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

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.

Graphical abstract

Fig. 1

The chemical structure of ABX464.

Fig. 2

Thermal proteome profiling and in silico docking. (A) Thermal shift plot for the melting curves (temperature gradient 37 ^°C–67 ^°C) of a potential Haemonchus contortus protein target of ABX464, HCON_00074590. Data from two replicates. (B) The predicted interaction of the three-dimensional structure of HCON_00074590 (predicted using the algorithm Alphafold 2; UniProt accession number: A0A7I5E8V5) with ABX464 using the algorithm AutoDock Vina (displayed using ChimeraX software), with an inset showing the predicted binding pocket and associated residues. Carbon (grey), oxygen (red), nitrogen (blue), fluorine (green), chlorine (purple) and hydrogen (white) atoms are colour-coded.