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

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.

Methodology for the identification of small molecule inhibitors of the Fanconi Anaemia ubiquitin E3 ligase complex

“…Five microlitres of master mix was incubated with 15 nL of a 5 mM compound stock (Compounds Australia, Griffith University) in DMSO, which corresponded to a final concentration of 0.2% DMSO. A total of 9,067 compounds were selected from two libraries, described previously 53,54 , from Compounds Australia. The first library -the Open Access Drug library -contained 2,667 compounds of primarily FDA-approved drugs.…”

Comparison of tumor related signaling pathways with known compounds to determine potential agents for lung adenocarcinoma

“…To obtain detailed information on how these novel drugs exert anti‐tumor functions, molecular docking between the compounds and the proteins of the hub genes enriched in the most significant pathway (the p53 signaling pathway) was carried out using the Surflex‐Dock program in Sybyl X‐2.0 (Tripos Inc., St Louis, MO, USA). Docking scores were calculated to represent binding affinities …”

Plant-Based Natural Products for the Discovery and Development of Novel Anthelmintics against Nematodes

“…Albendazole and mebendazole have been chosen for mass drug administration programs and work best for ascariasis and hookworm infections [6,10,15]. In the pharmaceutical industry, the progress of anthelmintic drug discovery and development has been quite slow over the past 40 years, even though some available anthelmintic drugs can show side-effects [13,16]. Tribendimidine has entered human clinical trials in the last four decades (approved in China in 2007) [10].…”

“…In contrast to human anthelmintic drugs, three new anthelmintic drugs have been commercialized in veterinary medicine over the last couple of years: emodepside, monepantel and derquantel [13]. However, anthelmintic resistance has become widespread in livestock worldwide [31].…”

“…The authors concluded that plants from the Leguminosae family may offer an alternative source for the control of gastrointestinal nematodes of small ruminants. (5,6,7,17,19,26,27,28,31,32,33,34,36), saponin (4,25), terpenoids (12,13,15,16,18,37), alkaloids (1,2,3,8,9), coumaric acid (14,29,30), miscellaneous (10,11,20,21,22,24).…”