Browsing by Author "Mavrova A.T."

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    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.
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    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.
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    In vitro Assessment of the Lipid Peroxidation of N,N'-Disubstituted Benzimidazole-2-Thiones: Hydrazides vs Esters
    (2022-01-01) Lazarević J.; Zvezdanović J.; Anastassova N.; Mavrova A.T.; Yancheva D.; Šmelcerović A.
    Introduction: Oxidative stress and resulting lipid peroxidation are involved in numerous pathological conditions. For this reason, the role of antioxidants attracts attention and the radical-scavenging capacity of many natural and synthetic supplements and drugs has been extensively evaluated. Material and methods: In the present study, seven N,N'-disubstituted benzimidazole-2-thiones with ester (1 - 4) and hydrazide (5 - 7) side chains were investigated for in vitro antioxidant activity using lipid peroxidation method. Results: Among the assayed compounds, three hydrazides, 1,3-bis[3-(hydrazinooxy)-3-oxopropyl]-1,3- dihydro-2H-benzimidazole-2-thione (5), 1,3-bis[3-(hydrazinooxy)-3-oxopropyl]-5-methyl-1,3-dihydro-2Hbenzimidazole- 2-thione (6) and 1,3-bis[3-(hydrazinooxy)-3-oxopropyl]-5-benzoyl-1,3-dihydro-2Hbenzimidazole- 2-thione (7) showed good antioxidant properties (IC50 < 100 μM), with the best lipid peroxidation inhibition values (IC50) shown for compound 5 (64 ± 10 μM) and compound 6 (73 ± 29 μM). Conclusion: Indicated hydrazide structures may constitute a sort of molecular basis, a promising starting point for the development of compounds for the prevention and treatment of diseases resulting from oxidative damage.
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    New C2-and N3-Modified Thieno[2,3-d]Pyrimidine Conjugates with Cytotoxicity in the Nanomolar Range
    (2022-04-01) Mavrova A.T.; Dimov S.; Yancheva D.; Rangelov M.; Wesselinova D.; Naydenova E.
    Aims: The aim of the current study was to develop and explore a series of new cytotoxic agents based on the conjugation between the thieno[2,3-d]pyrimidine moiety and a second pharmacophore at the C2 or N3 position. Background: As the thieno[2,3-d]pyrimidine core is a bioisostere of the 4-anilinoquinazoline, various new thienopyrimidine derivatives were synthesized by modifying the structure of the clinically used anticancer quinazoline EGFR inhibitors of the first generation – gefitinib, and second-generation – dacomitinib and canertinib. It was reported that some thieno[2,3-d]pyrimidine derivatives showed improved EGFR inhibitory activity. On the other hand, the benzimidazole heterocycle is present as a pharmacophore unit in the structure of many clinically used chemotherapeutic agents. Some 2-aminobenzimidazole derivatives, possessing anticancer activity, demonstrated EGFR inhibition and the benzimidazole derivative EGF816 is currently in the second phase of clinical trials. Objective: The objectives of the study were the design of a novel series thieno[2,3-d]pyrimidines, synthesis of the compounds and investigation of their effects towards human cancer HT-29, MDA-MB-231, HeLa, HepG2 and to normal human Lep3 cell lines. (American Type Culture Collection, ATCC, Rockville, MD, USA). Methods: The synthetic protocol implemented cyclocondensation of 2-amino-thiophenes and nitriles in an inert medium, azaMichael addition to benzimidazole derivatives and nucleophylic substitution at the N3 place. MTS test was used in order to establish the cytotoxicity of the tested compounds. SAR analysis and in silico assessment of the inhibitory potential towards human oncogenicV599EB-Raf were performed using Molinspiration tool and Molecular Operating environment software. Results: The MTS test data showed that almost all studied thieno[2,3-d]pyirimidines (9-13, 21-22 and 25) manifest high inhibitory effect on cell proliferation at nanomolar concentrations, whereas compounds 9 (IC50 = 130 nM) and 10 (IC50 = 261 nM) containing amino acid moiety, and 21 (IC50 = 108 nM) possessing two thienopyrimidine moieties attached to a 1,3-disubstituted benzimidazole linker, revealed many times lower toxicity against Lep3 cells compared to the cancer cells. Thienopyrimidines 11-13 possessed high selectivity against HeLa cells. Compound 13 showed high inhibitory activity against MDA-MB-231 and HepG2, with IC50 1.44 nM and 1.11 nM respectively. To outline the possible biological target of the studied coumpounds, their potential to interact with human oncogenicV599EB-Raf was explored by a docking study. As a result, it was suggested that the benzimidazolyl and glycyl fragments could enhance the binding ability of the new compounds by increasing the number of hydrogen bond acceptors and by stabilizing the inactive form of the enzyme. Conclusion: The thienopyrimidines tested in vitro for human cancer HT-29, MDA-MB-231, HeLa, HepG2 and normal human Lep3 cell lines demonstrated cytotoxicity in the nanomolar range. It was established that compounds 9, 10 and 21 showed many times lower toxicity against normal Lep3 cells that can provide a high selectivity towards all four cancer cell lines at small concentrations. Based on the analysis of the structure-activity relationship, the observed trends in the cytotoxicity could be related to the lipophilicity and the topological polar surface area of the tested compounds. The docking study on the potential of the new thieno[2,3-d]pyrimidine-4-ones to interact with mutantV599EB-Raf showed that the compounds might be able to stabilize the enzyme in its inactive form.