RESUMEN
Reductive amination of repromicin with polyfunctional amines has led to new macrolide antibacterial agents, some of which are highly potent against the Gram-negative pathogen Pasteurella multocida both in vitro and in a mouse infection model. A key element in this discovery was the recognition that among certain known macrolides increasing lipophilicity results in diminished in vivo activity. One repromicin derivative, 20-[N-[3-(dimethylamino)-propyl]-N-L-alanylamino]-20-deoxorepro micin (35), was selected for advanced evaluation. At 5 mg/kg, a single subcutaneous dose was found to control induced pasteurellosis in swine and induced respiratory disease in cattle.
Asunto(s)
Antibacterianos/farmacología , Macrólidos , Pasteurella multocida/efectos de los fármacos , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/uso terapéutico , Cromatografía Líquida de Alta Presión , Leucomicinas/síntesis química , Leucomicinas/química , Leucomicinas/aislamiento & purificación , Leucomicinas/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Infecciones por Pasteurella/tratamiento farmacológico , Infecciones por Pasteurella/veterinaria , Tilosina/análogos & derivados , Tilosina/farmacologíaRESUMEN
We have employed semisynthesis to enhance the anticoccidial potency of a polyether ionophore. CP-72,588 is the alpha-methyl analog of the fermentation-derived polyether ionophore UK-58,852. The parent ionophore required a dose of 15 ppm to achieve anticoccidial efficacy in chickens equivalent to that of salinomycin at 60 ppm. CP-72,588 demonstrated substantially improved potency, with efficacy at 5 to 7.5 ppm. The intrinsic antimicrobial potencies of the two ionophores are similar; however, CP-72,588 was found in chicken tissues at higher levels than those of the parent ionophore when each was administered at the same dose (8 ppm). The enhanced potency of CP-72,588 may be partially due to enhanced uptake into tissues.
Asunto(s)
Antibacterianos/uso terapéutico , Coccidiosis/tratamiento farmacológico , Coccidiostáticos/uso terapéutico , Eimeria/efectos de los fármacos , Éteres Cíclicos/uso terapéutico , Ionóforos/farmacología , Animales , Antibacterianos/farmacocinética , Pollos , Coccidiostáticos/farmacocinética , Éteres/farmacocinética , Éteres/uso terapéutico , Éteres Cíclicos/farmacocinética , Ionóforos/farmacocinética , Masculino , Pruebas de Sensibilidad MicrobianaRESUMEN
While fermentation-derived polyether ionophores such as salinomycin are the dominant class of anticoccidial feed additives, there is little information concerning the structural features which confer optimal potency/efficacy in this important series. The recently discovered microbial polyether 1a, featuring potent, broad-spectrum anticoccidial activity, was employed as a template to explore structure-activity relationships. A number of single-step synthetic modifications targeted structural changes in both the lipophilic carbon backbone and the ion-binding cavity of 1a. Although previous semisynthetic transformations among the polyether ionophores almost always resulted in a substantial loss of anticoccidial activity, we obtained several analogues, altered on the periphery of the ionophore-ion complex, which retain good potency and efficacy. Monoglycone 7 (semduramicin sodium) has the most impressive anticoccidial profile of this series, and is undergoing further biological testing under field conditions.
Asunto(s)
Coccidiostáticos/química , Ionóforos/química , Animales , Pollos , Coccidiostáticos/farmacología , Eimeria tenella/efectos de los fármacos , Ionóforos/farmacología , Espectroscopía de Resonancia Magnética , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
Activity against the coccidial pathogen Eimeria tenella in chickens has been discovered among alpha 2 adrenergic agonists. The clonidine analog 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine was active in feed at 7.5 ppm, a concentration similar to the use levels of potent commercial agents, e.g., maduramicin. Additional alpha 2 agonists were also found to have anticoccidial activity, for example, the catecholamine nordefrin, which is chemically unrelated to clonidine. However, alpha 1 agonists and alpha antagonists were inactive. These observations imply that anticoccidial effects reflect involvement of a receptor with the characteristics of the vertebrate alpha 2 adrenoceptor. alpha 2 agonists that permeate the blood-brain barrier (like clonidine) inhibit feed intake at efficacious levels, whereas those that are restricted to the peripheral compartment (such as catecholamines) do not inhibit feed intake as much. Hence, anticoccidial efficacy may be a peripheral adrenergic effect whereas depression of feed intake is likely centrally mediated.
