Avermectins

Two avermectins, abamectin (the avermectin B ) [71751 -41 -2] and ivermectin [70288-86-7] which is saturated at C22—C23, have been commercialized to date. These two marketed avermectins have been described in considerable detail (Table 1) (13). 

Kirk-Othmer Encyclopedia of Chemical Technology (4th Edition) 

Ivomec injection cattle, sheep, goats, pigs, camels 

Avemiectin is the most effective of the averniectia family of natural products against agriculturally important insects and mites (14). It has been commercialized for agricultural use under the nonproprietary name abamectin. This mixture of avermectins contains at least 80% of avermectin (C4gH 20 and not more than 20% of avermectin B Abamectin for use in foHar spray appHcations is formulated as an emulsiftable 

Mite species citms mst mite Phjllocoptruta oleivora 0.02 

Insect species Colorado potato beetle Eeptinotarsa decemlineata 0.03 

One important group of insecticides, the avermectins, works differently by being agonists and not antagonists as the other, acting on the chloride channels. The avermectins are produced by Streptomyces avermitilies. The binding site is different, and cross-resistance to fipronil, the cyclodienes, and lindane does not seem to occur. The toxic symptoms in insects and mammals are different. Mammals poisoned with avermectins exhibit hyperexcitability, incoordination, and tremor followed by ataxia and paralysis. In insects and nematodes, the hyperexcitation phase is absent. Their symptoms are 

It is important to note that the interaction with regulatory binding sites at the chloride channels does not involve making or breaking covalent bonds. Pesticides of this class may therefore be rather stable. 

In avermectin Bl, there is a double bond between C-22 and C-23, whereas in avermectin B2 R OH. The product ratio of B2 to Bl is 1.6 1. Since the Bl analog is much more effective as an antiparasite, there is a desire to improve the B1 B2 ratio, which can be achieved by a dehydratase domain [88, 89]. Its directed evolution and mutant screening led to a mutant giving an excellent fermentation titer of Bl B2 = 1 0.07 [90, 91]. As a result of understanding the biosynthesis, pathway engineering, and directed evolution, a biologically superior new product, doramectin (Dectomax ), was evolved from a mixture of eight natural products. 

The authors would like to thank Dr. Mel Luetkens of Elevance Renewable Sciences for generous support. J.T. would also like to thank Ben Borer, Stephen Bowlin, Shanghui Hu, Sean Kelly, Carlos Martinez, Ningqing Ran, Robert Scott, John Tucker, JeanXie, Lan Xu, Weihong Yu, and Lishan Zhao, who made this chapter possible. 

Mendez, C. and Salas, J.A. (2005) Proceedings of the National Academy of Sciences USA, 

33 Blanchard, S. and Thorson, J.S. (2006) Current Opinion in Chemical Biology, 

40 Hughes-Thomas, Z.A., Stark, C.B.W., Bohm, I.U., Staunton, J. and Leadlay, P.F. (2003) Angewandte Chemie International Edition, 42, 4475. 

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Avermectins and Ivermectin. The avermectias are pentacycHc lactones isolated from fermentation products of Streptomjces avermitilis and ivermectin is a semisynthetic chemical, 22,23-dihydroavermectia (46). Ivermectin is effective in very low doses for the control of red spider mites on deciduous fmits, in baits for the control of imported fire ants, and as a parasiticide for Onchocerca volvulus in humans and for catde gmbs. These insecticides appear to function as agonists for the neuroinhibitory transmitter y-aminobutyric acid (GABA) (see Antiparasitic agents, avermectins). 

Ivermectin is the catalytic reduction product of avermectin, a macroHde containing a spiroketal ring system. Two other related antibiotics having significantly different stmctural features and biological properties, moxidectin and milbemycin oxime, were more recentiy introduced into the market. Although these compounds have no antimicrobial activity, they are sometimes referred to as antibiotics because they are derived from fermentation products and have very selective toxicities. They have potent activity against worms or helminths and certain ectoparasites such as mites and ticks. 

In 1976 scientists at the Merck Corporation discovered a complex of eight closely related natural products, subsequently named avermectins A through in a culture of Streptomjces avermitilis MA-4680 (NRRL8165) originating from a soil sample collected at Kawana, Ito City, Shizuoka Prefecture, Japan and isolated by the Kitasato Institute. Their stmctures are shown in Figure 1 (1 6). They are among the most potent anthelmintic, insecticidal, and acaricidal compounds known. 

The avermectins are closely related to another group of pesticidal natural products, the milhemycins. First described by Japanese workers, milhemycins were later found to be more abundant in nature than the avermectins (7—12). Both the avermectins and milhemycins are sixteen-memhered lactones, with a spiroketal system containing two six-memhered rings. The principal difference between them is that the avermectins have an a-L-oleandrosyl-a-L-oleandrosyl disaccharide attached at the 13-position whereas the milhemycins have no 13-substituent. Milhemycin stmctures are shown in Figure 2. 

Table 2. Biological Activity of Abamectin (Avermectin B ) Against Mites and Insects ...

Selective reduction of the 22,23-olefin of avermectin yields the 22,23-dihydro derivative assigned the nonproprietary name ivermectin (18). The stmcture shown depicts the 25-j -butyl derivative [70161 -11-4] but it should be noted that both commercial products contain up to 20% of the 25-isopropyl... 

The proposed pathway for the biosynthesis of the avermectins (Fig. 3) has been described in a review (23). Some of the details are yet to be elucidated, although the steps, in general, are based on firm evidence from four types of studies incorporation of labeled precursors, conversion of putative intermediates by producing strains and blocked mutants, in vitro measurement of biosynthetic enzymes, and studies with enzyme inhibitors. The biosynthesis of the oleandrose units was elucidated from studies using and labeled glucose, which indicated a direct conversion of glucose to... 

Stability. Avermectins are highly lipophilic substances and dissolve in most organic solvents such as chloroform, methylene chloride, acetone, alcohols, toluene, cyclohexane, dimethylformamide, dimethyl sulfoxide, and tetrahydrofiiran. Thek solubiUty in water is correspondingly low, only 0.006-0.009 ppm (= mg/L). 

Since the avermectins exhibit unprecedented potency, they are used at unusually low doses of 6 —300 )-lg/kg, which makes the detection and isolation of residues and metaboUtes from animal tissue a new challenge. For this reason a sensitive analytical assay requires a derivative suitable for detection at concentrations down to 1/10 or 1/100 of one ppm. Ivermectin and avermectin B are therefore converted into an aromatic derivative which allows detection by fluorescence absorbance. To achieve this derivatization, avermectin B, ivermectin, or their derivatives are heated with acetic anhydride in pyridine at 100°C for 24 h (30). The reaction time can be reduced to 1 h by using /V-methylimidazole as a catalyst (31). The resultant... 

The maciocyclic lactone of all avermectins has an a-L-oleandtosyl-a-L-oleanchosyloxy substituent at carbon 13, which is a 2-deoxy sugar glycoside. 

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