Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, México.
Cátedra CONACyT, Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados del IPN, Unidad Mérida, Yucatán 97310, México.
Molecules. 2020 Feb 12;25(4):793. doi: 10.3390/molecules25040793.
We prepared a series of 10 carbamates derivatives based on two common antiprotozoal drugs: metronidazole (-) and secnidazole (-). The compounds were tested in vitro against a set of two amitochondriate protozoa: and . 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 (IC = 460 nM) and T. vaginalis (IC = 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 µM. Molecular dynamics of compounds 1-10, secnidazole, and metronidazole onto the ligand binding site of pyruvate-ferredoxin oxidoreductase of T. vaginalis and the modeled -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.
甲硝唑（-）和塞克硝唑（-）的 10 种氨基甲酸酯衍生物。这些化合物在体外对两组无线粒体原生动物进行了测试：和。化合物 1-10 表现出很强的抗原生动物活性，其效力值在低微摩尔至纳摩尔范围内，比它们的母体药物更有效。甲硝唑氨基甲酸酯（1）是该系列中最活跃的化合物，对十二指肠贾第鞭毛虫（IC = 460 nM）和阴道毛滴虫（IC = 60 nM）具有纳摩尔活性。化合物 1 的效力比甲硝唑对这两种寄生虫的效力高 10 倍。在 100 μM 下，没有一种化合物对 VERO 细胞显示出体外细胞毒性。化合物 1-10、塞克硝唑和甲硝唑在阴道毛滴虫的丙酮酸-ferredoxin 氧化还原酶的配体结合位点和十二指肠贾第鞭毛虫的建模 - 微管蛋白上的分子动力学揭示了与两种蛋白质的结合位点中的关键残基的可能分子相互作用，这些残基涉及母体药物的作用模式。
