Browsing by Author "Yancheva D."
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Item 2-Alkyl-Substituted-4-Amino-Thieno[2,3-d]Pyrimidines: Anti-Proliferative Properties to In Vitro Breast Cancer Models(2023-09-01) Iliev I.; Mavrova A.; Yancheva D.; Dimov S.; Staneva G.; Nesheva A.; Tsoneva I.; Nikolova B.Thienopyrimidines are structural analogs of quinazolines, and the creation of new 2-alkyl derivatives of ethyl 4-aminothienopyrimidine-6-carboxylates for the study of their anti-proliferative properties is of great pharmacological interest. Some 2-alkyl-4-amino-thieno[2,3-d]pyrimidines 2–5 were synthesized, and their cyto- and phototoxicity against BALB 3T3 cells were established by an in vitro 3T3 NRU test. The obtained results indicate that the tested compounds are not cytotoxic or phototoxic, and that they are appropriate to be studied for their anti-proliferative and anti-tumor properties. The anti-proliferative potential of the compounds was investigated on MCF-7 and MDA-MB-231 cancer cells, as well as a MCF-10A cell line (normal human mammary epithelial cells). The most toxic to MCF-7 was thienopyrimidine 3 with IC50 13.42 μg/mL (IC50 0.045 μM), followed by compound 4 (IC50 28.89 μg/mL or IC50 0.11 μM). The thienopyrimidine 4 revealed higher selectivity to MCF-7 and lower activity (IC50 367 μg/mL i.e., 1.4 μM) than compound 3 with MCF-10A cells. With respect to MDA-MB-231 cells, ester 2 manifested the highest effect with IC50 52.56 μg/mL (IC50 0.16 μM), and 2-ethyl derivative 4 revealed IC50 62.86 μg/mL (IC50 0.24 μM). It was estimated that the effect of the substances on the cell cycle progression was due to cell cycle arrest in the G2 stage for MDA-MB-231, while arrest in G1 was detected for the estrogen (ER)-positive MCF-7 cell line. The tested compound’s effects on the change of the zeta potential in the tumorigenic cells utilized in this study were determined. The calculation which we performed of the physicochemical properties and pharmacokinetic parameters influencing the biological activity suggested high intestinal absorption, as well as drug-likeness.Item 6-(Propan-2-yl)-3-methyl-morpholine-2,5-dione, a novel cyclodidepsipeptide with modulatory effect on rat thymocytes(2012-09-01) Pavlovic V.; Cherneva E.; Yancheva D.; Smelcerovic A.A study has been carried out on the potential effect of a novel cyclodidepsipeptide, 6-(propan-2-yl)-3-methyl-morpholine-2,5-dione (PMMD), on rat thymocytes. Rat thymocytes were cultivated with increasing PMMD concentrations (0.1, 1, 10 μg/well), for 24. h, and evaluated for proliferative activity, viability, reactive oxygen species and mitochondrial membrane potential. The higher PMMD concentrations inhibited thymocytes proliferative activity mainly through induction of oxidative stress and resulting cytotoxicity, without any mitochondrial membrane potential alterations in thymocytes. The obtained results are correlated with previously published data on effects of 6-(propan-2-yl)-4-methyl-morpholine-2,5-diones on rat thymocytes. The presence of methyl group in position 4 or/and the length of alkyl chain in position 3 of 6-(propan-2-yl)-morpholine-2,5-dione core plays a role for the obtained differences in the biological response between PMMD and two previously tested 6-(propan-2-yl)-4-methyl-morpholine-2,5-diones. © 2012 Elsevier Ltd.Item Benzimidazole-based dual dipeptidyl peptidase-4 and xanthine oxidase inhibitors(2020-01-05) Tomovic K.; Ilic B.S.; Smelcerovic Z.; Miljkovic M.; Yancheva D.; Kojic M.; Mavrova A.T.; Kocic G.; Smelcerovic A.Multiple-targeting compounds might reduce complex polypharmacy of multifactorial diseases, such as diabetes, and contribute to the greater therapeutic success. Targeting reactive oxygen species-producing enzymes, as xanthine oxidase (XO), might suppress progression of diabetes-associated vascular complications. In this study a small series of benzimidazole derivatives (1–9) was evaluated for inhibitory activity against dipeptidyl peptidase-4 (DPP-4) and XO. One 1,3-disubstituted-benzimidazole-2-imine (5) and 1,3-thiazolo[3,2-a]benzimidazolone derivative (8) were shown as effective dual DPP-4 and XO