A High-Throughput Phenotypic Screen of the 'Pandemic Response Box' Identifies a Quinoline Derivative with Significant Anthelmintic Activity.

Harrison T Shanley,Brad E Sleebs,Aya C Taki,Robin B Gasser,Abdul Jabbar,Peter R Boag,Joseph J Byrne,Tim N C Wells,Kirandeep Samby,Nghi Nguyen

doi:10.3390/ph15020257

Abstract

Parasitic nematodes cause diseases in livestock animals and major economic losses to the agricultural industry worldwide. Nematodes of the order Strongylida, including Haemonchus contortus, are particularly important. The excessive use of anthelmintic compounds to treat infections and disease has led to widespread resistance to these compounds in nematodes, such that there is a need for new anthelmintics with distinctive mechanisms of action. With a focus on discovering new anthelmintic entities, we screened 400 chemically diverse compounds within the ‘Pandemic Response Box’ (from Medicines for Malaria Venture, MMV) for activity against H. contortus and its free-living relative, Caenorhabditis elegans—a model organism. Using established phenotypic assays, test compounds were evaluated in vitro for their ability to inhibit the motility and/or development of H. contortus and C. elegans. Dose-response evaluations identified a compound, MMV1581032, that significantly the motility of H. contortus larvae (IC50 = 3.4 ± 1.1 μM) and young adults of C. elegans (IC50 = 7.1 ± 4.6 μM), and the development of H. contortus larvae (IC50 = 2.2 ± 0.7 μM). The favourable characteristics of MMV1581032, such as suitable physicochemical properties and an efficient, cost-effective pathway to analogue synthesis, indicates a promising candidate for further evaluation as a nematocide. Future work will focus on a structure-activity relationship investigation of this chemical scaffold, a toxicity assessment of potent analogues and a mechanism/mode of action investigation.

Highlights

IntroductionParasitic roundworms (nematodes) cause infections and diseases (nematodiases) in humans and animals that have a major adverse socioeconomic impact worldwide [1,2]
Parasitic roundworms cause infections and diseases in humans and animals that have a major adverse socioeconomic impact worldwide [1,2]
H. contortus is transmitted orally via a direct life cycle [7]; animals become infected by ingesting infective third-stage larvae (L3s), which exsheath in the forestomachs and develop, via fourth-stage larvae (L4s), to dioecious blood-feeding adult worms in the abomasum, where they reproduce, with females releasing eggs via faeces into the environment [7]

Summary

Introduction

Parasitic roundworms (nematodes) cause infections and diseases (nematodiases) in humans and animals that have a major adverse socioeconomic impact worldwide [1,2]. Agricultural perspective, productivity losses in livestock animals caused by nematodes are estimated at tens of billions of dollars [4]. Most losses in these animals relate to nematodes (order Strongylida) of the gastrointestinal and respiratory tracts. One key representative is Haemonchus contortus (family Trichostrongylidae), known as the ‘barber’s pole worm’, which causes haemonchosis—a disease of ruminant livestock, such. Pharmaceuticals 2022, 15, 257 as sheep and goats. H. contortus is transmitted orally via a direct life cycle [7]; animals become infected by ingesting infective third-stage larvae (L3s), which exsheath in the forestomachs and develop, via fourth-stage larvae (L4s), to dioecious blood-feeding adult worms in the abomasum, where they reproduce, with females releasing eggs via faeces into the environment [7]

Methods

Results

Conclusion