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The preparation and anthelmintic activities of a series of 2-pyridinyl-5-isothiocyanatobenzimidazoles are described. In the primary oral mouse screen, six derivatives showed 100% taeniacidal activity at 0.2% in diet. The most active member in this series, 1c, is potentially an effective gastrointestinal nematocide in sheep at 50 mg/kg po.
A series of 3-halo-5-phenyl- and 3-phenyl-5-haloisoxazoles has demonstrated anthelmintic activity at doses ranging from 16 to 500 mg/kg orally against the rat roundworm, Nippostrongylus braziliensis. In the 5-phenyl series a halogen at the 3 position of the isoxazole ring was required for activity. However, in the 3-phenyl series activity was maintained after replacement of the 5-halogen with certain alkoxyl, thioalkoxyl, or amino groups. The 3-phenyl and 5-phenyl series apparently are not acting biologically at a common receptor site. Synthetic methods and structure-activity relationships are discussed.
A series of 1-(substituted cinnamamido)-2,4-imidazolidinediones has been prepared from the corresponding cinnamoyl chlorides and 1-amino-2,4-imidazolidinedione hydrochloride in pyridine. These compounds possess a significant degree of anthelmintic activity against the mouse pinworm Syphacia obvelata. The most active compounds are those substituted with halogen or cyano groups.
The synthesis and antiparasitic properties of 22 isothiocyanato-2-pyridinylbenzoxazoles and benzothiazoles are described; the preparation and anthelmintic activities of 14 isothiocyanato-2-thienyl-, -furyl-, and -pyrrolylbenzoxazoles are outlined. In mice experimentally infected with Nematospiroides dubius (nematode) and Hymenolepis nana (tapeworm), three derivatives, i.e., 5-isothiocyanato-2-(2-furyl)benzoxazole (34), 5-isothiocyanato-2-(5-methyl-2-furyl)benzoxazole (35), and 5-isothiocyanato-2-(1-methyl-1H-2-pyrroly)benzoxazole (37), show 100% nematocidal activity and two, i.e., 5- and 6-isothiocyanato-2-(3-pyridinyl)benzoxazole (5) and 5- and 6-isothiocyanato-2-(3-pyridinyl)benzthiazole (21), show 10% taeniacidal activity at 0.2% in the diet. Two derivatives (5 and 21) show good nematocidal activity in sheep. Maximum activity requires 3-pyridinyl derivatives for both the benzoxazole and benzothiazole series.
Six analogues of the anthelmintic cyclodepsipeptide PF1022A were prepared, each containing a small ring fused to the macrocycle to restrict the number of conformations the larger ring can adopt. It was anticipated that such conformational changes could lead to enhanced biological activity and selectivity. The analogues form two series of three members each. In one series, a carbon-based molecular bridge joins the methyl of a leucine residue with the methyl of its closest lactic acid residue to form five-, six-, and seven-membered lactam rings. In the second series, a leucine residue is replaced with five-, six-, and seven-membered nitrogen heterocycles. Decreasing the size of the small ring in the lactam series increasingly distorts the macrocycle and consistently decreases activity relative to PF1022A. In the leucine series, a similar trend is observed. Molecular modeling of PF1022A along with the analogues described herein suggests that the ability to exist in a highly symmetrical conformational state is a necessary condition for biological activity.
The structure of the unusual anthelmintic pyrrolobenzoxazine terpenoid natural product CJ-12662 was established by X-ray crystallography and partial synthesis from 2-chloronitrobenzene. An unusual Meisenheimer-type rearrangement was used to provide the core pyrrolobenzoxazine heterocycle, and coupling of a tetracyclic pyrrolobenzoxazine lactone with the terpene alcohol was used to complete the synthesis of CJ-12662.
The study of the anthelmintic terpenoid components from the Fiji sponge Axinyssa fenestratus (senior synonym of Leucophloeus fenestratus) and two Thailand sponges, Acanthella cavernosa and Topsentia sp., has yielded several new nitrogen-containing sesqui- and diterpenes of known carbon skeletons. Amorphane sesquiterpenes from A. fenestratus included (1R, 6S, 7S, 10S)-10-isothiocyanato-4-amorphene [(+)-1] and new metabolites (1R*, 4S*, 6R*, 7S*)-4-isothiocyanato-9-amorphene [2], 10-isothiocyanato-4,6-amorphadiene [3], and (4S*, 10S*)-10-isothiocyanato-5-amorphen-4-ol [4]. The amorphene (+)-1 of this study may be antipodal to (-)-1 previously isolated from a Hawaiian sponge. A similar relationship may exist at C-1, C-6, C-7 between (+)-2 of this study and (-)-11 isolated from a Palauian sponge. Another known sesquiterpene, axisonitrile 3 [5] was obtained from Topsentia sp. The diterpenes obtained from A. cavernosa included known kalihinols X [6] and Y [8] and new kalihinols J [7] and I [9]. Those terpenoids with potent antiparasite activity include 1, 2, 3-5, and 7-9.
