Sensitivity of Haemonchus contortus to anthelmintics using different in vitro screening assays: a comparative study

Background: Helminthiasis and resistance to commercial anthelmintic compounds are major causes of economic
losses for livestock producers, resulting in an urgent need for new drugs and reliable in vitro screening tests capable
of detecting potentially active products. Considering this, a series of novel benzimidazole derivatives (5-methylbenzimidazole 1,2-disubstituted, 5-carboxybenzimidazole, 5-methylbenzimidazole 2-one) was screened on exsheathed L3 (xL3) and on the adult stage of Haemonchus contortus (Kirby anthelmintic-susceptible McMaster isolate).
Methods: This work presents the set-up of an automated motility assay on the xL3 stage of H. contortus using an
infrared tracking device (WMicrotracker One) together with a larval development test (xL3 to L4) and a motility assay
on the adult stage of H. contortus. A comparative study of the sensitivity of these in vitro assays using commercial
anthelmintics with different mechanisms of action was carried out, also evaluating anthelmintic activity of a series of
novel benzimidazole derivatives.
Results: The automated xL3 assay had the great advantage of being able to analyze many compounds simultaneously,
but it showed the limitation of having lower sensitivity, requiring higher concentrations of the commercial
anthelmintics tested compared to those needed for the adult motility or development assays. Although none of the
novel 1,2,5-tri-substituted benzimidazole derivatives could significantly decrease the motility of xL3s, one of them (1e)
significantly affected the development of xL3s to L4, and five new compounds (1b, 1d, 1e, 2a and 2c) reduced the
motility of H. contortus adult stage.
Conclusions: The analysis of the results strongly suggests that the in vitro xL3 to L4 development test, particularly
for the L4 stage, could be closer to the pharmacological sensitivity of the adult stage of H. contortus (target of interest)
for commercial anthelmintic selected, with different mechanisms of action, and for the series of benzimidazole
derivatives assayed. Therefore, an automated motility assay on L4 using the infrared tracking device is being set up.
Further studies will be conducted to evaluate the in vivo anthelmintic activity of the most active novel benzimidazole
derivatives.

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