Seite - (000072) - in Biomedical Chemistry: Current Trends and Developments

strains with different phenotypes. However the hybrid compounds were only moderately active against FP-2 in the low micromolar range. The authors ascribed the antiplasmodial activity of the compounds to the size of the artemisinin moiety inside the active site of falcipain, which might preclude optimal binding to the enzyme. Using the same rationale, Oliveira et al. synthesized 1,2,4,5- tetraoxane-based hybrid molecules (Fig. 1.2.8) containing dipeptidyl vinyl sulfone partners to deliver the FP-2 inhibitor once activated in the parasitic food vacuole (Oliveira, 2013). These compounds showed excellent antimalarial activity against both chloroquine-sensitive and chloroquine-resistant strains of P. falciparum. In spite of the low in vitro inhibitory activity against FP-2, the hybrid compounds inhibited hemoglobin digestion inside the parasites at low nanomolar concentrations, which was confirmed by the microscopic observation of swelling of the parasite digestive vacuoles. This result is consistent with a Fe(II)-triggered process inside the parasite that leads to the delivery of a potent vinyl sulfone (Fig. 1.2.9). Importantly, the authors were able to detect the intact parent vinyl sulfone in infected erythrocytes 48h post- treatment with the hybrid compounds, which strongly suggests that the vinyl sulfone inhibitor remained within infected erythrocytes long after the fast-acting endoperoxide moiety had exerted its effects. These results indicate that the intrinsic activity of the vinyl sulfone partner can be masked, suggesting that a tetraoxane-based delivery system offers the potential to attenuate the off-target effects of known drugs (e.g. irreversible enzyme inhibitors such as Michael acceptors).