Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors
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 provid...
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| Veröffentlicht in: | Molecules (Basel, Switzerland) Switzerland), 2021-09, Vol.26 (19), p.5782, Article 5782 |
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| creator | 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. |
| 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 H-1-NMR, C-13-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 IC50 value of 160 nM. Compound 13b exhibited an enzyme IC50 value of 4.9 mu M. However, it exhibited a potent antiviral EC50 value of 24 mu M in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 value of 2.4 mu M 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. |
| doi_str_mv | 10.3390/molecules26195782 |
| format | Article |
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Advanced Photon Source (APS)</creatorcontrib><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 H-1-NMR, C-13-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 IC50 value of 160 nM. Compound 13b exhibited an enzyme IC50 value of 4.9 mu M. However, it exhibited a potent antiviral EC50 value of 24 mu M in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 value of 2.4 mu M 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.</description><identifier>ISSN: 1420-3049</identifier><identifier>EISSN: 1420-3049</identifier><identifier>DOI: 10.3390/molecules26195782</identifier><identifier>PMID: 34641337</identifier><language>eng</language><publisher>BASEL: Mdpi</publisher><subject><![CDATA[3CLpro inhibitors ; Animals ; Anti-inflammatory agents ; Anti-Inflammatory Agents, Non-Steroidal - chemistry ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Antiviral activity ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Assaying ; BASIC BIOLOGICAL SCIENCES ; Binding sites ; Biochemistry & Molecular Biology ; Carboxylic acids ; Chemistry ; Chemistry, Multidisciplinary ; Chlorocebus aethiops ; Coronavirus 3C Proteases - antagonists & inhibitors ; Coronavirus 3C Proteases - metabolism ; Coronaviruses ; Covalent bonds ; covalent inhibitors ; COVID-19 ; COVID-19 Drug Treatment ; Enzymes ; Esters ; Esters - chemistry ; Esters - pharmacology ; Evaluation ; Gel chromatography ; Halogenation ; Humans ; Ibuprofen ; Ibuprofen - analogs & derivatives ; Ibuprofen - pharmacology ; ibuprofen derivative ; Indomethacin ; Indomethacin - analogs & derivatives ; Indomethacin - pharmacology ; indomethacin derivative ; Inflammation ; Life Sciences & Biomedicine ; Middle East respiratory syndrome ; Molecular Docking Simulation ; NMR ; Nonsteroidal anti-inflammatory drugs ; Nuclear magnetic resonance ; Physical Sciences ; Protease ; Protease inhibitors ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacology ; Proteinase inhibitors ; Pyridines - chemistry ; Pyridines - pharmacology ; Salicylic acid ; Salicylic Acid - chemistry ; Salicylic Acid - pharmacology ; salicylic acid derivative ; SARS-CoV-2 ; SARS-CoV-2 - drug effects ; SARS-CoV-2 - metabolism ; Science & Technology ; Severe acute respiratory syndrome ; Severe acute respiratory syndrome coronavirus 2 ; Silica ; Silica gel ; Spectral analysis ; Vero Cells]]></subject><ispartof>Molecules (Basel, Switzerland), 2021-09, Vol.26 (19), p.5782, Article 5782</ispartof><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>10</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000707969300001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c520t-9e0e835f6c330bc42e13e9a9cd0e9e327909062403655c5b98f8d76a8b9d956f3</citedby><cites>FETCH-LOGICAL-c520t-9e0e835f6c330bc42e13e9a9cd0e9e327909062403655c5b98f8d76a8b9d956f3</cites><orcidid>0000-0003-2472-1841 ; 0000-0002-9616-6149 ; 0000-0002-5637-3397 ; 0000-0003-3772-2317 ; 0000-0001-8601-6211 ; 0000-0003-2670-974X ; 0000000256373397 ; 000000032670974X ; 0000000337722317 ; 0000000324721841</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510097/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510097/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2115,27929,27930,39263,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34641337$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/servlets/purl/1983127$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Ghosh, Arun K.