Three Small Molecule Entities (MPK18, MPK334 and YAK308) with Activity against Haemonchus contortus In Vitro

Molecules

RobinB. Gasser¹  Guangxu Ma¹  AyaC. Taki¹  BillC. H. Chang¹  BradE. Sleebs¹  JosephJ. Byrne¹  Abdul Jabbar¹  Thomas Kurz²  Beate Lungerich²  Yodita Asfaha²  Marc Pflieger²  Fabian Fischer² 

[1] Department of Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville 3010, Victoria, Australia;Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany;

关键词: Haemonchus contortus;    phenotypic screening;    anthelmintics;    small molecules;   

DOI  :  10.3390/molecules26092819

来源: DOAJ

【 摘 要 】

Due to widespread multi-drug resistance in parasitic nematodes of livestock animals, there is an urgent need to discover new anthelmintics with distinct mechanisms of action. Extending previous work, here we screened a panel of 245 chemically-diverse small molecules for anti-parasitic activity against Haemonchus contortus—an economically important parasitic nematode of livestock. This panel was screened in vitro against exsheathed third-stage larvae (xL3) of H. contortus using an established phenotypic assay, and the potency of select compounds to inhibit larval motility and development assessed in dose-response assays. Of the 245 compounds screened, three—designated MPK18, MPK334 and YAK308—induced non-wildtype larval phenotypes and repeatedly inhibited xL3-motility, with IC₅₀ values of 45.2 µM, 17.1 µM and 52.7 µM, respectively; two also inhibited larval development, with IC₅₀ values of 12.3 µM (MPK334) and 6.5 µM (YAK308), and none of the three was toxic to human liver cells (HepG2). These findings suggest that these compounds deserve further evaluation as nematocidal candidates. Future work should focus on structure–activity relationship (SAR) studies of these chemical scaffolds, and assess the in vitro and in vivo efficacies and safety of optimised compounds against adults of H. contortus.

【 授权许可】

Unknown