Antagonism of sulfadoxine and pyrimethamine antimalarial activity in vitro by p-aminobenzoic acid, p-aminobenzoylglutamic acid and folic acid

Watkins, William M.; Sixsmith, David; Chulay, Jeffrey D.; Spencer, Harrison C.

doi:10.1016/0166-6851(85)90105-7

Cited by 67 publications

(47 citation statements)

References 8 publications

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“…18 They suggested that this may reflect poor use of intact folate by Plasmodia. However, the ability of Plasmodia to use intact exogenous folates has since been confirmed, [10][11][12][13] and the observation by McCormick and others more likely reflects a failure to achieve the appropriate folate to drug ratio necessary for significant antagonism to be observed. Yeo and others reversed the activity of WR99210 in the K1 strain of P. falciparum with FNA only at a drug to folate molar ratio Ͼ 1:400.…”

Section: Resultsmentioning

confidence: 99%

“…It is currently uncertain whether the inhibition of parasite DHFR is a major component of the action of these drugs. Several reports have demonstrated the ability of P. falciparum to use exogenous folate precursors if the de novo synthesis pathway is blocked, [10][11][12] and there is also direct evidence for a folate salvage pathway in P. falciparum. 13 Therefore, if the antiplasmodial activities of WR99210 and PS-15 involve the inhibition of parasite DHFR, addition of folic acid (FA) to the test system would significantly reduce drug action through competitive antagonism while FNA, by supplying the product of the inhibited enzyme, would completely reverse antifolate drug action.…”

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confidence: 99%

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The antimalarial triazine WR99210 and the prodrug PS-15: folate reversal of in vitro activity against Plasmodium falciparum and a non-antifolate mode of action of the prodrug.

Kinyanjui¹,

Mberu²,

Winstanley³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. We have studied the reversal of activity against Plasmodium falciparum of WR99210, a triazine antimalarial drug, and of the pro-drug PS-15 by folic acid (FA) and folinic acid (FNA). Folic acid and FNA inhibit the growth of P. falciparum in vitro at concentrations Ͼ 10 Ϫ4.5 and 10 Ϫ3.5 mol/L, respectively. The activity of pyrimethamine against Kenyan strains M24 and K39 is reduced 10-12-fold by 10 Ϫ5 mol/L of FA, and virtually eliminated by 10 Ϫ5 mol/L of FNA. Folates do not antagonise the action of WR99210 against Kenyan strains, and only partially antagonize the action of WR99210 action against the Southeast Asian strains V1/S and W282. Similarly, FA and FNA exerted weak or no antagonism of the action of PS-15. The inability of folates to antagonize the action of WR99210 can be explained in terms of high drug-enzyme affinity, but this does not account for the inability of FA and FNA to antagonize PS-15. These results suggest that action of PS-15 against P. falciparum is primarily due to a non-folate mechanism.Chemotherapy remains the mainstay in the control and treatment of malaria. However, parasite resistance to the available antimalarial drugs is spreading rapidly. Chloroquine is now almost totally ineffective in most parts of Africa and reports indicate that resistance to pyrimethaminesulfadoxine, the current first-line treatment for chloroquineresistant parasites in Africa, will soon become widespread, rendering the drug useless. 1 Therefore, there is an urgent need for new antimalarial drugs. WR99210 and its prodrug PS-15 represent a new class of highly active antifolate drugs that could be used in combination therapy against multidrugresistant parasites.WR99210 (4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[(2,4, 5-trichlorophenoxy)propyloxy]-1,3,5-triazine), is a close structural analog of the antimalarial antifolate drug cycloguanil, which has pronounced activity in vitro against all Plasmodium falciparum strains studied to date. 2-5 PS-15 (N-(3-(2,4,5-trichlorophenoxy)propyloxy)-NЈ-(1-methylethyl)-imidocarbonimidodiamide hydrochloride), a close analog of proguanil, 6,7 is a prodrug of WR99210 developed to overcome the low bioavailability and gastrointestinal intolerance that occurs with oral dosages of WR99210 in humans. 8 Several factors suggest that both WR99210 and PS-15 have antifolate activity directed against parasite dihydrofolate reductase: the close structural similarity between PS-15 and proguanil, and between WR99210 and cycloguanil; 4 the ability of folinic acid (FNA) to reverse the gastrointestinal intolerance caused by WR99210; 6 and the fact that both compounds interact synergistically with sulfonamide. 6,7 Conversely, the high level of activity of WR99210 against all isolates tested, 4-6 the lack of cross-resistance with other dihydrofolate reductase (DHFR) inhibitors, 1,4 and the synergistic interaction between PS-15 and atovoquone, a drug that inhibits parasite mitochondrial electron transport, 6,9 collectively imply that both WR99210 and PS-15 may inhibit P. falciparum by additi...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

The antimalarial triazine WR99210 and the prodrug PS-15: folate reversal of in vitro activity against Plasmodium falciparum and a non-antifolate mode of action of the prodrug.

