Seite - (000071) - in Biomedical Chemistry: Current Trends and Developments

activity or to overcome the emergence of resistance to treatments infectious diseases. It has been successfully used to optimize the targeting of reactive cysteine protease covalent inhibitors in the field of parasitic diseases. Falcipain-2 (FP-2) and falcipain-3 (FP-3) are cysteine proteases, located in the digestive vacuole of the malaria parasite and involved in the digestion of host hemoglobin essential for the survival of Plasmodium falciparum, the causing agent of the most lethal form of malaria. Rosenthal and co-workers demonstrated that inhibition of these enzymes allowed the cure of murine models of the disease and thus they constitute a validated target for its treatment. Generally, the inhibitors of falcipains have a backbone recognition element coupled with an electrophilic warhead such as aldehydes, fluoro methyl ketones, vinyl esters, vinyl sulfones (Fig. 1.2.6), and chalcones that can react with the catalytic cysteine residue (Shenai, 2003). However, the intrinsic reactivity of many of these warheads has prompted the development of hybrid compounds in order to modulate reactivity, improve selectivity and to avoid the emergence of resistant strains. Several hybrid compounds were prepared combining endoperoxides with different inhibitors of hemoglobin digestion. The goal was to bring together two drugs that can act in the digestive vacuole by two different mechanisms of action and taking advantage of the iron (II) coming from the digestion of the host hemoglobin (Meunier, 2008). 1.2.4.1 Hybrid Compounds Containing an Electrophilic Warhead In one of the first studies of hybrid compounds containing an electrophilic warhead, Capela et al. reported the synthesis of hybrids comprising artemisinin and dipeptidyl vinyl sulfones (Fig. 1.2.8) (Capela, 2009). These were designed to act in the parasite food vacuole − where host hemoglobin is decomposed to provide nutrients − via endoperoxide activation by Fe(II) and falcipain inhibition. All compounds were very potent against the P. falciparum W2 strain, with IC50 values in the low nanomolar range. Some of the compounds showed also superior activity than chloroquine or artemisinin, the golden standards to treat malaria, against four additional resistant P. falciparum