STUDIES ON THE TISSUE SCHIZONTICIDE OF MALARIA PARASITE:SYNTHESIS OF 5-TRIELUOROACETYL PRIMAQUINE AND ITS DERIVATIVES

Primaquine was acylated with trifluoroacetic anhydride to give 6-methoxy-8-(4-trifluoroacetamido-1-methylbutyl) aminoquinoline (compound 2 inTable)and 5-trifluoro-acetyl-6-methoxy-8-(4-trifluoroacetamido-1-mehylbutyl)aminequinoline (compound 6), bis (trifluoroacetyl) primaquine, which was subsequentlyhydrolyzed to yield 5-trifluoroacetyl-6-methoxy-8-(4-amino-1-methylbutyl)aminoquinoline (compound 11),5-trifluoroacetyprimaquine or trifluoroacetoprima-quine, coded M8506. Similarly, compounds 1, 3～5 and 7～l0 were also prepared. Among them, compound 11 appeared to be the most effective by evaluation in miceinfected with sporozoites of Plamodium yoelii. With intragastrical dosage of 0.75 mg/kg/d×3 d of compound 11 to monkeys infected with sporozoites of P. cynomolgi, the radicalcure rate of the compound was 92.3%, while that of primaquine was 55.6%. The acute toxicity of compound 11 was two times as low as that of Primaquine in mice. The compound did not appear to have mutagenicity, embryotoxicity and chromosomalaberrtion. When rats received intragastrical doses of 15, 30 and 60 mg/kg/d of compound 11 for 14 and 28 consecutive days respectively, no change was found inhistopathological examination at the two lower doses. However, reversible changes wereobserved at the highest dose. Compound 11, trifluoroacetoprimaquine, was shownto be a promising tissue schizonticide of malaria parasite.