Browsing by Author "Vuchev D."
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Item Benzimidazoles Containing Piperazine Skeleton at C-2 Position as Promising Tubulin Modulators with Anthelmintic and Antineoplastic Activity(2023-11-01) Anichina K.; Mavrova A.; Vuchev D.; Popova-Daskalova G.; Bassi G.; Rossi A.; Montesi M.; Panseri S.; Fratev F.; Naydenova E.Benzimidazole anthelmintic drugs hold promise for repurposing as cancer treatments due to their interference with tubulin polymerization and depolymerization, manifesting anticancer properties. We explored the potential of benzimidazole compounds with a piperazine fragment at C-2 as tubulin-targeting agents. In particular, we assessed their anthelmintic activity against isolated Trichinella spiralis muscle larvae and their effects on glioblastoma (U-87 MG) and breast cancer (MDA-MB-231) cell lines. Compound 7c demonstrated exceptional anthelmintic efficacy, achieving a 92.7% reduction in parasite activity at 100 μg/mL after 48 hours. In vitro cytotoxicity analysis of MDA-MB 231 and U87 MG cell lines showed that derivatives 7b, 7d, and 7c displayed lower IC50 values compared to albendazole (ABZ), the control. These piperazine benzimidazoles effectively reduced cell migration in both cell lines, with compound 7c exhibiting the most significant reduction, making it a promising candidate for further study. The binding mode of the most promising compound 7c, was determined using the induced fit docking–molecular dynamics (IFD–MD) approach. Regular docking and IFD were also employed for comparison. The IFD–MD analysis revealed that 7c binds to tubulin in a unique binding cavity near that of ABZ, but the benzimidazole ring was fitted much deeper into the binding pocket. Finally, the absolute free energy of perturbation technique was applied to evaluate the 7c binding affinity, further confirming the observed binding mode.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 Тreatment of hepatic and pulmonary hydatidosis with albendazole and praziquantel(2023-09-01) Popova G.; Vuchev D.; Anichina K.Conservative treatment of human hydatidosis (cystic echinococcosis) with albendazole has improved significantly the prognosis of the disease. But its therapeutic effectiveness is 30 – 70 %. Тhere is some evidence that the effectiveness of albendazole can be enhanced by praziquantel but there is no strict recommendation for the use of praziquantel as part of long-term drug therapy for hydatidosis. The aim of the study was to evaluate the effectiveness of the combination of albendazole and praziquantel in patients with hepatic and/or pulmonary hydatidosis. A total of 20 patients (aged 12 – 70 years old) were included in the study for a 5-year period. Fourteen patients (70 %) were with hepatic hydatidosis, 4 (20 %) with pulmonary and 2 (10 %) with hepatic and pulmonary hydatidosis. They were treated with albendazole (15 mg/kg/day) and praziquantel (40 mg/kg/weekly) for 2 – 9 one-month courses. The result of the therapy was followed using imaging (abdominal ultrasound, lung radiography, computed tomography) and serology. Seventeen (85 %) out of 20 patients showed evidence of response on imaging defined as improvement or cure of hydatid cysts. Seven (35 %) of the patients with multiple cystic echinococcosis took praziquantel once a week for 6 months. Only 3 patients (15 %) with multiple hydatidosis (2 with liver and 1 with pulmonary hydatidosis) failed to respond to the therapy with both drugs. No side effects have been reported by the patients. The combination of albendazole and praziquantel seems to be an option to improve the therapeutic effеctiveness of the conservative treatment of cystic echinococcosis.