Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication.
Identifieur interne : 001451 ( PubMed/Corpus ); précédent : 001450; suivant : 001452Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication.
Auteurs : Andrew V. Stachulski ; Chandrakala Pidathala ; Eleanor C. Row ; Raman Sharma ; Neil G. Berry ; Alexandre S. Lawrenson ; Shelley L. Moores ; Mazhar Iqbal ; Joanne Bentley ; Sarah A. Allman ; Geoffrey Edwards ; Alison Helm ; Jennifer Hellier ; Brent E. Korba ; J Edward Semple ; Jean-Francois RossignolSource :
- Journal of medicinal chemistry [ 1520-4804 ] ; 2011.
English descriptors
- KwdEn :
- Amides (chemical synthesis), Amides (chemistry), Amides (pharmacology), Antiviral Agents (chemical synthesis), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Cell Line, Hepacivirus (drug effects), Hepacivirus (genetics), Hepacivirus (physiology), Humans, Quantitative Structure-Activity Relationship, Thiazoles (chemical synthesis), Thiazoles (chemistry), Thiazoles (pharmacology), Virus Replication (drug effects).
- MESH :
- chemical , chemical synthesis : Amides, Antiviral Agents, Thiazoles.
- chemical , chemistry : Amides, Antiviral Agents, Thiazoles.
- chemical , pharmacology : Amides, Antiviral Agents, Thiazoles.
- drug effects : Hepacivirus, Virus Replication.
- genetics : Hepacivirus.
- physiology : Hepacivirus.
- Cell Line, Humans, Quantitative Structure-Activity Relationship.
Abstract
We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure-activity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5') generally correlates with potency. Among the related salicyloylanilides, the m-fluorophenyl analogue was most promising; niclosamide and close analogues suffered from very low solubility and bioavailability. Nitazoxanide (NTZ) 1 has performed well in clinical trials against HCV. We show here that the 5'-Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure-activity relationship (QSAR) model was obtained, showing good predictive models for cell safety. We conclude by updating the mode of action of the thiazolides and explain the candidate selection that has led to compound 4 entering preclinical development.
DOI: 10.1021/jm201264t
PubMed: 22059983
Links to Exploration step
pubmed:22059983Le document en format XML
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Row</name></author><author><name sortKey="Sharma, Raman" sort="Sharma, Raman" uniqKey="Sharma R" first="Raman" last="Sharma">Raman Sharma</name></author><author><name sortKey="Berry, Neil G" sort="Berry, Neil G" uniqKey="Berry N" first="Neil G" last="Berry">Neil G. Berry</name></author><author><name sortKey="Lawrenson, Alexandre S" sort="Lawrenson, Alexandre S" uniqKey="Lawrenson A" first="Alexandre S" last="Lawrenson">Alexandre S. Lawrenson</name></author><author><name sortKey="Moores, Shelley L" sort="Moores, Shelley L" uniqKey="Moores S" first="Shelley L" last="Moores">Shelley L. 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Inhibition of hepatitis C virus replication.</title><author><name sortKey="Stachulski, Andrew V" sort="Stachulski, Andrew V" uniqKey="Stachulski A" first="Andrew V" last="Stachulski">Andrew V. Stachulski</name><affiliation><nlm:affiliation>Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK. andrew.stachulski@bioch.ox.ac.uk</nlm:affiliation></affiliation></author><author><name sortKey="Pidathala, Chandrakala" sort="Pidathala, Chandrakala" uniqKey="Pidathala C" first="Chandrakala" last="Pidathala">Chandrakala Pidathala</name></author><author><name sortKey="Row, Eleanor C" sort="Row, Eleanor C" uniqKey="Row E" first="Eleanor C" last="Row">Eleanor C. Row</name></author><author><name sortKey="Sharma, Raman" sort="Sharma, Raman" uniqKey="Sharma R" first="Raman" last="Sharma">Raman Sharma</name></author><author><name sortKey="Berry, Neil G" sort="Berry, Neil G" uniqKey="Berry N" first="Neil G" last="Berry">Neil G. Berry</name></author><author><name sortKey="Lawrenson, Alexandre S" sort="Lawrenson, Alexandre S" uniqKey="Lawrenson A" first="Alexandre S" last="Lawrenson">Alexandre S. Lawrenson</name></author><author><name sortKey="Moores, Shelley L" sort="Moores, Shelley L" uniqKey="Moores S" first="Shelley L" last="Moores">Shelley L. Moores</name></author><author><name sortKey="Iqbal, Mazhar" sort="Iqbal, Mazhar" uniqKey="Iqbal M" first="Mazhar" last="Iqbal">Mazhar Iqbal</name></author><author><name sortKey="Bentley, Joanne" sort="Bentley, Joanne" uniqKey="Bentley J" first="Joanne" last="Bentley">Joanne Bentley</name></author><author><name sortKey="Allman, Sarah A" sort="Allman, Sarah A" uniqKey="Allman S" first="Sarah A" last="Allman">Sarah A. Allman</name></author><author><name sortKey="Edwards, Geoffrey" sort="Edwards, Geoffrey" uniqKey="Edwards G" first="Geoffrey" last="Edwards">Geoffrey Edwards</name></author><author><name sortKey="Helm, Alison" sort="Helm, Alison" uniqKey="Helm A" first="Alison" last="Helm">Alison Helm</name></author><author><name sortKey="Hellier, Jennifer" sort="Hellier, Jennifer" uniqKey="Hellier J" first="Jennifer" last="Hellier">Jennifer Hellier</name></author><author><name sortKey="Korba, Brent E" sort="Korba, Brent E" uniqKey="Korba B" first="Brent E" last="Korba">Brent E. Korba</name></author><author><name sortKey="Semple, J Edward" sort="Semple, J Edward" uniqKey="Semple J" first="J Edward" last="Semple">J Edward Semple</name></author><author><name sortKey="Rossignol, Jean Francois" sort="Rossignol, Jean Francois" uniqKey="Rossignol J" first="Jean-Francois" last="Rossignol">Jean-Francois Rossignol</name></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="eISSN">1520-4804</idno><imprint><date when="2011" type="published">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amides (chemical synthesis)</term><term>Amides (chemistry)</term><term>Amides (pharmacology)</term><term>Antiviral Agents (chemical synthesis)</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Cell Line</term><term>Hepacivirus (drug effects)</term><term>Hepacivirus (genetics)</term><term>Hepacivirus (physiology)</term><term>Humans</term><term>Quantitative Structure-Activity Relationship</term><term>Thiazoles (chemical synthesis)</term><term>Thiazoles (chemistry)</term><term>Thiazoles (pharmacology)</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Amides</term><term>Antiviral Agents</term><term>Thiazoles</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Amides</term><term>Antiviral Agents</term><term>Thiazoles</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Amides</term><term>Antiviral Agents</term><term>Thiazoles</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Hepacivirus</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Hepacivirus</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Hepacivirus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line</term><term>Humans</term><term>Quantitative Structure-Activity Relationship</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure-activity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5') generally correlates with potency. Among the related salicyloylanilides, the m-fluorophenyl analogue was most promising; niclosamide and close analogues suffered from very low solubility and bioavailability. Nitazoxanide (NTZ) 1 has performed well in clinical trials against HCV. We show here that the 5'-Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure-activity relationship (QSAR) model was obtained, showing good predictive models for cell safety. We conclude by updating the mode of action of the thiazolides and explain the candidate selection that has led to compound 4 entering preclinical development.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">22059983</PMID><DateCompleted><Year>2012</Year><Month>03</Month><Day>08</Day></DateCompleted><DateRevised><Year>2011</Year><Month>12</Month><Day>15</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1520-4804</ISSN><JournalIssue CitedMedium="Internet"><Volume>54</Volume><Issue>24</Issue><PubDate><Year>2011</Year><Month>Dec</Month><Day>22</Day></PubDate></JournalIssue><Title>Journal of medicinal chemistry</Title><ISOAbbreviation>J. Med. Chem.</ISOAbbreviation></Journal><ArticleTitle>Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication.</ArticleTitle><Pagination><MedlinePgn>8670-80</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1021/jm201264t</ELocationID><Abstract><AbstractText>We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure-activity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5') generally correlates with potency. Among the related salicyloylanilides, the m-fluorophenyl analogue was most promising; niclosamide and close analogues suffered from very low solubility and bioavailability. Nitazoxanide (NTZ) 1 has performed well in clinical trials against HCV. We show here that the 5'-Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure-activity relationship (QSAR) model was obtained, showing good predictive models for cell safety. We conclude by updating the mode of action of the thiazolides and explain the candidate selection that has led to compound 4 entering preclinical development.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Stachulski</LastName><ForeName>Andrew V</ForeName><Initials>AV</Initials><AffiliationInfo><Affiliation>Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK. andrew.stachulski@bioch.ox.ac.uk</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pidathala</LastName><ForeName>Chandrakala</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Row</LastName><ForeName>Eleanor C</ForeName><Initials>EC</Initials></Author><Author ValidYN="Y"><LastName>Sharma</LastName><ForeName>Raman</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Berry</LastName><ForeName>Neil G</ForeName><Initials>NG</Initials></Author><Author ValidYN="Y"><LastName>Lawrenson</LastName><ForeName>Alexandre S</ForeName><Initials>AS</Initials></Author><Author ValidYN="Y"><LastName>Moores</LastName><ForeName>Shelley L</ForeName><Initials>SL</Initials></Author><Author ValidYN="Y"><LastName>Iqbal</LastName><ForeName>Mazhar</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Bentley</LastName><ForeName>Joanne</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Allman</LastName><ForeName>Sarah A</ForeName><Initials>SA</Initials></Author><Author ValidYN="Y"><LastName>Edwards</LastName><ForeName>Geoffrey</ForeName><Initials>G</Initials></Author><Author ValidYN="Y"><LastName>Helm</LastName><ForeName>Alison</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Hellier</LastName><ForeName>Jennifer</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Korba</LastName><ForeName>Brent E</ForeName><Initials>BE</Initials></Author><Author ValidYN="Y"><LastName>Semple</LastName><ForeName>J Edward</ForeName><Initials>JE</Initials></Author><Author ValidYN="Y"><LastName>Rossignol</LastName><ForeName>Jean-Francois</ForeName><Initials>JF</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>N01-AI-30046</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2011</Year><Month>11</Month><Day>21</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Med Chem</MedlineTA><NlmUniqueID>9716531</NlmUniqueID><ISSNLinking>0022-2623</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C570544">2-acetoxybenzoyl-N-(5-chlorothiazol-2-yl)amide</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000577">Amides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D013844">Thiazoles</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000577" MajorTopicYN="N">Amides</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016174" MajorTopicYN="N">Hepacivirus</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D021281" MajorTopicYN="N">Quantitative Structure-Activity Relationship</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013844" MajorTopicYN="N">Thiazoles</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014779" MajorTopicYN="N">Virus Replication</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2011</Year><Month>11</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2011</Year><Month>11</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2012</Year><Month>3</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">22059983</ArticleId><ArticleId IdType="doi">10.1021/jm201264t</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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