Structure-activity relationship and target investigation of 2-aryl quinolines with nematocidal activity
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;...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320724000034 |
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| author | Harrison T. Shanley Aya C. Taki Nghi Nguyen Tao Wang Joseph J. Byrne Ching-Seng Ang Michael G. Leeming Shuai Nie Nicholas Williamson Yuanting Zheng Neil D. Young Pasi K. Korhonen Andreas Hofmann Bill C.H. Chang Tim N.C. Wells Cécile Häberli Jennifer Keiser Abdul Jabbar Brad E. Sleebs Robin B. Gasser |
| author_facet | Harrison T. Shanley Aya C. Taki Nghi Nguyen Tao Wang Joseph J. Byrne Ching-Seng Ang Michael G. Leeming Shuai Nie Nicholas Williamson Yuanting Zheng Neil D. Young Pasi K. Korhonen Andreas Hofmann Bill C.H. Chang Tim N.C. Wells Cécile Häberli Jennifer Keiser Abdul Jabbar Brad E. Sleebs Robin B. Gasser |
| author_sort | Harrison T. Shanley |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T09:04:46Z |
| format | Article |
| id | doaj.art-bd1202bcf63a4ff0ade2f378a914072b |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-03-08T09:04:46Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-bd1202bcf63a4ff0ade2f378a914072b2024-02-01T06:29:55ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072024-04-0124100522Structure-activity relationship and target investigation of 2-aryl quinolines with nematocidal activityHarrison T. Shanley0Aya C. Taki1Nghi Nguyen2Tao Wang3Joseph J. Byrne4Ching-Seng Ang5Michael G. Leeming6Shuai Nie7Nicholas Williamson8Yuanting Zheng9Neil D. Young10Pasi K. Korhonen11Andreas Hofmann12Bill C.H. Chang13Tim N.C. Wells14Cécile Häberli15Jennifer Keiser16Abdul Jabbar17Brad E. Sleebs18Robin B. Gasser19Department 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, AustraliaDepartment of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, AustraliaChemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, AustraliaDepartment of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, AustraliaDepartment of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, AustraliaMelbourne Mass Spectrometry and Proteomics Facility, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, AustraliaMelbourne Mass Spectrometry and Proteomics Facility, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, AustraliaMelbourne Mass Spectrometry and Proteomics Facility, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, AustraliaMelbourne Mass Spectrometry and Proteomics Facility, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, AustraliaDepartment of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, AustraliaDepartment of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, AustraliaDepartment of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, AustraliaDepartment 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, GermanyDepartment of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, AustraliaMedicines for Malaria Venture (MMV), 1215, Geneva, SwitzerlandMedical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4123, Allschwil, Switzerland; University of Basel, 4001, Basel, SwitzerlandMedical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4123, Allschwil, Switzerland; University of Basel, 4001, Basel, SwitzerlandDepartment of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, AustraliaDepartment 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; Corresponding author. Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia; Corresponding author. Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia.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.http://www.sciencedirect.com/science/article/pii/S2211320724000034AnthelminticsDrug discoveryHaemonchus contortusTarget identificationThermal proteome profilingIn silico docking |
| spellingShingle | Harrison T. Shanley Aya C. Taki Nghi Nguyen Tao Wang Joseph J. Byrne Ching-Seng Ang Michael G. Leeming Shuai Nie Nicholas Williamson Yuanting Zheng Neil D. Young Pasi K. Korhonen Andreas Hofmann Bill C.H. Chang Tim N.C. Wells Cécile Häberli Jennifer Keiser Abdul Jabbar Brad E. Sleebs Robin B. Gasser Structure-activity relationship and target investigation of 2-aryl quinolines with nematocidal activity International Journal for Parasitology: Drugs and Drug Resistance Anthelmintics Drug discovery Haemonchus contortus Target identification Thermal proteome profiling In silico docking |
| title | Structure-activity relationship and target investigation of 2-aryl quinolines with nematocidal activity |
| title_full | Structure-activity relationship and target investigation of 2-aryl quinolines with nematocidal activity |
| title_fullStr | Structure-activity relationship and target investigation of 2-aryl quinolines with nematocidal activity |
| title_full_unstemmed | Structure-activity relationship and target investigation of 2-aryl quinolines with nematocidal activity |
| title_short | Structure-activity relationship and target investigation of 2-aryl quinolines with nematocidal activity |
| title_sort | structure activity relationship and target investigation of 2 aryl quinolines with nematocidal activity |
| topic | Anthelmintics Drug discovery Haemonchus contortus Target identification Thermal proteome profiling In silico docking |
| url | http://www.sciencedirect.com/science/article/pii/S2211320724000034 |
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