Synthesis and evaluation of enantiomers of hydroxychloroquine against SARS-CoV-2 in vitro
[Display omitted] Since the end of 2019, the outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic. There is an urgent need for effective and low-toxic antiviral drugs to remedy Remdesivir’s limitation. Hydroxychloroquine, a broad spectrum anti-v...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2022-01, Vol.53, p.116523-116523, Article 116523 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Ni, Yong Liao, Jinbiao Qian, Zhenlong Wu, Chunxiu Zhang, Xiangyu Zhang, Ji Xie, Youhua Jiang, Sheng |
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Since the end of 2019, the outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic. There is an urgent need for effective and low-toxic antiviral drugs to remedy Remdesivir’s limitation. Hydroxychloroquine, a broad spectrum anti-viral drug, showed inhibitory activity against SARS-CoV-2 in some studies. Thus, we adopted a drug repurposing strategy, and further investigated hydroxychloroquine. We obtained different configurations of hydroxychloroquine side chains by using chiral resolution technique, and successfully furnished R-/S-hydroxychloroquine sulfate through chemical synthesis. The R configuration of hydroxychloroquine was found to exhibit higher antiviral activity (EC50 = 3.05 μM) and lower toxicity in vivo. Therefore, R-HCQ is a promising lead compound against SARS-CoV-2. Our research provides new strategy for the subsequent research on small molecule inhibitors against SARS-CoV-2. |
| doi_str_mv | 10.1016/j.bmc.2021.116523 |
| format | Article |
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Since the end of 2019, the outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic. There is an urgent need for effective and low-toxic antiviral drugs to remedy Remdesivir’s limitation. Hydroxychloroquine, a broad spectrum anti-viral drug, showed inhibitory activity against SARS-CoV-2 in some studies. Thus, we adopted a drug repurposing strategy, and further investigated hydroxychloroquine. We obtained different configurations of hydroxychloroquine side chains by using chiral resolution technique, and successfully furnished R-/S-hydroxychloroquine sulfate through chemical synthesis. The R configuration of hydroxychloroquine was found to exhibit higher antiviral activity (EC50 = 3.05 μM) and lower toxicity in vivo. Therefore, R-HCQ is a promising lead compound against SARS-CoV-2. Our research provides new strategy for the subsequent research on small molecule inhibitors against SARS-CoV-2.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2021.116523</identifier><identifier>PMID: 34875467</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Antiviral ; Antiviral Agents - chemical synthesis ; Antiviral Agents - pharmacology ; Antiviral Agents - toxicity ; Chlorocebus aethiops ; COVID-19 ; Drug Repositioning ; Enantiomers ; Female ; Hydroxychloroquine ; Hydroxychloroquine - chemical synthesis ; Hydroxychloroquine - pharmacology ; Hydroxychloroquine - toxicity ; Male ; Mice ; Microbial Sensitivity Tests ; SARS-CoV-2 ; SARS-CoV-2 - drug effects ; Stereoisomerism ; Vero Cells</subject><ispartof>Bioorganic & medicinal chemistry, 2022-01, Vol.53, p.116523-116523, Article 116523</ispartof><rights>2021 Elsevier Ltd</rights><rights>Copyright © 2021 Elsevier Ltd. All rights reserved.</rights><rights>2021 Elsevier Ltd. All rights reserved. 2021 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c451t-d45b52f4564887fa56036ad8ebdc7a46672411e705a4a77e977a96fb463cf7ed3</citedby><cites>FETCH-LOGICAL-c451t-d45b52f4564887fa56036ad8ebdc7a46672411e705a4a77e977a96fb463cf7ed3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089621005319$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34875467$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ni, Yong</creatorcontrib><creatorcontrib>Liao, Jinbiao</creatorcontrib><creatorcontrib>Qian, Zhenlong</creatorcontrib><creatorcontrib>Wu, Chunxiu</creatorcontrib><creatorcontrib>Zhang, Xiangyu</creatorcontrib><creatorcontrib>Zhang, Ji</creatorcontrib><creatorcontrib>Xie, Youhua</creatorcontrib><creatorcontrib>Jiang, Sheng</creatorcontrib><title>Synthesis and evaluation of enantiomers of hydroxychloroquine against SARS-CoV-2 in vitro</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
Since the end of 2019, the outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic. There is an urgent need for effective and low-toxic antiviral drugs to remedy Remdesivir’s limitation. Hydroxychloroquine, a broad spectrum anti-viral drug, showed inhibitory activity against SARS-CoV-2 in some studies. Thus, we adopted a drug repurposing strategy, and further investigated hydroxychloroquine. We obtained different configurations of hydroxychloroquine side chains by using chiral resolution technique, and successfully furnished R-/S-hydroxychloroquine sulfate through chemical synthesis. The R configuration of hydroxychloroquine was found to exhibit higher antiviral activity (EC50 = 3.05 μM) and lower toxicity in vivo. Therefore, R-HCQ is a promising lead compound against SARS-CoV-2. Our research provides new strategy for the subsequent research on small molecule inhibitors against SARS-CoV-2.