Bioisosteric replacement of the carboxylic acid group in Hepatitis-C virus NS5B thumb site II inhibitors: phenylalanine derivatives
Hepatitis C virus (HCV) is a global health concern and the NS5B RNA-dependent RNA polymerase (RdRp) of HCV is an attractive target for drug discovery due to its role in viral replication. This study focuses on NS5B thumb site II inhibitors, specifically phenylalanine derivatives, and explores bioiso...
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| Veröffentlicht in: | European journal of medicinal chemistry 2024-12, Vol.279, p.116832, Article 116832 |
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| container_title | European journal of medicinal chemistry |
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| creator | Camci, Merve Şenol, Halil Kose, Aytekin Karaman Mayack, Berin Alayoubi, Muhammed Moyasar Karali, Nilgun Gezginci, Mikail Hakan |
| description | Hepatitis C virus (HCV) is a global health concern and the NS5B RNA-dependent RNA polymerase (RdRp) of HCV is an attractive target for drug discovery due to its role in viral replication. This study focuses on NS5B thumb site II inhibitors, specifically phenylalanine derivatives, and explores bioisosteric replacement and prodrug strategies to overcome limitations associated with carboxylic acid functionality. The synthesized compounds demonstrated antiviral activity, with compound 6d showing the most potent activity with an EC50 value of 3.717 μM. The hydroxamidine derivatives 7a-d showed EC50 values ranging from 3.9 μM to 11.3 μM. However, the acidic heterocyclic derivatives containing the oxadiazolone (8a-d) and oxadiazolethione (9a-d) rings did not exhibit measurable activity. A methylated heterocycle 10b showed a hint of activity at 8.09 μM. The pivaloyloxymethyl derivatives 11a and 11b did not show antiviral activity. Further studies are warranted to fully understand the effects of these modifications and to explore additional strategies for developing novel therapeutic options for HCV.
[Display omitted]
•Compound 6d showed most promising activity.•Nitrile group is a suitable bioisostere of carboxylic acid group.•Acidic heterocyclic isosteres didn't have activity.•Methylation of one heterocyclic isostere showed activity.•Methyl might be acting as a prodrug-forming group. |
| doi_str_mv | 10.1016/j.ejmech.2024.116832 |
| format | Article |
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[Display omitted]
•Compound 6d showed most promising activity.•Nitrile group is a suitable bioisostere of carboxylic acid group.•Acidic heterocyclic isosteres didn't have activity.•Methylation of one heterocyclic isostere showed activity.•Methyl might be acting as a prodrug-forming group.</description><identifier>ISSN: 0223-5234</identifier><identifier>ISSN: 1768-3254</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2024.116832</identifier><identifier>PMID: 39288595</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Antiviral agents ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Azo Compounds - chemistry ; Azo Compounds - pharmacology ; Bioisosterism ; Carboxylic acid ; Carboxylic Acids - chemical synthesis ; Carboxylic Acids - chemistry ; Carboxylic Acids - pharmacology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Hepacivirus - drug effects ; Hepatitis C virus ; Humans ; Microbial Sensitivity Tests ; Molecular Structure ; NS5B RdRp ; Phenylalanine ; Phenylalanine - analogs & derivatives ; Phenylalanine - chemical synthesis ; Phenylalanine - chemistry ; Phenylalanine - pharmacology ; Prodrugs ; Structure-Activity Relationship ; Thiones - chemistry ; Thiones - pharmacology ; Viral Nonstructural Proteins - antagonists & inhibitors ; Viral Nonstructural Proteins - metabolism</subject><ispartof>European journal of medicinal chemistry, 2024-12, Vol.279, p.116832, Article 116832</ispartof><rights>2024 Elsevier Masson SAS</rights><rights>Copyright © 2024 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c241t-1dc0058fcfe6f724c930c23e67a18b759b857a284c95edda4e58238c18f1add73</cites><orcidid>0000-0003-0157-2839 ; 0009-0004-2543-7644</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S022352342400713X$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39288595$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Camci, Merve</creatorcontrib><creatorcontrib>Şenol, Halil</creatorcontrib><creatorcontrib>Kose, Aytekin</creatorcontrib><creatorcontrib>Karaman Mayack, Berin</creatorcontrib><creatorcontrib>Alayoubi, Muhammed Moyasar</creatorcontrib><creatorcontrib>Karali, Nilgun</creatorcontrib><creatorcontrib>Gezginci, Mikail Hakan</creatorcontrib><title>Bioisosteric replacement of the carboxylic acid group in Hepatitis-C virus NS5B thumb site II inhibitors: phenylalanine derivatives</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>Hepatitis C virus (HCV) is a global health concern and the NS5B RNA-dependent RNA polymerase (RdRp) of HCV is an attractive target for drug discovery due to its role in viral replication. This study focuses on NS5B thumb site II inhibitors, specifically phenylalanine derivatives, and explores bioisosteric replacement and prodrug strategies to overcome limitations associated with carboxylic acid functionality. The synthesized compounds demonstrated antiviral activity, with compound 6d showing the most potent activity with an EC50 value of 3.717 μM. The hydroxamidine derivatives 7a-d showed EC50 values ranging from 3.9 μM to 11.3 μM. However, the acidic heterocyclic derivatives containing the oxadiazolone (8a-d) and oxadiazolethione (9a-d) rings did not exhibit measurable activity. A methylated heterocycle 10b showed a hint of activity at 8.09 μM. The pivaloyloxymethyl derivatives 11a and 11b did not show antiviral activity. Further studies are warranted to fully understand the effects of these modifications and to explore additional strategies for developing novel therapeutic options for HCV.
