Avermectins anthelmintic activity

The spiroketal moiety is a common structural unit in a variety of biologically active products such as milbemycins (insecticides) [55], avermectins (anthelmintic activity) [56], and phyllanthosides (antileukemic) [57]. Iwata has described the... 

The microorganism was classified as a new species of actinomycete. Streptomyces avermitilis. Its anthelmintic activity was shown to reside in 8 closely related macrocyclic lactones, named avermectins, which were also found to possess activity against free-living and parasitic arthropods. One of the natural components, avermectin is now being evaluated as a pesticide for the control of mites of citrus and cotton crops and control of the Red Imported Fire Ant. A chemical derivative, 22,23-dihydroavermectin or ivermectin, has been developed as an antiparasitic agent. It is being marketed for use in cattle, horses and sheep and is expected to become available for swine and dogs. 

Based on a correlation of anthelmintic activity and HPLC analysis of the total avermectin complex, it was estimated that the third fermentation contained a minimum of 9 pg/ml. Improvement of the medium increased the yield by the original culture (MA-4680) to 120 yg/ml. A high-producing isolate (MA-4848) obtained from this culture produced nearly 500 pg/ml of total avermectins. Thus, this culture yielded readily to medium improvement and isolate selection to produce relatively large amounts of the avermectins. Accounts of the early fermentation studies and taxonomy have been published (1-2). 

A study of the structure-activity relationships of various acylated avemectins was done [227]. The 4"-0-acetates have the same potency as the unsubstituted compounds, whereas 5- and 23-acylation are generally detrimental to activity. In particular, the 5-hydroxy group is essential for good anthelmintic activity. The efficacy of acylated avermectins was also investigated against a broad spectram of parasites in sheep. 

In 1979, as a result of a joint research between the Kitasato Institute, Tokyo, Japan, headed by S. Omura, and Merck, USA, headed by E. O. Stapley, avermec-tins, which have a unique mode of action and potent anthelmintic activity, were discovered in culture mycelia of Streptomyces avermitilis. Ivermectin is a dihydro derivative of avermectin Bj, ensuring its efficacy and safety. It has an extremely broad-spectrum nematocidal activity. 

Avermectins are a series of eight related natural products with potent anthelmintic and insecticidal activities produced by Gram-positive, filamentous soil bacteria Streptomyces avermitlis [30]. All of these molecules share a 16-membered macrocyclic PK aglycon with the attachment of a dimeric o-methyl-a-L-oleandrose to C-13 (Figure 13.6). Avermectins differ in three substituents R1 R2 and R3. Rj can be either a hydroxyl or hydrogen, in which case there is a double bond between the C-22 and C-23. R2 can be either methyl or ethyl, and R3 can be either hydrogen or methyl. 

The avermectins, a family of compounds with potent anthelmintic, insecticidal and acaricidal activity, have vividly demonstrated that fermentation products can have entirely unanticipated activities. Besides their utility in animals, they show great promise for the control of insect pests of plants. Although antibiotics have found only a limited role in the control of plant diseases, the desire to find environmentally acceptable alternatives to the chemicals currently used has prompted new research efforts to discover fermentation products for use as pesticides. 

The third milestone in the history of the use of fermentation products in agriculture was the discovery of the avermectins. They were first detected in an anthelmintic assay using mice infected with nematospiroides dubius (13). This is one of the few assays in which they could have been detected since they lack antibacterial and antifungal activity. 

This dual activity against both nematode and arthropod parasites of animals was an unexpected bonus from a screen for anthelmintic agents. The reason for this broad activity lies in their mode of action. They act by interfering with y-aminobutyric acid (GABA) mediated neurotransmission. When treated with avermectin, the nematode Ascaris suum becomes paralyzed although it retains normal muscle tone (17). Picrotoxin, an antagonist of GABA, can reverse the effect of avermectin on neurotransmission vitro. 