Asunto(s)
Agonistas alfa-Adrenérgicos/uso terapéutico , Pollos/parasitología , Coccidiosis/veterinaria , Coccidiostáticos/uso terapéutico , Eimeria tenella , Imidazoles/uso terapéutico , Indazoles/uso terapéutico , Enfermedades de las Aves de Corral/tratamiento farmacológico , Agonistas alfa-Adrenérgicos/síntesis química , Agonistas alfa-Adrenérgicos/química , Animales , Peso Corporal/efectos de los fármacos , Clonidina/análogos & derivados , Clonidina/uso terapéutico , Coccidiosis/tratamiento farmacológico , Coccidiosis/parasitología , Coccidiostáticos/síntesis química , Coccidiostáticos/química , Imidazoles/síntesis química , Imidazoles/química , Indazoles/síntesis química , Indazoles/química , Masculino , Enfermedades de las Aves de Corral/parasitologíaRESUMEN
The anticoccidial activity of semduramicin against laboratory isolates of five species of poultry Eimeria was investigated. In laboratory scale battery trials, semduramicin at 20 to 30 ppm demonstrated broad-spectrum anticoccidial efficacy equivalent to salinomycin at 60 ppm. Also, semduramicin at 25 ppm was fed to uninfected cockerels in batteries for 21 days, and growth rate and feed efficiency were found to be equivalent to birds fed salinomycin at 60 ppm. Semduramicin was well tolerated when coadministered with tiamulin. Semduramicin demonstrated the same activity whether produced by semisynthesis or by direct fermentation.
Asunto(s)
Pollos/parasitología , Coccidiosis/veterinaria , Eimeria tenella/efectos de los fármacos , Nigericina/análogos & derivados , Enfermedades de las Aves de Corral/tratamiento farmacológico , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Coccidiosis/tratamiento farmacológico , Diterpenos/farmacología , Diterpenos/uso terapéutico , Quimioterapia Combinada/farmacología , Quimioterapia Combinada/uso terapéutico , Ionóforos/farmacología , Ionóforos/uso terapéutico , Masculino , Nigericina/síntesis química , Nigericina/farmacología , Nigericina/uso terapéuticoRESUMEN
An aspect of our work with quinoxaline 1,4-dioxides involved the synthesis and reactivity of (quinoxalin-2-yl)acrylonitrile 1,4-dioxide. We have found that treatment of a methanolic solution of this unsaturated nitrile (cis or trans) with primary alkylamines affords a novel series of pyrido[2,3-b]quinoxaline 5-oxides. These tricyclic pyridoquinoxalines represent a unique class of agents with oral activity against trichomoniasis.
Asunto(s)
Antitricomonas/síntesis química , Quinoxalinas/síntesis química , Animales , Fenómenos Químicos , Química , Masculino , Ratones , Quinoxalinas/farmacología , Quinoxalinas/uso terapéutico , Tricomoniasis/tratamiento farmacológicoRESUMEN
A series of novel 3,4-dihydropyrido[3,4-b]quinoxalin-1(2H)-one 5,10-dioxides was synthesized using an intramolecular amidation reaction. The lactams were screened in vitro and in vivo against Salmonella choleraesuis, Pasteurella multocida, and Escherichia coli. An N-methyl analogue was the most potent member of this series, with antibacterial activity comparable to that of the commercially important quinoxaline 1,4-dioxide carbadox.