Souza Julia M, Vieira Tatiana M, Candido Ana Carolina B B, Tezuka Daiane Y, Rao G Subba, de Albuquerque Sérgio, Crotti Antônio E M, Siqueira-Neto Jair L, Magalhães Lizandra G
Research Group on Natural Products, Center for Research in Sciences and Technology, University of Franca, Avenida Dr. Armando Salles de Oliveira, 201, Franca, CEP 14404-600, SP, Brazil.
Department of Chemistry, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, CEP 14040-901, SP, Brazil.
Curr Res Parasitol Vector Borne Dis. 2021 May 31;1:100031. doi: 10.1016/j.crpvbd.2021.100031. eCollection 2021.
Chagas disease is a tropical disease caused by the protozoan parasite and currently affects millions of people worldwide. Curcumin (CUR), the major constituent of turmeric spice (dry powder of L. plant rhizomes and roots), exhibits antiparasitic activity against protozoan parasites . However, because of its chemical instability, poor cellular uptake and limited bioavailability it is not suitable for clinical use. The objective of this study was to synthesize and evaluate CUR monoketone analog dibenzalacetone (DBA ) and its non-phenolic, methoxy () and chloro () derivatives for better stability and bioavailability against . Diveratralacetone, the tetramethoxy DBA (DBA ), was found to be the CUR analog with most enhanced activity against the amastigote forms of four strains of tested (Brazil, CA-I/72, Sylvio X10/4 and Sylvio X10/7) with 50% inhibitory concentration (IC) < 10 μM (1.51-9.63 μM) and selectivity index (SI) > 10 (C2C12 non-infected mammalian cells). This was supplemented by time-course assessment of its anti- activity. DBA and its dimethoxy (DBA ) and hexamethoxy (DBA ) derivatives were substantially less active. The inactivity of dichloro-DBA (DBA ) was indicative of the important role played by oxygenated groups such as methoxy in the terminal aromatic rings in the DBA molecule, particularly at position to form reactive oxygen species essential for anti- activity. Although the DBAs and CUR were toxic to infected mammalian cells , in a mouse model, both DBA and CUR did not exhibit acute toxicity or mortality. These results justify further optimization and anti- activity evaluation of the inexpensive diveratralacetone for its potential use in treating Chagas disease, a neglected parasitic disease in economically challenged tropical countries.
恰加斯病是一种由原生动物寄生虫引起的热带疾病，目前全球有数百万人受其影响。姜黄素（CUR）是姜黄香料（姜黄属植物根茎和根的干粉）的主要成分，对原生动物寄生虫具有抗寄生虫活性。然而，由于其化学稳定性差、细胞摄取不良和生物利用度有限，它不适合临床使用。本研究的目的是合成并评估CUR单酮类似物二苯甲酰丙酮（DBA）及其非酚类、甲氧基（）和氯（）衍生物，以获得更好的稳定性和针对的生物利用度。发现四甲氧基DBA（DBA）即二藜芦基丙酮是对测试的四种菌株（巴西、CA-I/72、西尔维奥X10/4和西尔维奥X10/7）的无鞭毛体形式活性增强最多的CUR类似物，其50%抑制浓度（IC）<10μM（1.51 - 9.63μM），选择性指数（SI）>10（C2C12未感染哺乳动物细胞）。通过对其抗活性的时间进程评估对此进行了补充。DBA及其二甲氧基（DBA）和六甲氧基（DBA）衍生物的活性明显较低。二氯 - DBA（DBA）无活性表明DBA分子末端芳环中的甲氧基等含氧基团所起的重要作用，特别是在位置形成抗活性所必需的活性氧。尽管DBA和CUR对受感染的哺乳动物细胞有毒性，但在小鼠模型中，DBA和CUR均未表现出急性毒性或致死性。这些结果证明进一步优化和评估廉价的二藜芦基丙酮的抗活性是合理的，因为其有潜力用于治疗恰加斯病，这是经济困难的热带国家中一种被忽视的寄生虫病。
