RESUMEN
Newly synthesized 7-chloro-4-aminoquinoline-benzimidazole hybrids were characterized by NMR and elemental analysis. Compounds were tested for their effects on the growth of the non-tumor cell line MRC-5 (human fetal lung fibroblasts) and carcinoma (HeLa and CaCo-2), leukemia, and lymphoma (Hut78, THP-1, and HL-60) cell lines. The obtained results, expressed as the concentration at which 50% inhibition of cell growth is achieved (IC50 value), show that the tested compounds affect cell growth differently depending on the cell line and the applied dose (IC50 ranged from 0.2 to >100 µM). Also, the antiplasmodial activity of these hybrids was evaluated against two P. falciparum strains (Pf3D7 and PfDd2). The tested compounds showed potent antiplasmodial activity, against both strains, at nanomolar concentrations. Quantitative structure-activity relationship (QSAR) analysis resulted in predictive models for antiplasmodial activity against the 3D7 strain (R2 = 0.886; Rext2 = 0.937; F = 41.589) and Dd2 strain (R2 = 0.859; Rext2 = 0.878; F = 32.525) of P. falciparum. QSAR models identified the structural features of these favorable effects on antiplasmodial activities.
Asunto(s)
Antimaláricos , Antineoplásicos , Bencimidazoles , Diseño de Fármacos , Plasmodium falciparum , Relación Estructura-Actividad Cuantitativa , Humanos , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/síntesis química , Antimaláricos/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/crecimiento & desarrollo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinolinas/química , Quinolinas/farmacología , Quinolinas/síntesis química , Estructura Molecular , AminoquinolinasRESUMEN
The newly synthesized quinoline-benzimidazole hybrids containing two types of triazole-methyl-phenoxy linkers were characterized via NMR and elemental analysis. Additional derivatization was achieved by introducing bromine at the C-2 position of the phenoxy core. These novel hybrids were tested for their effects on the growth of the non-tumor cell line MRC-5 (human fetal lung fibroblasts), leukemia and lymphoma cell lines: Hut78, THP-1 and HL-60, and carcinoma cell lines: HeLa and CaCo-2. The results obtained, presented as the concentration that achieves 50% inhibition of cell growth (IC50 value), show that the compounds tested affect tumor cell growth differently depending on the cell line and the dose applied (IC50 ranged from 0.2 to >100 µM). The quinoline-benzimidazole hybrids tested, including 7-chloro-4-(4-{[4-(5-methoxy-1H-1,3-benzo[d]imidazol-2-yl)phenoxy]methyl}-1H-1,2,3-triazol-1-yl)quinoline 9c, 2-(3-bromo-4-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride 10e, 2-{4-[(1-{2-[(7-chloroquinolin-4-yl)amino]ethyl}-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride 14e and 2-{3-bromo-4-[(1-{2-[(7-chloroquinolin-4-yl)amino]ethyl}-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride 15e, arrested the cell cycle of lymphoma (HuT78) cells. The calculated ADMET properties showed that the synthesized compounds violated at most two of Lipinski's rules, making them potential drug candidates, but mainly for parenteral use due to low gastrointestinal absorption. The quinoline-benzimidazole hybrid 14e, which was shown to be a potent and selective inhibitor of lymphoma cell line growth, obtained the highest binding energy (-140.44 kcal/mol), by docking to the TAO2 kinase domain (PDB: 2GCD).
