Abstract
Methotrexate resistance induced in cultured Plasmodium falciparum depends on an altered dihydrofolate reductase with decreased affinity for methotrexate as well as for pyrimethamine. In contrast, pyrimethamine-resistant field isolates of P. falciparum lack cross-resistance to methotrexate and 2,4-diamino-5-(substituted benzyl) pyrimidines. The structure of the latter class was optimized by the use of trimethoprim as a lead and the substitution of methoxy groups at the benzyl ring by 3-(4'-aminophenyl-4-sulfonylphenylamino)propoxy or by (4'-aminophenyl-4-sulfonylphenyl)methoxy, which resulted in antimalarials of high potency. The efficiency of these newly designed 2,4-diamino-5-(substituted benzyl) pyrimidines was confirmed by their strong inhibitory effect on plasmodial dihydrofolate reductase as well as by in vitro screening against drug-sensitive and -resistant strains of P. falciparum.
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