RESUMEN
Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Recently, we reported the synthesis and biological activity of potent imidazo[1,2-a]pyridine anticoccidial agents. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we report the synthesis and anticoccidial activity of a second set of such compounds, focusing on derivatization of the amine side chain at the imidazopyridine 7-position. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.
Asunto(s)
Coccidiostáticos/síntesis química , Coccidiostáticos/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Animales , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Eimeria/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we present the synthesis and biological activity of imidazo[1,2-a]pyridine anticoccidial agents. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.
Asunto(s)
Coccidiostáticos/síntesis química , Coccidiostáticos/farmacología , Eimeria/efectos de los fármacos , Imidazoles/síntesis química , Imidazoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Animales , Disponibilidad Biológica , Coccidiostáticos/química , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Eimeria/fisiología , Imidazoles/química , Concentración 50 Inhibidora , Piridinas/químicaRESUMEN
Compounds 10a (IC50 110 pM) and 21 (IC50 40 pM) are the most potent inhibitors of Eimeria tenella cGMP-dependent protein kinase activity reported to date and are efficacious in the in vivo antiparasitic assay when administered to chickens at 12.5 and 6.25 ppm levels in the feed. However, both compounds are positive in the Ames microbial mutagenesis assay which precludes them from further development as antiprotozoal agents in the absence of negative lifetime rodent carcinogenicity studies.