inhibitors, with IC50 values lower than 200 μM, and predicted binding modes with both target enzymes. Both selected dual inhibitors (compounds 5 and 8) did not show cytotoxicity to a greater extent on Caco-2 cells even at concentration of 250 μM. These structures represent new non-purine scaffolds bearing two therapeutic functionalities, being DPP-4 and XO inhibitors, more favorable in comparison to DPP-4 inhibitors with DPP-4 as a single target due to pleiotropic effects of XO inhibition.Item Biophysical properties and cytotoxicity of feruloylated helix lucorum hemocyanin(2020-03-20) Guncheva M.; Idakieva K.; Todinova S.; Stoyanova E.; Yancheva D.For the first time Helix lucorum hemocyanin (HlH) has been feruloylated. Two HlH conjugates with 40- and 120- ferulic acid residues were prepared, denoted as FA-HlH-1 and FA-HlH-2. Expectedly, the feruloylation of HlH induced a rearrangement of the protein molecule, a decrease in the α-helical structure at the expense of β-structures was observed. Besides, the FA-HlH conjugates were more prone to aggregation, which is probably due to the stabilization of the partially unfolded protein molecules by non-covalent bonding. Interestingly, the thermal stability of HlH was not affected by the modification. The native and feruloylated HlH were not toxic to normal fibroblasts (BJ cells). We observed a decrease in cell viability of breast cancer MCF-7 cells to about 66% after a 48h exposure to 70 µg/well of FA-HlH-2.Item Characterization of art materials and degradation processes in the exterior wall paintings of the main church of Rila Monastery, Bulgaria(2023-09-01) Stamboliyska B.; Tapanov S.; Kovacheva D.; Atanasova-Vladimirova S.; Ranguelov B.; Yancheva D.; Velcheva E.; Stoyanov S.; Guncheva M.; Fischer D.; Lederer A.The present study focused on the characterization of the art materials and the degradation processes in the exterior (exonarthex) mural paintings of the main church of the Nativity of the Virgin in Rila monastery, Bulgaria, which is believed to be the last large-scale example of Eastern Orthodox wall painting. For the first time the art materials used to create a unique and colourful polychrome decoration of the outer gallery and the possible degradation products, caused by atmospheric influence - permanent exposure to open air and moisture - were revealed by a multi-technique approach. The mineral pigments were identified by means of attenuated total reflectance Fourier transform infrared (ATR-FTIR), micro-Raman spectroscopy, scanning electron microscopy energy dispersive X-ray spectroscopy (SEM-EDS) and X-ray diffraction (XRD). The natural yellow, red ochre, and green earth pigments, as well as some synthetic ones such as ultramarine and vermillion, were found in stable condition. Minium and emerald green pigments showed chemical transformations due to adverse environmental conditions which lead to chromatic changes of wall paintings. Black discolouration occurred due to the conversion of orange minium to black plattnerite (PbO2) and white discolouration – due to its transformation to white lead carbon oxide (PbCO3). The copper acetoarsenite (Cu(CH3COO)2.3Cu(AsO2)2) in the emerald green pigment showed partial transformation to arsen-containing mineral phases clinoclase and lindackerite, which fortunately did not affect much the colour appearance. Gypsum and calcium oxalate were found in the majority of the microsamples as decay products. Analysis of the binders by enzyme-linked immunosorbent assay (ELISA) implied the use of the Orthodox Church post-Byzantine egg-tempera technique. The registered Ca metal oxalates in accordance with ELISA results suggested binder chemical degradation induced by external factors. Most of the used painting materials are close to the those found in other Eastern Orthodox Byzantine and post-Byzantine monuments which indicates that the wall painting decoration of the main church of Rila monastery continues the post-Byzantine traditions. On the other hand, the study showed that the exonarthex wall paintings of the main charge of Rila monastery bear some new features as the religious artists supplemented the