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

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 15; no. 2; p. 257
• Main Authors: Shanley, Harrison T, Taki, Aya C, Byrne, Joseph J, Jabbar, Abdul, Wells, Tim N C, Samby, Kirandeep, Boag, Peter R, Nguyen, Nghi, Sleebs, Brad E, Gasser, Robin B
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21-02-2022; MDPI
• Subjects: anthelmintics; Caenorhabditis elegans; Commercial markets; Genomes; Genotype & phenotype; Haemonchus contortus; Motility; Nematodes; Pandemic Response Box; Pandemics; Parasites; parasitic nematode; Poverty; small molecules; Tropical diseases; Australia; Caenorhabditis elegans; Haemonchus contortus; Pandemic Response Box; parasitic nematode; anthelmintics; phenotypic screening; small molecules
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph15020257

Parasitic nematodes cause diseases in livestock animals and major economic losses to the agricultural industry worldwide. Nematodes of the order Strongylida, including
, 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 '
' (from Medicines for Malaria Venture, MMV) for activity against
and its free-living relative,
-a model organism. Using established phenotypic assays, test compounds were evaluated in vitro for their ability to inhibit the motility and/or development of
and
. Dose-response evaluations identified a compound, MMV1581032, that significantly the motility of
larvae (IC
= 3.4 ± 1.1 μM) and young adults of
(IC
= 7.1 ± 4.6 μM), and the development of
larvae (IC
= 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.