RESUMEN
A series of imidazo[2,1-b][1,3,4]thiadiazole linked indolinone conjugates were synthesized and investigated for antiproliferative activity in different human cancer cell lines by changing various substitutions at indolinone and phenyl ring systems. Among them conjugates 7, 14 and 15 were exhibited potent antiproliferative activity with GI50 values from 0.13 to 3.8â¯µΜ and evaluated for cell cycle analysis, tubulin polymerization assay and apoptosis. Treatment with 7, 14 and 15 were resulted in accumulation of cells in G2/M phase, inhibition of tubulin assembly, disruption of microtubule network. Inhibition of tubulin polymerization was further supported by Western blot analysis. In addition, the conjugates (7, 14 and 15) also showed apoptosis in HeLa cell line, detailed biological studies such as Hoechst 33,258 staining, DNA fragmentation and caspase-3 assays suggested that these compounds induce cell death by apoptosis. Docking studies revealed that these compounds (7, 14 and 15) bind with αAsn101, αThr179, αSer178, ßCys241, ßLys254 and ßLys352 in the colchicine-binding site of the tubulin.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Imidazoles/farmacología , Oxindoles/farmacología , Tiadiazoles/farmacología , Moduladores de Tubulina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/metabolismo , Sitios de Unión , Caspasa 3/metabolismo , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxindoles/síntesis química , Oxindoles/química , Oxindoles/metabolismo , Unión Proteica , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/química , Tiadiazoles/metabolismo , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismoRESUMEN
A number of linezolid-like oxazolidino-sulfonamides (7a-y and 8a-b) were designed and synthesized with a view to develop antimicrobial agents with improved properties. Most of the synthesized compounds showed good to moderate activity against a panel of standard Gram-positive and Gram-negative bacteria and fungal strains. The compounds 7i and 7v exhibited significant activity, with a MIC value of 2.0-6.0 µg/mL against a panel of Gram-positive and Gram-negative bacteria. These compounds also showed activity against Candida albicans, with a MIC value of 4.0 µg/mL. A correlation of the antimicrobial activity with calculated lipophilicity values (C log P) is also presented.
Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Hongos/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Sulfonamidas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Oxazoles/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
In an effort to discover new anti-tubercular agents, a series of new diarylpyrrole-oxazolidinone conjugates have been designed and synthesized. The anti-tubercular activity of these new conjugates (4a-n and 5a-d) against Mycobacterium tuberculosis H37Rv and drug resistance strains such as M. tuberculosis Rif(R) and M. tuberculosis XDR are discussed, wherein compound 4i has been found to be the most potent amongst the series. MTT assay was performed on the active conjugates of the series (4b-f, 4i and 5c) against mouse macrophage (J-774) cells to evaluate cytotoxic effects and selective index values. In addition, these conjugates (4a-n and 5a-d) are also tested against a panel of Gram-positive and Gram-negative bacterial strains. The docking studies have been carried out to provide some insight into the mechanism of action for this class of compounds.
Asunto(s)
Antibacterianos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Oxazolidinonas/farmacología , Pirroles/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Línea Celular , Relación Dosis-Respuesta a Droga , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Oxazolidinonas/química , Pirroles/química , Relación Estructura-ActividadRESUMEN
A library of imidazopyridine-oxindole conjugates was synthesised and investigated for anticancer activity against various human cancer cell lines. Some of the tested compounds, such as 10 a, 10 e, 10 f, and 10 k, exhibited promising antiproliferative activity with GI50 values ranging from 0.17 to 9.31â µM. Flow cytometric analysis showed that MCF-7 cells treated by these compounds arrested in the G2 /M phase of the cell cycle in a concentration-dependent manner. More particularly, compound 10 f displayed a remarkable inhibitory effect on tubulin polymerisation. All the compounds depolarised mitochondrial membrane potential and caused apoptosis. These results are further supported by the decreased phosphorylation of Akt at Ser473. Studies on embryonic development revealed that the lead compounds 10 f and 10 k caused delay in the development of zebra fish embryos. Docking of compound 10 f with tubulin protein suggested that the imidazo[1,2-a]pyridine moiety occupies the colchicine binding site of tubulin.