title: Pyrimethamin-resistant Plasmodium falciparum lack cross-resistance to methotrexate and 2,4-diamino-5-(substituted benzyl) pyrimidines.
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.
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine, Department of Biochemistry and Protozoology, Hamburg, Federal Republic of Germany.
authors.forename: R D
authors.initials: RD
authors.lastname: Walter
authors.forename: B
authors.initials: B
authors.lastname: Bergmann
authors.forename: M
authors.initials: M
authors.lastname: Kansy
authors.forename: M
authors.initials: M
authors.lastname: Wiese
authors.forename: J K
authors.initials: JK
authors.lastname: Seydel
mesh_terms: D000818:Animals; D004351:Drug Resistance; D005493:Folic Acid Antagonists; D008727:Methotrexate / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011739:Pyrimethamine / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D005493:Folic Acid Antagonists; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine; D008727:Methotrexate; D011739:Pyrimethamine