The antimalarial activity of N-benzyloxydihydrotriazines

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Abstract
A series of N-benzyloxydihydrotriazines were prepared and found to have antimalarial activity against Plasmodium berghei infections in mice. One of the most active of these compounds. 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3,4 dichlorobenzyloxy)-1,3,5-triazine hydrochloride (clociguanil; BRL 50216) was selected for further evaluation. In the four day suppressive test against P. berghei in mice the ED50 of clociguanil was 0·16mg/kg and the ED90 was 0·39 mg/kg when given by the subcutaneous route. This is approximately 30 times more active than cycloguanil and ten times more active than chloroquine when compared in the same test system. In therapeutic experiments a single dose of 100 mg/kg clociguanil given by the oral or subcutaneous route completely cleared an established infection of P. berghei 72 hours after dosing. The acute LD50 in mice by the subcutaneous route was shown to be greater than 2·5 g/kg. Mode of action studies indicated that clociguanil is a dihydrofolate reductase inhibitor of Plasmodium and is capable of marked potentiation with a selected sulphonamide against both the sensitive N strain and the cycloguanil-resistant B line of P. berghei. The reasons why clociguanil has not been further developed for clinical use are discussed.

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