New derivatives of benzhydroxamic acid with nematocidal activity against Haemonchus contortus and Caenorhabditis elegans
Parasitic nematodes cause a wide range of diseases in animals, including humans. However, the efficacy of existing anthelmintic drugs, commonly used to treat these infections, is waning due to the increasing prevalence of drug resistance in nematode populations. This growing challenge underscores th...
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Elsevier
2025-08-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320725000223 |
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| author | Josef Krátký Markéta Zajíčková Aya C. Taki Oliver Michel Petra Matoušková Ivan Vokřál Karolína Štěrbová Ondřej Vosála Beate Lungerich Thomas Kurz Robin B. Gasser Karel Harant Lenka Skálová |
| author_facet | Josef Krátký Markéta Zajíčková Aya C. Taki Oliver Michel Petra Matoušková Ivan Vokřál Karolína Štěrbová Ondřej Vosála Beate Lungerich Thomas Kurz Robin B. Gasser Karel Harant Lenka Skálová |
| author_sort | Josef Krátký |
| collection | DOAJ |
| description | Parasitic nematodes cause a wide range of diseases in animals, including humans. However, the efficacy of existing anthelmintic drugs, commonly used to treat these infections, is waning due to the increasing prevalence of drug resistance in nematode populations. This growing challenge underscores the urgent need to discover and develop novel nematocidal drugs that target new molecular pathways. In the present study, 13 novel derivatives of benzhydroxamic acid (OMKs) were designed and synthesized. Their anthelmintic activity was tested in the parasitic nematode Haemonchus contortus (barber's pole worm) and the free-living nematode Caenorhabditis elegans and potential toxicity assessed in mammalian models. Compound OMK211 showed the most promising results. It decreased viability and motility of larval and adult stages of both nematode species and of both drug-sensitive and drug-resistant strains of H. contortus at micromolar concentrations with the highest efficacy in H. contortus adult males (IC50 ∼ 1 μM). Moreover, OMK211 was not toxic in mammalians cells in vitro and in mice in vivo. Consequently, thermal proteome profiling analysis was used to infer the putative molecular target of OMK211 in H. contortus. The results revealed C2-domain containing protein A0A6F7Q0A8, encoded by gene HCON_00184,900, as an interacting partner of OMK211. Using advanced structural prediction and docking tools, this protein is considered an interesting putative molecular target of new nematocidal drugs as its orthologs are present in several nematodes but not in mammals. In conclusion, novel derivatives of benzhydroxamic acid represent a promising new class of potential anthelmintics, which deserve further testing. |
| format | Article |
| id | doaj-art-2c01dfd7184f456da066e82a8826d396 |
| institution | DOAJ |
| issn | 2211-3207 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj-art-2c01dfd7184f456da066e82a8826d3962025-08-20T03:05:39ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072025-08-012810059910.1016/j.ijpddr.2025.100599New derivatives of benzhydroxamic acid with nematocidal activity against Haemonchus contortus and Caenorhabditis elegansJosef Krátký0Markéta Zajíčková1Aya C. Taki2Oliver Michel3Petra Matoušková4Ivan Vokřál5Karolína Štěrbová6Ondřej Vosála7Beate Lungerich8Thomas Kurz9Robin B. Gasser10Karel Harant11Lenka Skálová12Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech RepublicDepartment of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech RepublicDepartment of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, 3010, AustraliaInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech RepublicDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Hradec Králové, Czech RepublicDepartment of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech RepublicDepartment of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech RepublicInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine University, Düsseldorf, GermanyInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, 3010, AustraliaLaboratory of Mass Spectrometry, BIOCEV, Faculty of Science, Charles University, Vestec u Prahy, Czech RepublicDepartment of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic; Corresponding author. Dept. of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, EU, CZ-500 05, Hradec Králové, Czech Republic.Parasitic nematodes cause a wide range of diseases in animals, including humans. However, the efficacy of existing anthelmintic drugs, commonly used to treat these infections, is waning due to the increasing prevalence of drug resistance in nematode populations. This growing challenge underscores the urgent need to discover and develop novel nematocidal drugs that target new molecular pathways. In the present study, 13 novel derivatives of benzhydroxamic acid (OMKs) were designed and synthesized. Their anthelmintic activity was tested in the parasitic nematode Haemonchus contortus (barber's pole worm) and the free-living nematode Caenorhabditis elegans and potential toxicity assessed in mammalian models. Compound OMK211 showed the most promising results. It decreased viability and motility of larval and adult stages of both nematode species and of both drug-sensitive and drug-resistant strains of H. contortus at micromolar concentrations with the highest efficacy in H. contortus adult males (IC50 ∼ 1 μM). Moreover, OMK211 was not toxic in mammalians cells in vitro and in mice in vivo. Consequently, thermal proteome profiling analysis was used to infer the putative molecular target of OMK211 in H. contortus. The results revealed C2-domain containing protein A0A6F7Q0A8, encoded by gene HCON_00184,900, as an interacting partner of OMK211. Using advanced structural prediction and docking tools, this protein is considered an interesting putative molecular target of new nematocidal drugs as its orthologs are present in several nematodes but not in mammals. In conclusion, novel derivatives of benzhydroxamic acid represent a promising new class of potential anthelmintics, which deserve further testing.http://www.sciencedirect.com/science/article/pii/S2211320725000223Drug developmentDrug resistanceNematodesNew anthelmintics |
| spellingShingle | Josef Krátký Markéta Zajíčková Aya C. Taki Oliver Michel Petra Matoušková Ivan Vokřál Karolína Štěrbová Ondřej Vosála Beate Lungerich Thomas Kurz Robin B. Gasser Karel Harant Lenka Skálová New derivatives of benzhydroxamic acid with nematocidal activity against Haemonchus contortus and Caenorhabditis elegans International Journal for Parasitology: Drugs and Drug Resistance Drug development Drug resistance Nematodes New anthelmintics |
| title | New derivatives of benzhydroxamic acid with nematocidal activity against Haemonchus contortus and Caenorhabditis elegans |
| title_full | New derivatives of benzhydroxamic acid with nematocidal activity against Haemonchus contortus and Caenorhabditis elegans |
| title_fullStr | New derivatives of benzhydroxamic acid with nematocidal activity against Haemonchus contortus and Caenorhabditis elegans |
| title_full_unstemmed | New derivatives of benzhydroxamic acid with nematocidal activity against Haemonchus contortus and Caenorhabditis elegans |
| title_short | New derivatives of benzhydroxamic acid with nematocidal activity against Haemonchus contortus and Caenorhabditis elegans |
| title_sort | new derivatives of benzhydroxamic acid with nematocidal activity against haemonchus contortus and caenorhabditis elegans |
| topic | Drug development Drug resistance Nematodes New anthelmintics |
| url | http://www.sciencedirect.com/science/article/pii/S2211320725000223 |
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