Avermectins structure-activity relationship

The avermectins, particularly, have been the subject of intense commercial interest because they possess potent activity against both nematode and arthropod parasites of livestock (229). A full discussion of structure-activity relationships would be out of place here, not least because the data are voluminous, so we shall concentrate on the development of ivermectin, which has been a major success. 

This chapter deals with recent progress in the chemical modification and structure-activity relationships of 14- and 15-membered macrolides (mainly erythromycin derivatives), 16-membered macrolides (mainly the leucomycin and tylosin families), and the avermectin family of macrolides, showing nematocidal, insecticidal, and arachnidicidal activities. Previous reviews of these macrolides were given by Sakakibara and Omura in the first edition of this book in 1984 [1]. 

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. 

First structure-activity relationships relating to crop protection targets were reported by Fisher in 1984 [47]. This study showed that avermectin Bia was somewhat more active then mUbemydn D against Tetranychus urticae, Hdiothis virescens, and Mdoidogyne incognita. As milbemycin D can be viewed as the 22,23-dihydro-13-desoxy derivative of avermectin Bib, this comparison reflects the influence of the disaccharide portion of avermectins on their activity as pesticides. 

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). 

Fisher has also described the structure-activity relationships of several 4"-amino-avermectins against Tetranychus urticae and Spodoptera eridania [48]. 

M. H. Fisher, Structure-Activity Relationships of the Avermectins and Milbemycins, ACS Symposium Series No 658, American Chemical Society, Washington DC, pp. 221-238, 1997. 

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