RESUMO
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.
Assuntos
Aminoacetonitrila/farmacologia , Anti-Helmínticos/farmacologia , Haemonchus/efeitos dos fármacos , Trichostrongylus/efeitos dos fármacos , Aminoacetonitrila/análogos & derivados , Aminoacetonitrila/síntese química , Animais , Anti-Helmínticos/síntese química , Relação Dose-Resposta a Droga , Modelos Químicos , Testes de Sensibilidade Parasitária , Relação Estrutura-AtividadeRESUMO
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.
