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首页> 外文期刊>Parasitology >In vitro trichomonacidal activity and preliminary in silico chemometric studies of 5-nitroindazolin-3-one and 3-alkoxy-5-nitroindazole derivatives
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In vitro trichomonacidal activity and preliminary in silico chemometric studies of 5-nitroindazolin-3-one and 3-alkoxy-5-nitroindazole derivatives

机译：5-硝基吲哚并-3-一和3-烷氧基-5-硝基吲唑衍生物的体外毛滴虫酸活性和计算机化学初步研究

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A selection of 1,2-disubstituted 5-nitroindazolin-3-ones (1-19) and 3-alkoxy-5-nitroindazoles substituted at positions 1 (20-24) or 2 (25-39) from our in-house compound library were screened in vitro against the most common curable sexually transmitted pathogen, Trichomonas vaginalis. A total of 41% of the studied molecules (16/39) achieved a significant activity of more than 85% growth inhibition at the highest concentration assayed (100 mu g mL(-1)). Among these compounds, 3-alkoxy-5-nitroindazole derivatives 23, 24, 25 and 27 inhibited parasite growth by more than 50% at 10 mu g mL(-1). In addition, the first two compounds (23, 24) still showed remarkable activity at the lowest dose tested (1 mu g mL(-1)), inhibiting parasite growth by nearly 40%. Their specific activity towards the parasite was corroborated by the determination of their non-specific cytotoxicity against mammalian cells. The four mentioned compounds exhibited non-cytotoxic profiles at all of the concentrations assayed, showing a fair antiparasitic selectivity index (SI > 7.5). In silico studies were performed to predict pharmacokinetic properties, toxicity and drug-score using Molinspiration and OSIRIS computational tools. The current in vitro results supported by the virtual screening suggest 2-substituted and, especially, 1-substituted 3-alkoxy-5-nitroindazoles as promising starting scaffolds for further development of novel chemical compounds with the main aim of promoting highly selective trichomonacidal lead-like drugs with adequate pharmacokinetic and toxicological profiles.
机译：从我们的内部化合物中选择在位置1（20-24）或2（25-39）处取代的1,2-二取代的5-硝基吲唑啉-3-酮（1-19）和3-烷氧基-5-硝基吲唑针对最常见的可治愈的性传播病原体阴道毛滴虫，体外筛选文库。总共41％的研究分子（16/39）在最高测定浓度（100μg mL（-1））下实现了超过85％的显着抑制活性。在这些化合物中，3-烷氧基-5-硝基吲唑衍生物23、24、25和27在10μg mL（-1）时抑制寄生虫生长超过50％。此外，前两种化合物（23、24）在最低测试剂量（1μg mL（-1））下仍显示出显着的活性，将寄生虫的生长抑制了近40％。通过测定它们对哺乳动物细胞的非特异性细胞毒性，证实了它们对寄生虫的特异性活性。提到的四种化合物在所有测定的浓度下均表现出非细胞毒性，显示出良好的抗寄生虫选择性指数（SI> 7.5）。使用Molinspiration和OSIRIS计算工具进行了计算机模拟研究，以预测药代动力学特性，毒性和药物评分。虚拟筛选支持的当前体外结果表明，2-取代的，尤其是1-取代的3-烷氧基-5-硝基吲唑是有前途的原料，可以进一步开发新型化合物，其主要目的是促进高度选择性的滴虫酸铅-如具有足够药代动力学和毒理学特征的药物。

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