</creatorcontrib><creatorcontrib>Shahabi, Dana</creatorcontrib><creatorcontrib>Yadav, Monika</creatorcontrib><creatorcontrib>Kovela, Satish</creatorcontrib><creatorcontrib>Anson, Brandon J.</creatorcontrib><creatorcontrib>Lendy, Emma K.</creatorcontrib><creatorcontrib>Bonham, Connie</creatorcontrib><creatorcontrib>Sirohi, Devika</creatorcontrib><creatorcontrib>Brito-Sierra, Carlos A.</creatorcontrib><creatorcontrib>Hattori, Shin-Ichiro</creatorcontrib><creatorcontrib>Kuhn, Richard</creatorcontrib><creatorcontrib>Mitsuya, Hiroaki</creatorcontrib><creatorcontrib>Mesecar, Andrew D.</creatorcontrib><creatorcontrib>Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors</title><title>Molecules (Basel, Switzerland)</title><addtitle>MOLECULES</addtitle><addtitle>Molecules</addtitle><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 H-1-NMR, C-13-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 IC50 value of 160 nM. Compound 13b exhibited an enzyme IC50 value of 4.9 mu M. However, it exhibited a potent antiviral EC50 value of 24 mu M in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 value of 2.4 mu M 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.</description><subject>3CLpro inhibitors</subject><subject>Animals</subject><subject>Anti-inflammatory agents</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - chemistry</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Antiviral activity</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>Assaying</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Binding sites</subject><subject>Biochemistry & Molecular Biology</subject><subject>Carboxylic acids</subject><subject>Chemistry</subject><subject>Chemistry, Multidisciplinary</subject><subject>Chlorocebus aethiops</subject><subject>Coronavirus 3C Proteases - antagonists & inhibitors</subject><subject>Coronavirus 3C Proteases - metabolism</subject><subject>Coronaviruses</subject><subject>Covalent bonds</subject><subject>covalent inhibitors</subject><subject>COVID-19</subject><subject>COVID-19 Drug Treatment</subject><subject>Enzymes</subject><subject>Esters</subject><subject>Esters - chemistry</subject><subject>Esters - pharmacology</subject><subject>Evaluation</subject><subject>Gel chromatography</subject><subject>Halogenation</subject><subject>Humans</subject><subject>Ibuprofen</subject><subject>Ibuprofen - analogs & derivatives</subject><subject>Ibuprofen - pharmacology</subject><subject>ibuprofen derivative</subject><subject>Indomethacin</subject><subject>Indomethacin - analogs & derivatives</subject><subject>Indomethacin - pharmacology</subject><subject>indomethacin derivative</subject><subject>Inflammation</subject><subject>Life Sciences & Biomedicine</subject><subject>Middle East respiratory syndrome</subject><subject>Molecular Docking Simulation</subject><subject>NMR</subject><subject>Nonsteroidal anti-inflammatory drugs</subject><subject>Nuclear magnetic resonance</subject><subject>Physical Sciences</subject><subject>Protease</subject><subject>Protease inhibitors</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Proteinase inhibitors</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Salicylic acid</subject><subject>Salicylic Acid - chemistry</subject><subject>Salicylic Acid - pharmacology</subject><subject>salicylic acid derivative</subject><subject>SARS-CoV-2</subject><subject>SARS-CoV-2 - drug effects</subject><subject>SARS-CoV-2 - metabolism</subject><subject>Science & Technology</subject><subject>Severe acute respiratory syndrome</subject><subject>Severe acute respiratory syndrome coronavirus 2</subject><subject>Silica</subject><subject>Silica gel</subject><subject>Spectral analysis</subject><subject>Vero Cells</subject><issn>1420-3049</issn><issn>1420-3049</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>HGBXW</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>DOA</sourceid><recordid>eNqNks1uEzEUhUcIREvhAdggCzZIaMB_M2NvKkVDgUgRVC2wtTyeO4mjiR1sJyh7HhynKVELG1Y-uv587Ht9iuI5wW8Zk_jdyo9gNiNEWhNZNYI-KE4Jp7hkmMuHd_RJ8STGJcaUcFI9Lk4YrzlhrDktfrWL0Qe_3gXbW7cb0UVMECLyA_rs3V572-sRTVyy5dQNo16tdPJhhyZzcCki7Xp0BaNO0KP3EOxWJ7uFXI_o0qeMoOvJ1XXZ-u8lRaydocuQyzoCmrqF7Wz2ik-LR4MeIzy7Xc-Kbx8uvrafytmXj9N2MitNRXEqJWAQrBpqwxjuDKdAGEgtTY9BAqONxBLXlGNWV5WpOikG0Te1Fp3sZVUP7KyYHnx7r5dqHexKh53y2qqbgg9zpUOyZgQ1cGp4I7XhrOE167NoqKjyzNhAe6iy1_nBa73pVtCb3GnQ4z3T-zvOLtTcb5WoCMayyQYvDwY-JquisQnMwnjnwCRFpGCE7qHXt7cE_2MDMamVjQbGUTvwm6hoJYig-ftxRl_9hS79Jrg8zxsKYy4EzxQ5UCb4GAMMxxcTrPahUv-EKp95cbfV44k_KcrAmwPwEzo_5FbAGThiGOMGN7KWLCtMMi3-n25tyoHyrvUbl9hvHvPqxg</recordid><startdate>20210924</startdate><enddate>20210924</enddate><creator>Ghosh, Arun K.