Chondriamide C (3), a new bis(indole) amide, was isolated from the red alga Chondria atropurpurea, and its structure was established from spectroscopic data and chemical transformations. A new natural product, 3-indoleacrylamide (4), and the previously described chondriamides A and B (1, 2) and 3-indoleacrylic acid (5) were also isolated. The anthelmintic activities of compounds 1, 3, 4, and 6 (the O,N1,N1'-trimethyl derivative of compound 2) against Nippostrongylus brasiliensis in vitro were evaluated.
The anthelmintic efficacy of benzimidazoles (albendazole, fenbendazole and oxfendazole), levamisole, oral ivermectin and closantel was evaluated on a farm in Kenya using faecal egg count reduction test, larval cultures and a controlled slaughter trial. The results of this study indicated simultaneous resistance of Haemonchus contortus against benzimidazoles, levamisole and ivermectin, and of Trichostrongylus colubriformis and Oesophagostomum spp. against levamisole on the same farm. Ivermectin resistance developed to 47% within 15 months of first use. Closantel was effective against the benzimidazoles, levamisole and ivermectin resistant H. contortus.
Monitoring anthelmintic resistance in strongyle nematodes by the faecal egg count reduction test and a commercial larval development assay on an organized sheep farm in the semi-arid area of Rajasthan revealed the emergence of resistance to benzimidazoles and rafoxanide and a potential risk of the development of levamisole/tetramisole resistance. A benzimidazole/levamisole combination, avermectins and closantel were each found to be efficacious.
PURPOSE: The mechanism of excretion of the anthelmintic drug ivermectin was investigated in a novel experimental model of functionally intact proximal tubules isolated from a teleost fish (Fundulus heteroclitus). METHODS: Secretion into the lumens of freshly isolated proximal tubules was studied by means of confocal laser scanning microscopy and digital image analysis using ivermectin and fluorescent labelled ivermectin (BODIPY-ivermectin; BI) as substrates. RESULTS: The tubular cells rapidly accumulated BI from the medium and attained steady state within 25 minutes. Luminal fluorescence in the steady state was 5-7 times higher as compared to intracellular fluorescence. The secretion of BI into the tubular lumens was inhibited in a dose dependent manner by unlabelled ivermectin and inhibitors of the renal excretory membrane pump p-glycoprotein, namely SDZ PSC-833 and verapamil, but not by leukotriene C4, a substrate of the renal export protein mrp2. Accumulation inside the tubular cells was not affected by the added inhibitors. Ivermectin inhibited the renal secretion of the fluorescent cyclosporin derivative NBDL-CS, a substrate of p-glycoprotein, but not the secretion of the mrp2-substrate fluorescein-methotrexate, nor the secretion of fluorescein, a substrate of the classical renal organic anion transporter. CONCLUSIONS: The data are consistent with BI and ivermectin interacting in teleost kidney tubules exclusively with p-glycoprotein, but not with one of the other known excretory transport systems. In addition, the studies demonstrate that freshly isolated functionally intact kidney tubules from killifish are a useful tool to differentiate the substrate specificity of renal transport systems with respect to drug elimination.
Challenge with an equal mix of drug-resistant and drug-susceptible larvae of Teladorsagia circumcincta resulted in infections in groups of lambs (n = 6) either untreated or given controlled-release capsules, containing either albendazole or ivermectin. Lambs treated with albendazole capsules contained similar numbers of adult worms at necropsy to the other groups but had no detectable faecal egg count. Animals treated with ivermectin capsules had similar worm burdens and faecal egg counts to the control group but the worms had significantly higher numbers of eggs in utero. These results provide evidence for suppression of egg production by both anthelmintic treatments. The observation that albendazole caused a significant reduction in the developmental success of parasite eggs also has implications for the use of faecal egg count as an indicator for pasture contamination with resistant parasites. In two further groups of lambs, either untreated or given albendazole capsules, treatment caused a significant reduction in egg count and adult worm burden of Trichostrongylus colubriformis. No significant effects were observed on in utero egg counts or egg viability and the apparent effect on the number of eggs produced in faeces per adult female was not significant (p = 0.077). There was, therefore, no evidence that albendazole controlled-release capsules caused suppression of egg output in this species.
