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Two members of a novel class of anthelmintics, the aspergillimides, have been isolated from the Aspergillus strain IMI 337664. This novel fungus also produced two known and one structurally novel paraherquamide. This paper describes the fermentation, isolation, structure elucidation and anthelmintic activity of aspergillimide (VM55598, 1), 16-keto aspergillimide (SB202327, 2), and the paraherquamides VM54159 (3), SB203105 (4) and SB200437 (5). The aspergillimides are equivalent to paraherquamides which have lost both the dioxygenated 7-membered ring and the phenyl ring to which this is fused; gaining in their place a C8-keto group. SB203105 is the first example of a 4-substituted paraherquamide.

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Ten novel alpha and beta class milbemycins have been isolated and characterized from the Streptomyces sp. E225, which has previously been shown to produce four related milbemycins. Some of the metabolites contain new structural features including, VM48641 which possesses an alpha-methoxyl substituent at C-27, and VM48642 which contains a furan ring at the terminus of the C-26 side chain. Several of these new compounds were shown to possess potent anthelmintic activity. An analysis of NMR chemical shift trends in this series of metabolites is presented.

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In vitro, epsiprantel at a concentration of 10 micrograms ml-1 caused tegumental damage and death of protoscoleces, juveniles (seven-day-old) and adult (37-day-old) Echinococcus granulosus. Degenerative changes and death occurred more rapidly in the older parasites. Similarly, epsiprantel was more effective against adult (28-day-old) than seven-day-old experimental infections of E granulosus in dogs. Oral doses of 2.5, 5 and 7.5 mg kg-1 were greater than 96 per cent, 99.9 per cent and 99.99 per cent active, respectively, against mature worms, whereas in seven-day-old infections doses of 5, 7.5 and 10 mg kg-1 produced greater than 94 per cent, 90 per cent and 99.8 per cent reduction in worm burdens, respectively. No side effects from treatment were seen.

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Dogs with 41-day-old experimental infections of Echinococcus granulosus were treated orally with epsiprantel. Single doses of 2.5 mg kg-1, 5.0 mg kg-1 or 7.5 mg kg-1 were effective in removing more than 99 per cent of these parasites, but total clearances of worms only occurred in dogs given the highest dose.

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A novel series of milbemycin antibiotics were produced by soil isolate, strain E225 which was shown to be a Streptomyces species. The antibiotics displayed anthelmintic activity against Trichostrongylus colubriformis in the gerbil. Two of the compounds, VM 44857 and VM 44866 were shown to be potent anthelmintics against mixed nematode infections in sheep.

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A series of 1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-alpha][2] benzazepine derivatives was prepared and the cestocidal activity of the compounds evaluated in an in vitro Taenia crassiceps screen. Many of these derivatives proved to be highly active, and 2-(cyclohexylcarbonyl)-4-oxo-1,2,3,4,6,7,8,12b- octahydropyrazino[2,1-alpha][2]benzazepine, epsiprantel (BAN) (22), was selected for further development. The structure-activity relationships are discussed.

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RESUMEN

The anthelmintic potential of epsiprantel, 2-(cyclohexylcarbonyl)-4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazin [2,1-a] [2]benzapine, was revealed using the tapeworms Dipylidium caninum and Taenia taeniaeformis in the cat, and Taenia pisiformis and T. hydatigena in the dog. Subsequent controlled tests in cats demonstrated oral efficacy of 100% against D. caninum with a single dose of 2.5 mg/kg. Although consistently 100% effective against T. taeniaeformis at 5 mg/kg, a single worm was found in one cat treated at 7.5 mg/kg. In experimental infections of Taenia pisiformis in dogs, 100% activity was achieved from a single oral dose of 1 mg/kg. No adverse reaction or drug-associated toxicity were observed at dose levels used.

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A series of isothiourea derivatives of 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (tetramisole) is described. The compounds are prepared by the S-alkylation of the thioureas that were obtained either by the reaction of an amine with 6-(3-isothiocyanatophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b] thiazole or by the reaction of an isothiocyanate with 6-(3-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole. These derivatives have an improved spectrum of activity over tetramisole and are active against nematodes, cestodes, and trematodes. The structure-activity relationships are discussed.

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Experiments were carried out to define the haematological changes taking place during the first six weeks of a primary infection with Nematospiroides dubius. The general pattern of changes was observed to comprise a rapid increase in circulating leucocytes (4 to 5-fold increase) which consisted of a neutropl a, lymphocytosis, monocytosis and an eosinophilia. However, in strong responder NIH mice leucocyte counts returned to normal more rapidly than in other strains (by day 28). In contrast, in weak responder C57BL/10 mice the leucocyte counts whilst falling significantly relative to day 7 did not return to normal within the experimental period. Mice infected with irradiated larvae did not experience as high a leucocytosis as did mice given an identical number of normal larvae. The peak lymphocytosis, neutrophilia and monocytosis were all lower. The removal of adult worms from infected animals by treatment with pyrantel on days 9, 11, 13 and 16, also significantly altered the pattern of leucocytosis. The neutrophilia which was evident on day 7 returned rapidly to normal, whereas in mice which had retained their worms a peak neutrophilia was observed on day 14. These haematological changes were discussed and related to the failure of host-protective immunity to operate effectively during the early stages of a primary infection with N. dubius.

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