Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against <i>Haemonchus contortus</i> In Vitro
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 again...
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doaj-ca0994131bf34fffb846f111aeea11502021-05-31T23:35:42ZengMDPI AGMolecules1420-30492021-05-01262819281910.3390/molecules26092819Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against <i>Haemonchus contortus</i> In VitroAya C. Taki0Abdul Jabbar1Thomas Kurz2Beate Lungerich3Guangxu Ma4Joseph J. Byrne5Marc Pflieger6Yodita Asfaha7Fabian Fischer8Bill C. H. Chang9Brad E. Sleebs10Robin B. Gasser11Department of Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville 3010, Victoria, AustraliaDepartment of Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville 3010, Victoria, AustraliaInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, GermanyInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, GermanyDepartment of Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville 3010, Victoria, AustraliaDepartment of Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville 3010, Victoria, AustraliaInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, GermanyInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, GermanyInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, GermanyDepartment of Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville 3010, Victoria, AustraliaDepartment of Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville 3010, Victoria, AustraliaDepartment of Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville 3010, Victoria, AustraliaDue 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 <i>Haemonchus contortus</i>—an economically important parasitic nematode of livestock. This panel was screened in vitro against exsheathed third-stage larvae (xL3) of <i>H. contortus</i> 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 IC<sub>50</sub> values of 45.2 µM, 17.1 µM and 52.7 µM, respectively; two also inhibited larval development, with IC<sub>50</sub> 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 <i>H. contortus</i>.https://www.mdpi.com/1420-3049/26/9/2819<i>Haemonchus contortus</i>phenotypic screeninganthelminticssmall molecules |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Aya C. Taki Abdul Jabbar Thomas Kurz Beate Lungerich Guangxu Ma Joseph J. Byrne Marc Pflieger Yodita Asfaha Fabian Fischer Bill C. H. Chang Brad E. Sleebs Robin B. Gasser |
spellingShingle |
Aya C. Taki Abdul Jabbar Thomas Kurz Beate Lungerich Guangxu Ma Joseph J. Byrne Marc Pflieger Yodita Asfaha Fabian Fischer Bill C. H. Chang Brad E. Sleebs Robin B. Gasser Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against <i>Haemonchus contortus</i> In Vitro Molecules <i>Haemonchus contortus</i> phenotypic screening anthelmintics small molecules |
author_facet |
Aya C. Taki Abdul Jabbar Thomas Kurz Beate Lungerich Guangxu Ma Joseph J. Byrne Marc Pflieger Yodita Asfaha Fabian Fischer Bill C. H. Chang Brad E. Sleebs Robin B. Gasser |
author_sort |
Aya C. Taki |
title |
Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against <i>Haemonchus contortus</i> In Vitro |
title_short |
Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against <i>Haemonchus contortus</i> In Vitro |
title_full |
Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against <i>Haemonchus contortus</i> In Vitro |
title_fullStr |
Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against <i>Haemonchus contortus</i> In Vitro |
title_full_unstemmed |
Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against <i>Haemonchus contortus</i> In Vitro |
title_sort |
three small molecule entities (mpk18, mpk334 and yak308) with activity against <i>haemonchus contortus</i> in vitro |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2021-05-01 |
description |
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 <i>Haemonchus contortus</i>—an economically important parasitic nematode of livestock. This panel was screened in vitro against exsheathed third-stage larvae (xL3) of <i>H. contortus</i> 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 IC<sub>50</sub> values of 45.2 µM, 17.1 µM and 52.7 µM, respectively; two also inhibited larval development, with IC<sub>50</sub> 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 <i>H. contortus</i>. |
topic |
<i>Haemonchus contortus</i> phenotypic screening anthelmintics small molecules |
url |
https://www.mdpi.com/1420-3049/26/9/2819 |
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