ABSTRACT
Anthelmintic resistance has become a global phenomenon in gastro-intestinal nematodes of farm animals, including multi-drug resistance against the three major classes of anthelmintics. There is an urgent need for an anthelmintic with a new mode of action. The recently discovered amino-acetonitrile derivatives (AADs) offer a new class of synthetic chemicals with anthelmintic activity. The evaluation of AADs was pursued applying in vitro assays and efficacy and tolerability studies in rodents, sheep, and cattle. Amongst various suitable compounds, AAD 1566 eliminated many tested pathogenic nematode species, both at larval and adult stages, at a dose of 2.5 mg/kg bodyweight in sheep and 5.0 mg/kg bodyweight in cattle. The same doses were sufficient to cure animals infected with resistant or multi-drug-resistant nematode isolates. These findings, complemented by the good tolerability and low toxicity to mammals, suggest that AAD 1566, monepantel, would be a suitable anthelmintic drug development candidate.
Subject(s)
Aminoacetonitrile/analogs & derivatives , Aminoacetonitrile/pharmacology , Antinematodal Agents/chemistry , Antinematodal Agents/pharmacology , Nematoda/drug effects , Nematode Infections/veterinary , Aminoacetonitrile/administration & dosage , Aminoacetonitrile/toxicity , Animals , Antinematodal Agents/administration & dosage , Antinematodal Agents/toxicity , Cattle , Larva/drug effects , Molecular Structure , Nematode Infections/drug therapy , Rodentia , SheepABSTRACT
A short stereoselective synthesis of N-acylamino-1,3-dienes was developed starting from the cyclobutene lactam 8, which was obtained from 2-hydroxypyridine by a photochemical electrocyclic reaction. The tert-butoxycarbonyl derivative 17 was prepared to facilitate nucleophilic attacks to the carbonyl group, and the subsequent thermal ring opening provided dienes 18-21. One of these (20) was used in the synthesis of the cyclohexene nucleoside 30. A Diels-Alder reaction between diene 20 and maleic anhydride provided the endo-cycloadduct 22a. Three additional steps yielded amine 26. Construction of the uracil moiety afforded intermediate 29. Cyclization and removal of the protecting groups occurred in one step in the presence of ammonia, giving the target molecule 30. Diene 20 also underwent [4 + 2] cycloaddition with methyl acrylate to provide predominantly the endo-product 23a, regioselectively.