RESUMEN
Five series of novel carbazole derivatives containing an aminoguanidine, dihydrotriazine, thiosemicarbazide, semicarbazide or isonicotinic moiety were designed, synthesised and evaluated for their antimicrobial activities. Most of the compounds exhibited potent inhibitory activities towards different bacterial strains (including one multidrug-resistant clinical isolate) and one fungal strain with minimum inhibitory concentrations (MICs) between 0.5 and 16 µg/ml. Compounds 8f and 9d showed the most potent inhibitory activities (MICs of 0.5-2 µg/ml). Furthermore, compounds 8b, 8d, 8f, 8k, 9b and 9e with antimicrobial activities were not cytotoxic to human gastric cancer cell lines (SGC-7901 and AGS) or a normal human liver cell line (L-02). Structure-activity relationship analyses and docking studies implicated the dihydrotriazine group in increasing the antimicrobial potency and reducing the toxicity of the carbazole compounds. In vitro enzyme activity assays suggested that compound 8f binding to dihydrofolate reductase might account for the antimicrobial effect.
Asunto(s)
Antiinfecciosos/síntesis química , Proteínas Bacterianas/química , Carbazoles/síntesis química , Inhibidores Enzimáticos/síntesis química , Escherichia coli/efectos de los fármacos , Tetrahidrofolato Deshidrogenasa/química , Antiinfecciosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Sitios de Unión , Candida albicans/efectos de los fármacos , Candida albicans/enzimología , Candida albicans/crecimiento & desarrollo , Carbazoles/farmacología , Línea Celular , Línea Celular Tumoral , Inhibidores Enzimáticos/farmacología , Células Epiteliales/efectos de los fármacos , Escherichia coli/enzimología , Escherichia coli/crecimiento & desarrollo , Guanidinas/química , Hepatocitos/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Ácidos Isonicotínicos/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/enzimología , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Unión Proteica , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas , Semicarbacidas/química , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Staphylococcus aureus/crecimiento & desarrollo , Streptococcus mutans/efectos de los fármacos , Streptococcus mutans/enzimología , Streptococcus mutans/crecimiento & desarrollo , Relación Estructura-Actividad , Tetrahidrofolato Deshidrogenasa/metabolismo , Triazinas/químicaRESUMEN
The transforming growth factor-ß (TGF-ß), in which overexpression has been associated with various diseases, has become an attractive molecular target for the treatment of cancers. Thirty-two quinoxaline-derivatives of 3-substituted-4-(quinoxalin-6-yl) pyrazoles 14aâ»d, 15aâ»d, 16aâ»d, 17aâ»d, 18aâ»d, 19aâ»d, 25a, 25b, 25d, 26a, 26b, 26d, 27b, and 27d were synthesized and evaluated for their activin TGF-ß type I receptor kinase and p38α mitogen activated protein (MAP) kinase inhibitory activity in enzymatic assays. Among these compounds, the most active compound 19b inhibited TGF-ß type I receptor kinase phosphorylation with an IC50 value of 0.28 µM, with 98% inhibition at 10 µM. Compound 19b also had good selectivity index of >35 against p38α MAP kinase, with 9.0-fold more selective than clinical candidate, compound 3 (LY-2157299). A molecular docking study was performed to identify the mechanism of action of the synthesized compounds and their good binding interactions were observed. ADMET prediction of good active compounds showed that these ones possess good pharmacokinetics and drug-likeness behavior.