Evaluation of a non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold as a SARS 3CL protease inhibitor.
Identifieur interne : 002F97 ( Ncbi/Merge ); précédent : 002F96; suivant : 002F98Evaluation of a non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold as a SARS 3CL protease inhibitor.
Auteurs : Kouji Ohnishi [Japon] ; Yasunao Hattori [Japon] ; Kazuya Kobayashi [Japon] ; Kenichi Akaji [Japon]Source :
- Bioorganic & medicinal chemistry [ 1464-3391 ] ; 2019.
Descripteurs français
- KwdFr :
- Antiviraux (), Antiviraux (pharmacologie), Antiviraux (synthèse chimique), Cysteine endopeptidases (), Domaine catalytique, Inhibiteurs de la cystéine protéinase (), Inhibiteurs de la cystéine protéinase (pharmacologie), Inhibiteurs de la cystéine protéinase (synthèse chimique), Isoquinoléines (), Isoquinoléines (pharmacologie), Isoquinoléines (synthèse chimique), Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Simulation de docking moléculaire, Structure moléculaire, Virus du SRAS (enzymologie).
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Virus du SRAS.
- pharmacologie : Antiviraux, Inhibiteurs de la cystéine protéinase, Isoquinoléines.
- synthèse chimique : Antiviraux, Inhibiteurs de la cystéine protéinase, Isoquinoléines.
- Antiviraux, Cysteine endopeptidases, Domaine catalytique, Inhibiteurs de la cystéine protéinase, Isoquinoléines, Protéines virales, Simulation de docking moléculaire, Structure moléculaire.
English descriptors
- KwdEn :
- Antiviral Agents (chemical synthesis), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Catalytic Domain, Cysteine Endopeptidases (chemistry), Cysteine Proteinase Inhibitors (chemical synthesis), Cysteine Proteinase Inhibitors (chemistry), Cysteine Proteinase Inhibitors (pharmacology), Isoquinolines (chemical synthesis), Isoquinolines (chemistry), Isoquinolines (pharmacology), Molecular Docking Simulation, Molecular Structure, SARS Virus (enzymology), Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemical synthesis : Antiviral Agents, Cysteine Proteinase Inhibitors, Isoquinolines.
- chemical , chemistry : Antiviral Agents, Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, Isoquinolines, Viral Proteins.
- chemical , pharmacology : Antiviral Agents, Cysteine Proteinase Inhibitors, Isoquinolines.
- enzymology : SARS Virus.
- Catalytic Domain, Molecular Docking Simulation, Molecular Structure.
Abstract
A non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold was evaluated as a novel inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CLpro). The decahydroisoquinolin scaffold has been demonstrated to be an effective hydrophobic center to interact with S2 site of SARS 3CLpro, but the lack of interactions at S3 to S4 site is thought to be a major reason for the moderate inhibitory activity. In this study, the effects of an additional non-prime site substituent on the scaffold as well as effects of several warheads are evaluated. For the introduction of a desired non-prime site substituent, amino functionality was introduced on the decahydroisoquinolin scaffold, and the scaffold was constructed by Pd(II) catalyzed diastereoselective ring formation. The synthesized decahydroisoquinolin inhibitors showed about 2.4 times potent inhibitory activities for SARS 3CLpro when combined with a non-prime site substituent. The present results indicated not only the expected additional interactions with the SARS 3CLpro but also the possibility of new inhibitors containing a fused-ring system as a hydrophobic scaffold and a new warhead such as thioacetal.
