(6aR,10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetra­hydro-6H-benzo[c]­chromen-1-yl 4-methyl­benzene­sulfonate

In the crystal structure of the title compound, C28H36O4S, the p-tolyl ring is inclined at 35.8° to the aromatic ring. The cyclohexene ring adopts a boat conformation and the heterocyclic ring is in a slightly distorted screw boat conformation

Selective Inhibition of Plasmodium falciparum ATPase 6 by Artemisinins and Identification of New Classes of Inhibitors after Expression in Yeast

Treatment failures with artemisinin combination therapies (ACTs) threaten global efforts to eradicate malaria. They highlight the importance of identifying drug targets and new inhibitors and of studying how existing antimalarial classes work. Here, we report the successful development of a heterologous expression-based compound-screening tool. The validated drug target Plasmodium falciparum ATPase 6 (PfATP6) and a mammalian orthologue (sarco/endoplasmic reticulum calcium ATPase 1a [SERCA1a]) were functionally expressed in Saccharomyces cerevisiae, providing a robust, sensitive, and specific screening tool. Whole-cell and in vitro assays consistently demonstrated inhibition and labeling of PfATP6 by artemisinins. Mutations in PfATP6 resulted in fitness costs that were ameliorated in the presence of artemisinin derivatives when studied in the yeast model. As previously hypothesized, PfATP6 is a target of artemisinins. Mammalian SERCA1a can be mutated to become more susceptible to artemisinins. The inexpensive, low-technology yeast screening platform has identified unrelated classes of druggable PfATP6 inhibitors. Resistance to artemisinins may depend on mechanisms that can concomitantly address multitargeting by artemisinins and fitness costs of mutations that reduce artemisinin susceptibility

(2S,4aR,6aR,7R,9S,10aS,10bR)-7-Carb­oxy-2-(3-fur­yl)-6a,10b-dimethyl-4,10-dioxoperhydro­benzo[f]isochromen-9-yl acetate

The asymmetric unit of the title compound, C22H26O8, contains two crystallographically independent mol­ecules with closely comparable conformations (r.m.s. overlay = 0.54 Å for 30 non-H atoms). All six-membered rings display chair conformations, with a slight distortion for the lactone ring. The mol­ecules are connected by O—H⋯O hydrogen bonds into chains along [010], with the independent mol­ecules segregated into separate chains. The two mol­ecules in the asymmetric unit face each other in a head-to-tail fashion, with the furan ring of one mol­ecule turned towards the carboxylic acid terminal of the other mol­ecule

5-{[(3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyl­perhydro-3,12-ep­oxy-1,2-dioxepino[4,3-i]isochromen-10-yl]oxymeth­yl}benzene-1,3-diol

The title compound, C22H30O7, is a fused five-ring system that is of inter­est for its anti­cancer and anti­malarial activity. The six-membered C6 and C5O rings display chair conformations. The six-membered C3O3 ring containing the ether and per­oxy functionalities has a distorted boat conformation, with a C—O—O—C torsion angle of 42.6 (1)° for the per­oxy group. The seven-membered C6O ring has a distorted boat-type conformation, while the seven-membered C5O2 ring has a very distorted chair-type conformation. The structure contains inter­molecular O—H⋯O and O—H⋯(O,O) bonds that link the mol­ecules into sheets parallel to the (100) planes

EverGraze: A Partnership between Researchers, Farmers and Advisors to Deliver Effective Grassland Management

The profitable and sustainable management of livestock production from grassland systems is challenging and it can be difficult to develop a research structure that addresses farmer’s needs and has acceptable rigour and on-ground impact. This paper describes the attributes of research, development and extension (RD&E) programs that are required for a successful partnership between researchers, farmers and advisors. Insights are provided from the EverGraze program that designed, tested and implemented farming systems based on perennial pastures across southern Australia. With this project farmers and advisors were involved in setting research direction, designing experiments, providing strategic guidance over the management of the systems experiments and then the synthesis of regionally applicable key messages. This involvement ensured the relevance of the research and aided in the extension and uptake of the information. The result has been an effective partnership between researchers, farmers and advisors that had a high level of impact across the high rainfall zone (HRZ) of southern Australia, with 1950 farmers or ~8% of those in the HRZ documented as having changed practice over an area of 816,000 ha over a five year period (2009 to 2014)

Unusual hemiacetal structure derived from Salvinorin A

The salvinorin A analog dimethyl (2R,3aR,4R,6aR,7R,9S,9aS,9bS)-2-(3-fur­yl)-9,9a-dihydr­oxy-3a,6a-dimethyl­dodeca­hydro­benzo[de]chromene-4,7-dicarboxyl­ate, C22H30O8, has a relatively simple spatial arrangement in which mol­ecules are linked into layers by two pairs of O—H⋯O hydrogen bonds. Each mol­ecule has as the central feature a dodeca­hydro-1H-phenalene ring system. Its three six-membered rings are in the chair conformation, with two axial methyl groups, one axial OH, and one equatorial OH, these OH groups being directly responsible for linking of the mol­ecules in the crystal structure

Expression in Yeast Links Field Polymorphisms in PfATP6 to in Vitro Artemisinin Resistance and Identifies New Inhibitor Classes

Background. The mechanism of action of artemisinins against malaria is unclear, despite their widespread use in combination therapies and the emergence of resistance. Results. Here, we report expression of PfATP6 (a SERCA pump) in yeast and demonstrate its inhibition by artemisinins. Mutations in PfATP6 identified in field isolates (such as S769N) and in laboratory clones (such as L263E) decrease susceptibility to artemisinins, whereas they increase susceptibility to unrelated inhibitors such as cyclopiazonic acid. As predicted from the yeast model, Plasmodium falciparum with the L263E mutation is also more susceptible to cyclopiazonic acid. An inability to knockout parasite SERCA pumps provides genetic evidence that they are essential in asexual stages of development. Thaperoxides are a new class of potent antimalarial designed to act by inhibiting PfATP6. Results in yeast confirm this inhibition. Conclusions. The identification of inhibitors effective against mutated PfATP6 suggests ways in which artemisinin resistance may be overcom

7β-Hydroxy­artemisinin

Crystals of the title compound [systematic name: (3R,6R,7S,8aR,9R,12aR)-7-hydr­oxy-3,6,9-trimethyl­octa­hydro-3,12-ep­oxy[1,2]dioxepino[4,3-i]isochromen-10(3H)-one], C15H22O6, were obtained from microbial transformation of artemisinin by a culture of Cunninghamella elegans. The stereochemistry of the compound is consistent with the spectroscopic findings in previously published works. A weak O—H⋯O hydrogen bond occurs in the crystal structure, together with intermolecular C—H⋯O hydrogen bonds