Optimisation and in vivo validation of a new antimalarial chemotype agent – PlasmoSC

Malaria is one of the most widespread parasitic infections in the world, infecting more than 300 to 500 million people and is responsible for the death of 1 million people a year. The spreading of Plasmodium falciparum infection is due to the emergence of resistance to almost all available antimalarial drugs. Concerned by the need to produce cheap and easy-made drugs, most researchs devoted to find new antimalarial agents are restricted to improving existing drugs, even if their therapeutic potential can be endangered by existing resistances to the biological target(s). Within this context, our project goal is to develop a new and promising therapeutic agent with a new chemical scaffold and having an unprecedented pharmacophoric function (Spiro-Cyclohexadienone) for treating malaria, with the expectation that new mode of action(s) can be identified at the end.
Two important families of antimalarial agents, the quinine and the artemisinin, were isolated from plants, selected along human history (traditional pharmacopoeia) for their virtue to treat fevers. Inspired by this approach, a potent new class of antimalarial natural products, the aculeatins, were identified in 2000 from a plant used in traditional phytotherapy in Papoua-New-Guinea to treat fevers.
A few years ago, we have demonstrated that a highly efficient cascade reaction, enable to make multiple bonds formations via a biomimetic mechanism can ends up by forming the complex polyspirocycles structure of aculeatins, starting just from a simple phenol and a carbonyl groups. By mastering this biomimetic protocol, we were able to make quickly and simply the set of structurally complex molecules having the essential features of antiparasitic agents, given important insights on the structure/activity relationship.
We are working on the development of molecules having many advantageous points: i) an in vitro efficiency against P. falciparum at nanomolar concentration and with a selectivity index over 100 (efficiency on the parasite compared to the cytotoxicity on human erythroblaste), with a remarkably fast action, ii) a potency on the parasite at every blood stages and iii) a dual pharmacophoric group which amplify the biological effect.
During the 24 month of this project, we propose to extent the proof-of-concept with the objectives to enhance the in vitro activity by one order of magnitude (the low nanomolar range) and to be able to cure malaria at blood stage in a rodent model. The goal is to bring a new drug candidate at the drug development stage concerning its pharmacological profile and efficiency. This drug candidate can be further launched into regulatory preclinical trials that would include detailed toxicological studies in association with pharmaceutical groups (licence transfer).