Inhibition of Hemozoin Formation

FQ might thus strike the parasite not only via direct inhibition of hemozoin formation but also by production of lethal hydroxyl radicals. These radicals are known to be particularly aggressive toward unsaturated fatty acids present in... 

In conclusion, the activity of FQ is due to more than one route (Fig. 31). Due to its physicochemical properties, FQ could specifically target the lipid site of hemozoin formation. Its mechanism of action should be in part similar to that of CQ, based on the inhibition of hemozoin formation. Upon the specific (acidic and oxidizing) DV conditions, production of radical oxygen species (ROS) by FQ should be sufficient to promote significant damage on membranes of the parasite DV. The strong activity of FQ on CQ-resistant clones and isolates of P. falciparum suggests a fundamental difference in interaction with resistance mechanisms of the parasite. 

The antimalarial activity of FQ was initially compared with that of the purely organic CQ in an effort to understand how the presence of the ferrocene contributes to the antiplasmodial property. Over the years, the mechanism of CQ has been (and is still) the subject of many discussions and arguments. Nevertheless, there is strong evidence that the action of CQ is linked to its localization in the DV of the parasite and to the inhibition of the formation of hemozoin ([37], see [155-157]). 

Loup C, Lelievre J, Benoit-Vical F, Meunier B. (2007) Trioxaquines and heme-artemisinin adducts inhibit the in vitro formation of hemozoin better than chloroquine. Antimicrob Agents Chemother 51 3768-3770. 

In related work, Martiney et al. showed that metalloporphyrins with zinc or tin were capable of inhibiting hemozoin formation in trophozoite extracts [105]. Zn(II) and Sn(IV) analogs of heme were selected for study as a result of their known competitive interactions with heme in a number of systems and their use as pharmacological photosensitizers. The order of efficacy for these metalloporphyrins was ZnDPIX>SnPPIX ZnPPIX. This order is consistent with the proposed... 

Inspired by the bioorganometallic approach, two series of ferrocenyl pyrrolo[ 1,2-a] quinoxalines were designed and prepared (Fig. 17). The derivatives were tested in vitro against three different strains of P. falciparum F32, FcBl, and PFB [107]. The best results (IC50 between 30 and 70 nM in comparison to CQ IC5o = 225 nM) were observed in the first series with a bis(3-aminopropyl)piperazine as a linker. These compounds were tested for then ability to inhibit p-hematin formation. For all but one case, the derivatives did not interfere with hemozoin formation... 

The hydrophobic ferrocene moiety should establish favorable van der Waals interactions with lipid structures involved at the interface with aqueous content of the DV, positioning FQ in the same catalytic site as hematin [157]. This preferential location of FQ should cause inhibition of formation of hemozoin more efficiently than CQ does. 

Figure 2 Modes of hemozoin inhibition. On a neutrai iipid dropiet tempiate (T), heme can aggregate to form the biomineral HZ. Antimalarials may inhibit this aggregation by binding heme substrate, interacting with the iipid tempiate or trapping heme bound to the template. All actions serve to prevent the formation of HZ.

---