RESUMO
This work presents the design, synthesis and biological activity of novel N-substituted benzimidazole carboxamides bearing either a variable number of methoxy and/or hydroxy groups. The targeted carboxamides were designed to investigate the influence of the number of methoxy and/or hydroxy groups, the type of substituent placed on the N atom of the benzimidazole core and the type of substituent placed on the benzimidazole core on biological activity. The most promising derivatives with pronounced antiproliferative activity proved to be N-methyl-substituted derivatives with hydroxyl and methoxy groups at the phenyl ring and cyano groups on the benzimidazole nuclei with selective activity against the MCF-7 cell line (IC50 = 3.1 µM). In addition, the cyano-substituted derivatives 10 and 11 showed strong antiproliferative activity against the tested cells (IC50 = 1.2-5.3 µM). Several tested compounds showed significantly improved antioxidative activity in all three methods compared to standard BHT. In addition, the antioxidative activity of 9, 10, 32 and 36 in the cells generally confirmed their antioxidant ability demonstrated in vitro. However, their antiproliferative activity was not related to their ability to inhibit oxidative stress nor to their ability to induce it. Compound 8 with two hydroxy and one methoxy group on the phenyl ring showed the strongest antibacterial activity against the Gram-positive strain E. faecalis (MIC = 8 µM).
Assuntos
Antineoplásicos , Antioxidantes , Benzimidazóis , Proliferação de Células , Desenho de Fármacos , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/síntese química , Humanos , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Células MCF-7 , Antioxidantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Relação Estrutura-Atividade , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Amidas/química , Amidas/farmacologia , Amidas/síntese química , Estrutura Molecular , Testes de Sensibilidade Microbiana , Estresse Oxidativo/efeitos dos fármacosRESUMO
Continuing our research into the anticancer properties of acrylonitriles, we present a study involving the design, synthesis, computational analysis, and biological assessment of novel acrylonitriles derived from methoxy, hydroxy, and N-substituted benzazole. Our aim was to examine how varying the number of methoxy and hydroxy groups, as well as the N-substituents on the benzimidazole core, influences their biological activity. The newly synthesized acrylonitriles exhibited strong and selective antiproliferative effects against the Capan-1 pancreatic adenocarcinoma cell line, with IC50 values ranging from 1.2 to 5.3 µM. Consequently, these compounds were further evaluated in three other pancreatic adenocarcinoma cell lines, while their impact on normal PBMC cells was also investigated to determine selectivity. Among these compounds, the monohydroxy-substituted benzimidazole derivative 27 emerged with the most profound and broad-spectrum anticancer antiproliferative activity being emerged as a promising lead candidate. Moreover, a majority of the acrylonitriles in this series exhibited significant antioxidative activity, surpassing that of the reference molecule BHT, as demonstrated by the FRAP assay (ranging from 3200 to 5235 mmolFe2+/mmolC). Computational analysis highlighted the prevalence of electron ionization in conferring antioxidant properties, with computed ionization energies correlating well with observed activities.
Assuntos
Acrilonitrila , Antineoplásicos , Antioxidantes , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Pancreáticas , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Humanos , Acrilonitrila/química , Acrilonitrila/farmacologia , Acrilonitrila/análogos & derivados , Acrilonitrila/síntese química , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Relação Estrutura-Atividade , Estrutura Molecular , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/síntese química , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/síntese químicaRESUMO
Aim: The aim was synthesis of novel benzazoles bearing amidino and 2-hydroxyphenyl substituents to explore their biological activity. Methods: Condensation of 5-substituted salicylaldehydes and intermediates gave new benzazoles by previously published and developed procedures, which were tested for antibacterial and antiproliferative activity in vitro. Results: The best antibacterial activity showed benzimidazole with 2-imidazolinyl group 27 and benzothiazole with an unsubstituted amidine 48 (minimum inhibitory concentration 8 µg/ml). Benzothiazole 53 proved most potent at inhibiting proliferation of all cancer cells (IC50: 1.2-2.0 µM). Conclusion: Most active compounds have been recognized as lead compounds for additional optimization to improve their biological activity. The type of amidine moiety markedly influenced the biological activity. Benzothiazoles showed improved antiproliferative activity in comparison to benzimidazoles.
