10.1021/acs.jmedchem.8b01544.s001 Thuy G. Le Thuy G. Le Abhijit Kundu Abhijit Kundu Atanu Ghoshal Atanu Ghoshal Nghi H. Nguyen Nghi H. Nguyen Sarah Preston Sarah Preston Yaqing Jiao Yaqing Jiao Banfeng Ruan Banfeng Ruan Lian Xue Lian Xue Fei Huang Fei Huang Jennifer Keiser Jennifer Keiser Andreas Hofmann Andreas Hofmann Bill C. H. Chang Bill C. H. Chang Jose Garcia-Bustos Jose Garcia-Bustos Abdul Jabbar Abdul Jabbar Timothy N. C. Wells Timothy N. C. Wells Michael J. Palmer Michael J. Palmer Robin B. Gasser Robin B. Gasser Jonathan B. Baell Jonathan B. Baell Optimization of Novel 1‑Methyl‑1<i>H</i>‑Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber’s Pole Worm American Chemical Society 2018 focus analogue Pyrazole SAR Strong methyl inhibition LHS compound RHS Pole 0.01 μ M Methyl section High Potency Larval Development Inhibitors identification 0.29 μ M contrast assembly elucidate Optimization iterative larvae 50 μ M relationship nematode Haemonchus contortus phenotypic 1- IC 50 concentration epithelial cell line MCF 10A viability modification Medicinal chemistry optimization -5-carboxamide molecule pyrazole scaffold 2018-11-07 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Optimization_of_Novel_1_Methyl_1_i_H_i_Pyrazole-5-carboxamides_Leads_to_High_Potency_Larval_Development_Inhibitors_of_the_Barber_s_Pole_Worm/7396898 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-1<i>H</i>-pyrazole-5-carboxamide derivative with an IC<sub>50</sub> 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 <b>60</b> was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC<sub>50</sub> 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.