Structure-activity relationship and target investigation of 2-aryl quinolines with nematocidal activity.

Autor:	Shanley HT; Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia; Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia., Taki AC; Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia., Nguyen N; Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia., Wang T; Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia., Byrne JJ; Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia., Ang CS; Melbourne Mass Spectrometry and Proteomics Facility, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia., Leeming MG; Melbourne Mass Spectrometry and Proteomics Facility, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia., Nie S; Melbourne Mass Spectrometry and Proteomics Facility, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia., Williamson N; Melbourne Mass Spectrometry and Proteomics Facility, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia., Zheng Y; Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia., Young ND; Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia., Korhonen PK; Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia., Hofmann A; Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia; National Reference Centre for Authentic Food, Max Rubner-Institut, 95326, Kulmbach, Germany., Chang BCH; Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia., Wells TNC; Medicines for Malaria Venture (MMV), 1215, Geneva, Switzerland., Häberli C; Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4123, Allschwil, Switzerland; University of Basel, 4001, Basel, Switzerland., Keiser J; Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4123, Allschwil, Switzerland; University of Basel, 4001, Basel, Switzerland., Jabbar A; Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia., Sleebs BE; Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia; Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia. Electronic address: sleebs@wehi.edu.au., Gasser RB; Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia. Electronic address: robinbg@unimelb.edu.au.
Jazyk:	angličtina
Zdroj:	International journal for parasitology. Drugs and drug resistance [Int J Parasitol Drugs Drug Resist] 2024 Apr; Vol. 24, pp. 100522. Date of Electronic Publication: 2024 Jan 23.
DOI:	10.1016/j.ijpddr.2024.100522
Abstrakt:	Within the context of our anthelmintic discovery program, we recently identified and evaluated a quinoline derivative, called ABX464 or obefazimod, as a nematocidal candidate; synthesised a series of analogues which were assessed for activity against the free-living nematode Caenorhabditis elegans; and predicted compound-target relationships by thermal proteome profiling (TPP) and in silico docking. Here, we logically extended this work and critically evaluated the anthelmintic activity of ABX464 analogues on Haemonchus contortus (barber's pole worm) - a highly pathogenic nematode of ruminant livestock. First, we tested a series of 44 analogues on H. contortus (larvae and adults) to investigate the nematocidal pharmacophore of ABX464, and identified one compound with greater potency than the parent compound and showed moderate activity against a select number of other parasitic nematodes (including Ancylostoma, Heligmosomoides and Strongyloides species). Using TPP and in silico modelling studies, we predicted protein HCON_00074590 (a predicted aldo-keto reductase) as a target candidate for ABX464 in H. contortus. Future work aims to optimise this compound as a nematocidal candidate and investigate its pharmacokinetic properties. Overall, this study presents a first step toward the development of a new nematocide. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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