RESUMEN
In recent years, antioxidant compounds play an important role as a health-protecting factor. Antioxidants protect cells against the damaging effects of reactive oxygen species (ROS). An imbalance between antioxidants and ROS results in oxidative stress, which leads to cellular damage and it is linked to many vital diseases. It was shown that heme oxygenase (HO) provides efficient cytoprotection against oxidative stress. In this study, a series of indole-2-carboxamide and 3-acetamide derivatives was tested for in vitro effects on HO activity and 2,2-diphenyl-1-picrylhydrazyl (DPPH) inhibition. Among the synthesized compounds, N-[3-(dimethylamino)propyl]-1H-indole-2-carboxamide 3 was found as the most activator of HO and N-(2-(dimethylamino)ethyl)-2-(1H-indol-3-yl)acetamide 8 was found the most potent inhibitor for DPPH at 10(-4) M concentration.
Asunto(s)
Antioxidantes/síntesis química , Antioxidantes/farmacología , Hemo Oxigenasa (Desciclizante)/metabolismo , Indoles/química , Acetamidas/química , Antioxidantes/química , Compuestos de Bifenilo/metabolismo , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Indoles/farmacología , Picratos/metabolismo , Relación Estructura-ActividadRESUMEN
The in vitro antioxidant effects of novel N-substituted indole-3-carboxamides (I3CDs) 1-10 on rat liver microsomal NADPH-dependent lipid peroxidation (LP) levels and their free radicals scavenging properties were determined by the inhibition of superoxide anion formation (SOD). Among the synthesized compounds, 4, 5, 8 and 9 significantly inhibited SOD with an inhibition range at 84-100% at 10(-3) M concentration. The presence of halo substituents both ortho- and para- positions of these compounds resulted 100% inhibition of SOD. Comparison the activity results of halogenated and non-halogenated derivatives suggested that the halogenated compounds are more active than the non-halogenated compounds. On the other hand, the introduction of a para fluoro benzyl in the 1-position of indole (compounds 7, 8) has more impact on the SOD inhibition when the benzamide ring was mono halogenated. However, none of other compounds had a significant inhibitory effects on the level of lipid peroxidation.
Asunto(s)
Antioxidantes/química , Indoles/farmacología , Peroxidación de Lípido/efectos de los fármacos , Superóxidos/antagonistas & inhibidores , Animales , Antioxidantes/síntesis química , Antioxidantes/farmacología , Indoles/química , Microsomas Hepáticos/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Because of the physiologic importance of hyaluronidases, the identification of potent and selective inhibitors of hyaluronidases has become increasingly important. A variety of assay methods have been used for such a purpose, i.e. classical turbidimetric, viscometric and colorimetric. In this study, a modified enzymatic assay has been used to obtain a microtiter plate-based sensitive activity screening. All inhibitors were tested in a stains-all assay at pH 7 and in a Morgan-Elson assay at pH 3.5. Among the tested compounds, 1, 2, 3, 6, 7, 8, 16, 17 and 18 showed good inhibition of more than 50%, so the IC(50) values of these derivatives were determined in the range of 25-41 microm. The IC(50) value of the most active hyaluronidase inhibitor Vcpal (6-palmitoyl-L-ascorbic acid) was measured as 8.36 microm. All inhibitors including Vcpal showed twofold less activity at pH 3.5 in a Morgan-Elson assay. Examination of substituent effects on the activity showed that para-positions of benzamide needs to be chlorinated or fluorinated to obtain good inhibitory effect. It was found that the introduction of a p-fluoro benzyl ring in the indole nitrogen has a positive effect for the inhibitory effects of both indole-2- and 3-carboxamide derivatives.
Asunto(s)
Ácido Ascórbico/análogos & derivados , Bioensayo , Inhibidores Enzimáticos/química , Hialuronoglucosaminidasa/antagonistas & inhibidores , Indoles/química , Animales , Ácido Ascórbico/química , Evaluación Preclínica de Medicamentos , Humanos , Hialuronoglucosaminidasa/química , Concentración de Iones de HidrógenoRESUMEN
The antioxidant role of novel N-substituted indole-2-carboxamides (I2CDs) was investigated for their inhibitory effects on superoxide anion (O2-) and lipid peroxidation (LP). Among the synthesized I2CDs, 3, 4, 6, 8 and 9 significantly inhibited O2*- with an inhibition range at 70-98%. Examination of substituent effects on activity showed that both the ortho- and para- positions of the benzamide residue needs to be dichlorinated in order to get a maximum inhibitory effect on superoxide anion. In general, halogenated derivatives were found more active then the non-halogenated ones. However, none of the I2CDs had a significant inhibitory effects on the level of lipid peroxidation; only compounds 7 and 10 moderately decreased LP levels by over 50% at 10(-3) M concentrations.
