Chacon M O, Fonseca T H S, Oliveira S B V, Alacoque M A, Franco L L, Tagliati C A, Cassali G D, Campos-Mota G P, Alves R J, Capettini L S A, Gomes Maria Aparecida
Department of Parasitology, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
Department of Pharmaceutical Products, Faculdade de Farmárcia, UFMG, Belo Horizonte, MG, Brazil.
Parasitol Res. 2018 May;117(5):1333-1340. doi: 10.1007/s00436-018-5813-y. Epub 2018 Mar 3.
Trichomoniasis is the most common non-viral, sexually transmitted infection affecting humans worldwide. The main treatment for trichomoniasis is metronidazole (MTZ). However, adverse effects and reports of resistance have stimulated the development of therapeutic alternatives. The ease of manipulation of the side chains of MTZ coupled with its safety makes this molecule attractive for the development of new drugs. In this context, we evaluated the activity of the chlorinated MTZ derivative, MTZ-Cl, on sensitive and resistant strains of Trichomonas vaginalis. MTZ-Cl presented a remarkable activity against both sensitive and resistant strains. In vitro and in vivo toxicity assays indicated that the new molecule is safe for future clinical trials. Furthermore, we noticed different rates of free radical production between the sensitive and resistant strains. MTZ-Cl induced a higher release of nitric oxide (NO, ~ 9000 a.u.) by both sensitive and resistant strains. However, the sensitive strain produced a greater amount of HO (~ 1,800,000 a.u.) and superoxide radicals (~ 350,000 a.u.) in the presence of MTZ. In the resistant strain, production of these radicals was more prominent when MTZ-Cl was used. Collectively, these results suggest that NO is an important molecule in the trichomonacidal activity against resistant and sensitive strains, suggesting an alternative pathway for MTZ-Cl activation. We highlight the high trichomonacidal potential of MTZ-Cl, improving the effectiveness of treatment and reducing side effects. In addition, MTZ-Cl is derived from a well-established drug on the world market that presents low toxicity to human cells, suggesting its safety to proceed with future clinical trials.
滴虫病是全球影响人类的最常见的非病毒性性传播感染。滴虫病的主要治疗药物是甲硝唑（MTZ）。然而，不良反应和耐药性报告促使人们开发治疗替代品。MTZ侧链易于操作且具有安全性，这使得该分子对新药开发具有吸引力。在此背景下，我们评估了氯化MTZ衍生物MTZ-Cl对阴道毛滴虫敏感株和耐药株的活性。MTZ-Cl对敏感株和耐药株均表现出显著活性。体外和体内毒性试验表明，这种新分子对未来的临床试验是安全的。此外，我们注意到敏感株和耐药株之间自由基产生的速率不同。MTZ-Cl诱导敏感株和耐药株释放更高水平的一氧化氮（NO，约9000个任意单位）。然而，在MTZ存在的情况下，敏感株产生了更多的羟基自由基（约1800000个任意单位）和超氧自由基（约350000个任意单位）。在耐药株中，使用MTZ-Cl时这些自由基的产生更为显著。总体而言，这些结果表明NO是抗耐药株和敏感株滴虫活性中的重要分子，提示了MTZ-Cl激活的另一条途径。我们强调MTZ-Cl具有很高的杀滴虫潜力，可提高治疗效果并减少副作用。此外，MTZ-Cl源自一种在世界市场上已确立的药物，对人类细胞毒性低，表明其进行未来临床试验的安全性。
