Edward F. Rogers

Anticoccidial riboflavine antagonists.

4 types of riboflavine antagonists have broad-spectrum activity in poultry coccidiosis. 5-Deazariboflavine is most effective. 10-Benzyl analogs of riboflavine control intestinal species of coccidia.

ANTIPARASITIC DRUGS. V. ANTICOCCIDIAL ACTIVITY OF 4-AMINO-2-ETHOXY-BENZOIC ACID AND RELATED COMPOUNDS.

Summary 1. Preparations of the 4-amino, 4-acetamido and 4-benzamido derivatives of methyl-2-ethoxybenzoate and of 4-amino-2-ethylaminobenzoic acid are reported. 2. Anti-coccidial activity is demonstrated for 2-substituted PABAs, especially those containing 2-alkoxy, alkythio and alkylamino groups. 3. The most potent compounds are 4-amino-2-ethoxybenzoic acid and its ester and N-acyl derivatives. The authors gratefully acknowledge the help of Mr. J. L. Ciminera in designing the statistical procedure used in the bio assay.

Antiparasitic Drugs. II. Anticoccidial Activity of 4,5 imidazoledicarboxamide and Related Compounds

Summary 1. Preparation of 7 substituted imidazoles has been described. 2. Anticoccidial activity was demonstrated for imidazole-4-carboxamide and certain related compounds. 3. The most potent compound was 4,5-imidazoledicarboxamide (glycarbylamide). 4. Replacement of one or both carboxamides in the 4.5 positions on the imidazole ring reduced or completely eliminated the anticoccidial activity of glycarbylamide. Substitutions at the 1 or 2 positions on the imidazole ring produced compounds of less activity than glycarbylamide.

Eimeria tenella: Specific reversal of t-butylaminoethanol toxicity for parasite and host by choline and dimethylaminoethanol

Abstract t -Butylaminoethanol is an anticoccidial compound that is related structurally to the metabolically active substances, dimethylaminoethanol, and choline. Toxic effects of t -butylaminoethanol for chickens and Eimeria tenella are specifically overcome by feeding sufficient amounts of dimethylaminoethanol or choline. Dietary concentrations of the two above metabolites required to totally overcome toxic effiects of t -butylaminoethanol were determined and are expressed as the reversal ratio, inhibitor ( t -butylamino-ethanol): metabolite. The inhibitor:choline ratio for total reversal of toxic effects of the inhibitor in chickens is approximately 1:10 over a concentration range of inhibitor from 0.019 to 0.05%. The inhibitor:choline ratio for reversal of antiparasitic effects is approximately 1:200 with a concentration of 0.01% inhibitor. The inhibitor:Dimethylaminoethanol ratio for reversal of toxic effects of the inhibitor in the chicken is approximately 1:7 with a concentration of 0.015% inhibitor. The inhibitor:dimethylaminoethanol ratio for reversal of antiparasitic effects is approxmately 1:20 wth a concentration of 0.01% inhibitor.

Eimeria tenella: synergistic interaction of sulfaquinoxaline and t-butylaminoethanol in the chicken.

A significant (P < 0.001) synergistic interaction between sulfaquinoxaline and t-butylaminoethanol was demonstrated against a sulfaquinoxaline-resistant strain of Eimeria tenella in chickens. The t-butylaminoethanol is a dimethylaminoethanol- and choline-reversible anticoccidial whereas sulfaquinoxaline is a classic PABA-reversible anticoccidial.

Chapter 24: The Antimetabolite Concept in Drug Design

Publisher Summary Medicinal chemists were impressed by the success of the sulfa drugs and the accompanying theory, but became disenchanted when further applications met with persistent failure. Their skepticism was akin to the distrust entertained toward “electron-pushers” by the previous generation of organic chemists. The concept has widened considerably since then, with recognition of biochemical strategies other than growth factor antagonism. Today the term antimetabolite encompasses a multitude of compounds that inhibit the normal operations of enzymes, transport and binding proteins and receptors, by substitution for their usual substrates or cofactors and regulatory agents. Many apt illustrations of ways to achieve selectivity are drawn also from agricultural pest control, the other major area of applied comparative biochemistry. Discovery of the mechanism of action of an interesting drug at the enzyme level may be very profitable because the reward is the first chance at rational exploitation. The antihypertensive drug methyldopa provides an example of the difficulty in mechanism identification. The compound was designed to block norepinephrine synthesis at the DOPA decarboxylation step. Methyldopa does inhibit the decarboxylase, but its antihypertensive activity is now ascribed to the “false transmitter” activity of its metabolism product, a-methylnorepinephrine. In designing an antimetabolite, it is important to reduce or eliminate effects on off-target reactions. Several examples may be enlightening. Amprolium, previously cited as a thiamine transport inhibitor, lacks the hydroxyethyl group present in the vitamin and its classical antagonist pyrithiamine. Conversion to a pyrophosphate is impossible: hence the undesirable involvement in cocarboxylase (B1-PP)-mediated reactions, which happens with pyrithiamine–pyrophosphate, is avoided.