RESUMO
Following our discovery of the strong binding of thiadiazole 1 to the AF-2 neuropeptide receptor of gastrointestinal nematodes (e.g., Ascaris suum), we prepared two series of analogs. Only the series containing the thiadiazole ring had potencies comparable to that of compound 1. Analog 50 exhibited an apparent potency in the AF-2 binding assay 300 times that of compound 1.
Assuntos
Anti-Helmínticos/síntese química , Proteínas de Helminto/metabolismo , Neuropeptídeos/metabolismo , Tiadiazóis/síntese química , Animais , Anti-Helmínticos/química , Anti-Helmínticos/farmacologia , Ascaris suum , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Proteínas de Helminto/efeitos dos fármacos , Neuropeptídeos/efeitos dos fármacos , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacologiaRESUMO
We have prepared several anthelmintic coumarins based on the beta-hydroxyketoamide (BKA) template and have shown that this template remains valid over a wide range of changes to the coumarin moiety allowing for the inclusion of carbocyclic, bicyclic, and heterocyclic rings.
Assuntos
Anti-Helmínticos/síntese química , Cumarínicos/síntese química , Animais , Anti-Helmínticos/farmacologia , Cumarínicos/farmacologia , GerbillinaeRESUMO
A novel cyclodepsipeptide of fungal origin, PF1022A, recently was reported to have anthelmintic activity. To supplement published reports and determine potential utility of PF1022A as a ruminant anthelmintic, the compound was examined in in vitro and in vivo models. Assays used measured motility of Haemonchus contortus (intrinsic drug potency), ATP levels (parasite death), and activity against H. contortus, Ostertagia ostertagi, and Trichostrongylus colubriformis in the jird (spectrum, potency, and efficacy by various routes). The potency of PF1022A in reducing motility is greater than commercial anthelmintics. Examination of ATP levels in PF1022A-paralyzed H. contortus indicates that worms are not killed, suggesting the compound acts as a neurotoxin in nematodes. In the jird, PF1022A has activity orally against each of the parasites studied and at doses comparable to all commercial anthelmintics, except the macrocyclic lactones which are more potent. Unfortunately, for some nematode species, parenteral delivery is ineffective at realistic doses.