Design and synthesis of screening libraries based on the muurolane natural product scaffold

The plant-derived natural product 14-hydroxy-6,12-muuroloadien-15-oic acid (1) was identified as a unique scaffold that could be chemically elaborated to generate novel lead- or drug-like screening libraries. Prior to synthesis a virtual library was generated and prioritised based on drug-like physicochemical parameters such as log P, log D(5.5), hydrogen bond donors/acceptors, and molecular weight. The natural product scaffold (1) was isolated from the endemic Australian plant Eremophila mitchellii and then utilised in the parallel solution-phase generation of two series of analogues. The first library consisted of six semi-synthetic amide derivatives, whilst the second contained six carbamate analogues. These libraries have been evaluated for antimalarial activity using a chloroquine-sensitive Plasmodium falciparum line (3D7) and several compounds displayed low to moderate activity with IC(50) values ranging from 14 to 33 μM.     

The discovery,synthesis and antimalarial evaluation of natural product-based polyamine alkaloids

Bioassay-guided fractionation of an antimalarial extract derived from the fungus Ramaria subaurantiaca afforded the known polyamine alkaloid, pistillarin. Nine pistillarin analogues were synthesised via EDC-mediated chemistry and these compounds along with the previously reported natural product polyamines, ianthelliformisamines A–C and spermatinamine, were evaluated against Plasmodium falciparum (3D7) parasites and a normal human cell line to determine parasite-specific activity. Spermatinamine (IC₅₀ 0.23 μM) and pistillarin (IC₅₀ 1.9 μM) were the two most potent antimalarials identified during these studies.