Department of Chemistry; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
Molecules. 2021 Sep 24;26(19):5782. doi: 10.3390/molecules26195782.
We report the design and synthesis of a series of new 5-chloropyridinyl esters of salicylic acid, ibuprofen, indomethacin, and related aromatic carboxylic acids for evaluation against SARS-CoV-2 3CL protease enzyme. These ester derivatives were synthesized using EDC in the presence of DMAP to provide various esters in good to excellent yields. Compounds are stable and purified by silica gel chromatography and characterized using H-NMR, C-NMR, and mass spectral analysis. These synthetic derivatives were evaluated in our in vitro SARS-CoV-2 3CLpro inhibition assay using authentic SARS-CoV-2 3CLpro enzyme. Compounds were also evaluated in our in vitro antiviral assay using quantitative VeroE cell-based assay with RNAqPCR. A number of compounds exhibited potent SARS-CoV-2 3CLpro inhibitory activity and antiviral activity. Compound was the most potent inhibitor, with an enzyme IC value of 160 nM. Compound exhibited an enzyme IC value of 4.9 µM. However, it exhibited a potent antiviral EC value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC value of 2.4 µM in the same assay. We assessed the mode of inhibition using mass spectral analysis which suggested the formation of a covalent bond with the enzyme. To obtain molecular insight, we have created a model of compound bound to SARS-CoV-2 3CLpro in the active site.
我们报告了一系列新的 5-氯吡啶基水杨酸、布洛芬、吲哚美辛和相关芳香羧酸酯的设计和合成，用于评估它们对 SARS-CoV-2 3CL 蛋白酶的抑制作用。这些酯衍生物是使用 EDC 在 DMAP 的存在下合成的，以提供各种酯，产率良好到优秀。化合物通过硅胶色谱法稳定和纯化，并通过 H-NMR、C-NMR 和质谱分析进行表征。这些合成衍生物在我们使用真实 SARS-CoV-2 3CLpro 酶的体外 SARS-CoV-2 3CLpro 抑制测定中进行了评估。化合物还在我们使用定量 VeroE 细胞基于 RNAqPCR 的体外抗病毒测定中进行了评估。许多化合物表现出很强的 SARS-CoV-2 3CLpro 抑制活性和抗病毒活性。化合物 是最有效的抑制剂，酶 IC 值为 160 nM。化合物 表现出酶 IC 值为 4.9 µM。然而，它在 VeroE6 细胞中表现出很强的抗病毒 EC 值为 24 µM。瑞德西韦，一种 RdRp 抑制剂，在相同的测定中表现出抗病毒 EC 值为 2.4 µM。我们使用质谱分析评估了抑制模式，这表明与酶形成了共价键。为了获得分子见解，我们已经在活性位点创建了化合物 与 SARS-CoV-2 3CLpro 结合的模型。
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