Laboratório de Síntese de Sistemas Heterocíclicos (LaSSH), Institute of Physics and Chemistry, Federal University of Itajubá, 1303 BPS Avenue, Pinheirinho, Itajubá-MG, 37500-903, Brazil.
Laboratório de Biologia Estrutural (LBE), Oswaldo Cruz Institute, Fiocruz, 4365 Brasil Avenue, Manguinhos, Rio de Janeiro-RJ, 21040-900, Brazil; Programa de Pós-graduação em Biologia Parasitária, Oswaldo Cruz Institute- Fiocruz, Brazil.
Bioorg Med Chem. 2024 Mar 15;102:117679. doi: 10.1016/j.bmc.2024.117679. Epub 2024 Mar 7.
Trichomoniasis, a prevalent sexually transmitted infection (STI) caused by the protozoan Trichomonas vaginalis, has gained increased significance globally. Its relevance has grown in recent years due to its association with a heightened risk of acquiring and transmitting the human immunodeficiency virus (HIV) and other STIs. In addition, many publications have revealed a potential link between trichomoniasis and certain cancers. Metronidazole (MTZ), a nitroimidazole compound developed over 50 years ago, remains the first-choice drug for treatment. However, reports of genotoxicity and side effects underscore the necessity for new compounds to address this pressing global health concern. In this study, we synthesized ten pyrazole-nitroimidazoles 1(a-j) and 4-nitro-1-(hydroxyethyl)-1H-imidazole 2, an analog of metronidazole (MTZ), and assessed their trichomonacidal and cytotoxic effects. All compounds 1(a-j) and 2 exhibited IC values ≤ 20 μM and ≤ 41 μM, after 24 h and 48 h, respectively. Compounds 1d (IC 5.3 μM), 1e (IC 4.8 μM), and 1i (IC 5.2 μM) exhibited potencies equivalent to MTZ (IC 4.9 μM), the reference drug, after 24 h. Notably, compound 1i showed high anti-trichomonas activity after 24 h (IC 5.2 μM) and 48 h (IC 2.1 μM). Additionally, all compounds demonstrated either non-cytotoxic to HeLa cells (CC > 100 μM) or low cytotoxicity (CC between 69 and 100 μM). These findings suggest that pyrazole-nitroimidazole derivatives represent a promising heterocyclic system, serving as a potential lead for further optimization in trichomoniasis chemotherapy.
滴虫病是一种由原生动物阴道毛滴虫引起的常见性传播感染（STI），在全球范围内受到越来越多的关注。近年来，由于其与人类免疫缺陷病毒（HIV）和其他性传播感染（STI）的传播风险增加有关，其相关性有所增加。此外，许多出版物揭示了滴虫病与某些癌症之间的潜在联系。甲硝唑（MTZ）是一种 50 多年前开发的硝基咪唑化合物，仍然是治疗的首选药物。然而，关于遗传毒性和副作用的报告强调了需要新的化合物来解决这一紧迫的全球健康问题。在这项研究中，我们合成了十个吡唑-硝基咪唑 1(a-j)和 4-硝基-1-(羟乙基)-1H-咪唑 2，这是甲硝唑（MTZ）的类似物，并评估了它们的杀滴虫和细胞毒性作用。所有化合物 1(a-j)和 2 在 24 小时和 48 小时后分别显示出 IC 值≤20μM 和≤41μM。化合物 1d（IC 5.3μM）、1e（IC 4.8μM）和 1i（IC 5.2μM）在 24 小时后表现出与 MTZ（IC 4.9μM）相当的效力，MTZ 是参考药物。值得注意的是，化合物 1i 在 24 小时（IC 5.2μM）和 48 小时（IC 2.1μM）后表现出高抗滴虫活性。此外，所有化合物对 HeLa 细胞均无细胞毒性（CC>100μM）或低细胞毒性（CC 在 69 至 100μM 之间）。这些发现表明，吡唑-硝基咪唑衍生物代表了一种有前途的杂环系统，可作为进一步优化滴虫病化学疗法的潜在先导化合物。
