Anticoccidial activity

The polyether antibiotics exhibit a broad range of biological, antibacterial, antifungal, antiviral, anticoccidial, antiparasitic, and insecticidal activities. They improve feed efficiency and growth performance in mminant and monogastric animals. Only the anticoccidial activity in poultry and catde, and the effect on feed efficiency in mminants such as catde and sheep are of commercial interest. 

Anticoccidial Activity. The 1968 report that claimed monensin has activity against Eimeria sp., particularly E. tenella E. macdma., and E. acervulina greatly altered the prevention and control of coccidiosis in poultry (172). It is estimated that the polyether ionophores presently constitute more than 80% of the total worldwide usage of anticoccidials (173). Lasalocid and monensin have been approved for use in control of coccidiosis in cattle. 

In 1967 Agtarap et al. disclosed the isolation and structure of monensic acid (1).3 Compound 1, now known as monensin, is produced by a strain of Streptomyces cinamonensis, and exhibits broad-spectrum anticoccidial activity. Since its introduction on the market in 1971, monensin has been used very successfully to combat coccidial infections in poultry and as an additive in cattle feed.4 In the polyether family, monensin occupies a position of some historical significance. Although monensin was the fifth polyether... 

Replacement of one of the ethereal oxygen atoms by a methylene group is compatible with anticoccidial activity. For example, condensation of substituted aniline 35 with dimethyl ethoxymethylenemalonate affords aminoacrylate 36. Thermal cyclization in diphenyl ether gives neguinate (37).11... 

Anticoccidial activity, of polyether antibiotics, 20 135-136 Anticoccidials, 20 135—136 Anticorrosion agents, molybdenum compounds in, 17 39 Anticorrosion coatings, organic titanium compounds in, 25 134 Anti-corrosion metallic coatings, 1 713-714 Anticorrosion pigments, 19 411 Antidegradants... 

Some of these newer products are already taking an increasing share of the market. The discovery of the anticoccidial activity of monensin opened an entirely new field for the use of antibiotics in agriculture. 

Senidui-amicin is a relatively new polyether antibiotic that exhibits potent antimicrobial and anticoccidial activities. It is intended for use in broilers at a dosage of 25 ppm in the feed for 7 consecutive days. 

Although hundreds of different quinolone derivatives have been synthesized, only buquinolate, decoquinate, and methylbenzoquate have shown good efficacy against all species of chicken coccidia (Fig. 5.5). Their activity is essential coccidi-ostatic against the invading sporozoites as a result, if treatment is delayed after animals have become infected, anticoccidial activity is not effective. All quinolones are virtually insoluble in water and very poorly absorbed and, as a consequence, are nontoxic and result in low residue levels in the tissues of treated animals. 

Ethopabate (Fig. 5.7) is a substituted benzoic acid having anticoccidial activity against a number of Eimeria species. It is always used in combination with amprolium. 

Roxarsone has been used by the poultry industry due primarily to its ability to improve growth, feed conversion, and pigmentation to broilers. At least 50% of the poultry industry has used roxarsone as a growth promoter, although the drug also exhibits anticoccidial activity similar to that of arsanilic acid (3). Roxarsone is not approved for use as anticoccidial in the United States, but it is approved for use in chicken and turkey feeds as a growth promoter. It is added in poultry feeds at a rate of 50 ppm and in swine feeds at 25-37.5 ppm. 

Despite almost 10 years of intensive use in the production of broilers, this drug is remarkably free of resistance problems. Other ionophores have been tested and found to possess anticoccidial activity. Lasalocid (64) is in commerical use whilst salinomycin (65) and narasin (66) have recently been evaluated in field trials. 

Ethyl l-oxo-6-piperidino-l//-pyrimido[l,2-a]quinoline-2-carboxylate showed potent in vitro anticoccidial activity (92AAC2338). anhydro-1,3-Diethyl-2-hydroxy-4-oxo-4//-pyrimido[2,l-a]isoquinolinium hydroxyde (318) exhibits nonselective Ar and A2-adenosine receptor activities (84JMC1364) and proved to be an inhibitor of cyclic-AMP phosphodiesterase (81JMC1284). 8,9,10,ll-Tetrahydro-3-(l//-5-tetrazolyl)-4//-pyrimido[2,l-a]iso-quinolin-4-one exhibits antiulcer activity (84USP4457932). 

Ionophores, or polyether (PET) antibiotics, produced by various species of Streptomyces, possess broad spectrum anticoccidial activities. They are chemically characterized by several cyclic esters, a single terminal carboxylic acid group, and several hydroxyl groups. Representative members of this class include salinomycin (SAL), monensin (MON), lasalocid (LAS), narasin (NAR), maduramicin (MAD), and semduramicin (SEM). The main chemical properties of interest in the extraction methodology are their low polarities and instability under acidic conditions. They are able to form stable complexes with alkaline cations. All of these compounds, with the exception of LAS, bind monovalent cations (e.g., Na+ and K+). Lasalocid has a tendency to form dimers and can form complexes with divalent cations such as Mg2+ and Ca2+. The formation of metal complexes results in all of these compounds adopting a quasi-cyclic formation consequent to head-to-tail hydrogen bonding. No MRLs have yet been set by the EU for any of the carboxylic acid PETs (98). 

H-pyran synthesis from, 3, 739 tautomerism, 3, 644 UV spectra, 3, 598 Ionophore A23187 as antibiotic, 4, 374 Ionophore X14547A as antibiotic, 4, 374 Ionophores, 7, 732, 755 anticoccidial activity veterinary use, 1, 213... 

The use of antifolates in the treatment of coccidiosis in domestic animals has also been established. It has been found that compounds derived from 2,4-diamino-pyrimidines and 2,2-dialkyl-l-aryl-4,6-diamino-l,2-dihydro-s-triazines exhibit promising anticoccidial activity. The noteworthy compounds of this class were found to be pyrimethamine (33), diaverdine (35) and ormetoprim (36) [59]. The metabolites 31a,b of proguanil and chlorproguanil also exhibit marked activity against coccidiosis [60]. 

A few polysubstituted benzenes have been evaluated for their possible use in protozoal chemotherapy. RC-12 (57) is a pyrocatechol derivative, which was initially found to possess promising antimalarial activity. However, in clinical trials against P. vivax it failed to protect volunteers exposed to infected mosquitoes [16]. Another compound ethyl 4-acetamido-2-ethoxybenzoate (ethopabate, 58) has been found to exhibit anticoccidial activity [45,57]. Also some nitrobenzamides have been shown to have anticoccidial properties. The important drugs of this class are zoalene (59) [58], nitromide (60) [59] and alkomide (61) [45,60]. The detailed SAR on nitrobenzamides has been studied [59,61]. 

Among anticoccidials, polyether antibiotics have been the most widely used in the broiler industry over the last two decades because they provide excellent disease control and are refractory to resistance development (3). Polyether antibiotics are branch chained, polyoxygenated carboxylic acids that act as mobile carriers of cations (4) by rendering cations lipid-soluble, thereby enabling them to pass across membranes. This process disrupts cationic cross-membrane gradients and is responsible for their anticoccidial activity T3J. 

Semduramicin (Figure 1) is a new potent monocarboxylic polyether antibiotic with antimicrobial and anticoccidial activity (5). It is comparable to several widely used polyether antibiotics (6)y including the commercialized anticoccidial feed additives monesin, salinomycin, lasalo-cid, narasin and maduramicin. The discovery of semduramicin arose from an effort to identify fermentation-derived products for the treatment of coccidiosis in poultry (5). It is obtained from a fermentation of a mutated strain of Actinomadura roseorufa (7),... 

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