Abstract

Resistance developed to the majority of drugs used to treat infectious diseases warrants the design of new compounds effective against drug-resistant strains of pathogens. Recently, several groups of modified nucleosides have been synthesized and showed significant antibacterial activity in vitro, but their further studies were difficult to undertake because of their low solubility in aqueous solutions. Nevertheless, new compounds, well soluble in water-organic solutions, were synthesized and found to be more effective in inhibiting the growth of Gram-positive bacteria and mycobacteria. The water-soluble forms of modified nucleosides under study were assumed to be their depot forms. To check the assumption, the compounds were tested for hydrolysis in various media and their molecular docking was performed into the active center of the putative target, Mycobacterium tuberculosis flavin-dependent thymidylate synthase ThyX. Computer modelling showed that the water-soluble analogs do not act as ThyX inhibitors, supporting the assumption of their depot nature. The compounds were resistant to chemical hydrolysis but were hydrolyzed when incubated with porcine liver carboxylesterase, human serum, or Staphylococcus aureus 209P. The results demonstrate that the compounds are most likely depot forms of modified nucleosides.

中文翻译：

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4-和/或5-修饰的核苷的乙二醇和磷酸盐储库形式，具有抗菌活性

摘要

对大多数用于治疗传染病的药物产生的抗药性保证了可以有效对抗病原体抗药性菌株的新化合物的设计。最近，已经合成了几组修饰的核苷，它们在体外显示出显着的抗菌活性，但是由于它们在水溶液中的溶解度低，因此难以进行进一步的研究。然而，合成了在水-有机溶液中易溶的新化合物，发现它们在抑制革兰氏阳性细菌和分枝杆菌的生长方面更有效。所研究的修饰核苷的水溶性形式被认为是它们的贮库形式。为了检查假设，结核分枝杆菌黄素依赖性胸苷酸合酶ThyX。计算机模型表明，水溶性类似物不充当ThyX抑制剂，支持其贮库性质的假设。这些化合物对化学水解具有抗性，但在与猪肝羧酸酯酶，人血清或金黄色葡萄球菌209P孵育后会水解。结果表明该化合物最有可能是修饰核苷的贮库形式。