Kinyanjui¹,

Mberu²,

Winstanley³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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“…The second receptor, the folate binding protein or folate receptor, is specific for oxidized folate derivatives such as folic acid (1,24). Studies have demonstrated that both the oxidized and reduced folate (folic and folinic acid, respectively) can cross the membranes of the red blood cells parasitized with P. falciparum, because they can both negate the effects of antifolate drugs (12,42). Methotrexate, an analog of folic acid, uses the RFC receptor to gain intracellular access and has been shown to inhibit P. falciparum at IC 50 s similar to those that inhibit human cells (nanomolar range) (10,39).…”

Section: Discussionmentioning

confidence: 99%

Chemosensitization of Plasmodium falciparum by Probenecid In Vitro

Nzila

Mberu

Bray

et al. 2003

Antimicrob Agents Chemother

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Resistance to drugs can result from changes in drug transport, and this resistance can sometimes be overcome by a second drug that modifies the transport mechanisms of the cell. This strategy has been exploited to partly reverse resistance to chloroquine in Plasmodium falciparum. Studies with human tumor cells have shown that probenecid can reverse resistance to the antifolate methotrexate, but the potential for reversal of antifolate resistance has not been studied in P. falciparum. In the present study we tested the ability of probenecid to reverse antifolate resistance in P. falciparum in vitro. Probenecid, at concentrations that had no effect on parasite viability alone (50 M), was shown to increase the sensitivity of a highly resistant parasite isolate to the antifolates pyrimethamine, sulfadoxine, chlorcycloguanil, and dapsone by seven-, five-, three-, and threefold, respectively. The equivalent effects against an antifolate-sensitive isolate were activity enhancements of approximately 3-, 6-, 1.2-, and 19-fold, respectively. Probenecid decreased the level of uptake of radiolabeled folic acid, suggesting a transport-based mechanism linked to folate salvage. When probenecid was tested with chloroquine, it chemosensitized the resistant isolate to chloroquine (i.e., enhanced the activity of chloroquine). This enhancement of activity was associated with increased levels of chloroquine accumulation. In conclusion, we have shown that probenecid can chemosensitize malaria parasites to antifolate compounds via a mechanism linked to reduced folate uptake. Notably, this effect is observed in both folate-sensitive and -resistant parasites. In contrast to the activities of antifolate compounds, the effect of probenecid on chloroquine sensitivity was selective for chloroquine-resistant parasites (patent P407595GB [W. P. Thompson & Co., Liverpool, United Kingdom] has been filed to protect this intellectual property).

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“…Test organisms were maintained and tested in culture medium (RPMI medium 1640, containing 25 mM HEPES [N-2-hydroxyethylpiperazine-NЈ-2-ethanesulfonic acid], 25 mM bicarbonate, 10% normal pooled human serum, and physiological concentrations of p-aminobenzoic acid and folic acid) by methods previously reported (10,11,30,41). Fifty percent inhibitory concentrations (IC 50 s) were determined by radioisotope uptake (10).…”

Section: Methodsmentioning

confidence: 99%

In vitro activities of novel antifolate drug combinations against Plasmodium falciparum and human granulocyte CFUs

Winstanley

Mberu

Szwandt

et al. 1995

Antimicrob Agents Chemother

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The potency of antimalarial dihydrofolate reductase inhibitors, alone and in synergistic combination with dihydropteroate synthetase inhibitors, against the Kenyan K39 strain of Plasmodium falciparum (pyrimethamine resistant) and against normal replicating human bone marrow cells in in vitro culture has been studied. Therapeutic indices and rank order of synergistic potency were derived. Trimethoprim, pyrimethamine, and the quinazolines WR159412 and WR158122 had the smallest therapeutic indices (1.39, 4.38, 2.56, and 90.0, respectively), while the three triazines clociguanil, WR99210, and chlorcycloguanil had the largest (3,562, 3,000, and 2,000, respectively). In rank order of decreasing activity against P. falciparum, the six most potent drug combinations were WR99210-dapsone, chlorcycloguanil-dapsone, WR158122-dapsone, WR159412-dapsone, WR159412-sulfamethoxazole, and chlorcycloguanil-sulfamethoxazole; pyrimethaminesulfadoxine was the least potent combination. These experiments form a basis for the selection of rapidly eliminated antifolate combinations for further clinical testing.

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Antagonism of sulfadoxine and pyrimethamine antimalarial activity in vitro by p-aminobenzoic acid, p-aminobenzoylglutamic acid and folic acid

Cited by 67 publications

References 8 publications

The antimalarial triazine WR99210 and the prodrug PS-15: folate reversal of in vitro activity against Plasmodium falciparum and a non-antifolate mode of action of the prodrug.

The antimalarial triazine WR99210 and the prodrug PS-15: folate reversal of in vitro activity against Plasmodium falciparum and a non-antifolate mode of action of the prodrug.

Chemosensitization of Plasmodium falciparum by Probenecid In Vitro

In vitro activities of novel antifolate drug combinations against Plasmodium falciparum and human granulocyte CFUs

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