ABSTRACT
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.
Subject(s)
Anthelmintics/chemical synthesis , Indolizines/chemical synthesis , Spiro Compounds/chemical synthesis , Animals , Anthelmintics/pharmacology , Gerbillinae , Indolizines/pharmacology , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Anthelmintics/chemical synthesis , Helminth Proteins/metabolism , Neuropeptides/metabolism , Thiadiazoles/chemical synthesis , Animals , Anthelmintics/chemistry , Anthelmintics/pharmacology , Ascaris suum , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/physiology , Helminth Proteins/drug effects , Neuropeptides/drug effects , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/pharmacologyABSTRACT
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.
Subject(s)
Anthelmintics/pharmacology , Haemonchus/drug effects , Mitochondria, Liver/drug effects , Salicylanilides/pharmacology , Uncoupling Agents/pharmacology , Adenosine Triphosphate/metabolism , Amides , Animals , Anthelmintics/administration & dosage , Cell Line , Dose-Response Relationship, Drug , Female , Haemonchus/physiology , L-Lactate Dehydrogenase/analysis , Larva/drug effects , Larva/physiology , Mitochondria, Liver/metabolism , Oxidative Phosphorylation , Rats , Trichostrongylus/drug effects , Trichostrongylus/physiologyABSTRACT
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.
Subject(s)
Anthelmintics/chemical synthesis , Coumarins/chemical synthesis , Animals , Anthelmintics/pharmacology , Coumarins/pharmacology , GerbillinaeABSTRACT
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.
