The antimalarial activity of N-benzyl-oxydihydrotriazines

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Abstract
From a large series of chlorophenoxyalkoxy N-substituted triazines with antimalarial activity against Plasmodium berghei infections in mice, the 2,4,5-trichloropropyloxy-1,3,5-triazine hydrobromide (BRL 51084) and hydrochloride (BRL 6231) were selected. These two compounds were almost equally effective against both the drug-sensitive N strain and the cycloguanil- resistant B line. In four-day suppressive tests against the N strain, BRL 6231 had an ED90 of 0·34 mg kg−1 and against the B line an ED90 of 0·89 mg kg−1 when given subcutaneously for four days. A pyrimethamine-resistant line of P. berghei was found to be fully sensitive to BRL 6231 by the same dose route. A single subcutaneous dose of 100 mg kg−1 BRL 6231 completely cleared and eliminated an established infection of P. berghei N strain in mice, whereas similar infections in mice dosed at 100 mg kg−1 of cycloguanil or chloroquine recrudesced several days after initial clearance. Causal prophylaxis studies in mice showed that a single subcutaneous dose of 1 mg kg−1 before an intravenous sporozoite challenge of P. berghei gave complete protection. Similarly, ‘parallel’ studies with P. cynomolgi in pairs of rhesus monkeys demonstrated that ten subcutaneous doses of 1 mg kg−1 given daily prevented parasitaemia up to 69 days after challenge. Mode of action studies on BRL 6231 indicated that morphological effects upon an established infection of P. berghei N strain were similar to those seen with cycloguanil and pyrimethamine.