RESUMEN
Neuraminidase, which plays a critical role in the influenza virus life cycle, is a target for new therapeutic agents. The study of structure-activity relationships revealed that the C-5 position amino group of oseltamivir was pointed to 150-cavity of the neuraminidase in group 1. This cavity is important for selectivity of inhibitors against N1 versus N2 NA. A serial of influenza neuraminidase inhibitors with the oseltamivir scaffold containing lipophilic side chains at the C-5 position have been synthesized and evaluated for their influenza neuraminidase inhibitory activity and selectivity. The results indicated that compound 13o (H5N1 IC50 = 0.1 ± 0.04 µm, H3N2 IC50 = 0.26 ± 0.18 µm) showed better inhibitory activity and selectivity against the group 1 neuraminidase. This study may provide a clue to design of better group 1 neuraminidase inhibitors.
Asunto(s)
Inhibidores Enzimáticos/metabolismo , Neuraminidasa/antagonistas & inhibidores , Oseltamivir/metabolismo , Sitios de Unión , Dominio Catalítico , Inhibidores Enzimáticos/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Subtipo H3N2 del Virus de la Influenza A/enzimología , Subtipo H5N1 del Virus de la Influenza A/enzimología , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Neuraminidasa/metabolismo , Oseltamivir/química , Relación Estructura-ActividadRESUMEN
This paper described the preparation and liver targeting traits of new solid lipid nanoparticles (SLN) containing floxuridinyl dibutyrate (FUDRB) modified with beta-D-galactosides (G2). FUDRB-SLN and FUDRB-G2SLN were prepared by thin layer ultrasonic technique. Transmission electron microscopy micrograph analysis demonstrated that the particle sizes of FUDRB-SLN and FUDRB-G2SLN were (137.5 +/- 11.1) nm and (95.0 +/- 10.7) nm. Drug loading were 9.64% and 8.56%, and entrapment efficiency were 99.81% and 96.23%, respectively. The concentrations of floxuridine (FUDR) in serum and some organs (liver, kidney and lung) were determined by RP-HPLC after iv administration of SLN. FUDR release was confirmed, and a significant enrichment of SLN modified with G2 was observed in liver with G2 complex (targeting rates of SLN-G2 was 8.28 for liver) in comparison with FUDR-sol (targeting rate was 2.56). FUDR could be detected in liver in mice at 480 min after iv administration of FUDRB-G2SLN. These results suggested that incorporation of G2 (4%-5%, g/g) into SLN enhanced the liver targeting-ability of FUDRB. SLN containing G2 could be a useful drug carrier system for liver targeting.
