Authors
H Hameed1; R Nash4; B Bartholomew3; P Horrocks2; 1 Institute for Science and Technology in Medicine, Keele University, UK; 2 Keele University, UK; 3 PhtoQuest, UK; 4 PhytoQuest Ltd, UK Discussion
There is an urgent need to identify and evaluate novel chemical scaffolds to seed the drug discovery pipeline for parasitic diseases to meet the challenges of emerging resistance, toxicity and costs of current treatment. Whilst there is a significant investment in international efforts to screen massive small-chemical libraries, this search also encompasses the evaluation of natural products often identified from traditional medicines. Here we report the screen of a proprietary library of purified natural products, the PhytoPure library, that are predominantly sourced from temperate zone plants. As traditional medicines of tropical parasitic diseases focus on the local flora, the antiparasitic activity of temperate zone plants is relatively under evaluated. The Phytopure library screened here consists of 643 purified products (ie not plant extracts, which are mixes of active and inactive components), two thirds of which are novel, and the remaining one third not otherwise commercially available. These compounds have also been selected on the basis of their development potential: they have a high degree of functionality and physiochemical properties that meet Lipinski’s rules-of-five. We report here activity screens against intraerytrocytic Plasmodium falciparum, blood-stream form of Trypanosoma brucei and axenic Leishmania mexicana. Activity was confirmed by the determination of the EC50 and compared to the CC50 against HepG2 cells to explore their selectivity. In total, 33 compounds with EC50 <2µM were identified. Of these, three closely related sesquiterpenes (701155, 701157 and 701158) exhibited significant activity against all three parasite species trested. Seven compounds showed activity against both kinetoplastid parasites with 4 compounds showing T. brucei and P. falciparum. 
