Structure-activity relationship and target investigation of 2-aryl quinolines with nematocidal activity
- Author(s)
- Shanley, HT; Taki, AC; Nguyen, N; Wang, T; Byrne, JJ; Ang, CS; Leeming, MG; Nie, S; Williamson, N; Zheng, Y; Young, ND; Korhonen, PK; Hofmann, A; Chang, BCH; Wells, TNC; Häberli, C; Keiser, J; Jabbar, A; Sleebs, BE; Gasser, RB;
- Journal Title
- International Journal for Parasitology Drugs and Drug Resistance
- Abstract
- 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.
- Keywords
- Anthelmintics; Drug discovery; Haemonchus contortus; In silico docking; Target identification; Thermal proteome profiling
- Research Division(s)
- Chemical Biology
- PubMed ID
- 38134663
- Publisher's Version
- https://doi.org/10.1016/j.ijpddr.2024.100522
- Open Access at Publisher's Site
https://doi.org/10.1016/j.ijpddr.2024.100522- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-02-29 09:02:02
Last Modified: 2024-02-29 09:13:57