ABX464 – structure-activity relationship in a model parasitic nematode and target deconvolution

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 model nematode Caenorhabditis elegans; and predicted compound-target relationships by thermal proteome profiling (TPP) and in silico docking. Here, we logically extend(ed) this work and critically evaluate(d) 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 ABX464’s nematocidal pharmacophore, and identified one compound with greater potency than the parent compound, and also 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 the first steps towards the development of a new anthelmintic with a novel, distinct mechanism of action.