Comparison of Ivermectin, Doramectin, Selamectin, and Eleven Intermediates in a Nematode Larval Development Assay

Abstract

Chemical substitutions at pharmacologically relevant sites such as C-5, C-13, C-22,23, and C-25 were examined in ivermectin, doramectin, selamectin, and a series of 11 other intermediates using a larval development assay with Haemonchus contortus. A range of activities spanning 5 orders of magnitude were manifest with small changes in the substituents to the 14 avermectins. Within this compound series, there was no major potency advantage or disadvantage to a disaccharide over a monosaccharide substituent at C-13. Ivermectin and doramectin were each fully effective at a concentration of 0.001 microg/ml, and both were similar to their respective monosaccharide homologs. Specific patterns emerged among the analogs with substituents at C-5. Analogs possessing hydroxyl groups at C-5 were superior in activity by several orders of magnitude over those with oxo substituents. Replacement of the oxo with an oxime (NOH) restored activity to some degree but did not restore it to the level of those possessing the hydroxyl substituent. Consequently, ivermectin and doramectin that possess hydroxyl moieties at C-5 were superior against H. contortus to those like selamectin that have oxime substituents. There was no advantage for analogs with a single or double bond at C-22,23 within the cyclohexyl series, and these analogs had equivalent activity as those with a single bond at C-22,23 in the sec-butyl/isopropyl series. However, there was superior activity for the analog series that possessed the combination of a double-bond at C-22,23 and a sec-butyl/isopropyl substituent at C-25. As a result, the most potent compound in this test was not any of the 3 commercialized avermectins but was a monosaccharide with a double bond at C-22,23, an hydroxyl at C-5, and a sec-butyl/isopropyl moiety at C-25.

Isolation and Insecticidal/Anthelmintic Activity of Xanthonol, a Novel Bis-xanthone, from a Non-sporulating Fungal species

“…Details of the antiparasitic assays have been described elsewhere for Aedes aegypti [5]; Lucilia sericata [6]; and Haemonchus contortus [7].…”

“…Our continued interest in novel antiparasitic agents led us to screen extracts of fungal fermentations in in vitro antiparasitic assays using surrogate organisms such as blowfly larvae, Lucilia sericata [5], mosquito larvae, Aedes aegypti [6], and a parasitic nematode of sheep, Haemonchus contortus [7]. This screening strategy led to the isolation and identification of xanthonol (1), a new dimeric xanthone from an extract of a non-sporulating fungal species (Figure 1).…”

Anthelmintic Macrolactams from Nonomuraea turkmeniaca MA7381

“…To discover anthelmintic agents, our strategy has been to screen extracts of bacterial and fungal fermentations as well as plants for in vitro activity against H. contortus [2], a prevalent parasitic worm species that infects small ruminants. In vivo activity was evaluated using…”

“…An acetone extract of an actinomycete strain of Nonomuraea turkmeniaca MA7381 showed in vitro activity and was selected for further study. Bioassay-guided fractionation using the in vitro assay led to the isolation of three macrolactams fluvirucin B 0 (1), Sch 38516/fluvirucin B 1 (2), Sch 39185/fluvirucin B 3 (3) of the fluvirucin class. The isolation, structure and biological activities of these compounds are herein described.…”

“…1ϳ3 were first evaluated in the in vitro H. contortus assay as described earlier [2]. All three compounds reduced motility of L3 larvae and showed EC 90 (effective concentration of compounds that exhibited 90% reduction of larval motility) of Ͻ1.0, 1.5, and 1.7 mg/ml, respectively.…”