Optimization of Novel 1‑Methyl‑1H‑Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber’s Pole Worm

A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1H-pyrazole-5-carboxamide derivative with an IC₅₀ of 0.29 μM. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure–activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC₅₀ of 0.01 μM. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 μM.