Antimalarial Activity of some Kaurenes

摘要

The antimalarial activity of sixteen ent-kaurenes was assayed on male albino mice infected with Plasmodium berghei. Ent-kaur-16-en-19-oic acid (kaurenic acid), 15 alpha-hydroxy- ent-kaur-16-en-19-oic acid, 15 alpha-acetoxy-ent-kaur-16-en-19-oic acid, and ent-kaur-9(11)16-en-19-oic acid, natural kaurenes isolated from two species of Espelletiinae, were modified by semisynthesis to obtain methyl esters, glucopyranosyl esters, epoxides, 17-hydroxy, and isokaurenes (compounds with a 15,16-double bond). The kaurenes were first submitted to an in vitro test to measure their capacity to inhibit the formation of beta-hematin. Compared with chloroquine (95.7), the best effect was shown by 16,17-epoxy-ent-kauran-19-oic acid alpha-D- glucopyranosyl ester (2a), which produced 92.6 inhibition. Three other kaurenes showed good inhibition levels: ent-kaur-16-en-19-oic acid (1a, 73.5), 17-hydroxy- ent-kaur-15-en-19-oic acid methyl ester (3b, 76.5), and 15-oxo-16,17-epoxy-ent-kaur-16-en-19-oic acid alpha-D-glucopyranosyl ester (4b,76.1). These four compounds were assayed in a four day suppressive test in vivo (Peters' test) using chloroquine as a positive control. Two hours after infection the mice received the first treatment and then every 24 hours during four consecutive days. Blood smears from the tails were prepared on the fourth day and parasitemia was determined microscopically. Survivals were followed up to the 30(th) day post-infection, Once again compound 2a performed best, showing 4.5 of parasitemia on the fourth day post-infection (chloroquine 0.2) and a survival time of 25.5 days (chloroquine 29.5 days; 1a 18.8 days, 4b 12.7 days and 3b 10.3 days). A comparative examination of the effect of all compounds on the in vitro test permitted the inference that the presence of a C-19 carboxylic moiety was a requirement for the antimalarial activity and that a 16,17 epoxy group enhanced such activity.