The anthelmintic activity of Calotropis procera latex was investigated in sheep that had been infected with single oral doses of 12000 infective Haemonchus contortus larvae. Inappetence, dullness, erosive abomasitis, decreased haemoglobin concentration and increased eosinophils were the main features of haemonchosis in the sheep. In the sheep treated with single oral doses of 0.01 ml or 0.02 ml/kg body weight of C. procera latex, egg production was significantly reduced, but not completely suppressed, and fewer adult Haemonchus worms were found in the abomasum. Although the appetite improved, the haemoglobin concentration and serum copper, iron and zinc levels were still reduced after therapy with Calotropis latex. Calotropis latex showed a concentration-dependent larvicidal activity in vitro within 20 min of application.
Biopsy specimens from patients with psoriasis concomitant with chronic opisthorchiasis were examined. Severe clinical course of combined disease was associated with degenerative changes in epidermocytes, keratinization disorders, and diffuse inflammatory cell infiltration of the derma. Combined therapy including anthelmintic agents produced a positive effect: decreased the degree of acanthosis, increased intracellular regeneration of epidermocytes, and suppressed inflammatory reaction of the derma and hyperplasia of immunocompetent cells. These data attested to an important role of opisthorchiasis in the pathogenesis of psoriatic disease.
The comparative in vitro sulphoreduction of the (+) and (-) enantiomers of albendazole sulphoxide (ABZSO) and oxfendazole (OFZ) by ruminal fluid obtained from sheep and cattle, was investigated, under anaerobic conditions, in this study. Ruminal fluid samples were obtained from Holstein steers fitted with a permanent rumen fistula and from Corriedale lambs via an oesophageal tube. Albendazole sulphoxide, incubated as either the racemic (rac) mixture or as each individual enantiomeric form, was extensively sulphoreduced to form albendazole (ABZ) by ruminal fluid from both species. The concentrations of ABZ formed at different incubation times were between 55 and 158% greater after the incubation of cattle ruminal fluid with (+) ABZSO, compared with that produced when (-) ABZSO was the incubated substrate. Similarly, the concentrations of ABZ were 1.3--3.0-fold higher when (+) ABZSO was incubated with sheep ruminal fluid. Significantly higher rates of depletion were observed for the (+) enantiomeric form when ABZSO was incubated with ruminal fluid from both species. The rates of ABZ formation from both ABZSO enantiomeric forms were significantly higher in sheep compared with cattle ruminal fluid. Fenbendazole (FBZ) was the metabolite formed after the incubation of the racemic form of OFZ with ruminal fluid obtained from both species. The metabolic profile of both OFZ enantiomers followed a similar pattern to that observed for ABZSO enantiomers. A bi-directional chiral inversion of one enantiomer into its antipode was observed. The (+) enantiomer appeared in the incubation medium when (-) ABZSO was the incubated substrate, and also the (-) antipode was detected after (+) ABZSO incubation with ruminal fluid obtained from both species. The results reported here demonstrate an enantioselective ruminal sulphoreduction of ABZSO and OFZ (substrate enantioselectivity). These findings contribute to interpret the chiral behaviour of benzimidazole-sulphoxide anthelmintics.
Seven dairy-goat farms from the centerwest of france were investigated for morphology and ecology of first-stage larvae (L1) of Muellerius capillaris before and after treatment of goats with febantel, a probenzimidazole anthelmintic. The lengths, survivals at 20 and -20 degrees C, and infectivity of L1 to intermediate host Helix aspersa, were different between farms. The between farms differences in survivals were reduced after treatment of goats with febantel. The observed between farm differences in L1 did not seem to be related to farm characteristics (intensity of treatments, susceptibility to febantel, and intermediate host species).
A series of 3,6-disubstituted-7H-s-triazolo(3,4-b)(1,3,4)thiadiazines was synthesized by the condensation of the appropriate 3-substituted-4-amino-5-mercapto (1,2,4) triazoles with substituted phenacyl bromides in alcoholic medium. These compounds have been studied for their in vivo anthelmintic activity in albino mice. A number of compounds showed promising activity when given by the oral route.
Phytochemical studies using a range of chromatographic and spectroscopic techniques coupled with in vitro bioassays against larval Schistosoma mansoni, L4 larvae of Ostertagia circumcincta, and adults and larvae of Caenorhabditis elegans have led to the isolation of an active anthelmintic compound in the Chinese medicinal plant Evodia rutaecarpa (Rutaceae) and its identification as atanine (3-dimethylallyl-4-methoxy-2-quinolone). Atanine has not previously been found to possess antiparasitic activity.