Novel 1-Methyl-1H-pyrazole-5-carboxamide derivatives with potent anthelmintic activity
- Authors: Le, Thuy , Kundu, Abhijit , Ghoshal, Atanu , Nguyen, Nghi , Preston, Sarah , Jiao, Yaqing , Ruan, Banfeng , Xue, Lian , Huang, Fei , Keiser, Jennifer , Hofmann, Andreas , Chang, Bill , Garcia-Bustos, Jose , Wells, Timothy , Palmer, Michael , Jabbar, Abdul , Gasser, Robin , Baell, Jonathan
- Date: 2019
- Type: Text , Journal article
- Relation: Journal of Medicinal Chemistry Vol. 62, no. 7 (2019), p. 3367-3380
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- Description: A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure-activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth larval (L4) stage of H. contortus at sub-nanomolar potencies while displaying strong selectivity toward the parasite when tested in vitro against the human MCF10A cell line. In addition, compounds 9 and 27 showed promising activity against a panel of other parasitic nematodes, including hookworms and whipworms.
Structure-activity relationship studies of tolfenpyrad reveal subnanomolar inhibitors of haemonchus contortus development
- Authors: Le, Thuy , Kundu, Abhijit , Ghoshal, Atanu , Nguyen, Nghi , Preston, Sarah , Jiao, Yaqing , Ruan, Banfeng , Xue, Lian , Huang, Fei , Keiser, Jennifer , Hofmann, Andreas , Chang, Bill , Garcia-Bustos, Jose , Wells, Timothy , Palmer, Michael , Jabbar, Abdul , Gasser, Robin , Baell, Jonathan
- Date: 2019
- Type: Text , Journal article
- Relation: Journal of Medicinal Chemistry Vol. 62, no. 2 (2019), p. 1036-1053
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- Description: Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 mu M while displaying good selectivity, with an IC50 of 37.9 mu M for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure-activity relationships for this chemical. Modifications of the left-hand side (LHS), right-hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29, and 33 were shown to be the most potent compounds of the series, with IC50 values at a subnanomolar level of potency against the chemotherapeutically relevant fourth larval (L4) stage of H. contortus. Selected compounds from the series also showed promising activity against a panel of other different parasitic nematodes, such as hookworms and whipworms.
Optimization of novel 1-Methyl-1H-Pyrazole-5-carboxamides leads to high potency larval development inhibitors of the Barber's pole worm
- Authors: Le, Thuy , Kunda, Abhijit , Ghoshal, Atanu , Preston, Sarah , Jiao, Yaqing , Ruan, Banfeng , Xue, Lian , Huang, Fei , Keiser, Jennifer , Hofmann, Andreas , Chang, Bill , Garcia-Bustos, Jose , Jabbar, Abdul , Wells, Timothy , Palmer, Michael , Gasser, Robin , Baell, Jonathan
- Date: 2018
- Type: Text , Journal article
- Relation: Journal of Medicinal Chemistry Vol. 61, no. 23 (2018), p. 10875-10894
- Full Text: false
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- Description: 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 IC
Assessing the anthelmintic activity of pyrazole-5-carboxamide derivatives against Haemonchus contortus
- Authors: Jiao, Yaqing , Preston, Sarah , Song, Hongjian , Jabbar, Abdul , Liu, Yuxiu , Baell, Jonathan , Hofmann, Andreas , Hutchinson, Dana , Wang, Tao , Koehler, Anson , Fisher, Gillian , Andrews, Katherine , Laleu, Benoit , Palmer, Michael , Burrows, Jeremy , Wells, Timothy , Wang, Qingmin , Gasser, Robin
- Date: 2017
- Type: Text , Journal article
- Relation: Parasites and Vectors Vol. 10, no. 1 (2017), p. 1-7
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- Description: Background: In this study, we tested five series of pyrazole-5-carboxamide compounds (n = 55) for activity against parasitic stages of the nematode Haemonchus contortus (barber’s pole worm), one of the most pathogenic parasites of ruminants. Methods: In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility and development of H. contortus. Results: Amongst the 55 compounds, we identified two compounds (designated a-15 and a-17) that reproducibly inhibit xL3 motility as well as L4 motility and development, with IC50 values ranging between ~3.4 and 55.6 μM. We studied the effect of these two ‘hit’ compounds on mitochondrial function by measuring oxygen consumption. This assessment showed that xL3s exposed to each of these compounds consumed significantly less oxygen and had less mitochondrial activity than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods. Conclusions: The present findings provide a sound basis for future work, aimed at identifying the targets of compounds a-15 and a-17 and establishing the modes of action of these chemicals in H. contortus. © 2017 The Author(s).