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The mode of action of sulphonamides, proguanil and pyrimethamine on Plasmodium gallinaceum.

British journal of pharmacology and chemotherapy 07/1955; 10(2):208-14. DOI: 10.1111/j.1476-5381.1955.tb00084.x
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    ABSTRACT: Treatment with sulfadiazine prevented most of the increase in folic and folinic acid which otherwise occurred in the red blood cells of ducks infected with Plasmodium lophurae. The same effect was observed when a sulfadiazine-resistant strain of P. lophurae was treated with sulfadiazine at doses having no effect on the infection: the increase in folic and folinic acids was markedly less than that in untreated infections with the same strain. When the sulfadiazine-resistant strain was treated with pyrimethamine, to which it was also resistant, the increase in folinic acid was inhibited, but not that in folic acid. Each drug exerted its characteristic inhibitory effect on the folinic acid-synthesizing mechanism, yet the parasites of the resistant strain continued to multiply. This synthetic mechanism may reside in the infected red cells rather than in the parasites. The resistance to sulfadiazine and pyrimethamine appears to depend on a decreased requirement for the products of the reactions inhibited by these drugs.
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    ABSTRACT: It is known that malaria parasites are inhibited by sulfonamides and antifolate compounds, require 4-aminobenzoic acid for growth, and respond only partly to intact folic and folinic acids. Biochemical data obtained during the last decade on the synthesis of nucleic acid precursors and on folate enzymes in malaria support the hypothesis that malaria parasites are similar to microorganisms that synthesize folate cofactors de novo. Sulfa drugs inhibit plasmodial dihydropteroate synthase (EC 2.5.1.15). Pyrimethamine and many other antifolate compounds bind to tetrahydrofolate dehydrogenase (EC 1.5.1.3) of the parasite more tightly than to the host enzyme. However, the metabolic consequences of the depletion of folate cofactors as a result of drug inhibition are not yet known. Other areas to be studied are the origin of the pteridine moiety of folates, the addition of glutamate(s) in folate cofactor biosynthesis, the means by which intact, exogenous folates affect malarial growth, and demonstration of the enzymes and reactions involving N(5)-methyl tetrahydrofolate.
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    ABSTRACT: The binding of substrates and inhibitors to dihydrofolate reductase was studied by steady-state kinetics and high-field 1H-n.m.r. spectroscopy. A series of 5-substituted 2,4-diaminopyrimidines were examined and were found to be 'tightly binding' inhibitors of the enzyme (Ki less than 10(-9) M). Studies on the binding of 4-substituted benzenesulphonamides and benzenesulphonic acids also established the existence of a 'sulphonamide-binding site' on the enzyme. Subsequent n.m.r. experiments showed that there are two binding sites for the sulphonamides on the enzyme, one of which overlaps the coenzyme (NADPH) adenine-ring-binding site. An examination of the pH-dependence of the binding of sulphonamides to the enzyme indicated the influence of an ionizable group on the enzyme that was not directly involved in the sulphonamide binding. The change in pKa value from 6.7 to 7.2 observed on sulphonamide binding suggests the involvement of a histidine residue, which could be histidine-28.
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