A Metabolite of ‘Paludrine’ with High Antimalarial Activity

Carrington, H. C.; Crowther, A. F.; Davey, D. G.; Levi, A. A.; Rose, F. L.

doi:10.1038/1681080a0

Cited by 136 publications

(54 citation statements)

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“…The conventional view is that proguanil is metabolically converted to the cyclic metabolite cycloguanil, a potent inhibitor of parasite dihydrofolate reductase (7). Thus, through the action of this cyclic metabolite, proguanil inhibits folate biosynthesis.…”

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confidence: 99%

Biguanide-Atovaquone Synergy against Plasmodium falciparum In Vitro

Jones

Ward

2002

Antimicrob Agents Chemother

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The synergistic potential of a range of biguanides, their triazine metabolites, tetracyclines, and pyrimethamine in combination with atovaquone has been assessed. All five biguanides tested interacted synergistically with atovaquone against Plasmodium falciparum in vitro. All of the other compounds tested were either additive or antagonistic.The antimalarial Malarone is a novel combination of the napthoquinone atovaquone plus the biguanide proguanil. This drug combination, which is highly active even against multidrug resistant parasites (14), has recently been introduced into clinical practice for the treatment and prophylaxis of falciparum malaria (9).Atovaquone was originally developed as an antimalarial monotherapy (2, 5, 18). As early as the 1940s it was recognized that the hydroxynaphthoquinones inhibited mitochondrial respiration (1, 24). Atovaquone and related compounds share structural similarities with ubiquinone or coenzyme Q. Subsequently, it was demonstrated that the drug can selectively inhibit the mitochondrial electron transport chain of protozoa through its action at the bc 1 complex (complex III) of the respiratory chain (12). The existence of a functional citric acid cycle in malaria parasites is controversial, and it was originally proposed that the mechanism of action of atovaquone was due to inhibition of pyrimidine biosynthesis at the level of dihydroorotate dehydrogenase, an enzyme requiring a functional electron transport chain (13). Recent studies have demonstrated that at therapeutically relevant drug concentrations, atovaquone results in the depolarization of malarial mitochondrial membranes. It is unclear if this is a primary drug effect or the consequence of a related action. However the loss of mitochondrial membrane potential will cause wide-ranging disruption of essential parasite processes, resulting in cellular damage and cell death (22).Despite this novel mechanism of action, initial clinical studies with atovaquone monotherapy resulted in unacceptable failure rates (8,15,16). Moreover, analysis of paired parasites from recrudescing infections demonstrated a Ͼ1,000-fold reduction in in vitro sensitivity compared to that of the parasites at the start of treatment (15). This rapid development and selection of resistance to atovaquone monotherapy prompted the search for a partner compound with the potential to reduce resistance selection. The result of this search was the identification of proguanil as a drug that interacted synergistically with atovaquone in vitro (6).The biguanide proguanil is a well-established antimalarial prodrug which has been in clinical use for more than 50 years. The conventional view is that proguanil is metabolically converted to the cyclic metabolite cycloguanil, a potent inhibitor of parasite dihydrofolate reductase (7). Thus, through the action of this cyclic metabolite, proguanil inhibits folate biosynthesis. Proguanil itself has very weak inherent antimalarial activity (several-thousandfold weaker than cycloguanil). It rapidly became apparent that...

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Biguanide-Atovaquone Synergy against Plasmodium falciparum In Vitro

Jones

Ward

2002

Antimicrob Agents Chemother

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“…10,580 (Carrington et al, 1951) NH2 (Curd, Davey, Hendry, and Rose, 1950) 10,732 (Carrington et al, 1951) NH2 N NH2 C C C C2H5 Pyrimethamine (Falco, Goodwin, Hitchings, Rollo, and Russell, 1951) Previous studies of the effects of antimalarial drugs on the erythrocytic stages of malaria parasites in vitro have been done using the rocker-dilution technique of Geiman, Anfinsen, McKee, Ormsbee, and Ball (1946) or a modified Bass and Johns method (e.g., Hawking, 1947). In the present work it was found convenient to use a method developed by my colleague, Dr. D. G. Davey.…”

Section: Nh2mentioning

confidence: 99%

“…One such active metabolite was isolated from the urine of proguanil-treated rabbits by Carrington, Crowther, Davey, Levi, and Rose (1951), and shown to be 2:4-diamino-1-pchlorophenyl-1: 6-dihydro-6: 6-dimethyl-1 : 3 : 5-triazine, which bears a marked structural resemblance to pyrimethamine (see formulae).…”

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The Mode of Action of Proguanil and Related Antimalarial Drugs

Ryley¹

1953

British Journal of Pharmacology and Chemotherapy

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“…This communication describes in greater detail the isolation and characterization of this metabolite as recorded in a preliminary note (Carrington, Crowther, Davey, Levi, and Rose, 1951).…”

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confidence: 99%