Development of 2-substituted-N-(naphth-1-ylmethyl) and N-benzhydrylpyrimidin-4-amines as dual cholinesterase and Aβ-aggregation inhibitors: Synthesis and biological evaluation.
Identifieur interne : 000B65 ( PubMed/Corpus ); précédent : 000B64; suivant : 000B66Development of 2-substituted-N-(naphth-1-ylmethyl) and N-benzhydrylpyrimidin-4-amines as dual cholinesterase and Aβ-aggregation inhibitors: Synthesis and biological evaluation.
Auteurs : Tarek Mohamed ; Jacky C K. Yeung ; Praveen P N. RaoSource :
- Bioorganic & medicinal chemistry letters [ 1464-3405 ] ; 2011.
English descriptors
- KwdEn :
- Acetylcholinesterase (metabolism), Amyloid beta-Peptides (metabolism), Benzhydryl Compounds (chemical synthesis), Benzhydryl Compounds (chemistry), Benzhydryl Compounds (metabolism), Benzhydryl Compounds (pharmacology), Butyrylcholinesterase (metabolism), Cholinesterase Inhibitors (chemical synthesis), Cholinesterase Inhibitors (chemistry), Cholinesterase Inhibitors (metabolism), Cholinesterase Inhibitors (pharmacology), Dose-Response Relationship, Drug, Drug Design, Drug Evaluation, Preclinical, Humans, Models, Molecular, Molecular Structure, Molecular Targeted Therapy, Parkinson Disease (drug therapy), Parkinson Disease (pathology), Parkinson Disease (physiopathology), Parkinson Disease (prevention & control), Plaque, Amyloid (drug therapy), Plaque, Amyloid (pathology), Plaque, Amyloid (prevention & control), Pyrimidines (chemical synthesis), Pyrimidines (chemistry), Pyrimidines (metabolism), Pyrimidines (pharmacology), Structure-Activity Relationship.
- MESH :
- chemical , chemical synthesis : Benzhydryl Compounds, Cholinesterase Inhibitors, Pyrimidines.
- chemical , chemistry : Benzhydryl Compounds, Cholinesterase Inhibitors, Pyrimidines.
- chemical , metabolism : Acetylcholinesterase, Amyloid beta-Peptides, Benzhydryl Compounds, Butyrylcholinesterase, Cholinesterase Inhibitors, Pyrimidines.
- chemical , pharmacology : Benzhydryl Compounds, Cholinesterase Inhibitors, Pyrimidines.
- drug therapy : Parkinson Disease, Plaque, Amyloid.
- pathology : Parkinson Disease, Plaque, Amyloid.
- physiopathology : Parkinson Disease.
- prevention & control : Parkinson Disease, Plaque, Amyloid.
- Dose-Response Relationship, Drug, Drug Design, Drug Evaluation, Preclinical, Humans, Models, Molecular, Molecular Structure, Molecular Targeted Therapy, Structure-Activity Relationship.
Abstract
A group of 2-substituted N-(naphth-1-ylmethyl)pyrimidin-4-amines (6a-k) and N-benzhydrylpyrimidin-4-amines (7a-k) in conjunction with varying steric and electronic properties at the C-2 position were designed, synthesized and evaluated as dual cholinesterase and amyloid-β (Aβ)-aggregation inhibitors. The naphth-1-ylmethyl compound 6f (2-(4-cyclohexylpiperazin-1-yl)-N-(naphth-1-ylmethyl)pyrimidin-4-amine) exhibited optimum dual ChE (AChE IC(50)=8.0 μM, BuChE IC(50)=3.9 μM) and hAChE-promoted Aβ-aggregation inhibition (30.8% at 100 μM), whereas in the N-benzhydryl series, compound 7f (N-benzhydryl-2-(4-cyclohexylpiperazin-1-yl)pyrimidin-4-amine) exhibited optimum combination of dual ChE (AChE IC(50)=10.0 μM, BuChE IC(50)=7.6μM) and hAChE-promoted Aβ-aggregation inhibition (32% at 100 μM). These results demonstrate that a 2,4-disubstituted pyrimidine ring serves as a suitable template to target multiple pathological routes in AD, with a C-2 cyclohexylpiperazine substituent providing dual ChE inhibition and potency whereas a C-4 diphenylmethane substituent provides Aβ-aggregation inhibition.