Asunto(s)
Antioxidantes/síntesis química , Antioxidantes/farmacología , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/farmacología , Indoles/síntesis química , Indoles/farmacología , Animales , Antioxidantes/química , Evaluación Preclínica de Medicamentos , Depuradores de Radicales Libres/química , Técnicas In Vitro , Indoles/química , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Ratas , Ratas Wistar , Relación Estructura-Actividad , Superóxidos/metabolismoRESUMEN
A series of 3-(substituted-benzylidene)-1, 3-dihydro-indolin-2-thione derivatives were synthesized as modified congeners of 3-(substituted-benzylidene)-1, 3-dihydro-indolin-2-one series. All the synthesized compounds were examined for their in vitro anti-tyrosine kinase activity against p60c-Src. The activity results revealed that compounds (Z)-3-(4'-Dimethylamino-benzylidene)-1, 3-dihydro-indolin-2-thione (12) (E)-3-(2', 6'-Dichloro-benzylidene)-1, 3-dihydro-indolin-2-thione (13) and (E)-3-(3'-Hydroxy-4'-methoxy-benzylidene)-1, 3-dihydro-indolin-2-thione (19) exhibited anti-tyrosine kinase activity with IC50 value of 21.91, 21.20 and 30.92 microM, respectively. These results are comparable to PP1 [1-tert-Butyl-3-p-tolyl-1H-pyrazolo[3, 4-d]pyrimidine-4-yl-amine] (IC50=0.17 microM), which is reported as a potent and selective p60c-Src tyrosine kinase inhibitor. Some thio congeners are found to be more potent than oxo derivatives; however, no significant correlation was observed between the activity profiles of these two series. Docking program was used to investigate the docking mode of each compound at the active site. Among all of the compounds, only (Z)-3-(2'-Chloro-benzylidene)-1, 3-dihydro-indolin-2-one (8) and (E)-3-(3'-Nitro-benzylidene)-1, 3-dihydro-indolin-2-thione (16) were docked at the active site where the PP1 was embedded.
Asunto(s)
Compuestos de Bencilideno/química , Indoles/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Secuencia de Aminoácidos , Unión Competitiva , Indoles/síntesis química , Indoles/metabolismo , Modelos Químicos , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas pp60(c-src)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismo , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismoRESUMEN
The fundamental role that receptor tyrosine kinases play in cancer and other proliferative diseases has provided the impetus for an extensive effort on the part of both academic and pharmaceutical laboratories to develop highly specific inhibitors. In this study, inhibitory activity of previously synthesized arylacetic and arylcarboxylic acid derivatives were examined against substrate of tyrosine kinase. It can be assumed that the activity of compounds becomes higher when the -CH(2) linkage exist between aromatic ring and the amide group of the side chain. In addition, when the R(1) and R(2) substitutents are methyl group in both series, the higher activity observed. The data obtained from docking study (DOCK4.0) indicated that compounds 2, 4, 7, 8, 11 render satisfactory interaction with the active site of enzyme, Lys295 of p60(c-Src) tyrosine kinase. Comparison of this interaction and the evaluation of biological data showed that compound 4 is the most active among the entire derivatives.
Asunto(s)
Acetatos/farmacología , Ácidos Carboxílicos/farmacología , Proteína Oncogénica pp60(v-src)/metabolismo , Acetatos/química , Sitios de Unión , Ácidos Carboxílicos/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ensayo de Inmunoadsorción Enzimática , Humanos , Enlace de Hidrógeno , Modelos Moleculares , Conformación Molecular , Proteína Oncogénica pp60(v-src)/antagonistas & inhibidores , Proteína Oncogénica pp60(v-src)/químicaRESUMEN
Several indole esters were tested as inhibitors of tyrosine kinase p60(c-Src). Compound (4) was found fairly active against the enzyme with IC50 = 1.34 microM. DOCK methodology was used to asses our inhibitors for their inhibitory potency against tyrosine kinase. The docking results showed that compounds (4), (25) and (26) were bound to the active site of the enzyme Lys 295 of p60(c-Src) tyrosine kinase. Both activity and docking studies showed a parallel result, with compound (4) having a better interaction with the enzyme active site and also greater activity than the other compounds, indicating a potential role as new lead inhibitor.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Indoles/farmacología , Proteínas Proto-Oncogénicas pp60(c-src)/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Pollos , Inhibidores Enzimáticos/metabolismo , Ésteres , Indoles/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Secundaria de Proteína , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismo , Programas Informáticos , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
A series of novel N-substituted indole carboxylic, acetic and propionic acid esters have been prepared as possible cyclo-oxygenase-2 (COX-2) enzyme inhibitors. Compounds 20, 23 were found slightly active against COX-2. The synthesis of indole carboxylic, acetic and propionic acid esters were furnished by using dicyclohexyl carbodiimide (DCC), dimethylamino pyridine (DMAP) as carboxylate activators. N-substitution of indole esters was verified with several benzyl and benzoyl group in presence of NaH in DMF, respectively.