Moana Simpson

Aplysamine 6, an Alkaloidal Inhibitor of Isoprenylcysteine Carboxyl Methyltransferase from the Sponge Pseudoceratina sp.

The anticancer target isoprenylcysteine carboxyl methyltransferase (Icmt) was the focus of a natural product high-throughput screening campaign. The Australian marine sponge Pseudoceratina sp. yielded aplysamine 6, a new bromotyrosine derivative with an alpha,beta-unsaturated amide linkage, as the bioactive constituent. Its structure was determined by 1D and 2D NMR spectroscopy.

Screening the medicines for malaria venture pathogen box across multiple pathogens reclassifies starting points for open-source drug discovery

ABSTRACT Open-access drug discovery provides a substantial resource for diseases primarily affecting the poor and disadvantaged. The open-access Pathogen Box collection is comprised of compounds with demonstrated biological activity against specific pathogenic organisms. The supply of this resource by the Medicines for Malaria Venture has the potential to provide new chemical starting points for a number of tropical and neglected diseases, through repurposing of these compounds for use in drug discovery campaigns for these additional pathogens. We tested the Pathogen Box against kinetoplastid parasites and malaria life cycle stages in vitro. Consequently, chemical starting points for malaria, human African trypanosomiasis, Chagas disease, and leishmaniasis drug discovery efforts have been identified. Inclusive of this in vitro biological evaluation, outcomes from extensive literature reviews and database searches are provided. This information encompasses commercial availability, literature reference citations, other aliases and ChEMBL number with associated biological activity, where available. The release of this new data for the Pathogen Box collection into the public domain will aid the open-source model of drug discovery. Importantly, this will provide novel chemical starting points for drug discovery and target identification in tropical disease research.

An Overview of Australia’s Compound Management Facility: The Queensland Compound Library

T Queensland Compound Library (QCL) is Australia’s dedicated compound management facility that was established to augment pre-existing extensive capability in compound screening and biomedical research with Australian chemistry. The guiding principle behind the QCL is to broaden the reach of small molecules, including synthetic compounds, pure natural products, and natural product extracts, that originate from the collective effort of the Australian chemistry research community. A key function of the QCL is to actively source small molecules from this pool of mainly publicly funded research and to consolidate them into a central repository that facilitates subsequent screening of small molecule libraries. The QCL combines infrastructure and expertise to deliver fully automated and highly flexible compound management, encompassing sample lodgement, storage, formatting and reformatting, quality control, data handling, and distribution of assay-ready microplates. The resource allows academic and not-for-profit screening sites to access small molecule collections at a lower cost than if they were purchased internally. Additionally, it removes the need to also purchase and then maintain compound management infrastructure. The QCL’s operating model allows its members to lodge and access compounds and importantly does not claim any intellectual property owned or generated by members. Through conserving Australian chemistry and making compounds readily accessible for screening, the model maximizes the potential of the lodged compound collections, many of which comprise unique molecules, to seed collaborative research projects between QCL members. The QCL was established in 2008 with joint funding from the Queensland Government Smart State Research Facilities Fund and Griffith University. To date (2008−2013), over 645,000 samples have been lodged into the QCL, with more than 25,000 assay-ready microplates prepared and distributed. In this focus article we overview the QCL operations and QCL collaboration model, including the facility design, technologies and workflow. We also highlight the QCL Open Access Compound Collection.

Pim2 Inhibitors from the Papua New Guinean Plant Cupaniopsis macropetala

Bioassay-guided fractionation of an organic extract from the leaves of Cupaniopsis macropetala resulted in the isolation of a new alkaloid, galloyl tyramine ( 1), together with the known flavonoid glycoside quercitrin ( 2). The structure of 1 was determined following 1D and 2D NMR, IR, UV, and MS data analysis. Compounds 1 and 2 displayed IC 50 values of 161 and 25 microM, respectively, in a Pim2 enzyme assay.

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

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.