Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica

Chakroborty, Anand; Pritchard, Deiniol R.; Bouillon, Marc E.; Cervi, Anna; Kraehenbuehl, Rolf; Wild, Charlotte; Fenn, Caroline; Holdsworth, Peter; Capner, Colin; Padalino, Gilda; Forde-Thomas, Josephine E.; Payne, Joseph; Smith, Brendan G.; Fisher, Maggie; Lahmann, Martina; Baird, Mark S.; Hoffmann, Karl F.

doi:10.3390/pharmaceutics15071869

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Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica

Anand Chakroborty

, Deiniol R. Pritchard, Marc E. Bouillon, Anna Cervi, Rolf Kraehenbuehl, Charlotte Wild, Caroline Fenn, Peter Holdsworth

, Colin Capner

, Gilda Padalino

, Josephine E. Forde-Thomas

, Joseph Payne, Brendan G. Smith, Maggie Fisher, Martina Lahmann

, Mark S. Baird

, Karl F. Hoffmann

Pharmaceutics, Volume: 15, Issue: 7, Start page: 1869

Swansea University Author: Gilda Padalino

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DOI (Published version): 10.3390/pharmaceutics15071869

Abstract

Infection with Fasciola hepatica (liver fluke) causes fasciolosis (or fascioliasis) and poses a considerable economic as well as welfare burden to both the agricultural and animal health sectors. Here, we explore the ex vivo anthelmintic potential of synthetic derivatives of hederagenin, isolated in...

