Avermectin insecticidal 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. 

Emamectin benzoate is a semisynthetic avermectin that is derived from fermentation of avermectin B. It contains a mixture of 4" epimethylamino-4"-deoxy-avermectin B,a and Bjb benzoate salts. Emamectin benzoate is a stomach poison insecticide active against lepi-dopterous pests in vegetables, cotton, maize, peanuts, soybeans, and strawberries. Its oral LD50 in rats is 1516 mg/kg. 

It has been shown for avermectin B that the hydroxyl group at C-5 and a disaccharide moiety are essential for antiparasitic, mitocidal and selective insecticidal activities. Chemical modification of the macrolide-type avermectins resulted in ivermectin which was commercialized to be used in agriculture and animal health care as well as in human medicine. 

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. 

Mrozik et al. [23] have identified a series of novel 4"-amino-4"-deoxyavermect-ins with excellent insecticidal activity. The most effective members of this class are 12 and 13 which show 1,500 fold higher activity than avermectin (abamectin) against beet armyworm, Spodoptera exigua and other lepidopteran larvae. 

Like avermectins, the milbemycins have also undergone extensive molecular modifications. A number of synthetic milbemycins have been found to possess a wide-spectrum of parasiticidal and insecticidal activities [67-83]. The structure-achv-ity analysis would indicate that the milbemycins having different functional groups at positions 13,14 and 5 generally retain biological activity. The important milbemy-cin derivatives thus prepared include 13-substituted milbemycins of the type 31 [64,73-75] and 32 [76-78], 14-substituted milbemycins (33) [79], 5-keto/oximinomilbe-mycins (34) [81,82], 35 [80] and 36 [83]. 

Some older compounds such as toxaphene, lindane and cyclodiene insecticides have been around for some time without their mode of action being known. My third observation is that, almost as a tradition, some insecticidal activity has been found and then later a physiological lesion has been discovered. The initial acaricidal activity of chlordimeform, the nematicidal activity of avermectin, or the diptericidal activity of cyromazine are good examples. 

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... 

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... 

Table 29.6.4 shows the acaricidal and insecticidal activity of milbemectin, as described by Aold et al. [50]. Except for effects against some insects (Thrips and some Lepidoptera), milbemectin is mainly an acaricide. This is consistent with the structure-activity relationships observed with avermectin derivatives [28]. In general, compounds with Upophilic substituents on Cl 3 (or unsubstituted ones) are highly active, while polar substituents diminish the activity (cf Schemes 29.6.3 and 29.6.4). 

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... 

In the middle of the 20th century, the synthetic development of DDT and other chlorinated hydrocarbons (C.H.), increased insecticidal activity well beyond that of most natural products. Problems arose with bioaccumulation of C.H. residues in the food chain, human fat tissue, mother s milk, as well as the development of insecticide resistance. It became obvious there were limitations to synthetic technology as well. The modification of a natural product, for example, from chrysanthemum flowers and their pyrethrum extracts (7) to pyrethroids such as allethrin, resmethrin, permethrin (2), and deltamethrin created a model in which insecticides are created from the skeleton of insecticidally active natural molecules. Thus, the avermectin, abamectin, ivermectin family of pesticides originated from compounds produced by the soil bacterium, Streptomyces avermitilis (5), and the commercially successful chloronicotinyl insecticides, though not derived from nicotine, are chemically related 4). Both pyrethroids and chloronicotinyls are currently used commercially as termiticides. We have previously provided a detailed review of natural products as pesticidal agents for control of the Formosan subterranean termites, Coptotermes formosanus Shiraki (5). 

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. 

Another incentive to this screening may have arisen from the discovery of two remarkably potent families of fermentation products with insecticidal and acaricidal activity, the milbemycins and the avermectins. Abamectin (a mixture of not less than 80% avermectin and not more than 20% avermectin is already... 

Abamectin is a specific mixture of two components avermectin Bi and avermectin Bib. Both of these components possess a double bond between C22 and C23 and differ by a methylene group in the side-chain substituents on C25. The mixture containing not less than 80% avermectin Bu and not more than 20% avermectin B is known as abamectin. Abamectin has a broad spectrum of activity against nematodes, but is primarily used in agriculture as an acaricide and insecticide (46). 

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... 

R. K. Jansson R. A. Dybas, Avermectins Biochemical Mode of Action, Biological Activity and Agricultural Importance. In Insecticides with Novel Mode of Action I. Ishaaya, D. Degheele, Eds. Springer Berlin, 1998 pp 152-170. 

Abamectin is an insecticide/acaricide that contains a mixture of avermectin Bja (>80%) and avermectin Bjb (<20%) as active ingredients. Avermectins, which are macrocyclic lactones, are derived from the actinomycete, Streptomyces avermitilis (soil microorganism). It is used to control insect and mite pests of a wide range of agronomic, fruit, vegetable, and ornamental crops. It is also used by home owners for control of fire ants. It has an oral LD50 in rats of 300 mg/kg. 

Natural products such as the avermectins and milbemycin produce very active insecticides. Chemistry in this area is presented in one chapter. Juvenile hormone activity (36) still is of interest, and current work is described in this field. 

---