Syntheses and biological activities of 13-substituted avermectin aglycons

Abstract

The reactions of sulfonate esters of the allylic/homoallylic 13-alcohol of 5-O-(tert-butyldimethylsilyl)-22,23-dihydroavermectin B1a aglycon (1a) were investigated. Nucleophilic substitution gave 13 beta-chloro and 13 beta-iodo derivatives, while solvolytic reaction conditions yielded 13 alpha-methoxy, 13 alpha-fluoro, and 13 alpha-chloro products. A mixture of 13 alpha- and 13 beta-fluorides was obtained upon reaction with DAST. The 13 beta-iodide gave, upon elimination with lutidine, the 8(9),10(11),12(13),14(15)-tetraene. The 13 beta-alcohol and the rearranged 15-ol 13(14)-ene and 15-amino 13(14)-ene derivatives were obtained by substitution via the allylic carbonium ion. MEM ethers 11 and 12 of the two epimeric 13-ols were prepared by alkylation with MEM chloride. In contrast, methylation of 1a with MeI and Ag2O in CH2Cl2 occurred exclusively at the tertiary 7-hydroxy group and not at the secondary 13 alpha-ol. Oxidation of the allylic alcohol 1a proceeded under Swern conditions but not with MnO2 to the 13-oxo aglycon, which was reduced by NaBH4 exclusively to the natural 13 alpha-ol, while reductive amination with NaCNBH3-NH4OAc gave the 13 alpha-amine. The methoxime derivative was obtained in the form of the two geometric isomers. Anthelmintic activities against the sheep nematode Trichostrongylus colubriformis, miticidal activities against the two-spotted spider mite (Tetranychus urticae), and insecticidal activities against the southern armyworm (Spodoptera eridania) as well as the binding constants to a free living nematode (Caenorhabditis elegans) derived receptor assay were obtained and compared to avermectin B1a, 22,23-dihydroavermectin B1a, and the 13-deoxy-22,23-dihydroavermectin B1 aglycon related to the milbemycins. None of the newly prepared derivatives exceeded the potency of the three reference compounds. Lipophilic 13-substituents such as halogen, alkoxy, and methoxime retained high biological activities in all assays, while the more polar substituents hydroxy and amino had weaker activities. Rearranged 15-substituted 13(14)-ene derivatives were completely inactive. The 13-oxo and the 12,13-dehydro analogues were only weakly active in vivo despite having good binding affinity to the receptor, possibly due to instability or poor absorption.

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

“…[14][15][16][17][18][19][20] In general, tert-butyldimethylsilyl (TB-DMS) chloride or acetate is used as protective reagent, and once the substitution is over, the TBDSM moiety is removed by p-toluenesulphonic acid (p-TSA) to achieve the alkyl, acyl, acetyl amino, glycosyl etc. derivatives.…”

Preparation of magnetic molecularly imprinted polymers by atom transfer radical polymerization for the rapid extraction of avermectin from fish samples

“…Avermectin, which is a macrolide antibiotic with a large molecular weight from Streptomyces avemitilis , was introduced to the marketplace as an antiparasitic drug and an agricultural pesticide in the 1980s . It is widely employed in agriculture and fishery according to its efficient broad‐spectrum antiparasitic activity .…”

Identification of the Secondary Degradates of L-648,548 in an Animal Health Formulation

“…L-648,548 (1) is among the compounds which showed improved antiparasitic and insecticidal activities. 7 Similar to most avermectins, these new analogs are susceptible to oxidation and acid-basecatalyzed decomposition. One of the commonly observed degradation pathways in the formulation is the autocatalyzed oxidation with peroxides at the C8 and C5 positions to form 8a-oxo and 5-oxo degradates.…”