</description><subject>Animals</subject><subject>Antiviral</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - pharmacology</subject><subject>Antiviral Agents - toxicity</subject><subject>Chlorocebus aethiops</subject><subject>COVID-19</subject><subject>Drug Repositioning</subject><subject>Enantiomers</subject><subject>Female</subject><subject>Hydroxychloroquine</subject><subject>Hydroxychloroquine - chemical synthesis</subject><subject>Hydroxychloroquine - pharmacology</subject><subject>Hydroxychloroquine - toxicity</subject><subject>Male</subject><subject>Mice</subject><subject>Microbial Sensitivity Tests</subject><subject>SARS-CoV-2</subject><subject>SARS-CoV-2 - drug effects</subject><subject>Stereoisomerism</subject><subject>Vero Cells</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kN9KwzAUxoMobk4fwBvpC3QmbZq0CIIM_8FAcCp4FdLkdM3Ykpl0xb29HdWhN16dczjf9x3OD6FzgscEE3a5GJcrNU5wQsaEsCxJD9CQUEbjNC3IIRriguUxzgs2QCchLDDGCS3IMRqkNOcZZXyI3mdb29QQTIik1RG0crmRjXE2clUEVtquX4EPu7Heau8-t6peOu8-NsZCJOfS2NBEs5vnWTxxb3ESGRu1pvHuFB1Vchng7LuO0Ovd7cvkIZ4-3T9ObqaxohlpYk2zMksqmjGa57ySGcMpkzqHUisuKWM8oYQAx5mkknMoOJcFq0rKUlVx0OkIXfe56025Aq3ANl4uxdqblfRb4aQRfzfW1GLuWpEzzNIEdwGkD1DeheCh2nsJFjvOYiE6zmLHWfScO8_F76N7xw_YTnDVC6B7vTXgRVAGrAJtPKhGaGf-if8C57SP2w</recordid><startdate>20220101</startdate><enddate>20220101</enddate><creator>Ni, Yong</creator><creator>Liao, Jinbiao</creator><creator>Qian, Zhenlong</creator><creator>Wu, Chunxiu</creator><creator>Zhang, Xiangyu</creator><creator>Zhang, Ji</creator><creator>Xie, Youhua</creator><creator>Jiang, Sheng</creator><general>Elsevier Ltd</general><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>5PM</scope></search><sort><creationdate>20220101</creationdate><title>Synthesis and evaluation of enantiomers of hydroxychloroquine against SARS-CoV-2 in vitro</title><author>Ni, Yong ; Liao, Jinbiao ; Qian, Zhenlong ; Wu, Chunxiu ; Zhang, Xiangyu ; Zhang, Ji ; Xie, Youhua ; Jiang, Sheng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c451t-d45b52f4564887fa56036ad8ebdc7a46672411e705a4a77e977a96fb463cf7ed3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Antiviral</topic><topic>Antiviral Agents - chemical synthesis</topic><topic>Antiviral Agents - pharmacology</topic><topic>Antiviral Agents - toxicity</topic><topic>Chlorocebus aethiops</topic><topic>COVID-19</topic><topic>Drug Repositioning</topic><topic>Enantiomers</topic><topic>Female</topic><topic>Hydroxychloroquine</topic><topic>Hydroxychloroquine - chemical synthesis</topic><topic>Hydroxychloroquine - pharmacology</topic><topic>Hydroxychloroquine - toxicity</topic><topic>Male</topic><topic>Mice</topic><topic>Microbial Sensitivity Tests</topic><topic>SARS-CoV-2</topic><topic>SARS-CoV-2 - drug effects</topic><topic>Stereoisomerism</topic><topic>Vero Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ni, Yong</creatorcontrib><creatorcontrib>Liao, Jinbiao</creatorcontrib><creatorcontrib>Qian, Zhenlong</creatorcontrib><creatorcontrib>Wu, Chunxiu</creatorcontrib><creatorcontrib>Zhang, Xiangyu</creatorcontrib><creatorcontrib>Zhang, Ji</creatorcontrib><creatorcontrib>Xie, Youhua</creatorcontrib><creatorcontrib>Jiang, Sheng</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ni, Yong</au><au>Liao, Jinbiao</au><au>Qian, Zhenlong</au><au>Wu, Chunxiu</au><au>Zhang, Xiangyu</au><au>Zhang, Ji</au><au>Xie, Youhua</au><au>Jiang, Sheng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and evaluation of enantiomers of hydroxychloroquine against SARS-CoV-2 in vitro</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2022-01-01</date><risdate>2022</risdate><volume>53</volume><spage>116523</spage><epage>116523</epage><pages>116523-116523</pages><artnum>116523</artnum><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
Since the end of 2019, the outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has evolved into a global pandemic. There is an urgent need for effective and low-toxic antiviral drugs to remedy Remdesivir’s limitation. Hydroxychloroquine, a broad spectrum anti-viral drug, showed inhibitory activity against SARS-CoV-2 in some studies. Thus, we adopted a drug repurposing strategy, and further investigated hydroxychloroquine. We obtained different configurations of hydroxychloroquine side chains by using chiral resolution technique, and successfully furnished R-/S-hydroxychloroquine sulfate through chemical synthesis. The R configuration of hydroxychloroquine was found to exhibit higher antiviral activity (EC50 = 3.05 μM) and lower toxicity in vivo. Therefore, R-HCQ is a promising lead compound against SARS-CoV-2. Our research provides new strategy for the subsequent research on small molecule inhibitors against SARS-CoV-2.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>34875467</pmid><doi>10.1016/j.bmc.2021.116523</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Animals Antiviral Antiviral Agents - chemical synthesis Antiviral Agents - pharmacology Antiviral Agents - toxicity Chlorocebus aethiops COVID-19 Drug Repositioning Enantiomers Female Hydroxychloroquine Hydroxychloroquine - chemical synthesis Hydroxychloroquine - pharmacology Hydroxychloroquine - toxicity Male Mice Microbial Sensitivity Tests SARS-CoV-2 SARS-CoV-2 - drug effects Stereoisomerism Vero Cells |
| title | Synthesis and evaluation of enantiomers of hydroxychloroquine against SARS-CoV-2 in vitro |
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