ABSTRACT
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.
Subject(s)
Coccidiosis/drug therapy , Coccidiostats/pharmacology , Eimeria/drug effects , Pyrroles/pharmacology , Animals , Chickens , Coccidiostats/chemical synthesis , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Eimeria/enzymology , Female , Molecular Structure , Oocysts/drug effects , Oocysts/physiology , Protein Kinase Inhibitors/pharmacology , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Coccidiosis/drug therapy , Coccidiostats/pharmacology , Imidazoles/chemistry , Protein Kinase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Animals , Chemistry, Pharmaceutical/methods , Coccidiostats/chemistry , Cyclic GMP-Dependent Protein Kinases/metabolism , Drug Design , Eimeria tenella , Models, Chemical , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Coccidiostats/chemical synthesis , Coccidiostats/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Pyridines/chemistry , Pyridines/chemical synthesis , Pyridines/pharmacology , Animals , Coccidiostats/chemistry , Eimeria/drug effects , Imidazoles/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Coccidiostats/chemical synthesis , Coccidiostats/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Animals , Coccidiostats/chemistry , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Eimeria tenella/drug effects , Eimeria tenella/enzymology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Coccidiostats/chemistry , Coccidiostats/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Hydroxylation , Structure-Activity RelationshipABSTRACT
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.
