Browsing by Author "Todorova N."
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Item Additive Anticonvulsant Profile and Molecular Docking Analysis of 5,5′-Diphenylhydantoin Schiff Bases and Phenytoin(2023-11-01) Tchekalarova J.; Todorov P.; Rangelov M.; Stoyanova T.; Todorova N.Four 5,5′-diphenylhydantoin Schiff bases possessing different aromatic species (SB1–SB4) were recently synthesized and characterized using spectroscopic and electrochemical tools. The present study aimed to ascertain the anticonvulsant activity of the novel phenytoin derivatives SB1-Ph, SB2-Ph, SB3-Ph, and SB4-Ph, containing different electron-donor and electron-acceptor groups, and their possible mechanism of action. The SB2-Ph exhibited the highest potency to suppress the seizure spread with ED50 = 8.29 mg/kg, comparable to phenytoin (ED50 = 5.96 mg/kg). While SB2-Ph did not produce neurotoxicity and sedation, it decreased locomotion and stereotypy compared to control. When administered in combination, the four Schiff bases decreased the phenytoin ED50 by more than 2× and raised the protective index by more than 7× (phenytoin+SB2-Ph). The strongest correlation between in-vivo and docking study results was found for ligands’ interaction energies with kappa and delta receptors. These data, combined with the worst interaction energies of our ligands with the mu receptor, suggest that the primary mechanism of their action involves the kappa and delta receptors, where the selectivity to the kappa receptor leads to higher biological effects. Our findings suggest that the four Schiff bases might be promising candidates with potential applications as a safe and effective adjuvant in epilepsy.Item Antileukemic activity of epirubicin conjugated with biopolymer dextran against lymphoid leukemia l1210 as tumor model(2004-01-01) Todorova N.; Ilarionova M.; Todorov K.; Todorov D.The antileukemic activity of the original conjugate of anthracycline antitumor antibiotic epirubicin, covalently bound to the biopolymer dextran was studied. The ascitic lymphoid leukemia L 1210 (transplantation dose 1x105 tumor cells/mouse, i. p.), in hybrid mice BDF1, was used as tumor model. An antileukemic activity of the studied original conjugate was found. The criterion “increase of life span” (ILS%) reached maximally 136,6% for the conjugate. The studied conjugate of biopolymer dextran with epirubicin showed lower toxicity but also lower antileukemic activity in comparison with free epirubicin. The further experiments in this field are in progress, aiming to design better conjugates, with potential clinical use. © 2004 Taylor and Francis Group, LLC.Item Antileukemic effect of epirubicin conjugated with chitosan against mouse p388 ascitic leukemia(2003-01-01) Todorova N.; Maneva K.; Ilarionova M.; Dudov A.; Todorov D.The antileukemic activity of the original conjugate of anthracycline antitumor antibiotic epirubicin, covalently bond to the biopolymer chitosan was studied. The ascitic form of lymphocytic leukemia P388 (transplantation dose 1 × 106 tumor cells/mouse), in hybrid mice BDF1 was used as leukemic model. A strong antileukemic activity of the studied conjugate was found, with a clear “dose-effect” correlation. The criterion “increase of life span”(ILS%) reached maximally 553.4% for the conjugate, in comparison with maximally 170.8% for the free epirubicin. The conjugate showed several advantages over the free antitumor antibiotic epirubicin: lower toxicity, stronger antileukemic activity and higher therapeutic index. © 2003 Taylor and Francis Group, LLC.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 Modulation Effect on Tubulin Polymerization, Cytotoxicity and Antioxidant Activity of 1H-Benzimidazole-2-Yl Hydrazones(2023-01-01) Argirova M.; Guncheva M.; Momekov G.; Cherneva E.; Mihaylova R.; Rangelov M.; Todorova N.; Denev P.; Anichina K.; Mavrova A.; Yancheva D.1H-benzimidazol-2-yl hydrazones with varying hydroxy and methoxy phenyl moieties were designed. Their effect on tubulin polymerization was evaluated in vitro on porcine tubulin. The compounds elongated the nucleation phase and slowed down the tubulin polymerization comparably to nocodazole. The possible binding modes of the hydrazones with tubulin were explored by molecular docking at the colchicine binding site. The anticancer activity was evaluated against human malignant cell lines MCF-7 and AR-230, as well as against normal fibroblast cells 3T3 and CCL-1. The compounds demonstrated a marked antineoplastic activity in low micromolar concentrations in both screened in vitro tumor models. The most active were the trimethoxy substituted derivative 1i and the positional isomers 1j and 1k, containing hydroxy and methoxy substituents: they showed IC50 similar to the reference podophyllotoxin in both tumor cell lines, accompanied with high selectivity towards the malignantly transformed cells. The compounds exerted moderate to high ability to scavenge peroxyl radicals and certain derivatives—1l containing metha-hydroxy and para-methoxy group, and 1b-e with di/trihydroxy phenyl moiety, revealed HORAC values high or comparable to those of well-known phenolic antioxidants. Thus the 1H-benisimidazol-2-yl hydrazones with hydroxy/methoxy phenyl fragments were recognized as new agents exhibiting promising combined antioxidant and antineoplastic action.