Alcazar Wilmer, Alakurtti Sami, Padrón-Nieves Maritza, Tuononen Maija Liisa, Rodríguez Noris, Yli-Kauhaluoma Jari, Ponte-Sucre Alicia
Laboratory of Molecular Physiology, Institute of Experimental Medicine, School of Medicine Luis Razetti, Faculty of Medicine, Universidad Central de Venezuela, P.O. Box 50587, Caracas 1050, Venezuela.
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, P.O. Box 56, FI-00014 Helsinki, Finland.
Microorganisms. 2021 Feb 4;9(2):320. doi: 10.3390/microorganisms9020320.
Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of , isolated from patients with therapeutic failure.
We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, the activity of selected compounds was determined in intracellular amastigotes. Finally, to gain hints on their potential mechanism of action, the effect of the most promising compounds on plasma and mitochondrial membrane potential, and nitric oxide and superoxide production by infected macrophages was determined.
From the tested 28 compounds, those numbered and were chosen for additional studies. Both and were active (GI ≤ 2 µM, cytotoxic CC > 45 µM, SI > 20) for the reference strain LTB0016 and for patient isolates. The results suggest that significantly depolarized the plasma membrane potential ( < 0.05) and the mitochondrial membrane potential ( < 0.05) when compared to untreated cells. Although neither nor induced nitric oxide production in infected macrophages, induced superoxide production in infected macrophages.
Our results suggest that due to their efficacy and selectivity against intracellular parasites and the potential mechanisms underlying their leishmanicidal effect, the compounds and could be used as tools for designing new chemotherapies against leishmaniasis.
在此，我们在体外评估了桦木醇衍生物对从治疗失败患者中分离出的委内瑞拉利什曼原虫分离株的抗利什曼活性。
我们分析了前鞭毛体的体外敏感性以及所评估化合物的细胞毒性和选择性。此外，还测定了所选化合物在细胞内无鞭毛体中的活性。最后，为了了解其潜在的作用机制，测定了最有前景的化合物对血浆和线粒体膜电位以及感染巨噬细胞产生一氧化氮和超氧化物的影响。
从测试的28种化合物中，选择编号为 和 的化合物进行进一步研究。 和 对参考菌株LTB0016和患者分离株均有活性（GI≤2μM，细胞毒性CC>45μM，SI>20）。结果表明，与未处理的细胞相比， 使质膜电位（<0.05）和线粒体膜电位（<0.05）显著去极化。虽然 和 在感染的巨噬细胞中均未诱导一氧化氮的产生，但 在感染的巨噬细胞中诱导了超氧化物的产生。
我们的结果表明，由于化合物 和 对细胞内寄生虫的有效性和选择性以及其杀利什曼作用的潜在机制，它们可作为设计抗利什曼病新化疗药物的工具。