Asunto(s)
Linfoma , Quinolinas , Humanos , Triazoles/química , Relación Estructura-Actividad , Células CACO-2 , Quinolinas/farmacología , Quinolinas/química , Bencimidazoles/química , Simulación del Acoplamiento MolecularRESUMEN
In this study, new 7-chloro-4-aminoquinoline-benzimidazole compounds were synthesized and characterized by NMR, MS, and elemental analysis. These novel hybrids differ in the type of linker and in the substituent on the benzimidazole moiety. Their antiproliferative activities were evaluated on one non-tumor (MDCK1) and seven selected tumor (CaCo-2, MCF-7, CCRF-CEM, Hut78, THP-1, and Raji) cell lines by MTT test and flow cytometry analysis. The compounds with different types of linkers and an unsubstituted benzimidazole ring, 5d, 8d, and 12d, showed strong cytotoxic activity (the GI50 ranged from 0.4 to 8 µM) and effectively suppressed the cell cycle progression in the leukemia and lymphoma cells. After 24 h of treatment, compounds 5d and 12d induced the disruption of the mitochondrial membrane potential as well as apoptosis in HuT78 cells. The drug-like properties and bioavailability of the compounds were calculated using the Swiss ADME web tool, and a molecular docking study was performed on tyrosine-protein kinase c-Src (PDB: 3G6H). Compound 12d showed good solubility and permeability and bound to c-Src with an energy of -119.99 kcal/mol, forming hydrogen bonds with Glu310 and Asp404 in the active site and other residues with van der Waals interactions. The results suggest that compound 12d could be a leading compound in the further design of effective antitumor drugs.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Estructura Molecular , Relación Estructura-Actividad , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Células CACO-2 , Proliferación Celular , Antineoplásicos/química , Bencimidazoles/química , Ensayos de Selección de Medicamentos Antitumorales , ApoptosisRESUMEN
Trypanosoma cruzi is a hemoflagellated parasite causing Chagas disease, which affects 6-8 million people in the Americas. More than one hundred years after the description of this disease, the available drugs for treating the T. cruzi infection remain largely unsatisfactory. Chloroquinoline and arylamidine moieties are separately found in various compounds reported for their anti-trypanosoma activities. In this work we evaluate the anti-T. cruzi activity of a collection of 26 "chimeric" molecules combining choroquinoline and amidine structures. In a first screening using epimastigote forms of the parasite as a proxy for the clinically relevant stages, we selected the compound 7-chloro-4-[4-(4,5-dihydro-1H-imidazol-2-yl)phenoxy]quinoline (named here as A6) that performed better as an anti-T. cruzi compound (IC50 of 2.2 ± 0.3 µM) and showed a low toxicity for the mammalian cell CHO-K1 (CC50 of 137.9 ± 17.3 µM). We initially investigated the mechanism of death associated to the selected compound. The A6 did not trigger phosphatidylserine exposure or plasma membrane permeabilization. Further investigation led us to observe that under short-term incubations (until 6 hours), no alterations of mitochondrial function were observed. However, at longer incubation times (4 days), A6 was able to decrease the intracellular Ca2+, to diminish the intracellular ATP levels, and to collapse mitochondrial inner membrane potential. After analysing the cell cycle, we found as well that A6 produced an arrest in the S phase that impairs the parasite proliferation. Finally, A6 was effective against the infective forms of the parasite during the infection of the mammalian host cells at a nanomolar concentration (IC50(tryps) = 26.7 ± 3.7 nM), exhibiting a selectivity index (SI) of 5,170. Our data suggest that A6 is a promising hit against T. cruzi.
Asunto(s)
Puntos de Control del Ciclo Celular/efectos de los fármacos , Enfermedad de Chagas/parasitología , Imidazolinas/química , Imidazolinas/farmacología , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Interacciones Huésped-Parásitos/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estructura Molecular , Trypanosoma cruzi/fisiologíaRESUMEN
Novel imidazoline benzimidazole derivatives containing diversely substituted phenoxy moieties were synthesized with the aim of evaluating their antitrypanosomal activity, DNA/RNA binding affinity and in vitro ADME properties. The presence of the diethylaminoethyl subunit in 18a-18c led to enhanced antitrypanosomal potency, particularly for 18a and 18c, which contain unsubstituted and methoxy-substituted phenoxy moieties. They were found to be > 2-fold more potent against African trypanosomes than nifurtimox. Fluorescence and CD spectroscopy, thermal denaturation assays and computational analysis indicated a preference of 18a-18c toward AT-rich DNA and their minor groove binding mode. Replacement of the amidine group with less basic and ionisable nitrogen-containing moieties failed to improve membrane permeability of the investigated compounds. Due to structural diversification, the compounds displayed a range of physico-chemical features resulting in variable in vitro ADME properties, leaving space for further optimization of the biological profiles.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , ADN/metabolismo , Diseño de Fármacos , Imidazolinas/química , ARN/metabolismo , Trypanosoma/efectos de los fármacos , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Antiprotozoarios/metabolismo , Antiprotozoarios/farmacología , Bencimidazoles/química , Bencimidazoles/metabolismo , Técnicas de Química SintéticaRESUMEN
