Phenotypic screening of the ‘Kurz-box’ of chemicals identifies two compounds (BLK127 and HBK4) with anthelmintic activity in vitro against parasitic larval stages of Haemonchus contortus

Abstract

Background Due to anthelmintic resistance problems, there is a need to discover and develop new drugs for the treatment and control of economically important and pathogenic nematodes of livestock animals. With this focus in mind, we screened 236 compounds from a library (called the ‘Kurz-box’) representing chemically diverse classes such as heterocyclic compounds (e.g. thiazoles, pyrroles, quinolines, pyrimidines, benzo[1,4]diazepines), hydoxamic acid-based metalloenzyme inhibitors, peptidomimetics (bis- and tris-pyrimidoneamides, alkoxyamides) and various intermediates on Haemonchus contortus , one of the most important parasitic nematodes of ruminants. Methods In the present study, we tested these compounds, and measured the inhibition of larval motility and development of exsheathed third-stage (xL3) and fourth-stage (L4) larvae of H. contortus using an optimised, whole-organism phenotypic screening assay. Results Of the 236 compounds, we identified two active compounds (called BLK127 and HBK4) that induced marked phenotypic changes in the worm in vitro . Compound BLK127 induced an ‘eviscerated’ phenotype in the xL3 stage and also inhibited L4 development. Compound HBK4 exerted a ‘curved’ phenotype in both xL3s and L4s. Conclusions The findings from this study provide a basis for future work on the chemical optimisation of these compounds, on assessing the activity of optimised compounds on adult stages of H. contortus both in vitro and in vivo (in the host animal) and against other parasitic worms of veterinary and medical importance. Electronic supplementary material The online version of this article (10.1186/s13071-019-3426-7) contains supplementary material, which is available to authorized users.

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

“…YAK308 induced a “curved” phenotype in ~90% of xL3s ( Figure 1 ), distinct to phenotypes in all control wells (0.5% DMSO, monepantel and moxidectin). Although the curved phenotype seemed to be unique, a similar phenotype was observed previously in xL3s and L4s of H. contortus exposed in vitro to compound HBK4—an active benzimidazole-derivative from a previous chemical collection from the Kurz-laboratory [ 19 ].…”

UDP-Glycosyltransferases and Albendazole Metabolism in the Juvenile Stages of Haemonchus contortus

“…The nematode eggs were collected by differential sieving through three stacked sieves as described by Varady et al (2007) and recovered with a sucrose flotation technique followed by washing in tap water. The L1s were produced from isolated eggs cultivated in tap water at 27 • C for 48 h, while the L3s were cultivated from eggs in humidified feces from infected sheep at 27 • C for 1 week (Nguyen et al, 2019).…”

Drug Discovery and Development for Soil-Transmitted Helminthiasis: Current Anthelmentics and Compounds in the Pipeline

“…Interestingly, compound BLK127 exerted a phenotype that was similar to a recently described lethal evisceration phenotype. HBK4, a benzimidaxole derivative, was markedly more potent on L4s than L3s [71]. In a consequent study, BLK127 was found to decrease the viability of adult H. contortus both in sensitive and resistant strains and showed no hepatotoxic effect, even at the highest concentration tested while HBK4 had no impact on the viability of adults and exhibited significant hepatotoxicity.…”