Ivermectin biological activity

The avermectin family includes several analogs with different biological activities most are roughly 80 20 mixtures of isomers which are prohibitively difficult to separate. The complete synthesis of avermectin Au has been reported (7). Unmetabolized ivermectin or abamectin, and their monosaccharides and aglycones, are the major residues in meat and agricultural commodities (1). These are generally analyzed by HPLC. 

Extracted from the soil actinomycete Streptomyces avermitilis, the natural avermectins are 16-membered macrocyclic lactones that, on reduction of the C22-23 double bond, give rise to ivermectin (IVM), which is an 80 20 mixture of dihydroavermectin Bia and Bip, respectively. The natural avermectins have minimal biological activity, but IVM has proven to be quite beneficial in the treatment of various nematode infections. 

The Pesticide Manual A World Compendium, 13 edition, C. D. S. Tomlin (Ed.), British Crop Protection Council, 2003. 2 M. J. Turner, J. M. Schaeffer, Mode of Action of Ivermectin, in Ivermectin and Abamectin, W. C. Campbell (Ed.), Springer, New York, Berlin, Heidelberg, pp. 73-88,1989. 3 J. P. Arena, Parasitol. Today, 1994, 10, 35-37. 4 S. P. Rohrer, J. P. Arena, Molecular Action of Insecticides on Ion Channels, ACS Symposium Series No 591, American Chemical Society, Washington DC, pp. 264-283,1995. 5 R. K. Jansson, R. A. Dybas, Avermectins Biochemical Mode of Action, Biological Activity and Agricultural Importance, in Insecticides with Novel Modes of Action Mechanisms and Application,... 

In the universe of biologically active natural products, the spirocyclic moiety is a unique and key structural motif. For example, there are over 300 spiroketal natural products including the aver-mectins and milbemycins, which demonstrate a range of antiparasitic activity with low toxicity (Figure 7.4). ° A semisynthetic derivative, ivermectin, is used in animals to treat parasite infestations. The spongistatins exhibit anticancer activity by disrupting mbulin polymerization. Okadaic acid is a cytotoxin found in marine sponges. 

The critical three double bonds present in the anthelmintic ivermectin were introduced via the Wadsworth-Emmons or Julia reactions. The Mukaiyama procedure was used to construct 16-membered lactones. These analogs differ from ivermectin in lacking the diol system at C5 and C7, the alkyl substituents at C24 and C25, the oxymethylene fragment at Cs, and by replacement of the disaccharide at C13. A variation of this procedure was also successful in the synthesis of analogs of the miticidal milbemycin D. The biological activity of the synthetic analogs was inferior when compared to that of the naturally occurring compounds. 

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. 

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