Metronidazole and Secnidazole Carbamates: Synthesis, Antiprotozoal Activity, and Molecular Dynamics Studies
Metronidazole and Secnidazole Carbamates: Synthesis, Antiprotozoal Activity, and Molecular Dynamics Studies
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DOI：
10.3390/molecules25040793
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发表时间：
2020-02-02
期刊：
影响因子：
4.6
通讯作者：
Navarrete-Vazquez, Gabriel
中科院分区：
文献类型：
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作者：
Rocha-Garduno, Genaro;Angelica Hernandez-Martinez, Norma;Navarrete-Vazquez, Gabriel
我们以两种常见的抗原虫药物甲硝唑(1-5)和塞克硝唑(6-10)为原料，合成了10个氨基甲酸酯类化合物。这些化合物在体外对两种非线粒体原虫：十二指肠贾第虫和阴道毛滴虫进行了测试。化合物1-10表现出很强的抗原虫活性，效价在微摩尔到纳摩尔的低范围内，比它们的母体药物更有活性。甲硝唑氨基甲酸酯(1)对十二指肠球虫(IC50=460 nM)和阴道毛滴虫(IC50=60 nM)的纳摩尔活性最强。化合物1对这两种寄生虫的抑制力是甲硝唑的10倍。化合物1-10、塞克硝唑和甲硝唑在阴道毛滴虫丙酮酸铁氧还蛋白氧化还原酶的配基结合部位和模拟的十二指肠球虫3-微管蛋白上的分子动力学表明，与母体药物作用模式有关的两种蛋白质结合部位的关键残基可能存在分子相互作用。
We prepared a series of 10 carbamates derivatives based on two common antiprotozoal drugs: metronidazole (1-5) and secnidazole (6-10). The compounds were tested in vitro against a set of two amitochondriate protozoa: Giardia duodenalis and Trichomonas vaginalis. Compounds 1-10 showed strong antiprotozoal activities, with potency values in the low micromolar-to-nanomolar range, being more active than their parent drugs. Metronidazole carbamate (1) was the most active of the series, with nanomolar activities against G. duodenalis (IC50 = 460 nM) and T. vaginalis (IC50 = 60 nM). The potency of compound 1 was 10 times greater than that of metronidazole against both parasites. None of compounds showed in vitro cytotoxicity against VERO cells tested at 100 p.M. Molecular dynamics of compounds 1-10, secnidazole, and metronidazole onto the ligand binding site of pyruvate ferredoxin oxidoreductase of T. vaginalis and the modeled (3-tubulin of G. duodenalis revealed putative molecular interactions with key residues in the binding site of both proteins implicated in the mode of action of the parent drugs.