomal viability and the reduced glutathione levels; the effects were stronger than those of rasagiline and comparable to melatonin. All the tested compounds were capable to inhibit human monoamine oxidase-B enzyme to a significant extent, however, compound 7 exerted the most prominent inhibitory activity, similar to selegiline and rasagiline. The carried out molecular docking studies revealed that the activity is related to the appropriate molecular structure enabling the ligand to enter deeper in the narrow and highly lipophylic active site pocket of the human monoamine oxidase-B and has a favoring interaction with the key amino acid residues Tyr326 and Cys172. Since much scientific evidence points out the implication of iron dyshomeostasis in PD, the compounds were tested to reduce the ferrous iron induced oxidative molecular damage on biologically important molecules in an in vitro lecithin containing model system. All the investigated compounds denoted protection effect, stronger than the one of the referent melatonin. In order to support the assignments of the significant neuroprotective and antioxidant pharmacological activities, the radical-scavenging mechanisms of the most promising compound 7 were evaluated using DFT methods. It was found that the most probable free radicals scavenging mechanism in nonpolar phase is the hydrogen atom transfer from the amide group of compound 7, while in polar medium the process is expected to occur by a proton transfer. The current study outlines a perspective leading structure, bearing the potential for a new anti-PD drug. All performed procedures were approved by the Institutional Animal Care Committee of the Medical University of Sofia (Bulgarian Agency for Food Safety with Permission № 190, approved on February 6, 2020).Item EVALUATION OF THE IN VITRO NEUROTOXIC AND NEUROPROTECTIVE EFFECTS AT CELLULAR AND SUBCELLULAR LEVELS OF NEWLY SYNTHESIZED N-PYRROLYL HYDRAZONES(2022-01-01) Tzankova D.; Vladimirova S.; Stefanova D.; Peikova L.; Kondeva-Burdina M.; Georgieva M.The study presents the safety, antioxidant activity and neuroprotective effects of a series of newly synthesized N-pyrrolyl hydrazide-hydrazones (5, 5a-g) in two in vitro models: human neuronal cells SH-SY5Y and isolated rat brain synaptosomes. The performed in vitro toxicological evaluation in neuronal SH-SY5Y cell line models determined the lowest cytotoxicity and best safety profile for compound 5a, followed by 5d on both evaluated parameters. The protective effect of the newly synthesized hydrazone 5a was found to be comparable to melatonin used as a standard. The obtained results indicate that the presence of pyrrole ring, containing multiple phenyl nuclei and hydrazide-hydrazone group in the side chain, leads to increase in the antioxidant effect.Item Hepatotoxicity and antioxidant activity of some new N,N′-disubstituted benzimidazole-2-thiones, radical scavenging mechanism and structure-activity relationship(2018-03-01) Anastassova N.; Mavrova A.; Yancheva D.; Kondeva-Burdina M.; Tzankova V.; Stoyanov S.; Shivachev B.; Nikolova R.A new method for the synthesis of 1,3-disubstituted benzimidazole derivatives was developed using aza-Michael addition. The target compounds were synthesized in good yields and purity and tested on isolated hepatocytes for their toxicity and antioxidant activity. The antioxidant properties of the substances with lowest toxicity were evaluated using oxidative stress induced by tert-butyl hydroperoxide (tert-BOOH). Some of them as methyl 3-[3-(3-methoxy-3-oxopropyl)-5-benzoyl-2-thioxo-2,3-dihydro-1H-benzimidazol-1-yl]propanoate 10 and 1,3-bis[3-(hydrazinooxy)-3-oxopropyl]-5-benzoyl-1,3-dihydro-2H-benzimidazole-2-thione 15 exhibited statistically significant cytoprotective and antioxidant effects which were similar to those of quercetin. In order to estimate the influence of the structure on the biological properties, structural characterization of the studied compounds was performed by X-ray diffraction analysis and DFT methods. On the basis of the calculated reaction enthalpies of hydrogen atom abstraction (HAT mechanism) and single-electron transfer (SET mechanism) the mechanisms of the antioxidant action of the tested compounds were studied. Subsequently it was established that the HAT mechanism governs the radical scavenging of 10 and 15 in the lipid phase, while the SET mechanism is preferred in water medium for 10 and competitive to HAT for 15.Item New Indole-3-Propionic Acid and 5-Methoxy-Indole Carboxylic Acid Derived Hydrazone Hybrids as Multifunctional Neuroprotectors(2023-04-01) Anastassova N.; Stefanova D.; Hristova-Avakumova N.; Georgieva I.; Kondeva-Burdina M.; Rangelov M.; Todorova N.; Tzoneva R.; Yancheva D.In light of the known neuroprotective properties of indole compounds and the promising potential of hydrazone derivatives, two series of aldehyde-heterocyclic hybrids combining those pharmacophores were synthesized as new multifunctional neuroprotectors. The obtained derivatives of indole-3-propionic acid (IPA) and 5-methoxy-indole carboxylic acid (5MICA) had good safety profiles: Hemolytic effects < 5% (200 μM) and IC50 > 150 µM were found in the majority of the SH-SY5Y and bEnd3 cell lines. The 2,3-dihydroxy, 2-hydroxy-4-methoxy, and syringaldehyde derivatives of 5MICA exhibited the strongest neuroprotection against H2O2-induced oxidative stress in SH-SY5Y cells and 6-OHDA-induced neurotoxicity in rat-brain synaptosomes. All the compounds suppressed the iron-induced lipid peroxidation. The hydroxyl derivatives were also the most active in terms of deoxyribose-degradation inhibition, whereas the 3,4-dihydroxy derivatives were able to decrease the superoxide-anion generation. Both series of compounds showed an increased inhibition of hMAO-B, with greater expression detected in the 5MICA hybrids. The in vitro BBB model with the bEnd3 cell line showed that some compounds increased the permeability of the endothelial monolayer while maintaining the tight junctions. The combined results demonstrated that the derivatives of IPA and 5MICA showed strong neuroprotective, antioxidant, MAO-B inhibitory activity and could be considered as prospective multifunctional compounds for the treatment of neurodegenerative disorders.