Avermectin Bib

Ivermectin, a semisynthetic macrocyclic lactone, is a mixture of avermectin Bia and avermectin Bib. It... 

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 catalyst (10 mg) was dissolved in toluene (25 ml) and added under argon to the solution of a mixture (1.1 g) of avermectin Bla (96%) and avermectin Bib (4%) and of m9 °f triphenylphosphine in toluene (25 ml) in a stainless steel autoclave. This starting material was then hydrogenated at 88°C under a hydrogen pressure of 20 bar with stirring of the solution. After 10 hours, HPLC analysis revealed a content of 86% dihydro-avermectin Bla and of 4 % dihydroavermectin Blb, and also of 3% tetrahydroavermectin Bla. 

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. 

Eprinomectin is derived from the natural product abamectin by conversion of the 4 -hydroxy group to the 4 -cp -A-acetyl substituent. Like abamectin, eprinomectin is a mixture of two active constituents that contain more than 90% 4 -deoxy-4 -(ep/-acetylamino)avermectin B a and less than 10% 4 -deoxy-4 - epi-acetylaminojavermectin Bib. It is indicated for treatment of internal and external parasites in beef and dairy cattle at a dosage of 0.5 mg/kg bw and is applied along the midline of the animal s back (61). 

Ivermectins B1 are derived from the avermectines Bl, the natural fermentation products of Streptomyces avermitilis. The avermectins Bl have double bonds between carbon atoms at 22 and 23, whereas the ivermectins Bl have single bonds in these positions (Fig. 2a). They have an intermediate polarity. The ivermectins Bl are a mixture of two major homologs, ivermectins Bla (>80%) and ivermectins Bib (<20%), but a crude ivermectin complex also contains various minor components. Ivermectins Bl are broad-spectrum antiparasitic agents used against Onchocerca volvulus in human medicine and for food production animals such as cattle, swine, and horses. 

These molecules have an intermediary polarity (Fig. 2a). A two-phase solvent system, composed of n-hexane, ethyl acetate, methanol, and water, has been selected. In this case, the partition coefficients, K, are defined as the ratio of the solute concentration in the upper phase to its concentration in the lower one. A solvent mixture of n-hexane-ethyl acetate-methanol-water (19 1 10 10, v/v/v/v) yielded the best K values from 0-2.83. 25 mg of crude ivermectin separated in 4.0 h. This separation yielded 18.7 mg of 99.0% pure ivermectin Bla, 1.0 mg of 96.0 % pure ivermectin Bib, and 0.3 mg of 98.0% pure avermectin Bla. 

We have selected a two-phase solvent system composed of n-hexane, ethyl acetate, methanol, and water. As described above, this solvent system is conveniently used for the separation of components with a broad range of hydrophobicity by modifying the volume ratio between the four solvents. In the n-hexane/ethyl acetate/methanol/ water (8 2 5 5) system first examined, the K values of the components were 0, 0.46, 0.61 (avermectin Bla) oo, 1.86 (ivermectin Bib) 3.06 (ivermectin Bla) and 4.38,... 

The 3-dimensional molecular models of the avermectins helped us to define the subtle structural differences recognized by the MAbs, but these models must be viewed and interpreted with caution. Since we could not invoke solvent interactions, we have no way to know what the differences may be between these gas-phase representations and the conformations assumed in solution. On the other hand, data for other hydrophobic compounds, including some macrolide antibiotics, suggests that their gas-phase and solution structures are very similar, and the major differences we observed in Figure 4 were in hydrophobic parts of the molecule. For this reason, we did not attempt to model the last analog in Table I, the 4" deoxy-4"epimethylamino avermectin Bi hydrochloride, even though it was the best competitor in the EIAs, because it is far more water soluble than the others. Another concern is that the samples compared in the competition EIAs were mixtures of isomers, e.g., abamectin is actually avermectin Bia Bib 80 20. Because it is virtually impossible to obtain the purified individual isomers for the EIA or other tests of antibody specificity, we can only assume that the competition EIA results primarily reflected how each MAb bound to the maior isomer. 

One of these pairs, avermectin Bi, i.e., the mixture of avermectins Bia (>80%) and Bib (<20%), is commonly referred to as abamectin (Fig. 29.6.2). It was foimd to be active against nematodes [8, 9], insects [10-12], and mites [13]. Subsequently, abamectin was selected for development in crop protection, and it was introduced to the market-place as an agricultural pesticide against a broad spectrum of phytophagous mites and insects in 1985. Merck scientists performed a... 

Emamectin is prepared from abamectin in four chemical steps [14-17]. Therefore, it is also a mixture of the two homologs Bia and Bib. The allylic hydroxy group at C5 of avermectins is the most reactive in the molecule. It has to be protected before reactions on the C4" hydroxy group can be performed. Reaction with t-butyl-dimethylchlorosilane and imidazole in N,N-dimethylformamide gives the 5-0-t-butyldimethylsilyl ether (Scheme 29.6.1). 

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