Macrolides antiparasitic activity

This class of macrolide antibiotic has mostly antiparasitic activity. Avermectin Bia (45) and ivermectin (46) (O Scheme 18) are used mostly in veterinary medicine, however, some semisynthetic derivatives are also used for treatment of onchocerciasis in humans [59]. The action of avermectin is believed to stimulate specific chloride ion transport systems increasing the membrane permeability to Cl ions via GABA (y-butyrate) receptors and non-GABA receptors [60]. 

The aglycon of avermectin has poor antiparasitic activity. Positions 4 and 4" of the olean-drose moieties were modified partly because of feasibility. The synthesis of the 4 -amino-4 G deoxyoleandrose derivative of avermectin Bi and ivermectin was based on the observation that most macrolide antibiotics contained a basic amino group [61]. One of the derivatives, 4 -e/7t-acetamido-4 -deoxyavermectin Bi, is currently under development as a novel avermectin endectoside [61]. Besides, also 2"-a-fluoro (ax.) and 2"- 8-fluoro (eq.) derivatives of avermectins were prepared to strengthen the glycosidic bond. These derivatives have interesting activities in some bioassays compared to the parental compounds [62]. 

The naturally occuring avermectins are a family of eight, pentacyclic structures containing a sixteen-membered macrolide ring which are produced by Streptomyces avermitilis (Fig. 6) [60]. These eight compounds differ in structure due to the variability of PKS starter unit at C-25, the 0-methylation pattern at C-5, and the hydration-dehydration pattern at C-22/C-23. Other closely related natural products include the milbemycins and the nemadectins. The avermectins exhibit potent broad spectrum antiparasitic activity, and the semi-synthetic Ivermectin 29 (hydrogenated avermectin Bl) displays even greater efficacy [60,61]. 

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. 

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