Pyrimethamine derivatives

Compounds also found active include (among many others) tannins,145 the pharmaceutical products pyrimethamine (51, Scheme 15),146 ambroxol (52),147 the secre-tolytic ingredient in mucosolvan, or fluphenazine (53),147 an antipsychotic substance, as well as—and closer to real sugars—ascorbic acid derivatives (54).148... 

Knowledge of local resistance patterns is important to determine the treatment regimen. There is increasing chloroquine and pyrimethamine-sulfado-xine (Fansidar) resistance in Africa and in some areas at the border of Thailand there is resistance for almost all antimalarial drugs including halofantrine, mefloquine and quinine. In these areas only the artemisinin derivatives (artemether, arteether, arte-sunate, dihydroartemisinin) are effective. 

Trimethoprim is a pyrimidine derivative (diaminopyrimidine) related to antimalarial drug pyrimethamine, which selectively inhibits bacterial dihydrofolate reductase, necessary for the conversion of dihydrofolate to tetrahydrofolic acid. Sulfonamides act by inhibiting the incorporation of PABA into dihydrofolate by bacteria. A combination of... 

It is used as leucovorin calcium (calcium folinate). It is 5-formyl derivative of tetrahydrofolic acid and it acts as an antidote to folic acid antagonists like methotrexate or pyrimethamine which inhibit the enzyme dihydrofolate reductase. 

Chloroquine-resistant Quinine Artemisinin derivatives Atovaquone-proguanil Mefloquine Pyrimethamine-sulfadoxine Antibacterials (e.g., clindamycin, doxycycline, sulfamethoxazole, or tetracycline] ... 

Pyrimethamine may also be combined with other antimalarials such as artemisinin derivatives, but these regimens should only be used if the malarial parasites are not resistant to the specific drugs in the regimen.13 Pyrimethamine can also be combined with a sulfonamide drug such as dapsone, sulfadiazine, or sulfamethoxazole to treat protozoal infections that cause toxoplasmosis, or fungal infections that cause Pneumocystis pneumonia.These agents are administered orally. 

The major antimalarial agents are the 4-aminoquinoline derivative (e.g., chloroquine), 8-aminoquinoline derivative (e.g., primaquine), folic acid antagonist (e.g., pyrimethamine), and... 

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... 

The active form of folate is the tetrahydro-derivative that is formed through reduction by dihydrofolate reductase. This enzymatic reaction (Figure 29.5) is inhibited by trimethoprim, leading to a decrease in the folate coenzymes for purine, pyrimidine, and amino acid synthesis. Bacterial reductase has a much stronger affinity for trimethoprim than does the mammalian enzyme, which accounts for the drug s selective toxicity. [Note Examples of other folate reductase inhibitors include pyrimethamine, which is used with sulfonamides in parasitic infections (see p. 353), and methotrexate, which is used in cancer chemotherapy (see p. 378).]... 

The synthesis of MZP is shown in Scheme 3.1. Nitration of the readily available antimalarial diaminopyrimidine pyrimethamine (PYM) (113) yielded w-nitropyrimethamine (MNP) (114) exclusively, and reduction to the corresponding amine w-aminopyrimethamine (MAP) (115), followed by diazotisation and azidation afforded the azide (111) in excellent overall yield [135, 136]. The extremely poor aqueous solubility of MZP (22 4/water-soluble salt for biological evaluation, and m-azidopyrimethamine ethanesulphonate MZPES (112), with an aqueous solubility of 17.60 0.45 mg/ml at 20°C, was the most appropriate for this purpose. A series of derivatives (116)-(123), differing... 

Pyrimethamine and proguanil are used as oral antimalarials.and inhibit the utilization of folate by the malarial parasite, so are valuable in chemoprophylaxis and in preventing the transmission of malaria. (See ANTIMALARIALS.) Trimethoprim is a useful antibacterial, and as an antiprotozoal in antimalarial therapy. The selectivity of these agents derives, in part, from the fact that whereas mammals can obtain folic acid from the diet, bacteria and the asexual forms of the malarial parasite must synthesize it. Also, the dihydrofolate reductase enzyme in humans is less sensitive to these drugs than that of the parasites. 

As a response to increasing levels of antimalarial resistance. The World Health Organization (WHO) recommends that treatment policies in all countries experiencing resistance of Plasmodium falciparum to conventional monotherapies should be combination therapies, preferably those containing artemisinin derivatives. Currently WHO recommends the following therapeutic options artesunate-sulfadoxine/pyrimethamine, artesunate-amodiaquine,... 

There are several one-carbon derivatives of folate (of different redox states) that function as one-carbon carriers in different metabolic processes. In all of these reactions, the one-carbon moiety is carried in a covalent linkage to one or both of the nitrogen atoms at the 5- and 10-positions of the pteroic acid portion of tetrahydrofolate. Six known forms of carrier are shown in Figure 27-4. Folinic acid (N -formyl FH4), also called leucovorin or citrovorum factor, is chemically stable and is used clinically to prevent or reverse the toxic effect of folate antimetabolites, such as methotrexate and pyrimethamine. The formation and interconversion of some metabolites of... 

The use of antifolates in the treatment of coccidiosis in domestic animals has also been established. It has been found that compounds derived from 2,4-diamino-pyrimidines and 2,2-dialkyl-l-aryl-4,6-diamino-l,2-dihydro-s-triazines exhibit promising anticoccidial activity. The noteworthy compounds of this class were found to be pyrimethamine (33), diaverdine (35) and ormetoprim (36) [59]. The metabolites 31a,b of proguanil and chlorproguanil also exhibit marked activity against coccidiosis [60]. 

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 pyrimidine ring is a constituent of many pharmaceuticals, such as the chemotherapeutics trimethoprim 32 and sulfadiazine 33, the dihydrofolate reductase inhibitor pyrimethamine 34 and hexetidine 35 derived from hexahydropyrimidine and used as an oral antiseptic. 

W G Sorby DL, Plein EM and Benmaman D, Adsorption of phenothiazine derivatives by solid adsorbents, /. Pharm. Sci., 55, 785-794 (1966). NB See Chlorpromazine for details. This appears to be the same compound as pyrimethamine, but the discrepancy in die pJCa values is unexplained—possibly a difference in solvent. 

Derivatives of all three heterocyclic systems have been widely investigated for use in synthetic drugs (see also above) amongst the most commonly used compounds are the antibacterial Trimethoprim, the antimalarial Pyrimethamine and the anti-hypertensive agent Hydralazine (containing a phthalazine nucleus). Piperazine (hexahydropyrazine) is used in the treatment of intestinal nematode (worm) infections. 

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