Dataset Information

New derivatives of benzhydroxamic acid with nematocidal activity target nematode specific C2-domain containing protein A0A6F7Q0A8

ABSTRACT: 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 present study, 13 novel derivatives of benzhydroxamic acid (OMKs) were designed and synthesised. Their anthelmintic activity was tested in the nematodes Haemonchus contortus (barber’s pole worm) and Caenorhabditis elegans (elegant worm) and compared with classical anthelmintics. OMKs´ potential toxicity was assessed in mammalian models. Among others, one compound, designated OMK211, showed the most promising results, as it decreased viability and motility of larval and adult stages of both drug-sensitive and drug-resistant strains of H. contortus, and this was not toxic in mammalians cells in vitro and in mice in vivo. Consequently, thermal proteome profiling analysis was used to infer the molecular target of OMK211 in , H. contortus. The results revealed C2-domain containing protein A0A6F7Q0A8, encoded by gene HCON_00184900, as an interacting partner of OMK211. Using advanced structural prediction and docking tools, this protein is considered an interesting 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 with a novel mechanism of action

INSTRUMENT(S):

ORGANISM(S): Haemonchus Contortus (barber Pole Worm)

TISSUE(S): Whole Body

SUBMITTER: Karel Harant

LAB HEAD: prof. RNDr. Lenka Skálová, Ph.D.

PROVIDER: PXD059717 | Pride | 2025-06-16

REPOSITORIES: Pride

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New derivatives of benzhydroxamic acid with nematocidal activity against Haemonchus contortus and Caenorhabditis elegans.

Krátký Josef J Zajíčková Markéta M Taki Aya C AC Michel Oliver O Matoušková Petra P Vokřál Ivan I Štěrbová Karolína K Vosála Ondřej O Lungerich Beate B Kurz Thomas T Gasser Robin B RB Harant Karel K Skálová Lenka L

International journal for parasitology. Drugs and drug resistance 20250520

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 ...[more]

PMID: 40413827

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Project description:Infections and diseases caused by parasitic nematodes have a major adverse impact on the health and productivity of animals and humans worldwide. The control of these parasites often relies heavily on the treatment with commercially available chemical compounds (anthelmintics). However, the excessive or uncontrolled use of these compounds in livestock animals has led to major challenges linked to drug resistance in nematodes. Therefore, there is a need to develop new anthelmintics with novel mechanism(s) of action. Recently, we identified a small molecule, KM08948, with nematocidal activity against the free-living model organism Caenorhabditis elegans. Here, we evaluated KM08948’s potential as an anthelmintic in a structure-activity relationship (SAR) study in C. elegans and in the highly pathogenic, blood-feeding Haemonchus contortus (barber’s pole worm), and explored the compound-target relationship using thermal proteome profiling (TPP). First, we synthesised and tested a series of 25 KM08948 analogues for nematocidal activity in both H. contortus (larvae and adults) and C. elegans (young adults), establishing a preliminary nematocidal pharmacophore for both species. We identified several compounds with marked activity against either H. contortus or C. elegans which had greater efficacy than KM08948, and found a significant divergence in compound bioactivity between these two nematode species. We also identified a KM08948 analogue, 25, that moderately inhibited the motility of adult female H. contortus in vitro. Subsequently, we inferred three H. contortus proteins (HCON_00134350, HCON_00021470 and HCON_00099760) and five C. elegans proteins (F30A10.9, F15B9.8, B0361.6, DNC-4 and UNC-11) that interacted directly with KM08948; however, no conserved protein target was shared between the two nematode species. Future work aims to extend the SAR investigation in these and other parasitic nematode species, and validate individual proteins identified here as targets of KM08948. Overall, the present study describes an evaluation of this anthelmintic candidate and highlights some challenges associated with early anthelmintic discovery.

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