STSM - Libraries of analogues of Eucalyptus G-endoperoxides, antiparasite activities, mechanisms of action. Dafni Graikioti

A family of naturally occurring endoperoxides called G-factors (G1-G3), is developed by the team. They are structurally six-membered unsaturated cyclic endoperoxides fused to another six-carbon ring deriving from syncarpic acid. They are endogenous in the leaves of Eucalyptus grandis and some other myrtaceous plants. Two synthetic methodologies have already been elaborated and optimized, one giving access to carbon labelled derivatives. Our work concerning the antimalarial activity of the families synthetized indicated that: a) while G3 compound was very poorly active against P. falciparum (36µM), the G3Me presented a very interesting antimalarial activity (280nM), b) R1(or R2) and R positions when alkylated afforded compounds with very potent antiplasmodial activities c) hybrid highly potent molecules were synthetized (IC50 = 13nM and 31nM for chloroquine resistant W2 strain and 3D7 chloroquine susceptible strain); d) our first preliminary results (chemical spectroscopic means) indicated no alkylation, contrary to artemisinin, when reacting G3Me with Mn-porphyrin system, indicating that  these new antimalarial candidates could be particularly promising.

The aim of the integral project can be resumed in five main points: 1a: elaborate G3 compounds bearing same type of terminal alkynes (or azides) functions either on the peroxy-hemiketal position or on the lateral chain; 1b: construct focalized libraries for SAR studies, each compound bearing the alkyne (or azide) fragment. 2 and 3: in vitro activity and cytotoxicity evaluation of all compounds against P. falciparum wild and resistant strains. 4:Construct hybrids with other antimalarial pharmacophores, particularly with plasmodione, menadione and HDAC derivatives through click chemistry approaches. 5: Select the 4 most potent derivatives and synthetize them in their labelled forms. 6: Undertake in vitro and in vivo studies for elucidating the mechanism of action of two of the most promising compounds where a coumarin-based fluorescent probe will be also installed.

Finally, chemoproteomics and large-scale quantitative proteomics strategies studies will be performed using adequate Plasmodium parasites cell lines as cellular contexts.