Antimalarial selective toxicity

As described in section 4.1, the DNA double helix must unwind to allow access ofthe polymerase enzymes to produce two new strands ofDNA. This is facilitated by DNA gyrase, the target of the quinolones. Some agents interfere with the unwinding of the chromosome by physical obstruction. These include the acridine dyes, of which the topical antiseptic proflavine is the most familiar, and the antimalarial acridine, mepacrine. They prevent strand separation by insertion (intercalation) between base pairs from each strand, but exhibit very poor selective toxicity. 

Different antimalarials selectively kill the parasite s different developmental forms. The mechanism of action is known for some of them pyrimethamine and dapsone inhibit dihydrofolate reductase (p. 273), as does chlorguanide (proguanil) via its active metabolite. The sulfonamide sulfadoxine inhibits synthesis of dihydrofolic acid (p. 272). Chlo-roquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit polymerization of heme, the latter substance being toxic for the schizonts. 

Artemisinin compounds clear parasites from the blood more rapidly than any other antimalarial agent, by a unique pharmacodynamic action. They are concentrated in parasitized erythrocytes, and structure-activity relations (see Chapter 2) suggest that their endoperoxide bridge is essential for the antimalarial effect. A critical step in the mechanism of action seems to be a hemin-catalyzed reduction of the peroxide moiety, which results in free radicals and reactive aldehydes that subsequently kill the malaria parasites. The hemin-rich internal environment of the parasites is assumed to be responsible for the selective toxicity of artemisinin toward these organisms. 

Drug activation by iron and heme may explain why endoperoxides are selectively toxic to malaria parasites. The malaria parasites live in a milieu of heme iron, which the parasite converts into insoluble hemozoin. Chloroquine, which binds heme, antagonizes the antimalarial activity of artemisinin. 

The methyl esters of peroxyplakoric acids A3 (57) [Fig. (21)] and B3 (58) [Fig. (21)], isolated from Plakortis sp., showed a very good antimalarial activity against P. falciparum with IC50 = 50 ng/mL and a good selective toxicity index (about 200) [78]. Through the syntheses of some analogues of these active compounds, some conclusions about the structural requirements within these classes of antimalarials were drawn. For example, compound 59 [Fig. (22)] proved to be almost completely inactive, whereas compound 60 [Fig. (22)] retained the in vitro activity of peroxyplakoric acid B3 methyl ester, indicating the importance of the side chain for the antimalarial activity [79]. 

MECHANISMS OF ANTIMALARIAL ACTION AND RESISTANCE The 2,4-diaminopyrimidines inhibit dihydrofolate reductase of plasmodia at concentrations far lower than those required to inhibit the mammalian enzymes. The dihydrofolate reductase in malaria resides on the same polypeptide chain as thymidylate synthase and is not upregulated in the face of inhibition, which contributes to the selective toxicity of the antifolates. Synergism between pyrimethamine and the sulfonamides or sulfones has been attributed to inhibition of two steps in an essential metabolic pathway. 

Quinoline compounds and the plants that contain them have historically anchored the antimalarial arsenal, and they remain principal drugs today. Quinine and its diastereomer, quinidine, are quinoline alkaloids which were isolated in 1820 from the bark of the Cinchona tree, by virtue of the traditional South American use of this bark to treat intermittent fevers. Quinine is an effective schizonticide (i.e., it kills the form of the parasite in peripheral blood), but because it also affects mammalian lysosomes, the drug has been associated with significant adverse toxicity (48,50). The development of synthetic derivatives of quinine has resulted in improvement in potency and selectivity over the parent compound. Chloroquine and mefloquine are more potent and less toxic than quinine (49,51), thus, chloroquine had largely replaced quinine in clinical use however, resistance of P. falciparum to chloroquine has been reported... 

Under conditions of in vitro testing, compounds which inhibit the growth and survival of a variety of cell types can legitimately be called "antiplasmodial" however, the meaning of the term is obscured due to the promiscuous nature of the toxicity. The inclusion of a selectivity parameter along with "antimalarial" data rejxrrted in the literature, is suggested here to facilitate a more qualitative evaluation of compounds with genuine potential as antimalarial lead compounds. 

---