Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro

• Published in: International journal for parasitology -- drugs and drug resistance 2019-04, Vol.9, p.59-71
• Main Authors: Jiao, Yaqing, Preston, Sarah, Garcia-Bustos, Jose F., Baell, Jonathan B., Ventura, Sabatino, Le, Thuy, McNamara, Nicole, Nguyen, Nghi, Botteon, Antony, Skinner, Cameron, Danne, Jill, Ellis, Sarah, Koehler, Anson V., Wang, Tao, Chang, Bill C.H., Hofmann, Andreas, Jabbar, Abdul, Gasser, Robin B.
• Format: Article
• Language: English
• Subjects: Animals; Anthelmintic; Antinematodal Agents - pharmacology; Biological Assay; Drug Discovery; Evisceration (Evi) phenotype; Haemonchus; Haemonchus - drug effects; Haemonchus - physiology; Inhibitory Concentration 50; Larva - drug effects; Larva - physiology; Molting - drug effects; Moulting; Phenotype; Quinoxalines; Quinoxalines - pharmacology; Tyrphostins - pharmacology; Whole-organism screening
• ISSN: 2211-3207; 2211-3207
• DOI: 10.1016/j.ijpddr.2018.12.007

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 revealed that this eviscerated (Evi) phenotype occurs rapidly (