Abstract
In the present work we performed a combined experimental and computational study on the interaction of the natural antimalarial endoperoxide plakortin and its synthetic analogue 4a with heme. Obtained results indicate that the studied compounds produce reactive carbon radical species after being reductively activated by heme. In particular, similarly to artemisinin, the formation of radicals prone to inter-molecular reactions should represent the key event responsible for Plasmodium death. To our knowledge this is the first experimental investigation on the reductive activation of simple antimalarial endoperoxides (1,2-dioxanes) by heme and results were compared to the ones previously obtained from the reaction with FeCl2. The obtained experimental data and the calculated molecular interaction models represent crucial tools for the rational optimization of our promising class of low-cost synthetic antimalarial endoperoxides.
Highlights
In the present work we performed a combined experimental and computational study on the interaction of the natural antimalarial endoperoxide plakortin and its synthetic analogue 4a with heme
In the course of a search for new antimalarial lead compounds, we reported that plakortin (2) and dihydroplakortin (3) (Fig. 1), simple endoperoxide-containing polyketides isolated from the Caribbean sponge Plakortis simplex[3,4,5], show significant in vitro activity against chloroquine (CQ)-resistant strains of Plasmodium falciparum (Pf) (i.e., IC50 0.4 μM), promising in vivo activity (P. berghei infected mice), and no observed toxicity[3,4,6]
The preparation of several plakortin semi-synthetic derivatives[7] allowed the development of a first set of structure-activity relationships (SARs), which strongly suggested that the antimalarial mechanism of action of plakortins, to that of 18–11, could include a FeII-induced reductive activation which generates toxic carbon radicals leading to the death of the parasite
Summary
In the present work we performed a combined experimental and computational study on the interaction of the natural antimalarial endoperoxide plakortin and its synthetic analogue 4a with heme. To artemisinin, the formation of radicals prone to inter-molecular reactions should represent the key event responsible for Plasmodium death To our knowledge this is the first experimental investigation on the reductive activation of simple antimalarial endoperoxides (1,2-dioxanes) by heme and results were compared to the ones previously obtained from the reaction with FeCl2. Computational and SAR studies performed on the new series of synthetic 1,2-dioxane derivatives indicated that, as in the case of plakortins, the antimalarial activity is related to their ability to react with FeII generating carbon centered radicals (in this case at C3 and/or at C6 alkyl chain)[16,17,18,19]. Obtained data are discussed in the frame of our previous results[12,13,14,15,16,17,18,19] and a molecular interaction model of heme-FeII in complex with the studied ligands was generated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
