Pyrimethamine, structure

Competitive inhibitors of GST Pl-1 fall under two categories non-glutathione-and glutathione-based compounds. The former group covers a broad range of chemical structures such as tricyclic-based dibenzazepines, polyphenolic natural products, alkaloids, pyrimethamine, and dyes. The latter group, as its name indicates, covers compounds whose main structure or backbone is that of GSH. 

This sol-gel procedure is an elaboration on well established entrapment methods [29], but with the added advantage of stability and better flow properties. Interestingly, none of the examples presented thus far demonstrate competitive behavior between multiple ligands (i.e. displacement) in the FAC analysis of trimethoprim and pyrimethamine a reversed order of elution based on is described, but this could simply be due to the shift towards an on-rate limited situation for higher affinity compounds, as described earlier. Erosion of dynamic competition between ligands could occur if the sol-gel allows convective mixing of the entrapped protein however the bimodal pore structure of these materials would... 

A while later, pyrimethamine (33.1.60) was suggested as a result of intensive research of antimetabolites of folic acid. Trimethoprim (33.1.51) is the result of later research. The structural similarity of these drugs with the pteridine fragment of folic acid undoubtedly determines their affinity with binding regions of dihydrofolate reductase. 

VI.a.2.4. Diaminopyrimidines. Pyrimethamine is a dihydrofolate reductase inhibitor, like the biguanides, and is structurally related to trimethoprim. It is seldom used alone. Pyrimethamine in fixed combinations with dapsone or sulfadoxine is used for treatment and prophylaxis of chloroquine-resistant falciparum malaria. The synergistic activities of pyrimethamine and sulfonamides are similar to those of trimethoprim/sulfonamide combinations. Resistant strains of Plasmodium falciparum have appeared world wide. Prophylaxis against falciparum... 

Pyrimethamine does not belong to the group of known nephrotoxic agents [39]. Because pyrimethamine and trimethoprim have a similar 2, 4-diaminopyrimidine molecular structure, Opravil et d [197] reported a similar handling of tubular secretion of creatinine. In six healthy volunteers and nine patients with AIDS, pyrimethamine caused a reversible, small to moderate, similar between the two groups, but statistically significant increase (26%) in serum creatinine concentration with a concomitant... 

Pyrimethamine is an aminopyrimidine agent that is structurally related to trimethoprim but is more active against protozoa than bacteria. It is most effective against protozoa when administered... 

Sheffield H G, Melton M L 1975 Effect of pyrimethamine and sulfadiazine on the fine structure and multiplication of Toxoplasma gondii in cell cultures. Journal of Parasitology 61 704-712... 

Fig. 12.8 Structural relationships between dihydrofolate reductase inhibitors (trimethoprim and pyrimethamine), sulphonamides (sulphamethoxazole and dapsone) and dihydrofolic acid.

A novel structural type (5) was reported to have potent activity against resistant malaria strains. Minor modifications, including removal of the N-OH substituent eliminated activity.Limited clinical pharmacology, biochemistry and mode of action studies are available in the entire parasitology area. Two recent papers report the pharmacokinetics of amodiaquine, chlorguanide, chloraquine, pyrimethamine, quinine and sulfadoxine. 

Inhibitors of dihydrofolate reductase. Methotrexate, a structural analogue of dihydrofolate, is effective against intact mammalian cells but ineffective against protozoa and some bacteria owing to permeability barriers. Trimethoprim and pyrimethamine (2,4-diaminopyrimidines) are effective against microorganisms. The former is antibacterial and antimalarial the latter is primarily antimalarial. 

In the last few years, variations on the basic stracmre have been launched in combination with other antimalarials (usually variations on the chloroquine structure) such as dihydroartemismin and piperaquine phosphate (Artekin), artemether and lumefantrine (Coartem), artesunate/mefloquine (Artequin) and artesunate, sulfamethoxypyrazine, and pyrimethamine (Co-Arinate). Currently, there is another fixed dose combination with an artemisinin derivative in clinical trials, pyronaridine/artesunate (Pyramax in Phase III). However, the tri-oxo scaffold system in artemisinins has led to the synthesis of not only artemisinin variations but to totally synthetic molecules with the trioxane moiety included, such as arterolane tosylate (81). This compound is in Phase II trials as a single agent under Ranbaxy and is in Phase I trials in combination with piperaquine phosphate, also under Ranbaxy. 

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic drugs came this century when the two World Wars interrupted the supply of cinchona bark to the combatants. A structurally related 4-quinolinemethanol is mefloquine (65, Lari am [51773-92-3]), which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this drug such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

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