RESUMEN

The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7-bromo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, which is a selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti-inflammatory effect. It was found to inhibit mononuclear cell adhesion to the dysfunctional endothelium with minimal impact on neutrophil-endothelial cell interactions. The information obtained from our theoretical and experimental study can be useful in the search for inhibitors of SphK2 that play a prominent role in different diseases, especially in inflammatory and cardiovascular disorders.

Asunto(s)

Antiinflamatorios/síntesis química , Azepinas/síntesis química , Inhibidores Enzimáticos/síntesis química , Compuestos Epoxi/síntesis química , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antiinflamatorios/toxicidad , Azepinas/química , Azepinas/farmacología , Adhesión Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/inmunología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/toxicidad , Compuestos Epoxi/química , Compuestos Epoxi/farmacología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Simulación del Acoplamiento Molecular , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Unión Proteica , Relación Estructura-Actividad

RESUMEN

Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b]pyrimido[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands.

Asunto(s)

Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Relación Dosis-Respuesta a Droga , Modelos Moleculares , Estructura Molecular , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Teoría Cuántica , Relación Estructura-Actividad

RESUMEN

In current research, nine basic esters of para-alkoxyphenylcarbamic acid with incorporated 4-(4-fluoro-/3-trifluoromethylphenyl)piperazin-1-yl fragment, 6i-6m and 8f-8i, were screened for their in vitro antimicrobial activity against Candida albicans, Staphylococcus aureus and Escherichia coli, respectively. Taking into account the minimum inhibitory concentration assay (MIC), as the most active against given yeast was evaluated 8i (MIC = 0.20 mg/mL), the most lipophilic structure containing para-butoxy and trifluoromethyl substituents. Investigating the efficiency of the compounds bearing only a single atom of fluorine and appropriate para-alkoxy side chain against Candida albicans, the cut-off effect was observed. From evaluated homological series, the maximum of the effectiveness was noticed for the stucture 6 k (MIC = 0.39 mg/mL), containing para-propoxy group attached to phenylcarbamoyloxy fragment, beyond which the compounds ceased to be active. On the contrary, all the tested molecules were against Staphylococcus aureus and Escherichia coli (MICs > 1.00 mg/mL) practically inactive.

Asunto(s)

Antiinfecciosos/farmacología , Candida albicans/efectos de los fármacos , Carbamatos/farmacología , Escherichia coli/efectos de los fármacos , Piperazinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Antiinfecciosos/química , Carbamatos/química , Ésteres/química , Ésteres/farmacología , Pruebas de Sensibilidad Microbiana , Piperazinas/química , Relación Estructura-Actividad

RESUMEN

In current research, nine basic esters of para-alkoxyphenylcarbamic acid with incorporated 4-(4fluoro-/3-trifluoromethylphenyl)piperazin-1-yl fragment, 6i-6m and 8f-8i, were screened for their in vitro antimicrobial activity against Candida albicans, Staphylococcus aureus and Escherichia coli, respectively. Taking into account the minimum inhibitory concentration assay (MIC), as the most active against given yeast was evaluated 8i (MIC = 0.20 mg/mL), the most lipophilic structure containing para-butoxy and trifluoromethyl substituents. Investigating the efficiency of the compounds bearing only a single atom of fluorine and appropriate para-alkoxy side chain against Candida albicans, the cut-off effect was observed. From evaluated homological series, the maximum of the effectiveness was noticed for the stucture 6 k (MIC = 0.39 mg/mL), containing para-propoxy group attached to phenylcarbamoyloxy fragment, beyond which the compounds ceased to be active. On the contrary, all the tested molecules were against Staphylococcus aureus and Escherichia coli (MICs > 1.00 mg/mL) practically inactive.(AU)

Asunto(s)