Amidinobenzimidazole derivatives connected to 1-aryl-substituted 1,2,3-triazole through phenoxymethylene linkers 7a-7e, 8a-8e, and 9a-9e were designed and synthesised with the aim of evaluating their anti-bacterial and anti-trypanosomal activities and DNA/RNA binding affinity. Results from anti-bacterial evaluations of antibiotic-resistant pathogenic bacteria revealed that both o-chlorophenyl-1,2,3-triazole and N-isopropylamidine moieties in 8c led to strong inhibitory activity against resistant Gram-positive bacteria, particularly the MRSA strain. Furthermore, the non-substituted amidine and phenyl ring in 7a induced a marked anti-bacterial effect, with potency against ESBL-producing Gram-negative E. coli better than those of the antibiotics ceftazidime and ciprofloxacin. UV-Vis and CD spectroscopy, as well as thermal denaturation assays, indicated that compounds 7a and 8c showed also binding affinities towards ctDNA. Anti-trypanosomal evaluations showed that the p-methoxyphenyl-1,2,3-triazole moiety in 7b and 9b enhanced inhibitory activity against T. brucei, with 8b being more potent than nifurtimox, and having minimal toxicity towards mammalian cells.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Bencimidazoles/metabolismo , Bencimidazoles/farmacología , ADN/metabolismo , ARN/metabolismo , Antibacterianos/química , Antibacterianos/metabolismo , Antiprotozoarios/química , Antiprotozoarios/metabolismo , Bencimidazoles/síntesis química , Bencimidazoles/química , Relación Dosis-Respuesta a Droga , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Trypanosoma brucei brucei/efectos de los fármacosRESUMEN
A series of novel amidino 2-substituted benzimidazoles linked to 1,4-disubstituted 1,2,3-triazoles were synthesized by implementation of microwave and ultrasound irradiation in click reaction and subsequent condensation of thus obtained 4-(1,2,3-triazol-1-yl)benzaldehyde with o-phenylenediamines. In vitro antiproliferative screening of compounds performed on human cancer cell lines revealed that p-chlorophenyl-substituted 1,2,3-triazolyl N-isopropylamidine 10c and benzyl-substituted 1,2,3-triazolyl imidazoline 11f benzimidazoles had selective and potent cytostatic activities in the low nM range against non-small cell lung cancer cell line A549, which could be attributed to induction of apoptosis and primary necrosis. Additional Western blot analyses showed different mechanisms of cytostatic activity between compounds 10c and 11f that could be associated with the nature of aromatic substituent at 1-(1,2,3-triazolyl) and amidino moiety at C-5 position of benzimidazole ring. Specifically, compound 11f abrogated the activity of several protein kinases including TGM2, CDK9, SK1 and p38 MAPK, whereas compound 10c did not have profound effect on the activities of CDK9 and TGM2, but instead showed moderate downregulation of SK1 activity concomitant with a significant reduction in p38 MAPK. Further in silico structural analysis demonstrated that compound 11f bound slightly better to the ATP binding site of p38 MAPK compared to 10c, which correlated well with observed stronger decrement in the expression level of phospho-p38 MAPK elicited by 11f in comparison with 10c.
Asunto(s)
Amidinas/farmacología , Antineoplásicos/farmacología , Bencimidazoles/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Diseño de Fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Amidinas/síntesis química , Amidinas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Bencimidazoles/síntesis química , Bencimidazoles/química , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Pulmonares/patología , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
Four series of new hybrid molecules with 7-chloroquinoline and arylamidine moieties joined through the rigid -O- (groups I (2a-g) and II (5a-g)) or flexible -NH-CH2-CH2-O- (groups III (8a-g) and IV (10a-g)) linker were synthesized, and their DNA/RNA binding properties and cytotoxic activity were tested, against several human cancer lines. The compounds and their interaction with DNA and RNA were studied by UV-Vis and CD spectroscopy. The obtained results showed that the binding affinity of the investigated compounds increases proportionally with the increase of the length and number of groups able to form hydrogen bonds with ds-polynucleotides. Improvement of binding was additionally achieved by reduction of the structural rigidity of the investigated compounds, new hybrid compounds preferentially bind to ctDNA. For most of them the DNA/RNA grooves are dominant binding sites, except for the compounds from group II for which intercalation in polyA-polyU was the dominant binding mode. The antiproliferative effects were tested by the MTT test on normal (MDCK1), carcinoma (HeLa and CaCo2) and leukemia cell lines (Raji and K462). The GI50 values for all investigated compounds ranged from 5 to more than 100 × 10-6 mol dm-3. Carcinoma cells were more resistant to the investigated compounds than leukemia cells. The most effective compounds against leukemia cell lines were from group IV (10a-g), with GI50 values ranging from of 5 and 35 × 10-6 mol dm-3. The cell cycle arrest was investigated by flow cytometry and the obtained results indicate that the selected compounds, 2d, 2e, 8a, 10d, 10e, and 10f, induce changes in the cell cycle of treated cells, but the cycle phase distribution varies between them. A significant decrease in the number of cells in S phase (p < 0.001) was observed in all treated cells, but only 10d and 10f induce cell cycle arrest at G0/G1 phase, dominantly.
