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Assessing the Anthelmintic Candidates BLK127 and HBK4 for Their Efficacy on Haemonchus contortus Adults and Eggs, and Their Hepatotoxicity and Biotransformation

As a widely distributed parasitic nematode of ruminants, Haemonchus contortus has become resistant to most anthelmintic classes, there has been a major demand for new compounds against H. contortus and related nematodes. Recent phenotypic screening has revealed two compounds, designated as BLK127 an...

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Autores principales: Zajíčková, Markéta, Prchal, Lukáš, Vokřál, Ivan, Nguyen, Linh Thuy, Kurz, Thomas, Gasser, Robin, Bednářová, Klára, Mičundová, Magdalena, Lungerich, Beate, Michel, Oliver, Skálová, Lenka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024958/
https://www.ncbi.nlm.nih.gov/pubmed/35456588
http://dx.doi.org/10.3390/pharmaceutics14040754
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author Zajíčková, Markéta
Prchal, Lukáš
Vokřál, Ivan
Nguyen, Linh Thuy
Kurz, Thomas
Gasser, Robin
Bednářová, Klára
Mičundová, Magdalena
Lungerich, Beate
Michel, Oliver
Skálová, Lenka
author_facet Zajíčková, Markéta
Prchal, Lukáš
Vokřál, Ivan
Nguyen, Linh Thuy
Kurz, Thomas
Gasser, Robin
Bednářová, Klára
Mičundová, Magdalena
Lungerich, Beate
Michel, Oliver
Skálová, Lenka
author_sort Zajíčková, Markéta
collection PubMed
description As a widely distributed parasitic nematode of ruminants, Haemonchus contortus has become resistant to most anthelmintic classes, there has been a major demand for new compounds against H. contortus and related nematodes. Recent phenotypic screening has revealed two compounds, designated as BLK127 and HBK4, that are active against H. contortus larvae. The present study was designed to assess the activity of these compounds against H. contortus eggs and adults, hepatotoxicity in rats and sheep, as well as biotransformation in H. contortus adults and the ovine liver. Both compounds exhibited no inhibitory effect on the hatching of eggs. The benzyloxy amide BLK127 significantly decreased the viability of adults in sensitive and resistant strains of H. contortus and showed no hepatotoxic effect, even at the highest concentration tested (100 µM). In contrast, HBK4 had no impact on the viability of H. contortus adults and exhibited significant hepatotoxicity. Based on these findings, HBK4 was excluded from further studies, while BLK127 seems to be a potential candidate for a new anthelmintic. Consequently, biotransformation of BLK127 was tested in H. contortus adults and the ovine liver. In H. contortus, several metabolites formed via hydroxylation, hydrolysis and glycosidation were identified, but the extent of biotransformation was low, and the total quantity of the metabolites formed did not differ significantly between the sensitive and resistant strains. In contrast, ovine liver cells metabolized BLK127 more extensively with a glycine conjugate of 4-(pentyloxy)benzoic acid as the main BLK127 metabolite.
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spelling pubmed-90249582022-04-23 Assessing the Anthelmintic Candidates BLK127 and HBK4 for Their Efficacy on Haemonchus contortus Adults and Eggs, and Their Hepatotoxicity and Biotransformation Zajíčková, Markéta Prchal, Lukáš Vokřál, Ivan Nguyen, Linh Thuy Kurz, Thomas Gasser, Robin Bednářová, Klára Mičundová, Magdalena Lungerich, Beate Michel, Oliver Skálová, Lenka Pharmaceutics Article As a widely distributed parasitic nematode of ruminants, Haemonchus contortus has become resistant to most anthelmintic classes, there has been a major demand for new compounds against H. contortus and related nematodes. Recent phenotypic screening has revealed two compounds, designated as BLK127 and HBK4, that are active against H. contortus larvae. The present study was designed to assess the activity of these compounds against H. contortus eggs and adults, hepatotoxicity in rats and sheep, as well as biotransformation in H. contortus adults and the ovine liver. Both compounds exhibited no inhibitory effect on the hatching of eggs. The benzyloxy amide BLK127 significantly decreased the viability of adults in sensitive and resistant strains of H. contortus and showed no hepatotoxic effect, even at the highest concentration tested (100 µM). In contrast, HBK4 had no impact on the viability of H. contortus adults and exhibited significant hepatotoxicity. Based on these findings, HBK4 was excluded from further studies, while BLK127 seems to be a potential candidate for a new anthelmintic. Consequently, biotransformation of BLK127 was tested in H. contortus adults and the ovine liver. In H. contortus, several metabolites formed via hydroxylation, hydrolysis and glycosidation were identified, but the extent of biotransformation was low, and the total quantity of the metabolites formed did not differ significantly between the sensitive and resistant strains. In contrast, ovine liver cells metabolized BLK127 more extensively with a glycine conjugate of 4-(pentyloxy)benzoic acid as the main BLK127 metabolite. MDPI 2022-03-30 /pmc/articles/PMC9024958/ /pubmed/35456588 http://dx.doi.org/10.3390/pharmaceutics14040754 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zajíčková, Markéta
Prchal, Lukáš
Vokřál, Ivan
Nguyen, Linh Thuy
Kurz, Thomas
Gasser, Robin
Bednářová, Klára
Mičundová, Magdalena
Lungerich, Beate
Michel, Oliver
Skálová, Lenka
Assessing the Anthelmintic Candidates BLK127 and HBK4 for Their Efficacy on Haemonchus contortus Adults and Eggs, and Their Hepatotoxicity and Biotransformation
title Assessing the Anthelmintic Candidates BLK127 and HBK4 for Their Efficacy on Haemonchus contortus Adults and Eggs, and Their Hepatotoxicity and Biotransformation
title_full Assessing the Anthelmintic Candidates BLK127 and HBK4 for Their Efficacy on Haemonchus contortus Adults and Eggs, and Their Hepatotoxicity and Biotransformation
title_fullStr Assessing the Anthelmintic Candidates BLK127 and HBK4 for Their Efficacy on Haemonchus contortus Adults and Eggs, and Their Hepatotoxicity and Biotransformation
title_full_unstemmed Assessing the Anthelmintic Candidates BLK127 and HBK4 for Their Efficacy on Haemonchus contortus Adults and Eggs, and Their Hepatotoxicity and Biotransformation
title_short Assessing the Anthelmintic Candidates BLK127 and HBK4 for Their Efficacy on Haemonchus contortus Adults and Eggs, and Their Hepatotoxicity and Biotransformation
title_sort assessing the anthelmintic candidates blk127 and hbk4 for their efficacy on haemonchus contortus adults and eggs, and their hepatotoxicity and biotransformation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024958/
https://www.ncbi.nlm.nih.gov/pubmed/35456588
http://dx.doi.org/10.3390/pharmaceutics14040754
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