Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro
Yaqing Jiao, Sarah Preston, Jose F Garcia-Bustos, Jonathan B Baell, Sabatino Ventura, Thuy Le, Nicole McNamara, Nghi Nguyen, Antony Botteon, Cameron Skinner, Jill Danne, Sarah Ellis, Anson Koehler, Tao Wang, Bill CH Chang, Andreas Hofmann, Abdul Jabbar, Robin B Gasser
INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE | ELSEVIER SCI LTD | Published : 2019
In the present study, the anthelmintic activity of a human tyrosine kinase inhibitor, AG-1295, and 14 related tetrahydroquinoxaline analogues against Haemonchus contortus was explored. These compounds were screened against parasitic larvae - exsheathed third-stage (xL3) and fourth-stage (L4) - using a whole-organism screening assay. All compounds were shown to have inhibitory effects on larval motility, development and growth, and induced evisceration through the excretory pore in xL3s. The estimated IC50 values ranged from 3.5 to 52.0 μM for inhibition of larval motility or development. Cytotoxicity IC50 against human MCF10A cells was generally higher than 50 μM. Microscopic studies reveale..View full abstract
The present study was funded by the Australian Research Council (ARC) and the National Health and Medical Research Council of Australia (NHMRC). We thank our colleagues at Medicines for Malaria Ventures (MMV), Faculty of Veterinary and Agricultural Sciences (FVAS) of The University of Melbourne and Monash Institute of Pharmaceutical Sciences (MIPS), in particular Dr Anson Koehler, Dr Tao Wang and Ms Thuy Le, for their support. We also thank A/Prof Kaylene J. Simpson and Ms Karla J. Cowley, Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Parkville, Victoria, for cytotoxicity testing - this Centre is supported by funding from the Australian Government's Education Investment Fund through the Super Science Initiative and the Peter MacCallum Cancer Centre Foundation (KJS). YJ is the grateful recipient of scholarships from the Chinese Scholarships Council (CSC) and The University of Melbourne. The authors declare no conflicts of interest.