Browsing by Author "Anichina K."
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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 DEVELOPMENT OF BENZIMIDAZOLE DERIVATIVES AS NON-NUCLEOSIDE HIV-1 REVERSE TRANSCRIPTASE INHIBITORS (REVIEW)(2022-01-01) Anichina K.; Mavrova A.The benzimidazole heterocycle system is a very important structure in the medicinal chemistry due to its use as a building block of a wide range of bioactive compounds. This review highlights the progress of the synthesis and the optimization of benzimidazole compounds as Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) against Human Immunodeficiency Virus Type 1 (HIV-1). Since the discovery of NSC 625487 (1-(2’,6’-difluorophenyl)-lH,3H-thiazolo[3,4-a]benzimidazole) as potential anti-retroviral drug candidate, three structural subclasses of benzimidazole HIV-1 NNRTIs in the groups of 1H,3H-thiazolo[3,4-a]benzimidazoles, 2-aryl-1-benzylbenzimidazoles and 1,3-dihydro-benzimidazol-2-ones/2-thione were synthesized and studied up to now. In the current review we report their structural modifications in chronological order and discuss the structure-activity relationship (SAR) to demonstrate the sequential progress in this area. Thus, this study may contribute to the further development and synthesis of novel representatives of the benzimidazole family as anti-HIV-1 agents in the future.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 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 Novel Fluorescent Benzimidazole-Hydrazone-Loaded Micellar Carriers for Controlled Release: Impact on Cell Toxicity, Nuclear and Microtubule Alterations in Breast Cancer Cells(2023-06-01) Bryaskova R.; Georgiev N.; Philipova N.; Bakov V.; Anichina K.; Argirova M.; Apostolova S.; Georgieva I.; Tzoneva R.Fluorescent micellar carriers with controlled release of a novel anticancer drug were developed to enable intracellular imaging and cancer treatment simultaneously. The nanosized fluorescent micellar systems were embedded with a novel anticancer drug via the self-assembling behavior of well-defined block copolymers based on amphiphilic poly(acrylic acid)-block-poly(n-butyl acrylate) (PAA-b-PnBA) copolymer obtained by Atom Transfer Radical Polymerization (ATRP) and hydrophobic anticancer benzimidazole-hydrazone drug (BzH). Through this method, well-defined nanosized fluorescent micelles were obtained consisting of a hydrophilic PAA shell and a hydrophobic PnBA core embedded with the BzH drug due to the hydrophobic interactions, thus reaching very high encapsulation efficiency. The size, morphology, and fluorescent properties of blank and drug-loaded micelles were investigated using dynamic light scattering (DLS), transmission electron microscopy (TEM), and fluorescent spectroscopy, respectively. Additionally, after 72 h of incubation, drug-loaded micelles released 3.25 μM of BzH, which was spectrophotometrically determined. The BzH drug-loaded micelles were found to exhibit enhanced antiproliferative and cytotoxic effects on MDA-MB-231 cells, with long-lasting effects on microtubule organization, with apoptotic alterations and preferential localization in the perinuclear space of cancer cells. In contrast, the antitumor effect of BzH alone or incorporated in micelles on non-cancerous cells MCF-10A was relatively weak.Item Recent Advances in the Application of Nitro(het)aromatic Compounds for Treating and/or Fluorescent Imaging of Tumor Hypoxia(2024-08-01) Anichina K.; Lumov N.; Bakov V.; Yancheva D.; Georgiev N.This review delves into recent advancements in the field of nitro(het)aromatic bioreductive agents tailored for hypoxic environments. These compounds are designed to exploit the low-oxygen conditions typically found in solid tumors, making them promising candidates for targeted cancer therapies. Initially, this review focused on their role as gene-directed enzyme prodrugs, which are inert until activated by specific enzymes within tumor cells. Upon activation, these prodrugs undergo chemical