colourful scheme by emerald green as a new pigment and replaced smalt by the brighter synthetic ultramarine.Item Characterization of Zahari Zograph’s nave wall paintings in the church “The nativity of the virgin” of Rila Monastery (Bulgaria) by vibrational spectroscopy and SEM–EDX analysis(2017-12-15) Yancheva D.; Tapanov S.; Velcheva E.; Stamboliyska B.; Glavcheva Z.; Stoyanov S.; Haralampiev N.; Fischer D.; Lederer A.An analytical study on the nave mural paintings of the church “The Nativity of the Virgin” of Rila monastery, Bulgaria, painted by Zahari Zograph was carried out. Vibrational spectroscopy was applied to identify the pigments and organic materials used in the mural paintings. To complement the spectral information, elemental composition of the samples was determined by SEM-EDX. The data showed that smalt with carbohydrate binder was applied for the blue background, green colour was executed by green earths and red-orange colour–by red lead. Azurite is the pigment used to paint the blue colour of the saints’ hoods. The mordant for gilding was prepared of drying oil, resin and siccative metal oxides as evidenced by SEM-EDX, ATR-FTIR and pyrolysis GC-MS analysis. The use of azurite is related to Zahari Zograph’s works as it was not found in any of the previously studied murals in the church painted by other artists.Item Crystal structure of 2-{3-[2-(3-ethoxy-4-methoxy-phenyl)-vinyl]-5,5-dimethyl-cyclohex-2-enylidene}-malononitrile, C22H24N2O2(2001-04-01) Kolev T.; Kleb D.C.; Schümann M.; Preut H.; Bleckmann P.; Yancheva D.; Glavcheva Z.C22H24N2O2, monoclinic, P121/n1 (No. 14), a = 7.559(1) Å, b = 19.943(2) Å, c = 12.990(2) Å, β = 93.62(2)°, V= 1954.3 Å3, Z = 4, Rgt(F) = 0.044, wRref(F2) = 0.119, T= 291 K. © 2014 Oldenbourg Wissenschaftsverlag GmbH, Rosenheimer Str. 145, 81671 München. All rights reserved.Item Crystal structure of 3-methoxy-4-hydroxybenzylidene-malononitrile, C11H8N2O2(2001-04-01) Kolev T.; Schürmann M.; Kleb D.; Preut H.; Bleckmann P.; Yancheva D.; Glavcheva Z.C11H8N2O2, monoclinic, P121/n1 (No. 14), a = 4.836(1) Å, b = 13.031 (1) Å, c = 32.408(6) Å, β = 92.82(2)°, V = 2039.6Å3, Z = 8, Rgt(F) = 0.051, wRref(F2) = 0.140, T = 291 K. © 2014, Oldenbourg Wissenschaftsverlag GmbH, Rosenheimer Str. 145, 81671 München. All rights reserved.Item Crystal structure of 4-[(4-N,N-dimethylaminophenylene)amino]-3-ethoxy-3-cyclobutene-1,2-dione, C14H16N2O3(2001-04-01) Kolev T.; Schürmann M.; Kleb D.; Preut H.; Bleckmann P.; Yancheva D.C14H16N2O3, triclinic, P1 (No. 2), a = 6.3066(1) Å, b = 7.5559(2) Å, c = 14.7551(4) À, α = 88.5449(9)°, β = 82.533(I)°, γ = 69.205(1)°, V = 651.6 Å3, Z = 2, Rgt(F) = 0.046, wRref(F2) = 0.134, T = 291 K. © 2014, Oldenbourg Wissenschaftsverlag GmbH, Rosenheimer Str. 145, 81671 München. All rights reserved.Item Crystal structure of 4-benzoylpyridinium-1-squarate, C16H9NO4(2001-04-01) Kolev T.; Kleb D.; Schümann M.; Preut H.; Bleckmann P.; Yancheva D.C16H9NO4, orthorhombic, Pna21 (No. 33), a = 14.671(1) Å, b = 8.1155(9) Å, c= 10.494(1) Å, V= 1249.4 Å3, Z = 4, Rgt(F) = 0.034, wRref(F2) = 0.095, T= 291 K. © 2014 Oldenbourg Wissenschaftsverlag GmbH, Rosenheimer Str. 145, 81671 München. All rights reserved.Item Crystal structure of 4-hydroxy-3-methoxybenzaldehyde-4-nitrophenyl-hydrazone, C14H13N3O4(2001-04-01) Kolev T.; Schürmann M.; Kleb D.; Preut H.; Bleckmann P.; Yancheva D.; Glavcheva Z.C14H13N3O4, monoclinic, P121/n1 (No. 14), a = 12.593(2) Å, b = 6.9910(9) Å, c = 15.765(2) Å, β = 107.661(6)°, V= 1322.5 Å3, Z = 4, Rgt(F) = 0.043, wRref(F2) = 0.096, T = 291 K. © 2014, Oldenbourg Wissenschaftsverlag GmbH, Rosenheimer Str. 145, 81671 München. All rights reserved.Item Crystal structure of cesium 4,6-dinitroresorcinolate, CsC6H3O2(NO3)2(2001-04-01) Kolev T.; Kleb D.; Schümann M.; Preut H.; Bleckmann P.; Yancheva D.C6H3CsN2O6, triclinic, Pī (No. 2), a = 7.114(2) Å, b = 7.572(1) Å, c = 9.314(2) Å, α = 92.18(1)°, β = 111.82(2)°, γ = 107.64(2)°, V = 437.4 Å3, Z = 2, Rgt(F) = 0.019, wRref(F2) = 0.052, T=291 K. © 2014 Oldenbourg Wissenschaftsverlag GmbH, Rosenheimer Str. 145, 81671 München. All rights reserved.Item Design, Cytotoxicity and Antiproliferative