Silva-Silva João Victor, Moragas-Tellis Carla J, Chagas Maria S S, Souza Paulo Victor R, Moreira Davyson L, Hardoim Daiana J, Taniwaki Noemi N, Costa Vanessa F A, Bertho Alvaro L, Brondani Daniela, Zapp Eduardo, de Oliveira Aldo Sena, Calabrese Kátia S, Behrens Maria D, Almeida-Souza Fernando
Laboratory of Immunomodulation and Protozoology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil.
Laboratory of Natural Products for Public Health, Pharmaceutical Technology Institute, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil.
Pharmaceuticals (Basel). 2022 Mar 9;15(3):331. doi: 10.3390/ph15030331.
Carajurin is the main constituent of species with reported anti- activity. However, its mechanism of action has not been described. This study investigated the mechanisms of action of carajurin against promastigote forms of . Carajurin was effective against promastigotes with IC of 7.96 ± 1.23 μg.mL (26.4 µM), and the cytotoxic concentration for peritoneal macrophages was 258.2 ± 1.20 μg.mL (856.9 µM) after 24 h of treatment. Ultrastructural evaluation highlighted pronounced swelling of the kinetoplast with loss of electron-density in promastigotes induced by carajurin treatment. It was observed that carajurin leads to a decrease in the mitochondrial membrane potential ( = 0.0286), an increase in reactive oxygen species production ( = 0.0286), and cell death by late apoptosis ( = 0.0095) in parasites. Pretreatment with the antioxidant NAC prevented ROS production and significantly reduced carajurin-induced cell death. The electrochemical and density functional theory (DFT) data contributed to support the molecular mechanism of action of carajurin associated with the ROS generation, for which it is possible to observe a correlation between the LUMO energy and the electroactivity of carajurin in the presence of molecular oxygen. All these results suggest that carajurin targets the mitochondria in . In addition, when assessed for its drug-likeness, carajurin follows Lipinski''s rule of five, and the Ghose, Veber, Egan, and Muegge criteria.
卡拉朱林是具有抗活性报道的物种的主要成分。然而，其作用机制尚未得到描述。本研究调查了卡拉朱林对前鞭毛体形式的作用机制。卡拉朱林对前鞭毛体有效，IC50为7.96±1.23μg/mL（26.4μM），处理24小时后，对腹膜巨噬细胞的细胞毒性浓度为258.2±1.20μg/mL（856.9μM）。超微结构评估突出显示，卡拉朱林处理诱导的前鞭毛体中动质体明显肿胀，电子密度丧失。观察到卡拉朱林导致寄生虫线粒体膜电位降低（P = 0.0286）、活性氧产生增加（P = 0.0286）以及晚期凋亡导致的细胞死亡（P = 0.0095）。用抗氧化剂NAC预处理可阻止ROS产生，并显著降低卡拉朱林诱导的细胞死亡。电化学和密度泛函理论（DFT）数据有助于支持与ROS产生相关的卡拉朱林的分子作用机制，据此可以观察到在分子氧存在下卡拉朱林的最低未占分子轨道（LUMO）能量与电活性之间的相关性。所有这些结果表明，卡拉朱林靶向利什曼原虫中的线粒体。此外，在评估其类药性时，卡拉朱林符合Lipinski的五规则以及Ghose、Veber、Egan和Muegge标准。
