Abstract

Because of their superior antibacterial and pharmacokinetic capabilities, many nucleoside-based esters show potential against microorganisms, and may be used as pharmacological agents to address multidrug-resistant pathogenic problems. In this study, several aliphatic and aromatic groups were inserted to synthesize various 5′-O-decanoyluridine (2–5) and 5′-O-lauroyluridine derivatives (6–7) for antimicrobial, in silico computational, pharmacokinetic and POM (Petra/Osiris/Molinspiration). The chemical structures of the synthesized uridine derivatives were confirmed by physicochemical, elemental, and spectroscopic analyses. In vitro antimicrobial screening against five bacteria and two fungi, as well as the prediction of substance activity spectra (PASS), revealed that these uridine derivatives have promising antifungal properties when compared to the antibacterial activities. Density functional theory (DFT) was used to calculate the thermodynamic and physicochemical properties. Molecular docking was conducted against lanosterol 14a-demethylase CYP51A1 (3JUV) and Aspergillus flavus (1R4U) and revealed binding affinities and non-covalent interactions with the target. Then, a 150 ns molecular dynamic simulation was performed to confirm the behavior of the complex structure formed by microbial protein under in silico physiological conditions to examine its stability over time, which revealed a stable conformation and binding pattern in a stimulating environment of uridine derivatives. The acyl chain {CH₃(CH₂)₉CO-} and {CH₃(CH₂)₁₀CO-} in conjunction with sugar, was determined to have the most potent activity against bacterial and fungal pathogens in a structure-activity relationships (SAR) investigation. POM analyses were conducted with the presence of an antifungal (O ^δ− –- O’ ^δ−) pharmacophore site. Overall, the present study might be useful for the development of uridine-based novel multidrug-resistant antimicrobial.

摘要

由于其卓越的抗菌和药代动力学能力，许多基于核苷的酯显示出抗微生物的潜力，可用作解决多药耐药性致病问题的药物。在这项研究中，插入了几个脂肪族和芳香族基团来合成各种 5'- O-癸酰尿苷 ( 2-5 ) 和 5'- O-月桂酰尿苷衍生物 ( 6-7 )，用于抗菌、计算机计算、药代动力学和 POM (Petra /奥西里斯/莫林斯皮恩斯）。通过物理化学、元素和光谱分析证实了合成的尿苷衍生物的化学结构。体外针对五种细菌和两种真菌的抗菌筛选以及物质活性谱（PASS）的预测表明，与抗菌活性相比，这些尿苷衍生物具有良好的抗真菌特性。密度泛函理论（DFT）用于计算热力学和物理化学性质。对羊毛甾醇 14a-去甲基化酶 CYP51A1 (3JUV) 和黄曲霉(1R4U) 进行分子对接，并揭示了与靶标的结合亲和力和非共价相互作用。然后，进行了 150 ns 的分子动力学模拟，以确认微生物蛋白质在 silico下形成的复杂结构的行为。生理条件下检查其随时间的稳定性，这揭示了在尿苷衍生物的刺激环境中稳定的构象和结合​​模式。与糖结合的酰基链 {CH ₃ (CH ₂ ) ₉ CO-} 和 {CH ₃ (CH ₂ ) ₁₀ CO-} 被确定为在构效关系中对细菌和真菌病原体具有最有效的活性（特区）调查。POM 分析是在存在抗真菌剂 (O ^δ- –- O' ^δ- ) 药效团位点的情况下进行的。总体而言，本研究可能有助于开发基于尿苷的新型多药耐药抗菌剂。