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Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors

Journal Article · · Molecules
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  1. Purdue Univ., West Lafayette, IN (United States)
  2. Kumamoto University (Japan); National Center for Global Health and Medicine Research Institute (Japan)
  3. Kumamoto University (Japan); National Center for Global Health and Medicine Research Institute (Japan); National Cancer Institute, Bethesda, MD (United States)
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC); National Institutes of Health (NIH); National Center for Global Health and Medicine; Japan Agency for Medical Research and Development (AMED)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1983127
Journal Information:
Molecules, Journal Name: Molecules Journal Issue: 19 Vol. 26; ISSN 1420-3049
Publisher:
MDPICopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

3CLpro inhibitors
59 BASIC BIOLOGICAL SCIENCES
COVID-19
SARS-CoV-2
antiviral activity
covalent inhibitors
ibuprofen derivative
indomethacin derivative
salicylic acid derivative