Increased activity of CF3-derivatized levamisole at the ACC-2 receptor from the parasitic nematode Haemonchus contortus
The acetylcholine-gated chloride channel (ACC) family in parasitic nematodes represents a promising target for anthelmintic drug development. Levamisole, a widely known and utilized cholinergic agonist, has been used for decades to address many types of parasitic infections by targeting nematode nic...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-04-01
|
| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320725000107 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850203357607624704 |
|---|---|
| author | Autumn Collins Sierra Varley Tobias Clark Nathan Chubb Sean Forrester Jean-Paul Desaulniers |
| author_facet | Autumn Collins Sierra Varley Tobias Clark Nathan Chubb Sean Forrester Jean-Paul Desaulniers |
| author_sort | Autumn Collins |
| collection | DOAJ |
| description | The acetylcholine-gated chloride channel (ACC) family in parasitic nematodes represents a promising target for anthelmintic drug development. Levamisole, a widely known and utilized cholinergic agonist, has been used for decades to address many types of parasitic infections by targeting nematode nicotinic acetylcholine receptors (nAChRs) in nematodes. In this study, we report the synthesis and pharmacological evaluation of eight levamisole derivatives, five of which are novel, on the H. contortus ACC-2 receptor. This includes a CF3-derivatized compound we have identified as compound 6 whose structure contains levamisole as a backbone with the addition of a 2-trifluoromethyl benzyl group. Electrophysiological assays revealed that compound 6 exhibited a five-fold increase in sensitivity (EC50 20 μM) compared to levamisole (EC50 100 μM), our parent compound, with an EC50 comparable to that of acetylcholine (20 μM). Investigation of the in silico docking of compound 6 with H. contortus ACC-2 suggest that it interacts uniquely within the H. contortus ACC-2 binding pocket, which may contribute to its increased receptor sensitivity. These findings highlight the potential of structural modifications containing an electron-withdrawing group at the 2-position which can significantly enhance activity at the H. contortus ACC-2 receptor. This opens many avenues for the development of more effective treatments against parasitic nematodes, in an environment with increasing resistance. |
| format | Article |
| id | doaj-art-03b88a4f387445bc8aff558f229d9bb6 |
| institution | OA Journals |
| issn | 2211-3207 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj-art-03b88a4f387445bc8aff558f229d9bb62025-08-20T02:11:33ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072025-04-012710058710.1016/j.ijpddr.2025.100587Increased activity of CF3-derivatized levamisole at the ACC-2 receptor from the parasitic nematode Haemonchus contortusAutumn Collins0Sierra Varley1Tobias Clark2Nathan Chubb3Sean Forrester4Jean-Paul Desaulniers5Applied Bioscience Graduate Program, Faculty of Science, University of Ontario Institute of Technology, 2000 Simcoe Street North, Oshawa, ON, L1G 0C5, CanadaApplied Bioscience Graduate Program, Faculty of Science, University of Ontario Institute of Technology, 2000 Simcoe Street North, Oshawa, ON, L1G 0C5, CanadaZoetis, Veterinary Medicine Research and Development, 300 Portage Street, Kalamazoo, MI, 49007, USAZoetis, Veterinary Medicine Research and Development, 300 Portage Street, Kalamazoo, MI, 49007, USAApplied Bioscience Graduate Program, Faculty of Science, University of Ontario Institute of Technology, 2000 Simcoe Street North, Oshawa, ON, L1G 0C5, Canada; Corresponding author.Applied Bioscience Graduate Program, Faculty of Science, University of Ontario Institute of Technology, 2000 Simcoe Street North, Oshawa, ON, L1G 0C5, Canada; Corresponding author.The acetylcholine-gated chloride channel (ACC) family in parasitic nematodes represents a promising target for anthelmintic drug development. Levamisole, a widely known and utilized cholinergic agonist, has been used for decades to address many types of parasitic infections by targeting nematode nicotinic acetylcholine receptors (nAChRs) in nematodes. In this study, we report the synthesis and pharmacological evaluation of eight levamisole derivatives, five of which are novel, on the H. contortus ACC-2 receptor. This includes a CF3-derivatized compound we have identified as compound 6 whose structure contains levamisole as a backbone with the addition of a 2-trifluoromethyl benzyl group. Electrophysiological assays revealed that compound 6 exhibited a five-fold increase in sensitivity (EC50 20 μM) compared to levamisole (EC50 100 μM), our parent compound, with an EC50 comparable to that of acetylcholine (20 μM). Investigation of the in silico docking of compound 6 with H. contortus ACC-2 suggest that it interacts uniquely within the H. contortus ACC-2 binding pocket, which may contribute to its increased receptor sensitivity. These findings highlight the potential of structural modifications containing an electron-withdrawing group at the 2-position which can significantly enhance activity at the H. contortus ACC-2 receptor. This opens many avenues for the development of more effective treatments against parasitic nematodes, in an environment with increasing resistance.http://www.sciencedirect.com/science/article/pii/S2211320725000107Haemonchus contortusAnthelminticAcetylcholine-gated chloride channelLevamisoleDrug discovery |
| spellingShingle | Autumn Collins Sierra Varley Tobias Clark Nathan Chubb Sean Forrester Jean-Paul Desaulniers Increased activity of CF3-derivatized levamisole at the ACC-2 receptor from the parasitic nematode Haemonchus contortus International Journal for Parasitology: Drugs and Drug Resistance Haemonchus contortus Anthelmintic Acetylcholine-gated chloride channel Levamisole Drug discovery |
| title | Increased activity of CF3-derivatized levamisole at the ACC-2 receptor from the parasitic nematode Haemonchus contortus |
| title_full | Increased activity of CF3-derivatized levamisole at the ACC-2 receptor from the parasitic nematode Haemonchus contortus |
| title_fullStr | Increased activity of CF3-derivatized levamisole at the ACC-2 receptor from the parasitic nematode Haemonchus contortus |
| title_full_unstemmed | Increased activity of CF3-derivatized levamisole at the ACC-2 receptor from the parasitic nematode Haemonchus contortus |
| title_short | Increased activity of CF3-derivatized levamisole at the ACC-2 receptor from the parasitic nematode Haemonchus contortus |
| title_sort | increased activity of cf3 derivatized levamisole at the acc 2 receptor from the parasitic nematode haemonchus contortus |
| topic | Haemonchus contortus Anthelmintic Acetylcholine-gated chloride channel Levamisole Drug discovery |
| url | http://www.sciencedirect.com/science/article/pii/S2211320725000107 |
| work_keys_str_mv | AT autumncollins increasedactivityofcf3derivatizedlevamisoleattheacc2receptorfromtheparasiticnematodehaemonchuscontortus AT sierravarley increasedactivityofcf3derivatizedlevamisoleattheacc2receptorfromtheparasiticnematodehaemonchuscontortus AT tobiasclark increasedactivityofcf3derivatizedlevamisoleattheacc2receptorfromtheparasiticnematodehaemonchuscontortus AT nathanchubb increasedactivityofcf3derivatizedlevamisoleattheacc2receptorfromtheparasiticnematodehaemonchuscontortus AT seanforrester increasedactivityofcf3derivatizedlevamisoleattheacc2receptorfromtheparasiticnematodehaemonchuscontortus AT jeanpauldesaulniers increasedactivityofcf3derivatizedlevamisoleattheacc2receptorfromtheparasiticnematodehaemonchuscontortus |