Cargnin Simone Tasca, Staudt Andressa Finkler, Medeiros Patrícia, de Medeiros Sol Sol Daniel, de Azevedo Dos Santos Ana Paula, Zanchi Fernando Berton, Gosmann Grace, Puyet Antonio, Garcia Teles Carolina Bioni, Gnoatto Simone Baggio
Laboratório de Fitoquímica e Síntese Orgânica, Faculdade de Fármacia, UFRGS, Porto Alegre, RS, Brazil.
Plataforma de Bioensaios de Malária e Leishmaniose, FIOCRUZ, Porto Velho, RO, Brazil.
Bioorg Med Chem Lett. 2018 Feb 1;28(3):265-272. doi: 10.1016/j.bmcl.2017.12.060. Epub 2017 Dec 29.
In this report, we describe the semisynthesis of two series of ursolic and betulinic acid derivatives through designed by modifications at the C-3 and C-28 positions and demonstrate their antimalarial activity against chloroquine-resistant P. falciparum (W2 strain). Structural modifications at C-3 were more advantageous to antimalarial activity than simultaneous modifications at C-3 and C-28 positions. The ester derivative, 3β-butanoyl betulinic acid (7b), was the most active compound (IC = 3.4 µM) and it did not exhibit cytotoxicity against VERO nor HepG2 cells (CC > 400 µM), showing selectivity towards parasites (selectivity index > 117.47). In combination with artemisinin, compound 7b showed an additive effect (CI = 1.14). While docking analysis showed a possible interaction of 7b with the Plasmodium protease PfSUB1, with an optimum binding affinity of -7.02 kcal/mol, the rather low inhibition displayed on a Bacillus licheniformis subtilisin A protease activity assay (IC = 93 µM) and the observed accumulation of ring forms together with a delay of appearance of trophozoites in vitro suggests that the main target of 3β-butanoyl betulinic acid on Plasmodium may be related to other molecules and processes pertaining to the ring stage. Therefore, compound 7b is the most promising compound for further studies on antimalarial chemotherapy. The results obtained in this study provide suitable information about scaffolds to develop novel antimalarials from natural sources.
在本报告中，我们描述了通过对乌索酸和桦木酸的C-3和C-28位进行修饰设计而半合成的两个系列衍生物，并展示了它们对氯喹耐药恶性疟原虫（W2株）的抗疟活性。C-3位的结构修饰比C-3和C-28位同时修饰对抗疟活性更有利。酯衍生物3β-丁酰桦木酸（7b）是活性最高的化合物（IC₅₀ = 3.4 μM），对VERO细胞和HepG2细胞均无细胞毒性（CC₅₀ > 400 μM），显示出对寄生虫的选择性（选择性指数 > 117.47）。与青蒿素联合使用时，化合物7b显示出相加作用（CI = 1.14）。虽然对接分析表明7b与疟原虫蛋白酶PfSUB1可能存在相互作用，最佳结合亲和力为-7.02 kcal/mol，但在地衣芽孢杆菌枯草杆菌蛋白酶A活性测定中显示出相当低的抑制作用（IC₅₀ = 93 μM），并且在体外观察到环状体的积累以及滋养体出现的延迟表明，3β-丁酰桦木酸对疟原虫的主要靶点可能与环状体阶段的其他分子和过程有关。因此，化合物7b是进一步进行抗疟化疗研究最有前景的化合物。本研究获得的结果为从天然来源开发新型抗疟药物提供了有关骨架的合适信息。
