RESUMEN
Over the last decade, the isoxazoline motif has become the intense focus of crop protection and animal health companies in their search for novel pesticides and ectoparasiticides. Herein we report the discovery of sarolaner, a proprietary, optimized-for-animal health use isoxazoline, for once-a-month oral treatment of flea and tick infestation on dogs.
Asunto(s)
Antiparasitarios/química , Antiparasitarios/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Infestaciones por Pulgas/veterinaria , Isoxazoles/química , Isoxazoles/uso terapéutico , Infestaciones por Garrapatas/veterinaria , Animales , Antiparasitarios/farmacología , Ctenocephalides/efectos de los fármacos , Perros , Femenino , Infestaciones por Pulgas/tratamiento farmacológico , Isoxazoles/farmacología , Masculino , Rhipicephalus sanguineus/efectos de los fármacos , Siphonaptera/efectos de los fármacos , Infestaciones por Garrapatas/tratamiento farmacológico , Garrapatas/efectos de los fármacosRESUMEN
Synthetic approaches to the lantibiotics, a family of thioether-bridged antimicrobial peptides, require flexible synthetic routes to a variety of orthogonally protected derivatives of lanthionine 1. The most direct approaches to lanthionine involve the reaction of cysteine with an alanyl beta-cation equivalent. Several possibilities exist for the alanyl beta-cation equivalent, including direct activation of serine under Mitsunobu conditions: however, the low reactivity of sulfur nucleophiles in the Mitsunobu reaction has previously precluded its use in the synthesis of the lantibiotics. We report here a new approach to the synthesis of protected lanthionine, using a novel variant of the Mitsunobu reaction in which catalytic zinc tartrate is used to enhance the nucleophilicity of the thiol. In the course of these studies, we have also demonstrated that the synthesis of lanthionine from trityl-protected beta-iodoalanines is prone to rearrangement, via an aziridine, to give predominantly trityl-protected alpha-iodo-beta-alanines, and hence norlanthionines, as the major products.
Asunto(s)
Alanina/análogos & derivados , Alanina/síntesis química , Antibacterianos/síntesis química , Péptidos , Alanina/química , Antibacterianos/química , Estructura Molecular , Estereoisomerismo , SulfurosRESUMEN
Two diastereomeric analogues of ring C of nisin incorporating a novel norlanthionine residue have been synthesized via a triply orthogonal protecting group strategy. A full structural study was carried out by NMR, which elucidated the conformational properties of the two peptides and enabled the identity of each diastereoisomer to be proposed.