Page - (000074) - in Biomedical Chemistry: Current Trends and Developments

Figure 1.2.9: Tetraoxane-vinylsulfone hybrid compounds and their activation by Fe(II) from host hemoglobin in infected erythrocytes (Oliveira, 2013). Insert: delivery of the Michael acceptor (vinyl sulfone) via iron binding to oxygen-2 leads to the swelling of the parasitic digestive vacuole. 1.2.4.2 Hybrid Compounds Containing a Masked Electrophilic Warhead Based on Roche’s antimalarial arteflene, O’Neill reported a prodrug approach consisting of an endoperoxide containing cysteine protease inhibitors in a latent form. After entering the ferrous-rich food vacuole of the malaria parasite, the molecule will be fragmented by iron (II) releasing various antiparasiticidal elements (Fig. 1.2.10). These compounds exhibit significant antimalarial activity, in the low nanomolar range, and they can act by two different mechanisms, cytotoxicity exerted by the C-radicals species formed by the activation of the peroxide, and inhibiting falcipains due to the effect of the carbonyl inhibitor released in the activation process (O’Neill, 2004). They demonstrated that in the presence of Fe(II) the compounds liberated a chalcone and additional potential parasitocidal chemical species. Furthermore, they proved, by LC-MS analysis of pro-drug exposed parasites, that these systems are capable of liberating a chalcone in the living parasites (O’Neill, 2004).