Page - (000073) - in Biomedical Chemistry: Current Trends and Developments

Figure 1.2.8: Structures of endoperoxide-based hybrids containing an electrophilic warhead for cysteine protease inhibition. The hybrid approach was extended to tetraoxane derivatives designed to deliver FP-2 inhibitors based on peptidomimetic pyrimidine nitriles. Nitriles inhibit cysteine proteases by forming a reversible thioimidate intermediate resulting from the nucleophilic attack of the catalytic cysteine residue (Ehmke, 2011; Ehmke, 2012). Several heterocyclic and peptidomimetic compounds containing a nitrile warhead displayed excellent inhibitory activity against falcipain-2 and against cultured P. falciparum (Ehmke, 2011; Coterón, 2010). The pyrimidine nitrile tetraoxane hybrids (Fig. 1.2.8) displayed potent nanomolar activity against three strains of P. falciparum and FP-2, combined with low cytotoxicity. These hybrid compounds showed also significant effects on liver stage model in vitro using P. berghei infecting Huh-7 human hepatome cells and one derivative also showed in vivo efficacy when compared with a non-treated control group (Oliveira, 2014). As with their vinyl sulfone counterparts, the pyrimidine nitrile tetraoxane hybrids were shown to deliver the corresponding peptidomimetic pyrimidine nitrile inside the parasite upon activation by Fe(II).