Arrousse Nadia, Berdimurodov Elyor, Bogacheva Mariia, Zakham Fathiah, Esslali Soukaina, El Kadiri Sghir, Taleb Mustapha, Vapalahti Olli
School of Science and Engineering, Al Akhawayn University in Ifrane, Hassan II avenue, 53000 Ifrane, Morocco.
Laboratory of Engineering, Electrochemistry, Modelling and Environment (LIEME), Faculty of Sciences, University Sidi Mohamed Ben Abdellah, Fez, Morocco.
Heliyon. 2024 Sep 27;10(19):e38587. doi: 10.1016/j.heliyon.2024.e38587. eCollection 2024 Oct 15.
The threat of emerging viral outbreaks has increased the need for fast and effective development of therapeutics against emerging pathogens. One approach is to modify the structure of existing therapeutic agents to achieve the desired antiviral properties. Here, we attempted to synthesize a new antiviral compound by modifying the structure of chloroquine using the of the primary amine (N1,N1-diethylpentane-1,4-diamine) that is used in chloroquine synthesis. Chloroquine is commonly used to treat malaria. Like chloroquine, chloroquine is used for treating conditions such as rheumatoid arthritis, lupus, and malaria. For instance, in malaria treatment, it targets and inhibits the growth of the malaria parasite, aiding in its elimination from the body. The synthesized compounds MP1, C1, and TT1 were further tested in vitro against the B.1 lineage of SARS-CoV-2. One of the compounds, MP1, demonstrated minor effectiveness, with an IC50 of XX at only a high concentration (at a concentration of 60 μM) and decreased both the number of SARS-CoV-2 copies and the amount of infectious virus. Although the synthesized compounds failed to markedly inhibit SARS-CoV-2, this could be a pontial mechanism for manipulating the drug structure against other pathogens. MP1, TT1, C1, and chloroquine diphosphate were used as ligands for molecular docking to determine the principal interactions between these compounds and the active site of the protein downloaded from the Protein Data Bank (PDB ID: 6lzg). Finally, ADMET assays were performed on the synthesized compounds to determine their pharmacokinetics and bioavailability.
新出现的病毒爆发的威胁增加了快速有效地开发针对新出现病原体的治疗方法的需求。一种方法是改变现有治疗剂的结构以获得所需的抗病毒特性。在此，我们尝试通过使用氯喹合成中使用的伯胺（N1，N1-二乙基戊烷-1,4-二胺）来修饰氯喹的结构，从而合成一种新的抗病毒化合物。氯喹常用于治疗疟疾。与氯喹一样，氯喹也用于治疗类风湿性关节炎、狼疮和疟疾等病症。例如，在疟疾治疗中，它靶向并抑制疟原虫的生长，有助于将其从体内清除。合成的化合物MP1、C1和TT1在体外针对SARS-CoV-2的B.1谱系进一步进行了测试。其中一种化合物MP1显示出轻微的有效性，仅在高浓度（60μM浓度）下IC50为XX，并且减少了SARS-CoV-2的拷贝数和感染性病毒的量。尽管合成的化合物未能显著抑制SARS-CoV-2，但这可能是一种针对其他病原体操纵药物结构的潜在机制。MP1、TT1、C1和磷酸氯喹用作分子对接的配体，以确定这些化合物与从蛋白质数据库（PDB ID：6lzg）下载的蛋白质的活性位点之间的主要相互作用。最后，对合成的化合物进行了ADMET分析，以确定它们的药代动力学和生物利用度。
