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Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors
| Content Provider | MDPI |
|---|---|
| Author | Ghosh, Arun K. Shahabi, Dana Yadav, Monika Kovela, Satish Anson, Brandon J. Lendy, Emma K. Bonham, Connie Sirohi, Devika Brito-Sierra, Carlos A. Hattori, Shin-Ichiro Kuhn, Richard Mitsuya, Hiroaki Mesecar, Andrew D. |
| Copyright Year | 2021 |
| Description | 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$ ^{1}$H-NMR,$ ^{13}$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 $VeroE_{6}$ 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 $IC_{50}$ value of 160 nM. Compound 13b exhibited an enzyme $IC_{50}$ value of 4.9 µM. However, it exhibited a potent antiviral $EC_{50}$ value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral $EC_{50}$ 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. |
| Starting Page | 5782 |
| e-ISSN | 14203049 |
| DOI | 10.3390/molecules26195782 |
| Journal | Molecules |
| Issue Number | 19 |
| Volume Number | 26 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2021-09-24 |
| Access Restriction | Open |
| Subject Keyword | Molecules Medicinal Chemistry Indomethacin Derivative Antiviral Activity Covid-19 3clpro Inhibitors Covalent Inhibitors Ibuprofen Derivative Sars-cov-2 Salicylic Acid Derivative |
| Content Type | Text |
| Resource Type | Article |
