avermectin-b(1)a and avermectin

The avermectins are macrocyclic lactones produced by fermentation of the soil micro-organism Streptomyces avermitilis. They show activity against a broad range of nematodes and arthropod parasites of domestic animals at dose rates of 300 microgram/kg or less. Unlike the macrolide or polyene antibiotics, they lack significant antibacterial or antifungal activity. By oral or parenteral administration, avermectins are active against gastrointestinal nematodes and lungworms, and important ectoparasites such as lice, mange mites, ticks and larval stages of flies. They show excellent activity against parasites resistant to existing anthelmintics or ectoparasiticides. The avermectins appear to cause paralysis of nematodes and arthropods by opening gamma-aminobutyric acid-mediated chloride channels at the neuromuscular junction.

Topics: Animals; Anoplura; Anthelmintics; Antinematodal Agents; Cattle; Cattle Diseases; Dog Diseases; Dogs; Horse Diseases; Horses; Ivermectin; Lactones; Mite Infestations; Nematode Infections; Sheep; Sheep Diseases; Swine; Swine Diseases; Tick Infestations

Three new 1,19-seco-avermectin (AVE) analogues were isolated from the ΔaveCDE mutant Streptomyces avermectinius strain. Their structures were elucidated by detailed spectroscopic analysis. This is the first report of 1,19-seco-AVE analogues. In an in vitro assay these compounds displayed cytotoxicity against Saos-2, MG-63, and B16 cell lines.

Topics: Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; Humans; Ivermectin; Mice; Molecular Structure; Mutation; Streptomyces

Novel 4"-alkoxy avermectin derivatives were synthesized via rhodium carbenoid mediated O-H insertion reaction and tested for antiparasite activity against Artemia salina and Caenorhabditis elegans.

Topics: Animals; Caenorhabditis elegans; Crustacea; Drug Evaluation, Preclinical; Ivermectin

Horner-Emmons reaction of 4"-dehydro-5-O-TBDMS-avermectin B(1a) with a variety of phosphorus ylides using LHMDS gave novel 4"-alkylidene avermectin derivatives in high yields. Further modifications led to derivatives bearing diverse functional groups. The new avermectin derivatives showed potent growth inhibitory activity against Artemia salina and Caenorhabditis elegans.

Topics: Animals; Artemia; Caenorhabditis elegans; Growth Inhibitors; Indicators and Reagents; Ivermectin; Molecular Conformation

Chemical conversion of the potent anthelmintic natural products avermectin B1 (1) and avermectin B2 (3) to the corresponding 13-epi analogs (15 and 9) is described. The novel analogs retain the full potency of the natural products but are substantially safer.

Topics: Animals; Anthelmintics; Artemia; Ivermectin; Lethal Dose 50; Magnetic Resonance Spectroscopy; Male; Mice; Sheep; Structure-Activity Relationship

The reactions of sulfonate esters of the allylic/homoallylic 13-alcohol of 5-O-(tert-butyldimethylsilyl)-22,23-dihydroavermectin B1a aglycon (1a) were investigated. Nucleophilic substitution gave 13 beta-chloro and 13 beta-iodo derivatives, while solvolytic reaction conditions yielded 13 alpha-methoxy, 13 alpha-fluoro, and 13 alpha-chloro products. A mixture of 13 alpha- and 13 beta-fluorides was obtained upon reaction with DAST. The 13 beta-iodide gave, upon elimination with lutidine, the 8(9),10(11),12(13),14(15)-tetraene. The 13 beta-alcohol and the rearranged 15-ol 13(14)-ene and 15-amino 13(14)-ene derivatives were obtained by substitution via the allylic carbonium ion. MEM ethers 11 and 12 of the two epimeric 13-ols were prepared by alkylation with MEM chloride. In contrast, methylation of 1a with MeI and Ag2O in CH2Cl2 occurred exclusively at the tertiary 7-hydroxy group and not at the secondary 13 alpha-ol. Oxidation of the allylic alcohol 1a proceeded under Swern conditions but not with MnO2 to the 13-oxo aglycon, which was reduced by NaBH4 exclusively to the natural 13 alpha-ol, while reductive amination with NaCNBH3-NH4OAc gave the 13 alpha-amine. The methoxime derivative was obtained in the form of the two geometric isomers. Anthelmintic activities against the sheep nematode Trichostrongylus colubriformis, miticidal activities against the two-spotted spider mite (Tetranychus urticae), and insecticidal activities against the southern armyworm (Spodoptera eridania) as well as the binding constants to a free living nematode (Caenorhabditis elegans) derived receptor assay were obtained and compared to avermectin B1a, 22,23-dihydroavermectin B1a, and the 13-deoxy-22,23-dihydroavermectin B1 aglycon related to the milbemycins. None of the newly prepared derivatives exceeded the potency of the three reference compounds. Lipophilic 13-substituents such as halogen, alkoxy, and methoxime retained high biological activities in all assays, while the more polar substituents hydroxy and amino had weaker activities. Rearranged 15-substituted 13(14)-ene derivatives were completely inactive. The 13-oxo and the 12,13-dehydro analogues were only weakly active in vivo despite having good binding affinity to the receptor, possibly due to instability or poor absorption.