</creator><creator>Shahabi, Dana</creator><creator>Yadav, Monika</creator><creator>Kovela, Satish</creator><creator>Anson, Brandon J.</creator><creator>Lendy, Emma K.</creator><creator>Bonham, Connie</creator><creator>Sirohi, Devika</creator><creator>Brito-Sierra, Carlos A.</creator><creator>Hattori, Shin-Ichiro</creator><creator>Kuhn, Richard</creator><creator>Mitsuya, Hiroaki</creator><creator>Mesecar, Andrew D.</creator><general>Mdpi</general><general>MDPI AG</general><general>MDPI</general><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>COVID</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>OIOZB</scope><scope>OTOTI</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-2472-1841</orcidid><orcidid>https://orcid.org/0000-0002-9616-6149</orcidid><orcidid>https://orcid.org/0000-0002-5637-3397</orcidid><orcidid>https://orcid.org/0000-0003-3772-2317</orcidid><orcidid>https://orcid.org/0000-0001-8601-6211</orcidid><orcidid>https://orcid.org/0000-0003-2670-974X</orcidid><orcidid>https://orcid.org/0000000256373397</orcidid><orcidid>https://orcid.org/000000032670974X</orcidid><orcidid>https://orcid.org/0000000337722317</orcidid><orcidid>https://orcid.org/0000000324721841</orcidid></search><sort><creationdate>20210924</creationdate><title>Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors</title><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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c520t-9e0e835f6c330bc42e13e9a9cd0e9e327909062403655c5b98f8d76a8b9d956f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>3CLpro inhibitors</topic><topic>Animals</topic><topic>Anti-inflammatory agents</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - chemistry</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Antiviral activity</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>Assaying</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Binding sites</topic><topic>Biochemistry & Molecular Biology</topic><topic>Carboxylic acids</topic><topic>Chemistry</topic><topic>Chemistry, Multidisciplinary</topic><topic>Chlorocebus aethiops</topic><topic>Coronavirus 3C Proteases - antagonists & inhibitors</topic><topic>Coronavirus 3C Proteases - metabolism</topic><topic>Coronaviruses</topic><topic>Covalent bonds</topic><topic>covalent inhibitors</topic><topic>COVID-19</topic><topic>COVID-19 Drug Treatment</topic><topic>Enzymes</topic><topic>Esters</topic><topic>Esters - chemistry</topic><topic>Esters - pharmacology</topic><topic>Evaluation</topic><topic>Gel chromatography</topic><topic>Halogenation</topic><topic>Humans</topic><topic>Ibuprofen</topic><topic>Ibuprofen - analogs & derivatives</topic><topic>Ibuprofen - pharmacology</topic><topic>ibuprofen derivative</topic><topic>Indomethacin</topic><topic>Indomethacin - analogs & derivatives</topic><topic>Indomethacin - pharmacology</topic><topic>indomethacin derivative</topic><topic>Inflammation</topic><topic>Life Sciences & Biomedicine</topic><topic>Middle East respiratory syndrome</topic><topic>Molecular Docking Simulation</topic><topic>NMR</topic><topic>Nonsteroidal anti-inflammatory drugs</topic><topic>Nuclear magnetic resonance</topic><topic>Physical Sciences</topic><topic>Protease</topic><topic>Protease inhibitors</topic><topic>Protease Inhibitors - chemistry</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Proteinase inhibitors</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Salicylic acid</topic><topic>Salicylic Acid - chemistry</topic><topic>Salicylic Acid - pharmacology</topic><topic>salicylic acid derivative</topic><topic>SARS-CoV-2</topic><topic>SARS-CoV-2 - drug effects</topic><topic>SARS-CoV-2 - metabolism</topic><topic>Science & Technology</topic><topic>Severe acute respiratory syndrome</topic><topic>Severe acute respiratory syndrome coronavirus 2</topic><topic>Silica</topic><topic>Silica gel</topic><topic>Spectral analysis</topic><topic>Vero Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ghosh, Arun K.</creatorcontrib><creatorcontrib>Shahabi, Dana</creatorcontrib><creatorcontrib>Yadav, Monika</creatorcontrib><creatorcontrib>Kovela, Satish</creatorcontrib><creatorcontrib>Anson, Brandon J.</creatorcontrib><creatorcontrib>Lendy, Emma K.