Avermectin acyl derivatives with anthelmintic activity

• Published in: Journal of medicinal chemistry Vol. 25; no. 6; pp. 658 - 663
• Main Authors: Mrozik, Helmut, Eskola, Philip, Fisher, Michael H, Egerton, John R, Cifelli, Sam, Ostlind, Dan A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.06.1982
• Subjects: Animals; Anthelmintics - chemical synthesis; Chemical Phenomena; Chemistry; Gerbillinae; Haemonchiasis - drug therapy; Ivermectin - analogs & derivatives; Lactones - chemical synthesis; Lactones - pharmacology; Ostertagiasis - drug therapy; Sheep; Trichostrongylosis - drug therapy
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00348a010

Avermectins A2a, B1a, and B2a (1, 2, and 3) were acetylated to give 4"- and 23-acetates 4 and 5 and 4",23-diacetate 6 from 1, the 4"-and 5-acetates 7 and 8 and 4",5-diacetate 9 from 2, and triacetate 10 from 3. Structure proof by 300-MHz 1H NMR and mass spectral fragmentation is discussed for 10. Forcing acetylation conditions generated from both 1 and 3 the identical aromatic diacetate 11. Good anthelmintic activities in gerbils and sheep for 4"-acetylated derivatives 4 and especially 7 prompted the preparation of additional 4"-acylated derivatives of 2 with pivaloyl, n-octanoyl, succinoyl, carbamoyl, dimethylcarbamoyl and N-acetylglycyl substituents, prepared from the 5-O-tert-butyldimethylsilyl-protected intermediate 12. Other key intermediates were the trichloroethyoxysuccinoyl derivative 18 and 4-nitrophenyl carbonate 21. Anthelmintic activities against Trichostrongylus colubriformis in gerbils comparable in potency to the natural product 2 are shown by the more polar substituted derivatives 20, 23, and 27. Substitution of the 5-hydroxy group or its loss due to aromatization results in drastically reduced anthelmintic potency.