RESUMEN
Chlorophene-loaded nanospheres with various formulation parameters were evaluated. The optimal formulation was found at 0.1% w/v of poloxamer 407, 15 mL of ethyl acetate and 20% initial chlorophene loading that provided the suitable size (179 nm), the highest loading content (19.2%), encapsulation efficiency (88.0%) and yield (91.6%). Moreover, encapsulation of chlorophene in nanospheres was able to prolong and sustain drug release over one month. Chlorophene-loaded nanospheres were effective against Staphylococcus aureus (S. aureus) and Candida albicans (C. albicans), the main cause of hospital-acquired infections. Chlorophene-loaded nanospheres were effective against S. aureus (>46 µg/mL) and C. albicans (>184 µg/mL). These nanospheres appeared to have profound effect on the time-dependent hemolytic activity due to gradual release of chlorophene. At the concentration of 46 µg/mL, nearly no HRBC hemolysis in 24 h compared to 80% of hemolysis from free drug. In conclusion, polymeric nanospheres were successfully fabricated to encapsulate chlorophene which can eliminate inherent toxicity of drugs and have potential uses in prolonged release of antimicrobial.
Asunto(s)
Antiinfecciosos/síntesis química , Diclorofeno/análogos & derivados , Sistemas de Liberación de Medicamentos/métodos , Nanosferas/química , Antiinfecciosos/administración & dosificación , Candida albicans/efectos de los fármacos , Candida albicans/fisiología , Química Farmacéutica , Preparaciones de Acción Retardada , Diclorofeno/administración & dosificación , Diclorofeno/síntesis química , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Nanosferas/administración & dosificación , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiologíaRESUMEN
During our research using a high-throughput screening system for discovery of a new class of human liver glycogen phosphorylase a (hLGPa) inhibitors, a series of 3-(3,4-dichlorophenyl)acrylamide derivatives were synthesized, and their inhibitory activities toward hLGPa were evaluated. Among the derivatives, (2E,2'E)-N,N'-pentane-1,5-diylbis[3-(3,4-dichlorophenyl)acrylamide] (6c) inhibited hLGPa with an IC(50) value of 0.023 microM. An X-ray crystallographic study of the enzyme-6c complex showed that the inhibitor is bound at the dimer interface site, where the 3,4-dichlorophenyl moiety interacts hydrophobically with the enzyme.