DOI: 10.1016/j.bmc.2018.12.019
PubMed: 30558861
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Electronic address: akaji@mb.kyoto-phu.ac.jp.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412</wicri:regionArea><wicri:noRegion>Kyoto 607-8412</wicri:noRegion></affiliation></author></analytic><series><title level="j">Bioorganic & medicinal chemistry</title><idno type="eISSN">1464-3391</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral Agents (chemical synthesis)</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Catalytic Domain</term><term>Cysteine Endopeptidases (chemistry)</term><term>Cysteine Proteinase Inhibitors (chemical synthesis)</term><term>Cysteine Proteinase Inhibitors (chemistry)</term><term>Cysteine Proteinase Inhibitors (pharmacology)</term><term>Isoquinolines (chemical synthesis)</term><term>Isoquinolines (chemistry)</term><term>Isoquinolines (pharmacology)</term><term>Molecular Docking Simulation</term><term>Molecular Structure</term><term>SARS Virus (enzymology)</term><term>Viral Proteins (antagonists & inhibitors)</term><term>Viral Proteins (chemistry)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Antiviraux ()</term><term>Antiviraux (pharmacologie)</term><term>Antiviraux (synthèse chimique)</term><term>Cysteine endopeptidases ()</term><term>Domaine catalytique</term><term>Inhibiteurs de la cystéine protéinase ()</term><term>Inhibiteurs de la cystéine protéinase (pharmacologie)</term><term>Inhibiteurs de la cystéine protéinase (synthèse chimique)</term><term>Isoquinoléines ()</term><term>Isoquinoléines (pharmacologie)</term><term>Isoquinoléines (synthèse chimique)</term><term>Protéines virales ()</term><term>Protéines virales (antagonistes et inhibiteurs)</term><term>Simulation de docking moléculaire</term><term>Structure moléculaire</term><term>Virus du SRAS (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Antiviral Agents</term><term>Cysteine Proteinase Inhibitors</term><term>Isoquinolines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term><term>Cysteine Endopeptidases</term><term>Cysteine Proteinase Inhibitors</term><term>Isoquinolines</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Cysteine Proteinase Inhibitors</term><term>Isoquinolines</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term><term>Inhibiteurs de la cystéine protéinase</term><term>Isoquinoléines</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antiviraux</term><term>Inhibiteurs de la cystéine protéinase</term><term>Isoquinoléines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Catalytic Domain</term><term>Molecular Docking Simulation</term><term>Molecular Structure</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Antiviraux</term><term>Cysteine endopeptidases</term><term>Domaine catalytique</term><term>Inhibiteurs de la cystéine protéinase</term><term>Isoquinoléines</term><term>Protéines virales</term><term>Simulation de docking moléculaire</term><term>Structure moléculaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold was evaluated as a novel inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL<sup>pro</sup>). The decahydroisoquinolin scaffold has been demonstrated to be an effective hydrophobic center to interact with S2 site of SARS 3CL<sup>pro</sup>, but the lack of interactions at S3 to S4 site is thought to be a major reason for the moderate inhibitory activity. In this study, the effects of an additional non-prime site substituent on the scaffold as well as effects of several warheads are evaluated. For the introduction of a desired non-prime site substituent, amino functionality was introduced on the decahydroisoquinolin scaffold, and the scaffold was constructed by Pd(II) catalyzed diastereoselective ring formation. The synthesized decahydroisoquinolin inhibitors showed about 2.4 times potent inhibitory activities for SARS 3CL<sup>pro</sup> when combined with a non-prime site substituent. The present results indicated not only the expected additional interactions with the SARS 3CL<sup>pro</sup> but also the possibility of new inhibitors containing a fused-ring system as a hydrophobic scaffold and a new warhead such as thioacetal.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">30558861</PMID><DateCompleted><Year>2019</Year><Month>09</Month><Day>16</Day></DateCompleted><DateRevised><Year>2020</Year><Month>04</Month><Day>09</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1464-3391</ISSN><JournalIssue CitedMedium="Internet"><Volume>27</Volume><Issue>2</Issue><PubDate><Year>2019</Year><Month>01</Month><Day>15</Day></PubDate></JournalIssue><Title>Bioorganic & medicinal chemistry</Title><ISOAbbreviation>Bioorg. Med. Chem.</ISOAbbreviation></Journal><ArticleTitle>Evaluation of a non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold as a SARS 3CL protease inhibitor.