Villasmil Thayded, Rojas Julio, Aparicioa Rosa, Gamboa Neira, Acosta Maria Eugenia, Rodrigues Juan, Usubillaga Alfredo
Nat Prod Commun. 2017 Feb;12(2):217-220.
The antirnalarial activity of sixteen ent-kaurenes was assayed on male albino mice infected with Plasmodium berghei. Ent-kaur-16-en-19-oic acid (kaurenic acid), l5iα-hydroxy- ent-kaur-16-en-19-oic acid, 15α-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 β-hematin. Compared with chloroquine (95.7%), the best effect was shown by 16,17-epoxy-ent-kauran-19-oic acid α-D- glucopyranosyl ester (2a), which produced 92.6% inhibition. Three other kaurenes showed good inhibition levels: ent-kaur- 16-en-I 9-oic acid (1a, 73.5%), 17-hydroxy- ent-kaur- I5-en-19-oic acid methyl ester (3b, 76.5%), and 15-oxo-16,17-epoxy-ent-kaur-16-en-19-oic acid (X-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 30th 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; la 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.
在感染伯氏疟原虫的雄性白化小鼠身上测定了16种对映-贝壳杉烯的抗疟活性。从两种埃斯佩莱蒂亚属植物中分离得到的天然贝壳杉烯——对映-贝壳杉-16-烯-19-酸（贝壳杉烯酸）、15α-羟基-对映-贝壳杉-16-烯-19-酸、15α-乙酰氧基-对映-贝壳杉-16-烯-19-酸和对映-贝壳杉-9(11)16-烯-19-酸，通过半合成进行修饰，以获得甲酯、吡喃葡萄糖基酯、环氧化物、17-羟基化合物和异贝壳杉烯（具有15,16-双键的化合物）。首先对贝壳杉烯进行体外试验，以测量它们抑制β-疟色素形成的能力。与氯喹（95.7%）相比，16,17-环氧-对映-贝壳杉烷-19-酸α-D-吡喃葡萄糖基酯（2a）显示出最佳效果，产生了92.6%的抑制率。其他三种贝壳杉烯也表现出良好的抑制水平：对映-贝壳杉-16-烯-19-酸（1a，73.5%）、17-羟基-对映-贝壳杉-15-烯-19-酸甲酯（3b，76.5%）和15-氧代-16,17-环氧-对映-贝壳杉-16-烯-19-酸（α-D-吡喃葡萄糖基酯（4b，76.1%）。以氯喹作为阳性对照，在体内进行了为期四天的抑制试验（彼得斯试验），对这四种化合物进行了测定。感染后两小时，小鼠接受首次治疗，然后在连续四天中每24小时给药一次。在第四天制备尾血涂片，并通过显微镜检查确定疟原虫血症。对感染后第30天的存活情况进行了跟踪。化合物2a再次表现最佳，在感染后第四天显示出4.5%的疟原虫血症（氯喹为0.2%），存活时间为25.5天（氯喹为29.5天；1a为18.8天，4b为12.7天，3b为10.3天）。对所有化合物在体外试验中的效果进行比较检查后可以推断，C-19羧基部分的存在是抗疟活性的必要条件，并且16,17-环氧基团可增强这种活性。
