[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 in Table) and 5-trifluoro-acetyl-6-methoxy-8-(4-trifluoroacetamido-1-methylbutyl )- aminoquinoline (compound 6), bis (trifluoroacetyl) primaquine, which was subsequently hydrolyzed to yield 5-trifluoroacetyl-6-methoxy-8-(4-amino-1-methylbutyl)-aminoquinoline (compound 11), 5-trifluoroacetyprimaquine or trifluoroacetoprimaquine, coded M8506. Similarly, compounds 1, 3-5 and 7-10 were also prepared. Among them, compound 11 appeared to be the most effective by evaluation in mice infected with sporozoites of Plamodium yoelii. With intragastrical dosage of 0.75 mg/kg/d x 3 d of compound 11 to monkeys infected with sporozoites of P. cynomolgi, the radical cure rate of the compound was 92.3%, while that of primaquine was 55.6%. The acute toxicity of compound 11 was two times a low as that of primaquine in mice. The compound did not appear to have mutagenicity, embryotoxicity and chromosomal aberration. 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 in histopathological examination at the two lower doses. However, reversible changes were observed at the highest dose. Compound 11, trifluoroacetoprimaquine, was shown to be a promising tissue schizonticide of malaria parasite.