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Screening of the 'Open Scaffolds' collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes

Preston, Sarah and Jiao, Yaqing and Baell, Jonathan B. and Keiser, Jennifer and Crawford, Simon and Koehler, Anson V. and Wang, Tao and Simpson, Moana M. and Kaplan, Ray M. and Cowley, Karla J. and Simpson, Kaylene J. and Hofmann, Andreas and Jabbar, Abdul and Gasser, Robin B.. (2017) Screening of the 'Open Scaffolds' collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes. International Journal for Parasitology: Drugs and Drug Resistance, 7 (3). pp. 286-294.

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Abstract

The discovery and development of novel anthelmintic classes is essential to sustain the control of socioeconomically important parasitic worms of humans and animals. With the aim of offering novel, lead-like scaffolds for drug discovery, Compounds Australia released the 'Open Scaffolds' collection containing 33,999 compounds, with extensive information available on the physicochemical properties of these chemicals. In the present study, we screened 14,464 prioritised compounds from the 'Open Scaffolds' collection against the exsheathed third-stage larvae (xL3s) of Haemonchus contortus using recently developed whole-organism screening assays. We identified a hit compound, called SN00797439, which was shown to reproducibly reduce xL3 motility by ≥ 70%; this compound induced a characteristic, "coiled" xL3 phenotype (IC50 = 3.46-5.93 μM), inhibited motility of fourth-stage larvae (L4s; IC50 = 0.31-12.5 μM) and caused considerable cuticular damage to L4s in vitro. When tested on other parasitic nematodes in vitro, SN00797439 was shown to inhibit (IC50 = 3-50 μM) adults of Ancylostoma ceylanicum (hookworm) and first-stage larvae of Trichuris muris (whipworm) and eventually kill (>90%) these stages. Furthermore, this compound completely inhibited the motility of female and male adults of Brugia malayi (50-100 μM) as well as microfilariae of both B. malayi and Dirofilaria immitis (heartworm). Overall, these results show that SN00797439 acts against genetically (evolutionarily) distant parasitic nematodes i.e. H. contortus and A. ceylanicum [strongyloids] vs. B. malayi and D. immitis [filarioids] vs. T. muris [enoplid], and, thus, might offer a novel, lead-like scaffold for the development of a relatively broad-spectrum anthelmintic. Our future work will focus on assessing the activity of SN00797439 against other pathogens that cause neglected tropical diseases, optimising analogs with improved biological activities and characterising their targets.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Helminth Drug Development (Keiser)
UniBasel Contributors:Keiser, Jennifer
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
e-ISSN:2211-3207
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:13 Oct 2017 09:15
Deposited On:13 Oct 2017 09:15

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