Pyrimethamine antimalarial activity

Pyrimethamine is the most active antimalarial of the 2-4-diaminopyrimidines, its effect being due to inhibition of the conversion of foUc acid to its active form, folinic acid. It is also effective in toxoplasmosis. Its antiprotozoal and antimalarial activity is enhanced by the addition of sulfonamides. 

Synthetic antimalarials developed fiom herbals include chloroquine, primaquine, proguanil, pyrimethamine and mefloquine. Botanicals represent a diverse arsenal of molecules that could constitute lead compounds for new antimalarial dmgs, such as artemisinin, isolated from Artemisia annuaSeveral studies have been undertaken to evaluate the inhibitory effects of various plants extracts on P. falciparum in culture. The in vivo antiplasmodial effects of several plant extracts have been studied on Plasmodium berghei and P. yoelii The majority of the plants that we screened for antimalarial activities had similar ethnopharmacological use among different Kenyan ethnic groups. ... 

Table 2 Repository antimalarial activity of pyrimethamine salts against P. berghei in mice 36, 74,...

Alkaloids 39 and 40, which are enantiomers of one another and are both used as antimalarial agents, inhibited GST Pl-1 in the single-digit micromolar range (IC50 = 4 and 1 pM, respectively), indicating that the chirality of the secondary alcohol does not play a significant role in this activity. Pyrimethamine (41),... 

Rapidly dividing cells need an abundant supply of dTMP for DNA synthesis, and this creates a need for dihydrofolate reductase activity. Specific dihydrofolate reductase inhibitors have become especially useful as antibacterials, e.g. trimethoprim, and antimalarial drugs, e.g. pyrimethamine. 

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. 

Of interest is a recently described yeast-based, nutrient-dependent viability screen for inhibitors of protozoal dihydrofolate reductase (DHFR) [43,44], Antiprotozoal activity of DHFR inhibitors is well known, and DHFR- yeast complemented with the DHFR gene derived from the malaria parasite P. falciparum have been used to characterize the molecular pharmacology of resistance to the antimalarial DHFR inhibitors pyrimethamine and cycloguanil [45,46], The subsequent development of a screen was based on the demonstration that the protozoal... 

Pyrimethamine is a folic acid antagonist that for many years has been used as an antimalarial drug [193-195], specially for chloroquine-resistant P. falciparum. Due to its synergistic activity, pyrimethamine also has been used, in combination with sulfadiazine or dapsone for the treatment or prophylaxis of cerebral toxoplasmosis or PCP in patients with AIDS [196]. 

---