Abstract: Our previous studies indicated that 5-(p-fluorophenoxy)6-methoxy8-(4-amino-1-methylbutyl-amino)quinoline was 20 times less toxic to mice and somewhat less effective for radical cure of Plasmodium cynomolgi infection in monkeys when compared with primaquine. In addition, derivatives with a proper group introduced into the 2 position of primaquine exhibited significant tissue-schizonticidal activity in monkeys and thus resulted in the synthesis of a series of 2,5-bis-substituted phenoxy primaquine analogues.2, 5-Bis-substituted phenoxy primaquine derivatives were synthesized, starting from 6-methoxy-8-nitroquinoline. N-methylation, oxidation and chlorination of the starting material gave 2-chloro-6-methoxy-8-nitroquinoline, which through bromination gave the corresponding 5-bromo compound.The latter compound was then reacted with substituted phenols to yield 2,5-bis-substituted-phenoxy-6-methoxy-8-nitroquinolines (compounds 1～6, Table 1). These compounds were reduced by iron to form corresponding 8-aminoquinolines (compounds 7～12, Table 1), Compounds 7～12 by condensation with 4-bromo-1-phthalimidopentane in the presence of triethylamine gave 2,5-bis-substituted-phenoxy-8-(1-methyl-4-phthalimidobutyl-amino) quinolines (compounds 13～18, Table 2). They were subsequently hydrolyzed by hydrazine hydrate to form 2,5-bis-substituted-phenoxy-6-methoxy-8-(4-amino-1-methylbutylamino) quinolines (compounds 19～24, Table 2).Compounds 1,13 and 19 showed activity against the sporozoite-induced infection of P. yoelii in mice.