Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro

Publication date: Available online 30 December 2018Source: International Journal for Parasitology: Drugs and Drug ResistanceAuthor(s): 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 V. Koehler, Tao Wang, Bill C.H. Chang, Andreas Hofmann, Abdul Jabbar, Robin B. GasserAbstractIn 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 (<20 min) and relates to a protrusion of internal tissues and organs (evisceration) through the excretory pore in xL3s; severe pathological damage in L4s as well as a suppression of larval growth in both stages were also observed. Using a relatively low concentration (12.5 μM) of compound m10, it was establish...
Source: International Journal for Parasitology: Drugs and Drug Resistance - Category: Parasitology Source Type: research