Novel 1-Methyl-1H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity
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Kundu, Abhijit
Ghoshal, Atanu
Nguyen, Nghi H
Preston, Sarah
Jiao, Yaqing
Ruan, Banfeng
Xue, Lian
Huang, Fei
Keiser, Jennifer
Hofmann, Andreas
Chang, Bill CH
Garcia-Bustos, Jose
Wells, Timothy NC
Palmer, Michael J
Jabbar, Abdul
Gasser, Robin B
Baell, Jonathan B
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Abstract
Anthelmintic resistance imposes a huge burden on global animal healthcare, particularly livestock, with significant negative socioeconomic impacts.(1−3) This burden is caused by the excessive and uncontrolled use of marketed anthelmintics and the induced genetic change in parasite populations.(4−6) Since the ground-breaking discovery of monepantel as a novel class of anthelmintic in 2008,(7,8) there has been no new commercial chemical entity with potent anthelmintic activity approved for the control of parasitic worms in livestock. In addition, resistance has also been reported for monepantel as well as moxidectin, another anthelmintic agent for the treatment of haemonchosis.(9,10) Therefore, a sustained effort to discover and develop novel anthelmintics is an essential component of the battle against drug resistance. Our team is focused on the discovery and development of new anthelmintics for oral or percutaneous treatment of parasitic infections of livestock, preferably with a compound class that exhibits a broad spectrum of activity and may be applicable to human diseases caused by other parasitic helminths. In a previous work, we discovered that a registered pesticide called tolfenpyrad (TFP)(11) and an independent chemotype, designated SN00799639 (SN639) (Figure 1), were potent inhibitors of the motility and development of parasitic larvae of Haemonchus contortus, a blood-feeding parasitic nematode of major economic importance in ruminants. TFP showed IC50 values of 2.9 and 0.03 μM against the motility of exsheathed third-stage larvae (xL3s) and against their development to fourth-stage larvae (L4s), respectively, whereas SN639 displayed lower potency, with IC50 values of 8.4 μM (xL3 motility) and 0.29 μM (L4 development). Both hits displayed selectivity toward the parasite when tested in an assay measuring proliferation of a human breast epithelial cell line (MCF10A) in vitro, with an inhibitory IC50 value of 37.9 μM for TFP and >50 μM for SN639. Elaborations of the structure–activity relationships (SARs) for the two hits has been conducted by Le et al.(12,13) where potent molecules with good inherent physicochemistry were established. Importantly, both the hits share a 1-methyl-1H-pyrazole-5-carboxamide pharmacophore, indicating that hybrid analogues of these two hit molecules are worthy of investigation. Therefore, we herein report the synthesis and SAR exploration of a set of 30 analogues that incorporate structural elements from the two original hits. The objective of this study was to identify functional groups that lead to breakthrough activity while still maintaining drug-likeliness and selectivity toward the parasite.
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JOURNAL OF MEDICINAL CHEMISTRY
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62
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7
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Medicinal and biomolecular chemistry
Organic chemistry
Pharmacology and pharmaceutical sciences