Candida albicans , Infecciones , Factores de Virulencia , Bioensayo

RESUMEN

In current research, nine basic esters of para-alkoxyphenylcarbamic acid with incorporated 4-(4fluoro-/3-trifluoromethylphenyl)piperazin-1-yl fragment, 6i-6m and 8f-8i, were screened for their in vitro antimicrobial activity against Candida albicans, Staphylococcus aureus and Escherichia coli, respectively. Taking into account the minimum inhibitory concentration assay (MIC), as the most active against given yeast was evaluated 8i (MIC = 0.20 mg/mL), the most lipophilic structure containing para-butoxy and trifluoromethyl substituents. Investigating the efficiency of the compounds bearing only a single atom of fluorine and appropriate para-alkoxy side chain against Candida albicans, the cut-off effect was observed. From evaluated homological series, the maximum of the effectiveness was noticed for the stucture 6 k (MIC = 0.39 mg/mL), containing para-propoxy group attached to phenylcarbamoyloxy fragment, beyond which the compounds ceased to be active. On the contrary, all the tested molecules were against Staphylococcus aureus and Escherichia coli (MICs > 1.00 mg/mL) practically inactive.

Asunto(s)

Antiinfecciosos/farmacología , Candida albicans/efectos de los fármacos , Carbamatos/farmacología , Escherichia coli/efectos de los fármacos , Piperazinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Antiinfecciosos/química , Carbamatos/química , Ésteres/química , Ésteres/farmacología , Pruebas de Sensibilidad Microbiana , Piperazinas/química , Relación Estructura-Actividad

RESUMEN

In the present investigation, the basic esters of meta-alkoxyphenylcarbamic acid bearing variously substituted N-phenylpiperazine fragment were screened for their in vitro antimicrobial activity against Staphylococcus aureus, Escherichia coli and Candida albicans, respectively. The most effective against Escherichia coli was found the compound 6d (MIC=195,3 μg/mL) bearing simultaneously para-fluoro substituent at the 4‑phenylpiperazin-1-yl core and meta-methoxy side chain in the lipophilic part of the molecule. From whole analyzed set of the molecules the substance 8e with propoxy side chain forming meta-alkoxyphenylcarbamoyl fragment and lipophilic, sterically bulky meta-trifluoromethyl group attached at N-phenylpiperazine moiety was evaluated as the most active against Candida albicans (MIC=97,7 μg/mL). On the contrary, all investigated structures were practically inactive against Staphylococcus aureus (MIC>1000 μg/mL).

Asunto(s)

Humanos , Antibacterianos , Candida albicans/genética , Candida albicans/aislamiento & purificación , Resistencia a Medicamentos , Farmacorresistencia Microbiana , Escherichia coli/enzimología , Escherichia coli/genética , Predisposición Genética a la Enfermedad , Técnicas In Vitro , Métodos , Prevalencia , Virulencia

RESUMEN

In the present investigation, the basic esters of meta-alkoxyphenylcarbamic acid bearing variously substituted N-phenylpiperazine fragment were screened for their in vitro antimicrobial activity against Staphylococcus aureus, Escherichia coli and Candida albicans, respectively. The most effective against Escherichia coli was found the compound 6d (MIC=195,3 µg/mL) bearing simultaneously para-fluoro substituent at the 4-phenylpiperazin-1-yl core and meta-methoxy side chain in the lipophilic part of the molecule. From whole analyzed set of the molecules the substance 8e with propoxy side chain forming meta-alkoxyphenylcarbamoyl fragment and lipophilic, sterically bulky meta-trifluoromethyl group attached at N-phenylpiperazine moiety was evaluated as the most active against Candida albicans (MIC=97,7 µg/mL). On the contrary, all investigated structures were practically inactive against Staphylococcus aureus (MIC>1000 µg/mL).

RESUMEN

In the present investigation, the basic esters of meta-alkoxyphenylcarbamic acid bearing variously substituted N-phenylpiperazine fragment were screened for their in vitro antimicrobial activity against Staphylococcus aureus, Escherichia coli and Candida albicans, respectively. The most effective against Escherichia coli was found the compound 6d (MIC=195,3 g/mL) bearing simultaneously para-fluoro substituent at the 4phenylpiperazin-1-yl core and meta-methoxy side chain in the lipophilic part of the molecule. From whole analyzed set of the molecules the substance 8e with propoxy side chain forming meta-alkoxyphenylcarbamoyl fragment and lipophilic, sterically bulky meta-trifluoromethyl group attached at N-phenylpiperazine moiety was evaluated as the most active against Candida albicans (MIC=97,7 g/mL). On the contrary, all investigated structures were practically inactive against Staphylococcus aureus (MIC>1000 g/mL)