Activity of 4-Amino-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylates against MFC-7 and MDA-MB-231 Breast Cancer Cell Lines(2022-05-01) Mavrova A.; Dimov S.; Sulikovska I.; Yancheva D.; Iliev I.; Tsoneva I.; Staneva G.; Nikolova B.Novel 4-amino-thieno[2,3-d]pyrimidine-6-carboxylates substituted at the second position were prepared by cyclocondensation of 2-amino-3-cyano-thiophene and aryl nitriles in an acidic medium. The design of the target compounds was based on structural optimization. The derivatives thus obtained were tested in vitro against human and mouse cell lines. The examination of the compound effects on BLAB 3T3 and MFC-10A cells showed that they are safe, making them suitable for subsequent experiments to establish their antitumor activity. The photoirritancy factor of the compounds was calculated. Using the MTT test, the antiproliferative activity to MCF-10A, MCF-7 and MDA-MB-231 cell lines was estimated. The best antiproliferative effect in respect to the MCF-7 cell line revealed compound 2 with IC50 4.3 ± 0.11 µg/mL (0.013 µM). The highest selective index with respect to MCF-7 cells was shown by compound 3 (SI = 19.3), and to MDA-MB-231 cells by compound 2 (SI = 3.7). Based on energy analysis, the most stable conformers were selected and optimized by means of density functional theory (DFT). Ligand efficiency, ligand lipophilicity efficiency and the physicochemical parameters of the target 4-amino-thienopyrimidines were determined. The data obtained indicated that the lead compound among the tested substances is compound 2.Item Effects on MC3T3-E1 cells and in silico toxicological study of two 6-(propan-2-yl)-4-methyl-morpholine-2,5-diones(2015-08-01) Vukelić-Nikolić M.; Kolarević A.; Tomović K.; Yancheva D.; Cherneva E.; Najman S.; Smelcerović A.Recently, we found that two cyclodidepsipeptides, 3,6-di-(propan-2-yl)-4-methyl-morpholine-2,5-dione (1) and 3-(2-methylpropyl)-6-(propan-2-yl)-4-methylmorpholine-2,5-dione (2), are excellent inhibitors of xanthine oxidase. In order to obtain more information about the toxicological potential of compounds 1 and 2 on bone cells, the current study was designed to evaluate the effect of these compounds on viability and proliferation of MC3T3-E1 cells. Compound 1 showed neither cytotoxic nor stimulatory effect on cell viability, while compound 2 showed a slight stimulatory effect on cell viability. Both studied compounds showed slight stimulatory effects on proliferation of MC3T3-E1 cells, in a dose dependent manner. Additionally, an in silico toxicological study of compounds 1 and 2 was performed, and the results indicate that they have a good probability of safe biological intake.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 Fused Triazinobenzimidazoles Bearing Heterocyclic Moiety: Synthesis, Structure Investigations, and In Silico and In Vitro Biological Activity(2023-07-01) Anichina K.; Georgiev N.; Lumov N.; Vuchev D.; Popova-Daskalova G.; Momekov G.; Cherneva E.; Mihaylova R.; Mavrova A.; Atanasova-Vladimirova S.; Piroeva I.; Yancheva D.[1,3,5]Triazino[1,2-a]benzimidazole-2-amines bearing heterocyclic moiety in 4-position were synthesized. The compounds were characterized by elemental analysis, IR, 1H-NMR, 13C-NMR, and HRMS spectroscopy. The molecular geometry and electron structure of these molecules were theoretically studied using density functional theory (DFT) methods. The molecular structure of the synthesized fused triazinobenzimidazole was confirmed to correspond to the 3,4-dihydrotriazinobenzimidazole structure through the analysis of spectroscopic NMR data and DFT calculations. The antinematodic activity was evaluated in vitro on isolated encapsulated muscle larvae (ML) of Trichinella spiralis. The results showed that the tested triazinobenzimidazoles exhibit significantly higher efficiency than the conventional drug used to treat trichinosis, albendazole, at a concentration of 50 μg/mL. The compound 3c substituted with a thiophen-2-yl moiety exhibited the highest anthelmintic activity, with a larvicidal effect of 58.41% at a concentration of 50 μg/mL after 24 h of incubation. Following closely