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1.
Bioorg Med Chem Lett ; 28(4): 630-636, 2018 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-29395969

RESUMEN

An efficient, one-pot multicomponent reaction of novel pyrazolo-oxothiazolidine derivatives was achieved by condensation of 1-(benzofuran-2-yl)-3-(substituted-arylprop-2-en-1-ones, thiosemicarbazide and dialkyl acetylenedicarboxylates under the optimized reaction conditions. Synthesised compounds were evaluated for their antiproliferative activity against A549 human lung cancer cell line. Among all the tested compounds, 4a (IC50 - 0.930 µg/mL), 4e (IC50 - 1.207 µg/mL), 4f (IC50 - 0.808 µg/mL), 4g (IC50 - 1.078 µg/mL), 4h (IC50 - 0.967 µg/mL) and 4j (IC50 - 2.445 µg/mL) showed promising activity compared with standard drug Sorafenib (IC50 - 3.779 µg/mL). Molecular docking studies indicated that compound 4f had the greatest affinity for catalytic site of receptors EGFR (PDB ID code: 1 M17) and VEGFR2 (PDB ID code: 4AGD, 4ASD). These novel pyrazolo-oxothiazolidine derivatives can be promising therapeutic agents for A549 human lung cancer cell line.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Pirazoles/farmacología , Tiazolidinas/farmacología , Células A549 , Antineoplásicos/síntesis química , Antineoplásicos/química , Dominio Catalítico , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/química , Humanos , Enlace de Hidrógeno , Simulación del Acoplamiento Molecular , Estructura Molecular , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos de Fenilurea/farmacología , Pirazoles/síntesis química , Pirazoles/química , Sorafenib , Tiazolidinas/síntesis química , Tiazolidinas/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/química
2.
Bioorg Med Chem Lett ; 27(6): 1451-1457, 2017 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-28209374

RESUMEN

An efficient four-component reaction of 6-amino-1,3-dimethyluracil, N,N-dimethylformamide dimethylacetal, 1-phenyl-3-(4-substituted-phenyl)-4-formyl-1H-pyrazoles and aromatic amines was conducted in the presence of [Bmim]FeCl4 ionic liquid as a promoting medium. This strategy provided a convenient route without any additional catalyst or metal salt under mild conditions. All the synthesized pyrazolo-pyrimido[4,5-d]pyrimidines derivatives were evaluated for their antibacterial, minimum bactericidal concentration (MBC), biofilm inhibition, intracellular ROS accumulation and protein leakage activities. The results revealed that among all the screened derivatives, the compounds 5c, 5i, 5l and 5m were quite promising with MIC values ranging between 3.9 and 15.6µg/mL, while the MBC values were 2-fold the antibacterial activity values. The biofilm inhibition activity revealed that the compounds 5l and 5m exhibited promising activity with IC50 values ranging between 1.8 and 8.2µg/mL. It was observed that at a concentration of 0.5µg/mL, the compound 5l treated biofilms of Micrococcus luteus showed increased levels of intracellular ROS accumulation. Further, the protein leakage study revealed that the Micrococcus luteus cells treated with compound 5l caused membrane permeability which resulted in protein leakage and subsequent bacterial cell death.


Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Pirazoles/química , Pirimidinas/química , Pirimidinas/farmacología , Antibacterianos/síntesis química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Pirimidinas/síntesis química , Especies Reactivas de Oxígeno/metabolismo
3.
Bioorg Med Chem ; 24(16): 3808-17, 2016 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-27344213

RESUMEN

An efficient domino protocol has been developed for the synthesis of new pyrimidine scaffolds, through a one-pot four-component cascade transformation via [Bmim]HSO4 ionic liquid mediated reaction, using an equimolar mixture of thiochroman-4-one, benzaldehyde, thiourea and 3-bromo-1-phenylpropan-1-one leading to the formation of a double electrophilic pyrimidine-2(5H)-thione intermediate. The intermediate regioselectively undergoes cyclization through intramolecular NH bond activation followed by CS bond formation leading to highly functionalized thiazolo[3,2-a]thiochromeno[4,3-d]pyrimidines. The ionic liquid operates efficiently under mild conditions. The recyclability and scope for recovery of the ionic liquid makes this protocol environmentally benign. Further, the compounds 5d, 5g and 5k showed promising antimicrobial activity against the tested Gram-positive bacterial strains. Among them, the compound 5d was identified as a lead molecule exhibiting promising anti-biofilm activity towards Staphylococcus aureus MTCC 96, Bacillus subtilis MTCC 121, Staphylococcus aureus MLS16 MTCC 2940 and Micrococcus luteus MTCC 2470 with IC50 values of 2.1, 1.9, 2.4 and 5.3µg/mL, respectively. Further, the compound 5d showed increased levels of intracellular ROS accumulation in Staphylococcus aureus MTCC 96 suggesting that oxidative stress resulted in bacterial cell lysis and death.


Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Pirimidinas/síntesis química , Pirimidinas/farmacología , Bacillus subtilis/efectos de los fármacos , Cristalografía por Rayos X , Pruebas de Sensibilidad Microbiana , Micrococcus luteus/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad
4.
Bioorg Chem ; 68: 159-65, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27522461

RESUMEN

An efficient synthesis of thiochromeno[3,4-d]pyrimidine derivatives has been achieved successfully via a one-pot three-component reaction of thiochrome-4-one, aromatic aldehyde and thiourea in the presence of 1-butyl-3-methyl imidazolium hydrogen sulphate [Bmim]HSO4. This new protocol has the advantages of environmental friendliness, high yields, short reaction times, and convenient operation. Furthermore, among all the tested derivatives, compounds 4b and 4c exhibited promising antibacterial, minimum bactericidal concentration and anti-biofilm activities against Staphylococcus aureus MTCC 96, Staphylococcus aureus MLS16 MTCC 2940 and Bacillus subtilis MTCC 121. The compound 4c also showed promising intracellular ROS accumulation in Staphylococcus aureus MLS16 MTCC 2940 comparable to that of ciprofloxacin resulting in apoptotic cell death of the bacterium.


Asunto(s)
Antibacterianos/farmacología , Bacillus subtilis/efectos de los fármacos , Biopelículas/efectos de los fármacos , Cromanos/farmacología , Pirimidinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Bacillus subtilis/metabolismo , Cromanos/síntesis química , Cromanos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Staphylococcus aureus/metabolismo , Relación Estructura-Actividad
5.
ISRN Org Chem ; 2013: 635384, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24052866

RESUMEN

A series of novel pyranochromene-containing tetrazoles fused with pyrimidinethiones, pyrimidines, and diazepines 3a-f, 4a-f, and 5a-f were synthesized by condensation of the corresponding tetrazoles 2a-f with carbon disulfide, benzaldehyde, and 4-methoxy phenacyl bromide, respectively. The compound 2a-f was obtained by reaction of pyrano[3,2-c]chromenes 1a-f with sodium azide. The structures of the newly synthesized compounds 2a-f to 5a-f were established on the basis of their elemental analyses, IR, (1)H NMR, (13)C NMR, and mass spectral data. All of the title compounds were subjected to in vitro antibacterial testing against four pathogenic strains and antifungal screening against two fungi. Preliminary results indicate that some of them exhibited promising activities and that they deserve more consideration as potential antimicrobials.

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