The high cost of developing compounds with limited markets has reversed the trend to narrower spectrum agents. The reversal began with the pyrethroids and has continued with the discovery, from fermentation sources, of the avermectins. In addition to their anthelmintic properties (see Section 1.08.2), a semisynthetic derivative, ivermectin (16), is in use in the control of lice, mites and warbleflies. Activity against Boophilus ticks, including all... 

The avermectins (Figure 3.67) have no antibacterial activity, but possess anthelmintic, insecticidal, and acaricidal properties, and these are exploited in human and veterinary medicine. The avermectins are also 16-membered macrolides, but their structures are made up from a much longer... 

Little is known about the nervous systems of cestodes and trematodes except that they probably differ from those of nematodes, since milbemycins and avermectins have no effect on them. However, a highly effective anti schistosomal and antitapeworm agent, praziquantel (see Chapter 54 Clinical Pharmacology of the Anthelmintic Drugs), is known to enhance Ca2+ influx and induce muscular contraction in those parasites, though it exerts no action on nematodes or insects. Some benzodiazepine derivatives have activities similar to those of praziquantel these activities are unrelated to the anxiolytic activities in the mammalian central nervous system. The nerves and muscles in schistosomes and tapeworms are thus interesting subjects for future chemotherapeutic studies. 

Dutton and coworkers [21] have isolated about 36 avermectins (10) which are produced through mutational biosynthesis by Streptomyces avermitilis, a mutant strain ATCC-53568. These antibiotics exhibit broad-spectrum of antiparasitic activity. Several avermectin homologues (11) were produced by S. avermitilis in presence of externally supplied sodium 2-methylpentanoate and sodium 2-methylhexanoate. The homologues, thus produced, carry 2-pentyl and 2-hexyI groups, respectively, at the C-25 position of the aglycone moiety. These antibiotics are designated as avermectin "c" and "d", respectively, which possess high anthelmintic and insecticidal activities 1221. 

We have shown that the anthelmintics pyrantel, morantel and levamisole, activate acetylcholine (Ach) receptors on the muscle cell membranes of Ascaris suum and also that the avermectin 22,23-dihydroavermectin Bla (DHAVM) blocks the function of muscle cell gamma-aminobutyric acid (GABA) receptors. In experiments using micro-iontophoresis, the cholinergic anthelmintics were found to act directly on the muscle bag membrane, evoking a depolarizing response. 

The avermectins (AVM) are a family of naturally occurring macrolides which are produced by Streptomyces avermitilis and possess potent broad-spectrum anthelmintic, acaricidal and insecticidal activity (25-27). One of the major components of the avermectin complex is AVM Bla. This has been shown to interfere with neurotransmission at excitatory neuronal (nerve-nerve) synapses in the ventral nerve cord of A. suum where the mode of action seems to involve a GABA-ergic mechanism (1, 3) AVM Bla also abolishes the hyper polarizing potentials recorded from muscle bags of A. suum in response to stimulation of inhibitory motorneurones O, 3.). Kass and co-workers (2, 28) suggest that the effect on inhibitory neuromuscular transmission results from blockade of GABA receptors present on the postsynaptic muscle membrane. As the postsynaptic receptors are... 

Avermectins and milbemycins are naturally occurring 16-membered macrolactones that show a broad spectrum of anthelmintic and pesticidal activity with relatively low toxicity to both humans and animals. The milbemycins differ from the avermectins primarily in the lack of a disaccharide moiety and oxygen functionality at Cl3,... 

Since the discovery of avermectin (AVM), its outstanding antiparasitic activity has attracted great attention from many people, and investigations into the mechanism of its specific biological activity have been actively conducted. From the beginning, AVM was presumed to be a blocker of neurotransmitters, such as ibotenic acid, because of its immediate antiparasitic and anthelmintic effects. 

The avermectins, which possess potent anthelmintic and insecticidal activities, have structural features similar to the milbemycins. The C-15 to C-28 spiroketal-containing unit (690) of avermectin Bia aglycone (691) is s)mthesized in optically pure form by coupling L-malic acid-derived lactone 687 with D-glucose-derived acetylene 688. Partial reduction of the... 

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