RESUMO
Diaryl-(4-piperidinyl)-pyrrole derivatives bearing cyclic amine substituents have been synthesized and evaluated as anticoccidial agents. Improvements in potency of Et-PKG inhibition, such as azetidine derivative 3a, and broad spectrum anticoccidial activities in feed, such as morpholine derivative 8c, have been achieved.
Assuntos
Coccidiose/tratamento farmacológico , Coccidiostáticos/farmacologia , Eimeria/efeitos dos fármacos , Pirróis/farmacologia , Animais , Galinhas , Coccidiostáticos/síntese química , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Eimeria/enzimologia , Feminino , Estrutura Molecular , Oocistos/efeitos dos fármacos , Oocistos/fisiologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/síntese química , Pirróis/química , Relação Estrutura-AtividadeRESUMO
Diaryl imidazo[1,2-a]pyridine derivatives, such as 6a and 7i, have been synthesized and found to be potent inhibitors of parasite PKG activity. The most potent compounds are the 7-isopropylaminomethyl analog 6a and 2-isopropylamino analog 7i. These compounds are also fully active in in vivo assay as anticoccidial agents at 25 ppm in feed.
Assuntos
Coccidiose/tratamento farmacológico , Coccidiostáticos/farmacologia , Imidazóis/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Piridinas/farmacologia , Animais , Química Farmacêutica/métodos , Coccidiostáticos/química , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Desenho de Fármacos , Eimeria tenella , Modelos Químicos , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Compounds 10a-10d and 10i are very potent inhibitors of Eimeria tenella cGMP-dependent protein kinase (0.081-0.32 nM) and are very efficacious antiparasitic agents in vivo when administered to chickens at 12.5-25 ppm levels in the feed.
Assuntos
Coccidiostáticos/síntese química , Coccidiostáticos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Piridinas/química , Piridinas/síntese química , Piridinas/farmacologia , Animais , Coccidiostáticos/química , Eimeria/efeitos dos fármacos , Imidazóis/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
2-(4-Fluorophenyl)-3-(4-pyridinyl)-5-substituted pyrroles were prepared and evaluated as anticoccidial agents in both in vitro and in vivo assays. Among the compounds evaluated, the dimethylamine-substituted pyrrole 19a is the most potent inhibitor of Eimeria tenella PKG (cGMP-dependent protein kinase). Further SAR studies on the side chain of the 2-pyrrolidine nitrogen did not enhance in vivo anticoccidial activity.
Assuntos
Coccidiostáticos/síntese química , Coccidiostáticos/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Animais , Coccidiostáticos/química , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Eimeria tenella/efeitos dos fármacos , Eimeria tenella/enzimologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Pirróis/química , Relação Estrutura-AtividadeRESUMO
Diaryl-(4-piperidinyl)-pyrrole derivatives bearing hydroxylated N-alkyl substituents have been synthesized and evaluated as anticoccidial agents. High potency in Et-PKG inhibition and broad-spectrum anticoccidial activities have been observed on compounds, such as 4b and 5h, which are fully efficacious in vivo at 50 ppm in feed.
Assuntos
Coccidiostáticos/química , Coccidiostáticos/farmacologia , Pirróis/química , Pirróis/farmacologia , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Hidroxilação , Relação Estrutura-AtividadeRESUMO
Several analogs of 2,3-diaryl pyrroles were synthesized and evaluated as inhibitors of Eimeria tenella cGMP-dependent protein kinase and in in vivo anticoccidial assays. A 4-fluorophenyl group enhances both in vitro and in vivo activities. The most potent analogs are the 5-(N-methyl, N-ethyl, and N-methylazetidine methyl) piperidyl derivatives 12, 23, and 34. These compounds have a broad spectrum of activity. Based on the in vivo efficacy and cost of synthesis, the N-ethyl analog 23 was chosen as a novel anticoccidial agent for a field trial.