Kocek Hugo, Chalupská Dominika, Dejmek Milan, Dvořáková Alexandra, Zgarbová Michala, Šála Michal, Chalupský Karel, Krafčíková Petra, Otava Tomáš, Drexler Matúš, Procházková Eliška, Klepetářová Blanka, Štefek Milan, Kozic Ján, Mertlíková-Kaiserová Helena, Boura Evzen, Weber Jan, Nencka Radim
Institute of Organic Chemistry, and Biochemistry of the Czech Academy of Sciences Prague Czech Republic
Faculty of Chemical Technology, University of Chemistry and Technology Prague Czech Republic.
RSC Med Chem. 2024 Aug 1;15(10):3469-76. doi: 10.1039/d4md00422a.
The emergence of SARS-CoV-2, the causative agent of COVID-19, has highlighted the need for advanced antiviral strategies. Targeting the coronaviral methyltransferase nsp14, which is essential for RNA capping, offers a promising approach for the development of small-molecule inhibitors. We designed and synthesized a series of adenosine 5'-carboxamide derivatives as potential nsp14 inhibitors and identified coumarin analogs to be particularly effective. Structural modifications revealed the importance of the 5'-carboxyl moiety for the inhibitory activity, showing superior efficacy compared to other modifications. Notably, compound 18l () demonstrated high selectivity and favorable pharmacokinetic properties and exhibited moderate antiviral activity in cell-based assays. These findings provide a robust foundation for developing targeted nsp14 inhibitors as a potential treatment for COVID-19 and related diseases.
导致 COVID-19 的严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的出现凸显了先进抗病毒策略的必要性。靶向对 RNA 加帽至关重要的冠状病毒甲基转移酶 nsp14，为小分子抑制剂的开发提供了一种有前景的方法。我们设计并合成了一系列腺苷 5'-羧酰胺衍生物作为潜在的 nsp14 抑制剂，并确定香豆素类似物特别有效。结构修饰揭示了 5'-羧基部分对抑制活性的重要性，与其他修饰相比显示出更高的效力。值得注意的是，化合物 18l（）表现出高选择性和良好的药代动力学性质，并在基于细胞的试验中表现出中等抗病毒活性。这些发现为开发靶向 nsp14 抑制剂作为 COVID-19 和相关疾病的潜在治疗方法提供了坚实的基础。