transformations that convert them into potent cytotoxic agents, selectively targeting cancerous tissue while sparing healthy cells. Additionally, this review discusses recent developments in prodrug conjugates containing nitro(het)aromatic moieties, designed to activate under low-oxygen conditions within tumors. This approach enhances their efficacy and specificity in cancer treatment. Furthermore, this review covers innovative research on using nitro(het)aromatic compounds as fluorescent probes for imaging hypoxic tumors. These probes enable non-invasive visualization of low-oxygen regions within tumors, providing valuable insights for the diagnosis, treatment planning, and monitoring of therapeutic responses. We hope this review will inspire researchers to design and synthesize improved compounds for selective cancer treatment and early diagnostics.Item Self-Assembled Molecular Complexes of 1,10-Phenanthroline and 2-Aminobenzimidazoles: Synthesis, Structure Investigations, and Cytotoxic Properties(2024-02-01) Anichina K.; Kaloyanov N.; Zasheva D.; Rusew R.; Nikolova R.; Yancheva D.; Bakov V.; Georgiev N.Three new molecular complexes (phen)3(2-amino-Bz)2(H+)(BF4−)·3H2O 5, (phen)3(2-amino-5(6)-methyl-Bz)2(H+)(BF4−)·H2O 6, and (phen)(1-methyl-2-amino-Bz)(H+)(BF4−) 7, were prepared by self-assembly of 1,10-phenanthroline (phen) and various substituted 2-aminobenzimidazoles. Confirmation of their structures was established through spectroscopic methods and elemental analysis. The X-ray diffraction analysis revealed that the crystal structure of 7 is stabilized by the formation of hydrogen bonds and short contacts. In addition, the molecular geometry and electron structure of molecules 5 and 6 were theoretically evaluated using density functional theory (DFT) methods. According to the DFT B3LYP/6-311+G* calculations, the protonated benzimidazole (Bz) units act as NH hydrogen bond donors, binding two phenanthrolines and a BF4− ion. Non-protonated Bz unit form hydrogen bonds with the N-atoms of a third molecule phen. The molecular assembly is held together by π-π stacking between benzimidazole and phenanthroline rings, allowing for N-atoms to associate with water molecules. The complexes were tested in vitro for their tumor cell growth inhibitory effects on prostate (PC3), breast (MDA-MB-231 and MCF-7), and cervical (HeLa) cancer cell lines using MTT-dye reduction assay. The in vitro cytotoxicity analysis and spectrophotometric investigation in the presence of ct-DNA, showed that self-assembled molecules 5–7 are promising DNA-binding anticancer agents warranting further in-depth exploration.Item Synthesis of some novel 2-substituted-[1,3]thiazolo[3,2-a]benzimidazol-3(2h)-ones as potent cytostatic agents(2016-01-01) Mavrova A.; Wesselinova D.; Anichina K.An optimized method for the synthesis of new 2-substituted-thiazolo[2,3-a]benzimidazole-3(2H)-ones was developed which enabled the target compounds to be obtained in relative good yields through one pot process.Four cancer cell lines: human colorectal cancer cell line HT-29, breast cancer cells MDA-MB-231, cervical cancer cells HeLa, human liver carcinoma cell line HepG2 and human diploid cell line Lep-3 were used to estimate the effects of the newly synthesized compounds on cell proliferation. The initial biological screening in vitro, using MTS tetrazolium assay showed that the tested thiazolobenzimidazolones (compounds 7 and 11) demonstrated selective cytotoxicity against HT-29 cells (IC50 - 3.5.10-2 μM and IC50 - 5.0.10-2 μM, respectively), while compound 9 manifested selective cytotoxicity against Hep G2. Beside that the compounds 9 and 11 induced proliferation activity towards Lep3 cells at extremely low concentrations. EC50 values were 3.4.10-2 μM and 1.410-2 μM, correspondingly. The activity results towards HT-29 and Hep G2 cells indicated the necessity for further investigation in vivo to estimate the exact inhibition pathway of the cellular processes.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.