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Article

Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against Haemonchus contortus In Vitro

1
Department of Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville 3010, Victoria, Australia
2
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
3
Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia
4
Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville 3010, Victoria, Australia
*
Author to whom correspondence should be addressed.
Academic Editor: Maria Chatzopoulou
Molecules 2021, 26(9), 2819; https://doi.org/10.3390/molecules26092819
Received: 24 March 2021 / Revised: 3 May 2021 / Accepted: 4 May 2021 / Published: 10 May 2021
(This article belongs to the Special Issue Phenotypic Screening)
Due to widespread multi-drug resistance in parasitic nematodes of livestock animals, there is an urgent need to discover new anthelmintics with distinct mechanisms of action. Extending previous work, here we screened a panel of 245 chemically-diverse small molecules for anti-parasitic activity against Haemonchus contortus—an economically important parasitic nematode of livestock. This panel was screened in vitro against exsheathed third-stage larvae (xL3) of H. contortus using an established phenotypic assay, and the potency of select compounds to inhibit larval motility and development assessed in dose-response assays. Of the 245 compounds screened, three—designated MPK18, MPK334 and YAK308—induced non-wildtype larval phenotypes and repeatedly inhibited xL3-motility, with IC50 values of 45.2 µM, 17.1 µM and 52.7 µM, respectively; two also inhibited larval development, with IC50 values of 12.3 µM (MPK334) and 6.5 µM (YAK308), and none of the three was toxic to human liver cells (HepG2). These findings suggest that these compounds deserve further evaluation as nematocidal candidates. Future work should focus on structure–activity relationship (SAR) studies of these chemical scaffolds, and assess the in vitro and in vivo efficacies and safety of optimised compounds against adults of H. contortus. View Full-Text
Keywords: Haemonchus contortus; phenotypic screening; anthelmintics; small molecules Haemonchus contortus; phenotypic screening; anthelmintics; small molecules
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MDPI and ACS Style

Taki, A.C.; Jabbar, A.; Kurz, T.; Lungerich, B.; Ma, G.; Byrne, J.J.; Pflieger, M.; Asfaha, Y.; Fischer, F.; Chang, B.C.H.; Sleebs, B.E.; Gasser, R.B. Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against Haemonchus contortus In Vitro. Molecules 2021, 26, 2819. https://doi.org/10.3390/molecules26092819

AMA Style

Taki AC, Jabbar A, Kurz T, Lungerich B, Ma G, Byrne JJ, Pflieger M, Asfaha Y, Fischer F, Chang BCH, Sleebs BE, Gasser RB. Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against Haemonchus contortus In Vitro. Molecules. 2021; 26(9):2819. https://doi.org/10.3390/molecules26092819

Chicago/Turabian Style

Taki, Aya C., Abdul Jabbar, Thomas Kurz, Beate Lungerich, Guangxu Ma, Joseph J. Byrne, Marc Pflieger, Yodita Asfaha, Fabian Fischer, Bill C.H. Chang, Brad E. Sleebs, and Robin B. Gasser 2021. "Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against Haemonchus contortus In Vitro" Molecules 26, no. 9: 2819. https://doi.org/10.3390/molecules26092819

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