Avermectin chemistry: problems of conjugation, deconjugation, and epimerization

Fraser‐Reid, Bert; Wolleb, Heinz; Faghih, Ramin; Barchi, Joseph J.

doi:10.1021/ja00237a068

Cited by 49 publications

(18 citation statements)

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“…46,47) An investigation demonstrating hydroxide ion mediated isomerization was previously reported for ivermectin, 48) where DP was used as an internal standard for HPLC analysis.…”

Section: Effect Of Alkaline Conditionsmentioning

confidence: 92%

“…Kinetic evidence suggested that base catalyzed conversion of AVM to conjugated Δ2,3 isomer, proceeded through the 2-epi isomer as an intermediate, 48) although there is a possibility of parallel conversion to both geometric forms to the conjugated isomer, as shown in Fig. 6 for AVM B1.…”

Section: Effect Of Alkaline Conditionsmentioning

confidence: 99%

“…47,48) Recent interest in total synthesis of the AVM B1 has revolved around the issue of deconjugating a Δ2,3 precursor with simultaneous establishment of the proper stereochemistry at the C2 position. [46][47][48] The equilibrium nature of the epimerization, as well as the total absence of deconjugation under equilibrium conditions, establish structural proof for both isomers 2-epi and Δ2,3-isomer. 46) Furthermore, AVMs are known to be most stable at pH 6.2-6.3, 49) hence, there is possibility to avoid based catalyzed degradation when formulations are designed at/around the pH 6.25.…”

Section: Effect Of Alkaline Conditionsmentioning

confidence: 99%

“…In addition, there are also detailed reports available on C2 epimerization of AVM in presence of methanolic potassium hydroxide (KOH) solution. 48) Pivnichny and coworkers have shown that treatment of AVM B with methanolic KOH solution affords a mixture of 2-epi isomer and the Δ2,3-isomer. 47) Whereas, a subsequent study also showed the formation of 2-epi-(25%) and Δ2,3-(70%) from parent compound using methanolic aqueous sodium hydroxide (NaOH) solution.…”

Section: Effect Of Alkaline Conditionsmentioning

confidence: 99%

“…After investigating a number of reagents and conditions, it was found that imidazole in benzene was an effective reagent for the partial conversion of the 2-epi isomers in to the parent compound at about 40% isolated yields. 48) 3.3 Effect of Oxidation AVMs, like their counterparts milbemycin, are prone to radical-induced oxidation at the C2-C8 oxahydrindene positions. 50) Catagerocially, depending on the position and chemical reactions, oxidation can take place at either on hydrocarbon position (e.g.…”

Section: Effect Of Alkaline Conditionsmentioning

confidence: 99%

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An Overview on Chemical Derivatization and Stability Aspects of Selected Avermectin Derivatives

Awasthi

Razzak

Al‐Kassas

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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Naturally occurring avermectins (AVMs) and its derivatives are potent endectocide compounds, wellknown for their novel mode of action against a broad range of nematode and anthropod animal parasites. In this review, chemical and pharmaceutical aspects of AVM derivatives are described including stability, synthetic and purification processes, impurities and degradation pathways, and subsequent suggestions are made to improve the chemical stability. It has been found out that unique structure of AVM molecules and presence of labile groups facilitated the derivatization of AVM into various compounds showing strong anthelmintic activity. However, the same unique structure is also responsible for labile nature related to sensitive stability profile of molecules. AVMs are found to be unstable in acidic and alkaline conditions. In addition, these compounds are sensitive to strong light, and subsequently presence of photo-isomer in animals treated topically with AVM product is well known. The pharmacoepial recommendations for addition of antioxidant into drug substance, as well as its products, arises from the fact that AVM are very sensitive to oxidation. Formations of solvates, salts, epoxides, reduction of double bonds and developing liquid formulation around pH 6.2, were some chemical approaches used to retard the degradation in AVM. This coherent review will contribute towards the better understanding of the correlation of chemical processes, stability profile and biological activity; therefore, it will help to design the shelf-life stable formulations containing AVMs.

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“…46,47) An investigation demonstrating hydroxide ion mediated isomerization was previously reported for ivermectin, 48) where DP was used as an internal standard for HPLC analysis.…”

Section: Effect Of Alkaline Conditionsmentioning

confidence: 92%

Section: Effect Of Alkaline Conditionsmentioning

confidence: 99%