</creatorcontrib><creatorcontrib>Bonham, Connie</creatorcontrib><creatorcontrib>Sirohi, Devika</creatorcontrib><creatorcontrib>Brito-Sierra, Carlos A.</creatorcontrib><creatorcontrib>Hattori, Shin-Ichiro</creatorcontrib><creatorcontrib>Kuhn, Richard</creatorcontrib><creatorcontrib>Mitsuya, Hiroaki</creatorcontrib><creatorcontrib>Mesecar, Andrew D.</creatorcontrib><creatorcontrib>Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 2021</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Coronavirus Research Database</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV - Hybrid</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Molecules (Basel, Switzerland)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ghosh, Arun K.</au><au>Shahabi, Dana</au><au>Yadav, Monika</au><au>Kovela, Satish</au><au>Anson, Brandon J.</au><au>Lendy, Emma K.</au><au>Bonham, Connie</au><au>Sirohi, Devika</au><au>Brito-Sierra, Carlos A.</au><au>Hattori, Shin-Ichiro</au><au>Kuhn, Richard</au><au>Mitsuya, Hiroaki</au><au>Mesecar, Andrew D.</au><aucorp>Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors</atitle><jtitle>Molecules (Basel, Switzerland)</jtitle><stitle>MOLECULES</stitle><addtitle>Molecules</addtitle><date>2021-09-24</date><risdate>2021</risdate><volume>26</volume><issue>19</issue><spage>5782</spage><pages>5782-</pages><artnum>5782</artnum><issn>1420-3049</issn><eissn>1420-3049</eissn><abstract>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-1-NMR, C-13-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 IC50 value of 160 nM. Compound 13b exhibited an enzyme IC50 value of 4.9 mu M. However, it exhibited a potent antiviral EC50 value of 24 mu M in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 value of 2.4 mu M 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.</abstract><cop>BASEL</cop><pub>Mdpi</pub><pmid>34641337</pmid><doi>10.3390/molecules26195782</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-2472-1841</orcidid><orcidid>https://orcid.org/0000-0002-9616-6149</orcidid><orcidid>https://orcid.org/0000-0002-5637-3397</orcidid><orcidid>https://orcid.org/0000-0003-3772-2317</orcidid><orcidid>https://orcid.org/0000-0001-8601-6211</orcidid><orcidid>https://orcid.org/0000-0003-2670-974X</orcidid><orcidid>https://orcid.org/0000000256373397</orcidid><orcidid>https://orcid.org/000000032670974X</orcidid><orcidid>https://orcid.org/0000000337722317</orcidid><orcidid>https://orcid.org/0000000324721841</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1420-3049 |
| ispartof | Molecules (Basel, Switzerland), 2021-09, Vol.26 (19), p.5782, Article 5782 |
| issn | 1420-3049 1420-3049 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2581822610 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; MDPI - Multidisciplinary Digital Publishing Institute; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 3CLpro inhibitors Animals Anti-inflammatory agents Anti-Inflammatory Agents, Non-Steroidal - chemistry Anti-Inflammatory Agents, Non-Steroidal - pharmacology Antiviral activity Antiviral Agents - chemistry Antiviral Agents - pharmacology Assaying BASIC BIOLOGICAL SCIENCES Binding sites Biochemistry & Molecular Biology Carboxylic acids Chemistry Chemistry, Multidisciplinary Chlorocebus aethiops Coronavirus 3C Proteases - antagonists & inhibitors Coronavirus 3C Proteases - metabolism Coronaviruses Covalent bonds covalent inhibitors COVID-19 COVID-19 Drug Treatment Enzymes Esters Esters - chemistry Esters - pharmacology Evaluation Gel chromatography Halogenation Humans Ibuprofen Ibuprofen - analogs & derivatives Ibuprofen - pharmacology ibuprofen derivative Indomethacin Indomethacin - analogs & derivatives Indomethacin - pharmacology indomethacin derivative Inflammation Life Sciences & Biomedicine Middle East respiratory syndrome Molecular Docking Simulation NMR Nonsteroidal anti-inflammatory drugs Nuclear magnetic resonance Physical Sciences Protease Protease inhibitors Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Proteinase inhibitors Pyridines - chemistry Pyridines - pharmacology Salicylic acid Salicylic Acid - chemistry Salicylic Acid - pharmacology salicylic acid derivative SARS-CoV-2 SARS-CoV-2 - drug effects SARS-CoV-2 - metabolism Science & Technology Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Silica Silica gel Spectral analysis Vero Cells |
| title | Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors |
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