</ArticleTitle><Pagination><MedlinePgn>425-435</MedlinePgn></Pagination><ELocationID EIdType="pii" ValidYN="Y">S0968-0896(18)31916-3</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.bmc.2018.12.019</ELocationID><Abstract><AbstractText>A non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold was evaluated as a novel inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL<sup>pro</sup>). The decahydroisoquinolin scaffold has been demonstrated to be an effective hydrophobic center to interact with S2 site of SARS 3CL<sup>pro</sup>, but the lack of interactions at S3 to S4 site is thought to be a major reason for the moderate inhibitory activity. In this study, the effects of an additional non-prime site substituent on the scaffold as well as effects of several warheads are evaluated. For the introduction of a desired non-prime site substituent, amino functionality was introduced on the decahydroisoquinolin scaffold, and the scaffold was constructed by Pd(II) catalyzed diastereoselective ring formation. The synthesized decahydroisoquinolin inhibitors showed about 2.4 times potent inhibitory activities for SARS 3CL<sup>pro</sup> when combined with a non-prime site substituent. The present results indicated not only the expected additional interactions with the SARS 3CL<sup>pro</sup> but also the possibility of new inhibitors containing a fused-ring system as a hydrophobic scaffold and a new warhead such as thioacetal.</AbstractText><CopyrightInformation>Copyright © 2018 Elsevier Ltd. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Ohnishi</LastName><ForeName>Kouji</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hattori</LastName><ForeName>Yasunao</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Center for Instrumental Analysis, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kobayashi</LastName><ForeName>Kazuya</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Akaji</LastName><ForeName>Kenichi</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan. Electronic address: akaji@mb.kyoto-phu.ac.jp.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2018</Year><Month>12</Month><Day>12</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Bioorg Med Chem</MedlineTA><NlmUniqueID>9413298</NlmUniqueID><ISSNLinking>0968-0896</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D015853">Cysteine Proteinase Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D007546">Isoquinolines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014764">Viral Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.22.-</RegistryNumber><NameOfSubstance UI="C099456">3C-like proteinase, Coronavirus</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.22.-</RegistryNumber><NameOfSubstance UI="D003546">Cysteine Endopeptidases</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020134" MajorTopicYN="N">Catalytic Domain</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003546" MajorTopicYN="N">Cysteine Endopeptidases</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015853" MajorTopicYN="N">Cysteine Proteinase Inhibitors</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007546" MajorTopicYN="N">Isoquinolines</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D062105" MajorTopicYN="N">Molecular Docking Simulation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015394" MajorTopicYN="N">Molecular Structure</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D045473" MajorTopicYN="N">SARS Virus</DescriptorName><QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014764" MajorTopicYN="N">Viral Proteins</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">Decahydroisoquinolin</Keyword><Keyword MajorTopicYN="Y">Inhibitor</Keyword><Keyword MajorTopicYN="Y">Non-prime site</Keyword><Keyword MajorTopicYN="Y">SARS 3CL protease</Keyword><Keyword MajorTopicYN="Y">Thioacetal</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2018</Year><Month>11</Month><Day>12</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2018</Year><Month>12</Month><Day>10</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2018</Year><Month>12</Month><Day>11</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2018</Year><Month>12</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2019</Year><Month>9</Month><Day>17</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2018</Year><Month>12</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">30558861</ArticleId><ArticleId IdType="pii">S0968-0896(18)31916-3</ArticleId><ArticleId IdType="doi">10.1016/j.bmc.2018.12.019</ArticleId><ArticleId IdType="pmc">PMC7126642</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>N Engl J Med. 2003 May 15;348(20):1953-66</Citation><ArticleIdList><ArticleId 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IdType="pubmed">12730501</ArticleId></ArticleIdList></Reference></ReferenceList></PubmedData></pubmed><affiliations><list><country><li>Japon</li></country></list><tree><country name="Japon"><noRegion><name sortKey="Ohnishi, Kouji" sort="Ohnishi, Kouji" uniqKey="Ohnishi K" first="Kouji" last="Ohnishi">Kouji Ohnishi</name></noRegion><name sortKey="Akaji, Kenichi" sort="Akaji, Kenichi" uniqKey="Akaji K" first="Kenichi" last="Akaji">Kenichi Akaji</name><name sortKey="Hattori, Yasunao" sort="Hattori, Yasunao" uniqKey="Hattori Y" first="Yasunao" last="Hattori">Yasunao Hattori</name><name sortKey="Kobayashi, Kazuya" sort="Kobayashi, Kazuya" uniqKey="Kobayashi K" first="Kazuya" last="Kobayashi">Kazuya Kobayashi</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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