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Published in:	Pharmaceutics
ISSN:	1999-4923
Published:	MDPI AG 2023
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URI:	https://cronfa.swan.ac.uk/Record/cronfa64496
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Thirty-six compounds were initially screened against F. hepatica newly excysted juveniles (NEJs) of the Italian strain. Eleven of these compounds were active against NEJs and were selected for further study, using adult F. hepatica derived from a local abattoir (provenance unknown). From these eleven compounds, six demonstrated activity and were further assessed against immature liver flukes of the Italian strain. Subsequently, the most active compounds (n = 5) were further evaluated in ex vivo dose response experiments against adult Italian strain liver flukes. Overall, MC042 was identified as the most active molecule and the EC50 obtained from immature and adult liver fluke assays (at 24 h post co-culture) are estimated as 1.07 μM and 13.02 μM, respectively. When compared to the in vitro cytotoxicity of MDBK bovine cell line, MC042 demonstrated the highest anthelmintic selectivity (44.37 for immature and 3.64 for adult flukes). 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spelling	v2 64496 2023-09-08 Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica 7e5526209f02734f57ba19b0d17604ec 0000-0001-8580-1293 Gilda Padalino Gilda Padalino true false 2023-09-08 PHAR Infection with Fasciola hepatica (liver fluke) causes fasciolosis (or fascioliasis) and poses a considerable economic as well as welfare burden to both the agricultural and animal health sectors. Here, we explore the ex vivo anthelmintic potential of synthetic derivatives of hederagenin, isolated in bulk from Hedera helix. Thirty-six compounds were initially screened against F. hepatica newly excysted juveniles (NEJs) of the Italian strain. Eleven of these compounds were active against NEJs and were selected for further study, using adult F. hepatica derived from a local abattoir (provenance unknown). From these eleven compounds, six demonstrated activity and were further assessed against immature liver flukes of the Italian strain. Subsequently, the most active compounds (n = 5) were further evaluated in ex vivo dose response experiments against adult Italian strain liver flukes. Overall, MC042 was identified as the most active molecule and the EC50 obtained from immature and adult liver fluke assays (at 24 h post co-culture) are estimated as 1.07 μM and 13.02 μM, respectively. When compared to the in vitro cytotoxicity of MDBK bovine cell line, MC042 demonstrated the highest anthelmintic selectivity (44.37 for immature and 3.64 for adult flukes). These data indicate that modified hederagenins display properties suitable for further investigations as candidate flukicides. Journal Article Pharmaceutics 15 7 1869 MDPI AG 1999-4923 Fasciola hepatica; anthelmintic drug discovery; Hedera helix; saponins and hederagenin 3 7 2023 2023-07-03 10.3390/pharmaceutics15071869 http://dx.doi.org/10.3390/pharmaceutics15071869 COLLEGE NANME Pharmacy COLLEGE CODE PHAR Swansea University This research work was supported and funded by UK Research and Innovation: Innovate UK grant number 102101. 2024-01-08T14:13:17.3979869 2023-09-08T15:56:34.3815159 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Pharmacy Anand Chakroborty 0000-0003-4987-2646 1 Deiniol R. Pritchard 2 Marc E. Bouillon 3 Anna Cervi 4 Rolf Kraehenbuehl 5 Charlotte Wild 6 Caroline Fenn 7 Peter Holdsworth 0009-0007-9173-5369 8 Colin Capner 0000-0001-7179-3755 9 Gilda Padalino 0000-0001-8580-1293 10 Josephine E. Forde-Thomas 0000-0002-7202-3565 11 Joseph Payne 12 Brendan G. Smith 13 Maggie Fisher 14 Martina Lahmann 0000-0002-8513-1952 15 Mark S. Baird 0000-0001-5340-8745 16 Karl F. Hoffmann 17 64496__28708__7c910a8811a24de0b3f18010b6661ffd.pdf 64496.VOR.pdf 2023-10-04T17:11:56.3130502 Output 2114203 application/pdf Version of Record true © 2023 by the authors. Licensee MDPI, Basel, Switzerland. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title	Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica
spellingShingle	Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica Gilda Padalino
title_short	Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica
title_full	Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica
title_fullStr	Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica
title_full_unstemmed	Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica
title_sort	Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica
author_id_str_mv	7e5526209f02734f57ba19b0d17604ec
author_id_fullname_str_mv	7e5526209f02734f57ba19b0d17604ec_***_Gilda Padalino
author	Gilda Padalino
author2	Anand Chakroborty Deiniol R. Pritchard Marc E. Bouillon Anna Cervi Rolf Kraehenbuehl Charlotte Wild Caroline Fenn Peter Holdsworth Colin Capner Gilda Padalino Josephine E. Forde-Thomas Joseph Payne Brendan G. Smith Maggie Fisher Martina Lahmann Mark S. Baird Karl F. Hoffmann
format	Journal article
container_title	Pharmaceutics
container_volume	15
container_issue	7
container_start_page	1869
publishDate	2023
institution	Swansea University
issn	1999-4923
doi_str_mv	10.3390/pharmaceutics15071869
publisher	MDPI AG
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id	facultyofmedicinehealthandlifesciences
hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id	facultyofmedicinehealthandlifesciences
hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Pharmacy{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Pharmacy
url	http://dx.doi.org/10.3390/pharmaceutics15071869
document_store_str	1
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description	Infection with Fasciola hepatica (liver fluke) causes fasciolosis (or fascioliasis) and poses a considerable economic as well as welfare burden to both the agricultural and animal health sectors. Here, we explore the ex vivo anthelmintic potential of synthetic derivatives of hederagenin, isolated in bulk from Hedera helix. Thirty-six compounds were initially screened against F. hepatica newly excysted juveniles (NEJs) of the Italian strain. Eleven of these compounds were active against NEJs and were selected for further study, using adult F. hepatica derived from a local abattoir (provenance unknown). From these eleven compounds, six demonstrated activity and were further assessed against immature liver flukes of the Italian strain. Subsequently, the most active compounds (n = 5) were further evaluated in ex vivo dose response experiments against adult Italian strain liver flukes. Overall, MC042 was identified as the most active molecule and the EC50 obtained from immature and adult liver fluke assays (at 24 h post co-culture) are estimated as 1.07 μM and 13.02 μM, respectively. When compared to the in vitro cytotoxicity of MDBK bovine cell line, MC042 demonstrated the highest anthelmintic selectivity (44.37 for immature and 3.64 for adult flukes). These data indicate that modified hederagenins display properties suitable for further investigations as candidate flukicides.
published_date	2023-07-03T14:13:19Z
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Modified Hederagenin Derivatives Demonstrate Ex Vivo Anthelmintic Activity against Fasciola hepatica

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