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1.
Bioorg Med Chem Lett ; 11(4): 553-4, 2001 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-11229769

RESUMO

2-Deoxo- and 3-epi-paraherquamide A were synthesized from paraherquamide A. 2-Deoxoparaherquamide A has good activity against HC and TC in our jird model comparable to the parent compound, while 3-epi-paraherquamide A showed no activity.


Assuntos
Anti-Helmínticos/síntese química , Indolizinas/síntese química , Compostos de Espiro/síntese química , Animais , Anti-Helmínticos/farmacologia , Gerbillinae , Indolizinas/farmacologia , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 9(12): 1727-32, 1999 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-10397509

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/farmacologia
3.
J Vet Pharmacol Ther ; 21(3): 190-8, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9673959

RESUMO

PNU-87407 and PNU-88509, beta-ketoamide anthelmintics that are structurally related to each other and to the salicylanilide anthelmintic closantel, exhibit different anthelmintic spectra and apparent toxicity in mammals. The basis for this differential pharmacology was examined in experiments that measured motility and adenosine triphosphate (ATP) levels in larval and adult stages of the gastrointestinal nematode, Haemonchus contortus, and in a vertebrate liver cell line and mitochondria. PNU-87407 and PNU-88509 both exhibited functional cross-resistance with closantel in larval migration assays using closantel-resistant and -sensitive isolates of H. contortus. Each compound reduced motility and ATP levels in cultured adult H. contortus in a concentration- and time-dependent manner; however, motility was reduced more rapidly by PNU-88509, and ATP levels were reduced by lower concentrations of closantel than the beta-ketoamides. Tension recordings from segments of adult H. contortus showed that PNU-88509 induces spastic paralysis, while PNU-87407 and closantel induce flaccid paralysis of the somatic musculature. Marked differences in the actions of these compounds were also observed in the mammalian preparations. In Chang liver cells, ATP levels were reduced after 3 h exposures to > or = 0.25 microM PNU-87407, > or = 1 microM closantel or > or = 10 microM PNU-88509. Reductions in ATP caused by PNU-88509 were completely reversible, while the effects of closantel and PNU-87407 were irreversible. PNU-87407, closantel and PNU-88509 uncoupled oxidative phosphorylation in isolated rat liver mitochondria, inhibiting the respiratory control index (with glutamate or succinate as substrate) by 50% at concentrations of 0.14, 0.9 and 7.6 microM, respectively.


Assuntos
Anti-Helmínticos/farmacologia , Haemonchus/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Salicilanilidas/farmacologia , Desacopladores/farmacologia , Trifosfato de Adenosina/metabolismo , Amidas , Animais , Anti-Helmínticos/administração & dosagem , Linhagem Celular , Relação Dose-Resposta a Droga , Feminino , Haemonchus/fisiologia , L-Lactato Desidrogenase/análise , Larva/efeitos dos fármacos , Larva/fisiologia , Mitocôndrias Hepáticas/metabolismo , Fosforilação Oxidativa , Ratos , Trichostrongylus/efeitos dos fármacos , Trichostrongylus/fisiologia
4.
Bioorg Med Chem Lett ; 8(23): 3415-8, 1998 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-9873744

RESUMO

The dioxepinoindole ring found in marcfortine A (1) is unique among natural products. In order to determine the importance of the substitution pattern of the C24-C25 olefin, we synthesized a variety of analogs at these positions. With the exception of compound 5, none of these compounds exhibited any anthelmintic activity.


Assuntos
Anti-Helmínticos/síntese química , Compostos Bicíclicos com Pontes/síntese química , Indolizinas , Compostos de Espiro/síntese química , Animais , Anti-Helmínticos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Haemonchus/efeitos dos fármacos , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 8(23): 3317-20, 1998 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-9873726

RESUMO

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 , Gerbillinae
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