Avermectin acyl derivatives with anthelmintic activity.
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.
D000818:Animals; D000871:Anthelmintics / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D005849:Gerbillinae; D006188:Haemonchiasis / Q000188:drug therapy; D007559:Ivermectin / Q000031:analogs & derivatives*; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology; D010029:Ostertagiasis / Q000188:drug therapy; D012756:Sheep; D014253:Trichostrongylosis / Q000188:drug therapy
D000871:Anthelmintics; D007783:Lactones; D007559:Ivermectin; C019264:avermectin