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.

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.

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.

Activity against the coccidial pathogen Eimeria tenella in chickens has been discovered among a2 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 a2 agonists were also found to have anticoccidial activity, for example, the catecholamine nordefrin, which is chemically unrelated to clonidine. However, al agonists and a antagonists were inactive. These observations imply that anticoccidial effects reflect involvement of a receptor with the characteristics of the vertebrate a2 adrenoceptor. a2 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.Coccidiosis, an intestinal disease of great economic importance in the poultry industry, is caused by intracellular protozoan parasites of the genus Eimeria. Although more than 20 different anticoccidial agents have been commercialized, the current drugs of choice belong to a single class: the polyether ionophores. Because of the ever-present threat that coccidia will develop resistance to these agents, there is a continuing need to discover new classes of anticoccidial agents.In the course of evaluating compounds from our files, 7-bromo-N-(2-imidazolidinylidene)-lH-indazol-6-amine (compound I) proved to be active against Eimeria tenella infections in chickens; however, it led to low weight gains. Compound I was prepared originally as a clonidine analog. Clonidine produces a variety of effects, owing to its a2 adrenergic agonist activities, and has found clinical use as an antihypertensive agent (7). Compound I also shows a2 agonist properties (3). We therefore explored the possibility that the observed anticoccidial activity was dependent upon stimulation of a2 adrenoceptors. If this were the case, it would follow that other a2 agonists, those structurally unrelated to clonidine, would show this effect. Conversely, a1 adrenergic agonists and a antagonists should be inactive. To test this hypothesis, we evaluated the anticoccidial activities of a variety of a adrenergic agents.We discovered that (i) among a adrenergic agents, anticoccidial activity is associated only with a2 agonists; (ii) a2 agonists other than clonidine analogs are also effective; and (iii) a2 agonists that cannot cross the blood-brain barrier, such as catecholamines, are effective and at the same time not as weight suppressive.MATERIALS AND METHODS General. Melting points are uncorrected. Yields were not maximized. All compounds had 'H nuclear magnetic resonance spectra that were consistent with their assigned structures. The following agents were either purchased from * Corresponding author. 7-Bromo-lH-indazol-6-amine. A solu...

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.