PDF(Pubmed)
Abstract：
Nucleoside precursors and nucleoside analogs occupy an important place in the treatment of viral respiratory pathologies, especially during the current COVID-19 pandemic. From this perspective, the present study has been designed to explore and evaluate the synthesis and spectral characterisation of 5́-O-(lauroyl) thymidine analogs 2-6 with different aliphatic and aromatic groups through comprehensive in vitro antimicrobial screening, cytotoxicity assessment, physicochemical aspects, molecular docking and molecular dynamics analysis, along with pharmacokinetic prediction. A unimolar one-step lauroylation of thymidine under controlled conditions furnished the 5́-O-(lauroyl) thymidine and indicated the selectivity at C-5́ position and the development of thymidine based potential antimicrobial analogs, which were further converted into four newer 3́-O-(acyl)-5́-O-(lauroyl) thymidine analogs in reasonably good yields. The chemical structures of the newly synthesised analogs were ascertained by analysing their physicochemical, elemental, and spectroscopic data. In vitro antimicrobial tests against five bacteria and two fungi, along with the prediction of activity spectra for substances (PASS), indicated promising antibacterial functionality for these thymidine analogs compared to antifungal activity. In support of this observation, molecular docking experiments have been performed against the main protease of SARS-CoV-2, and significant binding affinities and non-bonding interactions were observed against the main protease (6LU7, 6Y84 and 7BQY), considering hydroxychloroquine (HCQ) as standard. Moreover, the 100 ns molecular dynamics simulation process was performed to monitor the behaviour of the complex structure formed by the main protease under in silico physiological conditions to examine its stability over time, and this revealed a stable conformation and binding pattern in a stimulating environment of thymidine analogs. Cytotoxicity determination confirmed that compounds were found less toxic. Pharmacokinetic predictions were investigated to evaluate their absorption, distribution, metabolism and toxic properties, and the combination of pharmacokinetic and drug-likeness predictions has shown promising results in silico. The POM analysis shows the presence of an antiviral (O1δ-, O2δ-) pharmacophore site. Overall, the current study should be of great help in the development of thymidine-based, novel, multiple drug-resistant antimicrobial and COVID-19 drugs.
摘要：
核苷前体和核苷类似物在病毒性呼吸道病变的治疗中占有重要地位，特别是在当前的COVID-19大流行期间。从这个角度来看,本研究旨在通过全面的体外抗菌筛选来探索和评估具有不同脂肪族和芳香族基团的5-O-（月桂酰）胸苷类似物2-6的合成和光谱表征，细胞毒性评估，物理化学方面，分子对接和分子动力学分析，以及药代动力学预测。在受控条件下对胸苷进行单摩尔的一步月桂基化提供了5^-O-（月桂酰）胸苷，并表明了C-5^位置的选择性以及基于胸苷的潜在抗微生物类似物的发展，以相当好的产率进一步转化为四个较新的3^-O-（酰基）-5^-O-（月桂酰）胸苷类似物。通过分析新合成的类似物的物理化学结构来确定它们的化学结构，元素，和光谱数据。对五种细菌和两种真菌的体外抗菌试验，随着物质活性谱(PASS)的预测，与抗真菌活性相比，这些胸苷类似物具有有希望的抗菌功能。为了支持这一观点，已经针对SARS-CoV-2的主要蛋白酶进行了分子对接实验，并且观察到针对主要蛋白酶（6LU7，6Y84和7BQY）的显着结合亲和力和非键合相互作用，考虑羟氯喹（HCQ）为标准。此外，进行了100ns分子动力学模拟过程，以监测由主要蛋白酶在硅生理条件下形成的复杂结构的行为，以检查其随时间的稳定性，这揭示了在胸苷类似物的刺激环境中稳定的构象和结合模式。细胞毒性测定证实发现化合物毒性较低。研究了药代动力学预测以评估其吸收，分布，新陈代谢和毒性，药代动力学和药物相似度预测的结合在计算机上显示了有希望的结果。POM分析显示存在抗病毒药物(O1δ-，O2δ-)药效基团位点。总的来说,目前的研究应该对基于胸苷的发展有很大的帮助，小说,多重耐药抗菌药物和COVID-19药物。