Topics: Animals; Anthelmintics; Ivermectin; Structure-Activity Relationship

Topics: Animals; Anthelmintics; Cattle; Cattle Diseases; Central Nervous System Diseases; Female; Ivermectin; Male

Streptomyces avermitilis produces avermectin, oligomycin and a polyene antifungal. The latter two compounds account for the antifungal activity in the methanol extracts of the fermentation broth. Pure avermectin does not inhibit fungi or affect fungal chitin metabolism.

Topics: Antifungal Agents; Cell Wall; Chitin; Ivermectin; Lactones; Microbial Sensitivity Tests; Mucor; Oligomycins

Avermectin B1a concentrations corresponding to the KD value of a specific high affinity binding site for [3H]avermectin B1a are sufficient to stimulate the specific high affinity binding of [3H]flunitrazepam to its receptors. This stimulation of [3H]flunitrazepam binding by low concentrations of avermectin B1a was enhanced by chloride ions and picrotoxinin and reduced by the GABA agonists THIP and PSA. The similar modulation by chloride ions, GABA agonists and picrotoxinin and the resistance against washing of membranes of avermectin B1a bound to its specific high affinity binding site or to the site modulating [3H]flunitrazepam binding indicate a close association of the specific high affinity binding site for [3H]avermectin B1a with the GABA-benzodiazepine receptor complex.

Topics: Animals; Binding Sites; Binding, Competitive; Cell Membrane; Cerebellar Cortex; Chlorides; Flunitrazepam; In Vitro Techniques; Ivermectin; Lactones; Picrotoxin; Rats; Receptors, Cell Surface; Receptors, GABA-A; Sesterterpenes; Temperature

Avermectins A2a, B1a, and B2a (1, 2, and 3) were acetylated to give 4"- and 23-acetates 4 and 5 and 4",23-diacetate 6 from 1, the 4"-and 5-acetates 7 and 8 and 4",5-diacetate 9 from 2, and triacetate 10 from 3. Structure proof by 300-MHz 1H NMR and mass spectral fragmentation is discussed for 10. Forcing acetylation conditions generated from both 1 and 3 the identical aromatic diacetate 11. Good anthelmintic activities in gerbils and sheep for 4"-acetylated derivatives 4 and especially 7 prompted the preparation of additional 4"-acylated derivatives of 2 with pivaloyl, n-octanoyl, succinoyl, carbamoyl, dimethylcarbamoyl and N-acetylglycyl substituents, prepared from the 5-O-tert-butyldimethylsilyl-protected intermediate 12. Other key intermediates were the trichloroethyoxysuccinoyl derivative 18 and 4-nitrophenyl carbonate 21. Anthelmintic activities against Trichostrongylus colubriformis in gerbils comparable in potency to the natural product 2 are shown by the more polar substituted derivatives 20, 23, and 27. Substitution of the 5-hydroxy group or its loss due to aromatization results in drastically reduced anthelmintic potency.

Topics: Animals; Anthelmintics; Chemical Phenomena; Chemistry; Gerbillinae; Haemonchiasis; Ivermectin; Lactones; Ostertagiasis; Sheep; Trichostrongylosis

Topics: Animals; Cattle; Cattle Diseases; Ivermectin; Lactones; Tick Infestations

22,23-Dihydroavermectin B1, ivermectin, derived from avermectin B1 by selective hydrogenation using Wilkinson's homogenous catalyst [Ph3P)3RhCl], was shown to be a highly effective drug for the treatment of a wide variety of metazoan parasitic diseases in animals.

Topics: Animals; Anthelmintics; Cattle; Disaccharides; Helminthiasis; Intestinal Diseases, Parasitic; Ivermectin; Lactones; Sheep