Asunto(s)
Amidinas/farmacología , Antineoplásicos/farmacología , ADN de Neoplasias/antagonistas & inhibidores , Quinolinas/farmacología , ARN Neoplásico/antagonistas & inhibidores , Amidinas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Sitios de Unión/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , ADN de Neoplasias/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Quinolinas/química , ARN Neoplásico/química , Relación Estructura-ActividadRESUMEN
The reactivity of new biologically active thymine derivatives substituted with 2-(arylsulfonamidino)ethyl group at N1 and N3 position was investigated in the gas phase using CID experiments (ESI-MS/MS) and by density functional theory (DFT) calculations. Both derivatives show similar chemistry in the negative mode with a retro-Michael addition (Path A(-)) being the most abundant reaction channel, which correlate well with the fluoride induced retro-Michael addition observed in solution. The difference in the fragmentation of N-3 substituted thymine 5 and N-1 substituted thymine 1 in the positive mode relates to the preferred cleavage of the sulfonyl group (m/z 155, Path B) in N-3 isomer and the formation of the acryl sulfonamidine 3 (m/z 309) via Path A in N-1 isomer. Mechanistic studies of the cleavage reaction conducted by DFT calculations give the trend of the calculated activation energies that agree well with the experimental observations. A mechanism of the retro-Michael reaction was interpreted as a McLafferty type of fragmentation, which includes Hß proton shift to one of the neighboring oxygen atoms in a 1,5-fashion inducing N1(N3)-Cα bond scission. This mechanism was found to be kinetically favorable over other tested mechanisms. Significant difference in the observed fragmentation pattern of N-1 and N-3 isomers proves the ESI-MS/MS technique as an excellent method for tracking the fate of similar sulfonamidine drugs. Also, the observed N-1 and/or N-3 thymine alkylation with in situ formed reactive acryl sulfonamidine 3 as a Michael acceptor may open interesting possibilities for the preparation of other N-3 substituted pyrimidines.
Asunto(s)
Antineoplásicos/química , Modelos Moleculares , Sulfonamidas/química , Timina/análogos & derivados , Compuestos de Tosilo/química , Catálisis , Estabilidad de Medicamentos , Transferencia de Energía , Calor , Indicadores y Reactivos/química , Isomerismo , Estructura Molecular , Compuestos de Amonio Cuaternario/química , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem , Timina/químicaRESUMEN
BACKGROUND: Various studies have been conducted to evaluate the effect of phenolic compounds on production animals. Supplementation of animal diets with phytogenic compounds, such as different essential oils and polyphenols, could improve animal productivity as well as the chemical composition and oxidative stability of food derived from those animals. RESULTS: During the trial, 80 male broilers of the Ross 308 strain were allocated to four dietary groups: control and three groups supplemented with thymol, tannic acid and gallic acid. Feed utilisation was improved in all experimental groups and tannic acid also improved final body weight. Gallic acid significantly increased n-3 long-chain polyunsaturated fatty acids. A hypocholesterolaemic effect was noticed in all groups in liver, but not in muscle. The glucose lowering effect in serum was noticed in the tannic acid group in comparison to other experimental groups. Oxidative susceptibility was improved by tannic acid in liver and breast and by gallic acid in breast muscle. CONCLUSION: The inclusion of phenolic compounds enhanced growth performance, decreased lipid oxidation, decreased cholesterol value and increased beneficial fatty acids content. Positive effects varied depending on phenolic compound used and, therefore, it would be interesting to further investigate synergistic effects of investigated phenolic compound.
Asunto(s)
Peso Corporal/efectos de los fármacos , Pollos , Suplementos Dietéticos , Peroxidación de Lípido/efectos de los fármacos , Carne/análisis , Extractos Vegetales/farmacología , Polifenoles/farmacología , Alimentación Animal , Animales , Anticolesterolemiantes/farmacología , Mama/efectos de los fármacos , Mama/metabolismo , Pollos/sangre , Pollos/crecimiento & desarrollo , Pollos/metabolismo , Ácidos Grasos Omega-3/sangre , Ácido Gálico/farmacología , Humanos , Hipoglucemiantes/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Músculos/efectos de los fármacos , Músculos/metabolismo , Valor Nutritivo , Taninos/farmacología , Timol/farmacologíaRESUMEN
Chamomile, common yarrow and immortelle ethanolic extracts were chemically analysed with respect to phenolics. Twelve phenolic acids were separated and identified by HPLC-DAD and the presence of rosmarinic acid was additionally confirmed by LC-MS. Five methods were applied for the evaluation of extracts' antioxidant properties (FRAP, DPPH, ABTS, chelating activity, Briggs-Rauscher reaction), while the antibacterial activity was tested against some of the major food-borne pathogens (Campylobacter coli, Escherichia coli, Salmonella Infantis, Bacillus cereus, Listeria monocytogenes and Staphylococcus aureus). Immortelle extract was the richest in phenolics with a dominant flavonoid fraction, while the other two extracts contained higher amount of non-flavonoids. The phenolic acid profile also varied; high concentration of rosmarinic acid was found in chamomile and common yarrow, while caffeic acid was dominant in immortelle. The best antioxidant properties were obtained for chamomile extract, while good antimicrobial activity, especially against Gram-positive bacterial species, was detected for immortelle. The obtained results could be used as a tool for chemotaxonomic classification of the investigated plants or for their potential application as natural antioxidants/antimicrobials.