RESUMO
Herein we present the design and the synthesis of novel substituted coumarin-benzimidazole/benzothiazole hybrids bearing a cyclic amidino group on the benzazole core as biologically active agents. All prepared compounds were evaluated for their in vitro antiviral and antioxidative activity as well as for their in vitro antiproliferative activity against a panel of several human cancer cell lines. Coumarin-benzimidazole hybrid 10 (EC50 9.0-43.8 µM) displayed the most promising broad spectrum antiviral activity, while two other coumarin-benzimidazole hybrids 13 and 14 showed the highest antioxidative capacity in the ABTS assay, superior to the reference standard BHT (IC50 0.17 and 0.11 mM, respectively). Computational analysis supported these results and demonstrated that these hybrids benefit from the high C-H hydrogen atom releasing tendency of the cationic amidine unit, and the pronounced ease with which they can liberate an electron, promoted by the electron-donating diethylamine group on the coumarin core. The coumarin ring substitution at position 7 with a N,N-diethylamino group also caused a significant enhancement of the antiproliferative activity, with the most active compounds being derivatives with a 2-imidazolinyl amidine group 13 (IC50 0.3-1.9 µM) and benzothiazole derivative with a hexacyclic amidine group 18 (IC50 1.3-2.0 µM).
RESUMO
Herein, we present the design and synthesis of novel N-substituted benzimidazole-derived Schiff bases, and the evaluation of their antiviral, antibacterial, and antiproliferative activity. The impact on the biological activity of substituents placed at the N atom of the benzimidazole nuclei and the type of substituents attached at the phenyl ring were examined. All of the synthesized Schiff bases were evaluated in vitro for their antiviral activity against different viruses, antibacterial activity against a panel of bacterial strains, and antiproliferative activity on several human cancer cell lines, thus enabling the study of the structure-activity relationships. Some mild antiviral effects were noted, although at higher concentrations in comparison with the included reference drugs. Additionally, some derivatives showed a moderate antibacterial activity, with precursor 23 being broadly active against most of the tested bacterial strains. Lastly, Schiff base 40, a 4-N,N-diethylamino-2-hydroxy-substituted derivative bearing a phenyl ring at the N atom on the benzimidazole nuclei, displayed a strong antiproliferative activity against several cancer cell lines (IC50 1.1-4.4 µM). The strongest antitumoral effect was observed towards acute myeloid leukemia (HL-60).
Assuntos
Antineoplásicos , Humanos , Antineoplásicos/farmacologia , Bases de Schiff/farmacologia , Proliferação de Células , Relação Estrutura-Atividade , Benzimidazóis/farmacologia , Antivirais/farmacologiaRESUMO
As a result of our previous research focussed on benzimidazoles, herein we present design, synthesis, QSAR analysis and biological activity of novel N-substituted benzimidazole derived carboxamides. Carboxamides were designed to study the influence of the number of methoxy groups, the type of the substituent placed at the benzimidazole core on biological activity. Pronounced antioxidative activity displayed unsubstituted 28 (IC50 ≈ 3.78 mM, 538.81 mmolFe2+/mmolC) and dimethoxy substituted derivative 34 (IC50 ≈ 5.68 mM, 618.10 mmolFe2+/mmolC). Trimethoxy substituted 43 and unsubstituted compound 40 with isobutyl side chain at N atom showed strong activity against HCT116 (IC50 ≈ 0.6 µM, both) and H 460 cells (IC50 ≈ 2.5 µM; 0.4 µM), being less cytotoxic towards non-tumour cell. Antioxidative activity in cell generally confirmed relatively modest antioxidant capacity obtained in DPPH/FRAP assays of derivatives 34 and 40. The 3D-QSAR models were generated to explore molecular properties that have the highest influence on antioxidative activity.
Assuntos
Antineoplásicos , Relação Quantitativa Estrutura-Atividade , Antineoplásicos/química , Antioxidantes/química , Antioxidantes/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-AtividadeRESUMO
We used classical linear and microwave-assisted synthesis methods to prepare novel N-substituted, benzimidazole-derived acrylonitriles with antiproliferative activity against several cancer cells in vitro. The most potent systems showed pronounced activity against all tested hematological cancer cell lines, with favorable selectivity towards normal cells. The selection of lead compounds was also tested in vitro for tubulin polymerization inhibition as a possible mechanism of biological action. A combination of docking and molecular dynamics simulations confirmed the suitability of the employed organic skeleton for the design of antitumor drugs and demonstrated that their biological activity relies on binding to the colchicine binding site in tubulin. In addition, it also underlined that higher tubulin affinities are linked with (i) bulkier alkyl and aryl moieties on the benzimidazole nitrogen and (ii) electron-donating substituents on the phenyl group that allow deeper entrance into the hydrophobic pocket within the tubulin's ß-subunit, consisting of Leu255, Leu248, Met259, Ala354, and Ile378 residues.