behind, the pyrrole analog 3f demonstrated 49.90% effectiveness at the same concentration. The preliminary structure-anti-T. spiralis activity relationship (SAR) of the analogues in the series was discussed. The cytotoxicity of the benzimidazole derivatives against two normal fibroblast cells (3T3 and CCL-1) and two cancer human cell lines (MCF-7 breast cancer cells and chronic myeloid leukemia cells AR-230) was evaluated using the MTT-dye reduction assay. The screening results indicated that the compounds showed no cytotoxicity against the tested cell lines. An in silico study of the physicochemical and pharmacokinetic characteristics of the novel synthesized fused triazinobenzimidazoles showed that they were characterized by a significant degree of drug-likeness and optimal properties for anthelmintic agents.Item Fused Triazinobenzimidazoles Bearing Heterocyclic Moiety: Synthesis, Structure Investigations, and In Silico and In Vitro Biological Activity(2023-07-01) Anichina K.; Georgiev N.; Lumov N.; Vuchev D.; Popova-Daskalova G.; Momekov G.; Cherneva E.; Mihaylova R.; Mavrova A.; Atanasova-Vladimirova S.; Piroeva I.; Yancheva D.[1,3,5]Triazino[1,2-a]benzimidazole-2-amines bearing heterocyclic moiety in 4-position were synthesized. The compounds were characterized by elemental analysis, IR, 1H-NMR, 13C-NMR, and HRMS spectroscopy. The molecular geometry and electron structure of these molecules were theoretically studied using density functional theory (DFT) methods. The molecular structure of the synthesized fused triazinobenzimidazole was confirmed to correspond to the 3,4-dihydrotriazinobenzimidazole structure through the analysis of spectroscopic NMR data and DFT calculations. The antinematodic activity was evaluated in vitro on isolated encapsulated muscle larvae (ML) of Trichinella spiralis. The results showed that the tested triazinobenzimidazoles exhibit significantly higher efficiency than the conventional drug used to treat trichinosis, albendazole, at a concentration of 50 μg/mL. The compound 3c substituted with a thiophen-2-yl moiety exhibited the highest anthelmintic activity, with a larvicidal effect of 58.41% at a concentration of 50 μg/mL after 24 h of incubation. Following closely behind, the pyrrole analog 3f demonstrated 49.90% effectiveness at the same concentration. The preliminary structure-anti-T. spiralis activity relationship (SAR) of the analogues in the series was discussed. The cytotoxicity of the benzimidazole derivatives against two normal fibroblast cells (3T3 and CCL-1) and two cancer human cell lines (MCF-7 breast cancer cells and chronic myeloid leukemia cells AR-230) was evaluated using the MTT-dye reduction assay. The screening results indicated that the compounds showed no cytotoxicity against the tested cell lines. An in silico study of the physicochemical and pharmacokinetic characteristics of the novel synthesized fused triazinobenzimidazoles showed that they were characterized by a significant degree of drug-likeness and optimal properties for anthelmintic agents.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 In vitro antioxidant properties of 2-imino-benzimidazole and 1,3-thiazolo[3,2-a]benzimidazolone derivatives Antioksidativna aktivnost 2-imino-benzimidazol i 1,3-tiazolo[3,2-a]benzimidazolon derivata: In vitro studija(2020-01-01) Tomović K.; Mrmošanin J.; Yancheva D.; Mavrova A.T.; Šmelcerović A.Antioxidant properties of 2-[2-imino-5-nitro-3-(2-oxo-2-phenylethyl)-2,3-dihydro-1H-benzimidazol-1-yl]-1-phenylethanone (compound 1) and 2-(4-fluorobenzylidene)-6-(phenylcarbonyl)[1,3]thiazolo[3,2-a]benzimidazol-3(2H)-one (compound 2) were evaluated in vitro. Compounds 1 and 2 did not show significant radical scavenging activity. It has been suggested that antioxidant strategies should not be based on direct scavengers but rather on the potentiation of endogenous antioxidant defenses, or on the reduction of the sources of reactive species. Although a direct scavenging mechanism is missing, the assayed compounds (1 and 2) as evidenced inhibitors of xanthine oxidase and dipeptidyl peptidase-4 might act antioxidatively by employing other mechanisms.