Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors.
Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors.
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DOI：
10.3390/molecules26195782
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发表时间：
2021-09-24
期刊：
影响因子：
--
通讯作者：
Mesecar AD
中科院分区：
文献类型：
--
作者：
Ghosh AK;Shahabi D;Yadav M;Kovela S;Anson BJ;Lendy EK;Bonham C;Sirohi D;Brito-Sierra CA;Hattori SI;Kuhn R;Mitsuya H;Mesecar AD
我们报道了一系列新的5-氯吡啶水杨酸酯、布洛芬、吲哚美辛和相关的芳香族羧酸的设计和合成，用于评价SARS-CoV-2 3CL蛋白酶的活性。这些酯衍生物是在DMAP存在下使用EDC合成的，以很好到很好的产率提供了各种酯。用硅胶层析法对化合物进行了纯化，并用1H-核磁共振、13C-核磁共振和质谱分析对化合物进行了表征。在我们的SARS-CoV-2 3CLPro体外抑制实验中，用真实的SARS-CoV-2 3CLPro酶对这些合成的衍生物进行了评价。化合物也在我们的体外抗病毒试验中进行了评估，使用基于RNAqPCR的VeroE6细胞定量试验。部分化合物具有较强的SARS-CoV-2 3CLPro抑制活性和抗病毒活性。化合物9a的抑制作用最强，其IC50值为160 nM。化合物13b的IC50值为4.9微米，但在VeroE6细胞中显示出24微米的有效抗病毒EC50值。在同一试验中，RdRp抑制剂Remdesivir的抗病毒EC50值为2.4µM。我们用质谱分析评估了抑制模式，这表明它与酶形成了共价键。为了获得分子洞察力，我们建立了化合物9a与SARS-CoV-2 3CLPro活性部位结合的模型。
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 1H-NMR, 13C-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 VeroE6 cell-based assay with RNAqPCR. A number of compounds exhibited potent SARS-CoV-2 3CLpro inhibitory activity and antiviral activity. Compound 9a was the most potent inhibitor, with an enzyme IC50 value of 160 nM. Compound 13b exhibited an enzyme IC50 value of 4.9 µM. However, it exhibited a potent antiviral EC50 value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 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 9a bound to SARS-CoV-2 3CLpro in the active site.
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影响因子：
158.5
作者：
Li, Qun;Guan, Xuhua;Feng, Zijian
通讯作者：
Feng, Zijian
影响因子：
--
作者：
Ghosh, Arun K.;Xi, Kai;Johnson, Michael E.;Baker, Susan C.;Mesecar, Andrew D.
通讯作者：
Mesecar, Andrew D.
影响因子：
5
作者：
Grum-Tokars, Valerie;Ratia, Kiira;Begaye, Adrian;Baker, Susan C.;Mesecar, Andrew D.
通讯作者：
Mesecar, Andrew D.
影响因子：
16.6
作者：
Hattori SI;Higashi-Kuwata N;Hayashi H;Allu SR;Raghavaiah J;Bulut H;Das D;Anson BJ;Lendy EK;Takamatsu Y;Takamune N;Kishimoto N;Murayama K;Hasegawa K;Li M;Davis DA;Kodama EN;Yarchoan R;Wlodawer A;Misumi S;Mesecar AD;Ghosh AK;Mitsuya H
通讯作者：
Mitsuya H
影响因子：
5.4
作者：
Deng, Xufang;Sarah, E. St. John;Baker, Susan C.
通讯作者：
Baker, Susan C.