Page - (000075) - in Biomedical Chemistry: Current Trends and Developments

Figure 1.2.10: Fragmentation of arteflene-related peroxide to secondary carbon centered radical species and protease inhibitor, active against falcipain-2 from P. falciparum. Adapted from O’Neill, 2004. The same group extended the concept to a new type of hybrids combining a 1,2,4-trioxolane moiety with peptidic cysteine protease inhibitors. They demonstrated that in the presence of Fe(II) the 1,2,4- trioxolane scaffold decomposes into a potentially toxic carbon radical that alkylates the heme in vitro, and a Michael acceptor that acts as a cysteine protease inhibitor (Fig. 1.2.11). The most potent compound of the series presented an IC50 value in the low nanomolar region (35 nM) against the 3D7 strain of P. falciparum. Remarkably, although the same compound showed inhibitory activity of FP-2 in the submicromolar range (0.5 µM), the corresponding aldehyde released upon Fe(II) activation (Fig. 1.2.11) was shown to inhibit FP-2 with an IC50 value of 16 nM, thus confirming 1,2,4-trioxolane scaffold as a site-specific delivery system for electrophilic aldehydes and ketones (Gibbons, 2010).