Synthesis and antimalarial evaluation of a screening library based on a tetrahydroanthraquinone natural product scaffold

Abstract

As part of a research program aimed at discovering new antimalarial leads from Australian macrofungi a unique fungi-derived prefractionated library was screened against a chloroquine-sensitive Plasmodium falciparum line (3D7) using a radiometric growth inhibition assay. A library fraction derived from a Cortinarius species displayed promising antimalarial activity. UV-guided fractionation on the CH(2)Cl(2)/MeOH extract from this fungus resulted in the isolation of four known compounds: (1S,3R)-austrocortirubin (1), (1S,3S)-austrocortirubin (2), 1-deoxyaustrocortirubin (3), and austrocortinin (4). Compound 2 was used as a natural product scaffold in the parallel solution-phase synthesis of a small library of N-substituted tetrahydroanthraquinones (5-15). All compounds (1-15) were tested in vitro against P. falciparum 3D7 parasites and (1S,3S)-austrocortirubin (2), the major fungal constituent, was shown to be the most active compound with an IC(50) of 1.9 μM. This compound displayed moderate cytotoxicity against neonatal foreskin fibroblast (NFF) cells with an IC(50) of 15.6 μM.

Entonalactams A–C: Isoindolinone derivatives from an Australian rainforest fungus belonging to the genus Entonaema

“…The details of the antimalarial screening of the pre-fractionated fungal-derived library have been reported previously (Choomuenwai et al, 2012(Choomuenwai et al, , 2013 This paper describes the bioassay-guided fractionation and structure elucidation of three new isoindolinones, which we have named entonalactams A-C (1-3), along with the known natural products 3-methoxy-5-methylbenzene-1,2-diol (4), daldinal B (5), and ergosta-4, 6,8(14),22-tetraen-3-one (6) (Fig. 1) from the rainforest fungus Entonaema sp.…”

Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2

“…78,79 Approximately 15% of the entries of this library were semisynthetic natural product analogues, 80,76 while a small percentage (∼5%) are known commercial drugs or synthetic compounds inspired by natural products. The Atanasov and Krenn databases consisted of 51 and 13 in-house available natural products, respectively, from the Department of Pharmacognosy at the University of Vienna, Austria.…”

Carbon‐14 radiolabeling and tissue distribution evaluation of MMV390048

“…The rats were placed in separate cages. For each of the Long Evans and Sprague Dawley rats groups, 6 rats were anesthetized by isoflurane and euthanized by cardiac puncture at 3, 6, 24, and 48 hours, post-injection to allow for adequate 14 C-labeled MMV390048 uptake. Eyes, skin, brain, lung, heart, spleen, liver, small intestine, large intestine, stomach, genitals, muscle, blood, bladder, and kidneys from each species were pooled by gross dissection.…”

“…Although many other research efforts (including clinical trials) are ongoing on derivatives of chloroquine and artemisinin as well as vaccines, there is an urgent need for novel and structurally diverse medicinal agents with potent antiplasmodial activity and new mechanism of action. MMV390048 has shown to be a promising and affordable component meeting these criteria …”

“…MMV390048 has shown to be a promising and affordable component meeting these criteria. [13][14][15][16] MMV390048, an aminopyridine derivative developed from a collaboration between Medicines for Malaria Venture (MMV) and the University of Cape Town Drug Discovery and Development Centre (H3D), exhibited promising in vitro activities against different P. falciparum K1 and NF54, 3D7, and Dd2. Preliminary in vivo studies showed that it has a potential to be used as a single oral dose cure for malaria.…”