Sánchez Alberti Andrés, Beer María F, Cerny Natacha, Bivona Augusto E, Fabian Lucas, Morales Celina, Moglioni Albertina, Malchiodi Emilio L, Donadel Osvaldo J, Sülsen Valeria P
Instituto de Microbiología y Parasitología Médica (IMPaM), CONICET-Universidad de Buenos Aires, Paraguay 2155. Piso 13, 1121 Buenos Aires, Argentina.
Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 4°P, 1113 Buenos Aires, Argentina.
ACS Omega. 2021 Dec 20;7(1):968-978. doi: 10.1021/acsomega.1c05560. eCollection 2022 Jan 11.
The sesquiterpene lactones cumanin, helenalin, and hymenin and their semisynthetic derivatives were evaluated against epimastigotes. The cytotoxicity of the compounds was evaluated on murine splenocytes. Cumanin diacetate was one of the most active and selective compounds [IC = 3.20 ± 0.52 μg/mL, selectivity index (SI) = 26.0]. This sesquiterpene lactone was selected for its evaluation on trypomastigote and amastigote forms of the parasite. The diacetylated derivative of cumanin showed moderate activity on trypomastigotes (IC = 32.4 ± 5.8 μg/mL). However, this compound was able to efficiently inhibit parasite replication with an IC value of 2.2 ± 0.05 μg/mL against the amastigote forms. Cumanin diacetate showed selectivity against the intracellular forms of with an SI value of 52.7. This cumanin analogue was also active on an model of Chagas disease, leading to a reduction in the parasitemia levels in comparison with nontreated animals. Histopathological analysis of skeletal muscular tissues from treated mice showed only focal interstitial lymphocyte inflammatory infiltrates with slight myocyte necrosis; in contrast, nontreated animals showed severe lymphocyte inflammatory infiltrates with necrosis of the myocytes. A molecular docking study of cumanin and its derivatives on trypanothione reductase from (TcTR) was performed. The results of Δ docking achieved let the identification of diacetylated and -alkylated derivatives of cumanin as good inhibitors of TcTR. Cumanin diacetate could be considered a potential candidate for further studies for the development of new therapies against Chagas disease.
对倍半萜内酯类化合物库马宁、海伦内酯和膜边内酯及其半合成衍生物进行了抗无鞭毛体活性评估。在小鼠脾细胞上评估了这些化合物的细胞毒性。二乙酸库马宁是活性最强且最具选择性的化合物之一[IC = 3.20 ± 0.52 μg/mL，选择性指数（SI）= 26.0]。选择该倍半萜内酯对寄生虫的锥鞭毛体和无鞭毛体形式进行评估。库马宁的二乙酰化衍生物对锥鞭毛体表现出中等活性（IC = 32.4 ± 5.8 μg/mL）。然而，该化合物能够有效抑制寄生虫复制，对无鞭毛体形式的IC值为2.2 ± 0.05 μg/mL。二乙酸库马宁对细胞内形式表现出选择性，SI值为52.7。这种库马宁类似物在恰加斯病模型上也具有活性，与未治疗的动物相比，导致寄生虫血症水平降低。对治疗小鼠骨骼肌组织的组织病理学分析显示仅存在局灶性间质淋巴细胞炎性浸润，伴有轻微的肌细胞坏死；相比之下，未治疗的动物表现出严重的淋巴细胞炎性浸润和肌细胞坏死。对库马宁及其衍生物与克氏锥虫的锥虫硫醇还原酶（TcTR）进行了分子对接研究。对接结果表明库马宁的二乙酰化和 - 烷基化衍生物是TcTR的良好抑制剂。二乙酸库马宁可被视为进一步研究开发治疗恰加斯病新疗法的潜在候选药物。
