{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T21:58:12Z","timestamp":1770328692738,"version":"3.49.0"},"reference-count":43,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,24]],"date-time":"2021-09-24T00:00:00Z","timestamp":1632441600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI158649"],"award-info":[{"award-number":["AI158649"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI150466"],"award-info":[{"award-number":["AI150466"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HHSN272201700060C"],"award-info":[{"award-number":["HHSN272201700060C"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 \u00b5M. However, it exhibited a potent antiviral EC50 value of 24 \u00b5M in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 value of 2.4 \u00b5M 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.<\/jats:p>","DOI":"10.3390\/molecules26195782","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T21:40:30Z","timestamp":1632778830000},"page":"5782","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2472-1841","authenticated-orcid":false,"given":"Arun K.","family":"Ghosh","sequence":"first","affiliation":[{"name":"Department of Chemistry; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana","family":"Shahabi","sequence":"additional","affiliation":[{"name":"Department of Chemistry; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3772-2317","authenticated-orcid":false,"given":"Monika","family":"Yadav","sequence":"additional","affiliation":[{"name":"Department of Chemistry; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satish","family":"Kovela","sequence":"additional","affiliation":[{"name":"Department of Chemistry; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2670-974X","authenticated-orcid":false,"given":"Brandon J.","family":"Anson","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma K.","family":"Lendy","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Connie","family":"Bonham","sequence":"additional","affiliation":[{"name":"Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devika","family":"Sirohi","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos A.","family":"Brito-Sierra","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5637-3397","authenticated-orcid":false,"given":"Shin-ichiro","family":"Hattori","sequence":"additional","affiliation":[{"name":"Departments of Hematology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan"},{"name":"Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo 162-8655, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroaki","family":"Mitsuya","sequence":"additional","affiliation":[{"name":"Departments of Hematology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan"},{"name":"Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo 162-8655, Japan"},{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew D.","family":"Mesecar","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/S0140-6736(20)30185-9","article-title":"A novel coronavirus outbreak of global health concern","volume":"395","author":"Wang","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-020-2012-7","article-title":"A pneumonia outbreak associated with a new coronavirus of probable bat origin","volume":"579","author":"Zhou","year":"2020","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1056\/NEJMoa2001316","article-title":"Early transmission dynamics in Wuhan, China, of novel coronavirus\u2013infected pneumonia","volume":"382","author":"Li","year":"2020","journal-title":"N. 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