ABSTRACT
A new series of amino-acetonitrile derivatives (AAD) have been discovered that exhibit high anthelmintic activity against parasitic nematode species such as Haemonchus contortus and Trichostrongylus colubriformis. Significantly, these compounds also demonstrate activity against nematode strains resistant to the currently available broad-spectrum anthelmintics. The discovery, synthesis, structure-activity relationship and biological results are presented.
Subject(s)
Aminoacetonitrile/pharmacology , Anthelmintics/pharmacology , Haemonchus/drug effects , Trichostrongylus/drug effects , Aminoacetonitrile/analogs & derivatives , Aminoacetonitrile/chemical synthesis , Animals , Anthelmintics/chemical synthesis , Dose-Response Relationship, Drug , Models, Chemical , Parasitic Sensitivity Tests , Structure-Activity RelationshipABSTRACT
Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics--the benzimidazoles, imidazothiazoles and macrocyclic lactones--has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics.
Subject(s)
Aminoacetonitrile/analogs & derivatives , Aminoacetonitrile/pharmacology , Anthelmintics/classification , Anthelmintics/pharmacology , Drug Resistance , Nematoda/drug effects , Parasitic Diseases, Animal/parasitology , Aging , Amino Acid Sequence , Aminoacetonitrile/adverse effects , Aminoacetonitrile/pharmacokinetics , Animals , Anthelmintics/chemistry , Anthelmintics/pharmacokinetics , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/chemistry , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Cattle , Cattle Diseases/drug therapy , Cattle Diseases/parasitology , Drug Resistance/genetics , Larva/drug effects , Larva/genetics , Molecular Sequence Data , Nematoda/genetics , Nematoda/physiology , Parasitic Diseases, Animal/drug therapy , Receptors, Nicotinic/chemistry , Receptors, Nicotinic/genetics , Receptors, Nicotinic/metabolism , Sheep/parasitology , Sheep Diseases/drug therapy , Sheep Diseases/parasitologyABSTRACT
The asymmetric synthesis of a series of 2-(1-aminoalkyl) piperidines using (-)-2-cyano-6-phenyloxazolopiperidine 1 is described. LiAlH(4) reduction of 1 followed by hydrogenolysis led to the diamine 3. The same strategy applied to C-2-methylated compound 7 afforded [(2S)-2-methylpiperidin-2-yl]methanamine (9). Addition of lithium derivatives to the cyano group of 1 resulted in the formation of an intermediate imino bicyclic system (11a-c) which could be diastereoselectively reduced to substituted diamino alcohols 13a-c. The addition of an excess of PhLi to 1 in the presence of LiBr furnished disubstituted amine 19, the precursor of diphenyl[(2S)-piperidin-2-yl]methanamine (22).