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.Item Preparation and antileukemic activity of epirubicin conjugate with chitosan(2004-01-01) Todorova N.; Maneva K.; Todorov D.Condensation of the antitumor antibiotic epirubicin with oxidized chitosan provided a new conjugated antibiotic. The resultant compound was characterized by IR and UV-Vis-spectra with support the conjugate structure. The amount of epirubicin bound to the matrix was 22.5% or 315 epirubicin residues. The biological activity of epirubicin-chitosan conjugate showed an antibacterial action against Bacillus Subtilis AT 6633 on the level of the initial antibiotic. The ascetic form of lymphocytic leukemia P 388 and lymphoid leukemia L1210 (transplantation dose 106 tumor cells) in hybrid mice BDF1 was used as leukemic model. Antileukemic activity of the studied conjugate was found with a clear “dose-effect” correlation. The criterion “increase of live span” is maximally 342.1% in P338 and 371.5% in L1210 for the conjugate in comparation with maximally 179.0% in P388 and 197.2% in L1210 for the free epirubicin. The conjugate showed lower toxicity and higher therapeutic index. © 2004 Taylor and Francis Group, LLC.Item Preparation and antileukemic activity of the conjugate of doxorubicin with chitosan ax2(2005-01-01) Todorova N.; Maneva K.; Todorov D.Condensation of the antitumor antibiotic doxorubicin with oxidized chitosan in the presence of sodium borohydride provided a new conjugated antibiotic AC2.A ring involving a N-atom from the 31-amino group of the doxorubicin—sugar moiety and the residue of the oxidized glucosamine ring of chitosan was formed during reductive alkilation. The resulting conjugate was studied spectroscopicaly. The resultant compound was characterized by IR- and UV-Vis spectra which support the conjugate structure. The quantity of the bound antibiotic was evaluated using the spectra of doxorubicin-chitosan conjugate in 20% acetic acid. The bound doxorubicin was evaluated as 397.1 residues or 24.6%. The antibacterial activity of the conjugate was studied against Bacillus subtilis ATCC6633. Compared to unmodified doxorubicin the activity of the conjugate was 88.1%. The antileukemic activity of the conjugate AC2 of doxorubicin were studied against ascitic form of lymphocytic leukemia P388. A strong antileukemic activity of the conjugate AC2 was found and the criterion “increase of life span” (T/C) reached 412.8% in comparition with 167.6% at doxorubicin (at dose 0.25 mg/kg). © 2005 Taylor and Francis Group, LLC.Item 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(2022-05-01) Anastassova N.; Aluani D.; Hristova‐avakumova N.; Tzankova V.; Kondeva‐burdina M.; Rangelov M.; Todorova N.; Yancheva D.Oxidative stress is a key contributing factor in the complex degenerating cascade in Par-kinson’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 anti-oxidant effect in the ferrous iron induced lipid peroxidation assay was observed for the three cate-chols—3h and 3j, 3q. The catecholic compound 3h showed scavenging capability against superox-ide 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.Item Synthesis, molecular docking, electrochemical and fluorimetric analysis of new caffeic and cinnamic acid-conjugated hemorphin derivatives designed as potential anticonvulsant and antinociceptive agents(2024-02-01) Todorov P.; Georgieva S.; Peneva P.; Nikolov S.; Rangelov M.; Todorova N.; Pechlivanova D.; Tchekalarova J.Based on the pharmacophore model of opioid receptors, our team recently synthesized a series of short‐chain hemorphin peptide analogs containing non‐natural amino acids. They demonstrated anticonvulsant and antinociceptive activity with low neurotoxicity. In the present study, a series of novel bioconjugates of N-modified hemorphin analogs containing second pharmacophore cinnamic acids (CA) or caffeic (KA) were synthesized by a traditional solid-phase Fmoc chemistry method for peptide synthesis. Electrochemical and fluorimetric analysis, in vivo anticonvulsant and antinociceptive activity in mice were conducted on the compounds. The three CA acid- (H4-CA, H5-CA, and H7-CA) and three KA acid- (H4-KA, H5-KA, and H7-KA) conjugated hemorphin derivatives exhibited potency at the highest doses of 2 µg/5 µl, administered by intracerebroventricular (icv) mode, against seizure spread in the maximal electroshock test (MES) in mice. The KA-conjugated H5-KA derivate, at the lowest dose, was the only compound that suppressed clonic seizures in the subcutaneous pentylenetetrazol (scPTZ) test. Except for the H5-CA, all tested CA acid- and KA acid-conjugated peptide derivates had the potency to increase the latency for clonic seizures in a dose-dependent mode. The activity against the psychomotor seizures in the 6-Hz test was detected only for the H4-CA (0.5 µg) and H4-KA (0.5 µg and 1 µg), respectively. All investigated peptides showed a more pronounced antinociceptive effect in the “intraplantar formalin” test compared to the “hot plate” test. Shorter chain analogs showed a better antinociceptive profile against tonic pain. The data suggest a DOR and KOR-mediated mechanism of action. According to the docking analysis, H7-CA showed a different antinociceptive profile than other investigated peptides. The novel peptide derivates did not exhibit neurotoxicity in the rotarod test. Our findings suggest that conjugated CA and KA morphine peptides can be used to develop novel morphine-related analogs with anticonvulsant and antinociceptive activity.Item Zinc resinate's influence on the properties of silica filled composites based on natural rubber(2014-01-01) Todorova N.; Mihaylov M.; Damyankin I.; Dishovsky N.The aim of this study is to investigate the zinc resinate's influence on the rheological, vulcanization, mechanical and dynamic properties of the composites based on silica filled natural rubber, containing bi-functional organosilanes in the presence or absence of zinc oxide. The results obtained demonstrate that the presence of zinc resinate leads to considerable decrease of Mooney viscosity of the rubber compounds investigated. The mixture of zinc oxide and zinc resinate has a strong anti-reversion effect. The reversion absence found in the cure curves results in retaining the mechanical properties of the vulcanizate obtained regardless of the curing duration.