[Display omitted]
•Compound 6d showed most promising activity.•Nitrile group is a suitable bioisostere of carboxylic acid group.•Acidic heterocyclic isosteres didn't have activity.•Methylation of one heterocyclic isostere showed activity.•Methyl might be acting as a prodrug-forming group.</description><subject>Antiviral agents</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>Azo Compounds - chemistry</subject><subject>Azo Compounds - pharmacology</subject><subject>Bioisosterism</subject><subject>Carboxylic acid</subject><subject>Carboxylic Acids - chemical synthesis</subject><subject>Carboxylic Acids - chemistry</subject><subject>Carboxylic Acids - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Hepacivirus - drug effects</subject><subject>Hepatitis C virus</subject><subject>Humans</subject><subject>Microbial Sensitivity Tests</subject><subject>Molecular Structure</subject><subject>NS5B RdRp</subject><subject>Phenylalanine</subject><subject>Phenylalanine - analogs & derivatives</subject><subject>Phenylalanine - chemical synthesis</subject><subject>Phenylalanine - chemistry</subject><subject>Phenylalanine - pharmacology</subject><subject>Prodrugs</subject><subject>Structure-Activity Relationship</subject><subject>Thiones - chemistry</subject><subject>Thiones - pharmacology</subject><subject>Viral Nonstructural Proteins - antagonists & inhibitors</subject><subject>Viral Nonstructural Proteins - metabolism</subject><issn>0223-5234</issn><issn>1768-3254</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1u1DAURi0EokPhDRDykk0G_yYOCyQ6onSkii6AteXYN4xHSRxsZ8Ss--J1lcKSlRf3fPfzPQi9pWRLCa0_HLdwHMEetowwsaW0Vpw9Qxva1KriTIrnaEMY45VkXFygVykdCSGyJuQluuAtU0q2coPur3zwKaQM0VscYR6MhRGmjEOP8wGwNbELf85DmRrrHf4VwzJjP-EbmE322adqh08-Lgl_-y6vSmYZO5x8BrzfF-7gO59DTB_xfIDpPJjBTH4C7ErhqSw4QXqNXvRmSPDm6b1EP6-__NjdVLd3X_e7z7eVZYLmijpbDlC97aHuGyZsy4llHOrGUNU1su2UbAxTZSDBOSNAKsaVpaqnxrmGX6L36945ht8LpKxHnywM5UcQlqQ5JbWQbStUQcWK2hhSitDrOfrRxLOmRD_q10e96teP-vWqv8TePTUs3QjuX-iv7wJ8WgEod548RJ2sh8mC8xFs1i74_zc8AHZhmfY</recordid><startdate>20241205</startdate><enddate>20241205</enddate><creator>Camci, Merve</creator><creator>Şenol, Halil</creator><creator>Kose, Aytekin</creator><creator>Karaman Mayack, Berin</creator><creator>Alayoubi, Muhammed Moyasar</creator><creator>Karali, Nilgun</creator><creator>Gezginci, Mikail Hakan</creator><general>Elsevier Masson SAS</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>7X8</scope><orcidid>https://orcid.org/0000-0003-0157-2839</orcidid><orcidid>https://orcid.org/0009-0004-2543-7644</orcidid></search><sort><creationdate>20241205</creationdate><title>Bioisosteric replacement of the carboxylic acid group in Hepatitis-C virus NS5B thumb site II inhibitors: phenylalanine derivatives</title><author>Camci, Merve ; Şenol, Halil ; Kose, Aytekin ; Karaman Mayack, Berin ; Alayoubi, Muhammed Moyasar ; Karali, Nilgun ; Gezginci, Mikail Hakan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c241t-1dc0058fcfe6f724c930c23e67a18b759b857a284c95edda4e58238c18f1add73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Antiviral agents</topic><topic>Antiviral Agents - chemical synthesis</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>Azo Compounds - chemistry</topic><topic>Azo Compounds - pharmacology</topic><topic>Bioisosterism</topic><topic>Carboxylic acid</topic><topic>Carboxylic Acids - chemical synthesis</topic><topic>Carboxylic Acids - chemistry</topic><topic>Carboxylic Acids - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Hepacivirus - drug effects</topic><topic>Hepatitis C virus</topic><topic>Humans</topic><topic>Microbial Sensitivity Tests</topic><topic>Molecular Structure</topic><topic>NS5B RdRp</topic><topic>Phenylalanine</topic><topic>Phenylalanine - analogs & derivatives</topic><topic>Phenylalanine - chemical synthesis</topic><topic>Phenylalanine - chemistry</topic><topic>Phenylalanine - pharmacology</topic><topic>Prodrugs</topic><topic>Structure-Activity Relationship</topic><topic>Thiones - chemistry</topic><topic>Thiones - pharmacology</topic><topic>Viral Nonstructural Proteins - antagonists & inhibitors</topic><topic>Viral Nonstructural Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Camci, Merve</creatorcontrib><creatorcontrib>Şenol, Halil</creatorcontrib><creatorcontrib>Kose, Aytekin</creatorcontrib><creatorcontrib>Karaman Mayack, Berin</creatorcontrib><creatorcontrib>Alayoubi, Muhammed Moyasar</creatorcontrib><creatorcontrib>Karali, Nilgun</creatorcontrib><creatorcontrib>Gezginci, Mikail Hakan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Camci, Merve</au><au>Şenol, Halil</au><au>Kose, Aytekin</au><au>Karaman Mayack, Berin</au><au>Alayoubi, Muhammed Moyasar</au><au>Karali, Nilgun</au><au>Gezginci, Mikail Hakan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bioisosteric replacement of the carboxylic acid group in Hepatitis-C virus NS5B thumb site II inhibitors: phenylalanine derivatives</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2024-12-05</date><risdate>2024</risdate><volume>279</volume><spage>116832</spage><pages>116832-</pages><artnum>116832</artnum><issn>0223-5234</issn><issn>1768-3254</issn><eissn>1768-3254</eissn><abstract>Hepatitis C virus (HCV) is a global health concern and the NS5B RNA-dependent RNA polymerase (RdRp) of HCV is an attractive target for drug discovery due to its role in viral replication. This study focuses on NS5B thumb site II inhibitors, specifically phenylalanine derivatives, and explores bioisosteric replacement and prodrug strategies to overcome limitations associated with carboxylic acid functionality. The synthesized compounds demonstrated antiviral activity, with compound 6d showing the most potent activity with an EC50 value of 3.717 μM. The hydroxamidine derivatives 7a-d showed EC50 values ranging from 3.9 μM to 11.3 μM. However, the acidic heterocyclic derivatives containing the oxadiazolone (8a-d) and oxadiazolethione (9a-d) rings did not exhibit measurable activity. A methylated heterocycle 10b showed a hint of activity at 8.09 μM. The pivaloyloxymethyl derivatives 11a and 11b did not show antiviral activity. Further studies are warranted to fully understand the effects of these modifications and to explore additional strategies for developing novel therapeutic options for HCV.
[Display omitted]
•Compound 6d showed most promising activity.•Nitrile group is a suitable bioisostere of carboxylic acid group.•Acidic heterocyclic isosteres didn't have activity.•Methylation of one heterocyclic isostere showed activity.•Methyl might be acting as a prodrug-forming group.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>39288595</pmid><doi>10.1016/j.ejmech.2024.116832</doi><orcidid>https://orcid.org/0000-0003-0157-2839</orcidid><orcidid>https://orcid.org/0009-0004-2543-7644</orcidid></addata></record> |
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| subjects | Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology Azo Compounds - chemistry Azo Compounds - pharmacology Bioisosterism Carboxylic acid Carboxylic Acids - chemical synthesis Carboxylic Acids - chemistry Carboxylic Acids - pharmacology Dose-Response Relationship, Drug Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Hepacivirus - drug effects Hepatitis C virus Humans Microbial Sensitivity Tests Molecular Structure NS5B RdRp Phenylalanine Phenylalanine - analogs & derivatives Phenylalanine - chemical synthesis Phenylalanine - chemistry Phenylalanine - pharmacology Prodrugs Structure-Activity Relationship Thiones - chemistry Thiones - pharmacology Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - metabolism |
| title | Bioisosteric replacement of the carboxylic acid group in Hepatitis-C virus NS5B thumb site II inhibitors: phenylalanine derivatives |
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