Drug repurposing from veterinary to human medicine has been the main strategy to develop the four recommended human anthelminthics,
albendazole,
mebendazole,
levamisole, and
pyrantel pamoate, for the treatment of soil-transmitted
helminthiasis. A systematic, head-to-head comparison of the anthelminthic activity profile of derivatives of these drugs and other anthelminthics developed in succession has not been conducted to date. We studied eight
benzimidazoles, five macrocyclic
lactones,
tribendimidine,
levamisole, and
pyrantel pamoate in laboratory models of human intestinal
nematode infections. In vitro studies were performed on Trichuris muris L1 larval stage and adults, as well as Ancylostoma ceylanicum, Necator americanus, Heligmosomoides polygyrus, and Strongyloides ratti L3 larvae and adults. The
benzimidazoles showed pronounced differences against larval and adult stages, with low activity against larvae and the highest activity observed against adult N. americanus (IC50 of
flubendazole 1.1 μM). The macrocyclic
lactones, on the other hand, revealed a higher activity on the larval stages, with the lowest IC50 values observed against N. americanus L3 (IC50 values of 0.03-3 μM). In vivo studies were performed in the T. muris and H. polygyrus mice models, with
moxidectin and
milbemycin oxime showing the highest activity against H. polygyrus (ED50 values of 0.009 and 0.006 mg/kg, respectively) and
moxidectin and
abamectin being the most effective drugs against T. muris (ED50 values of 0.2 and 0.5 mg/kg, respectively). Laboratory models for soil-transmitted
helminthiasis can assist characterizing potential drug candidates. Drugs should be evaluated against different species, and both the adult and larval stages as activities could differ considerably.