DOI: 10.1016/j.bmcl.2011.07.091
PubMed: 21873056
Links to Exploration step
pubmed:21873056Le document en format XML
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Rao</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2011">2011</date><idno type="RBID">pubmed:21873056</idno><idno type="pmid">21873056</idno><idno type="doi">10.1016/j.bmcl.2011.07.091</idno><idno type="wicri:Area/PubMed/Corpus">000B65</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000B65</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Development of 2-substituted-N-(naphth-1-ylmethyl) and N-benzhydrylpyrimidin-4-amines as dual cholinesterase and Aβ-aggregation inhibitors: Synthesis and biological evaluation.</title><author><name sortKey="Mohamed, Tarek" sort="Mohamed, Tarek" uniqKey="Mohamed T" first="Tarek" last="Mohamed">Tarek Mohamed</name><affiliation><nlm:affiliation>Department of Biology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1.</nlm:affiliation></affiliation></author><author><name sortKey="Yeung, Jacky C K" sort="Yeung, Jacky C K" uniqKey="Yeung J" first="Jacky C K" last="Yeung">Jacky C K. Yeung</name></author><author><name sortKey="Rao, Praveen P N" sort="Rao, Praveen P N" uniqKey="Rao P" first="Praveen P N" last="Rao">Praveen P N. Rao</name></author></analytic><series><title level="j">Bioorganic & medicinal chemistry letters</title><idno type="eISSN">1464-3405</idno><imprint><date when="2011" type="published">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acetylcholinesterase (metabolism)</term><term>Amyloid beta-Peptides (metabolism)</term><term>Benzhydryl Compounds (chemical synthesis)</term><term>Benzhydryl Compounds (chemistry)</term><term>Benzhydryl Compounds (metabolism)</term><term>Benzhydryl Compounds (pharmacology)</term><term>Butyrylcholinesterase (metabolism)</term><term>Cholinesterase Inhibitors (chemical synthesis)</term><term>Cholinesterase Inhibitors (chemistry)</term><term>Cholinesterase Inhibitors (metabolism)</term><term>Cholinesterase Inhibitors (pharmacology)</term><term>Dose-Response Relationship, Drug</term><term>Drug Design</term><term>Drug Evaluation, Preclinical</term><term>Humans</term><term>Models, Molecular</term><term>Molecular Structure</term><term>Molecular Targeted Therapy</term><term>Parkinson Disease (drug therapy)</term><term>Parkinson Disease (pathology)</term><term>Parkinson Disease (physiopathology)</term><term>Parkinson Disease (prevention & control)</term><term>Plaque, Amyloid (drug therapy)</term><term>Plaque, Amyloid (pathology)</term><term>Plaque, Amyloid (prevention & control)</term><term>Pyrimidines (chemical synthesis)</term><term>Pyrimidines (chemistry)</term><term>Pyrimidines (metabolism)</term><term>Pyrimidines (pharmacology)</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Benzhydryl Compounds</term><term>Cholinesterase Inhibitors</term><term>Pyrimidines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Benzhydryl Compounds</term><term>Cholinesterase Inhibitors</term><term>Pyrimidines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Acetylcholinesterase</term><term>Amyloid beta-Peptides</term><term>Benzhydryl Compounds</term><term>Butyrylcholinesterase</term><term>Cholinesterase Inhibitors</term><term>Pyrimidines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Benzhydryl Compounds</term><term>Cholinesterase Inhibitors</term><term>Pyrimidines</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Parkinson Disease</term><term>Plaque, Amyloid</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Parkinson Disease</term><term>Plaque, Amyloid</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Parkinson Disease</term><term>Plaque, Amyloid</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Dose-Response Relationship, Drug</term><term>Drug Design</term><term>Drug Evaluation, Preclinical</term><term>Humans</term><term>Models, Molecular</term><term>Molecular Structure</term><term>Molecular Targeted Therapy</term><term>Structure-Activity Relationship</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A group of 2-substituted N-(naphth-1-ylmethyl)pyrimidin-4-amines (6a-k) and N-benzhydrylpyrimidin-4-amines (7a-k) in conjunction with varying steric and electronic properties at the C-2 position were designed, synthesized and evaluated as dual cholinesterase and amyloid-β (Aβ)-aggregation inhibitors. The naphth-1-ylmethyl compound 6f (2-(4-cyclohexylpiperazin-1-yl)-N-(naphth-1-ylmethyl)pyrimidin-4-amine) exhibited optimum dual ChE (AChE IC(50)=8.0 μM, BuChE IC(50)=3.9 μM) and hAChE-promoted Aβ-aggregation inhibition (30.8% at 100 μM), whereas in the N-benzhydryl series, compound 7f (N-benzhydryl-2-(4-cyclohexylpiperazin-1-yl)pyrimidin-4-amine) exhibited optimum combination of dual ChE (AChE IC(50)=10.0 μM, BuChE IC(50)=7.6μM) and hAChE-promoted Aβ-aggregation inhibition (32% at 100 μM). These results demonstrate that a 2,4-disubstituted pyrimidine ring serves as a suitable template to target multiple pathological routes in AD, with a C-2 cyclohexylpiperazine substituent providing dual ChE inhibition and potency whereas a C-4 diphenylmethane substituent provides Aβ-aggregation inhibition.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">21873056</PMID><DateCreated><Year>2011</Year><Month>09</Month><Day>12</Day></DateCreated><DateCompleted><Year>2012</Year><Month>04</Month><Day>16</Day></DateCompleted><DateRevised><Year>2011</Year><Month>09</Month><Day>12</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1464-3405</ISSN><JournalIssue CitedMedium="Internet"><Volume>21</Volume><Issue>19</Issue><PubDate><Year>2011</Year><Month>Oct</Month><Day>01</Day></PubDate></JournalIssue><Title>Bioorganic & medicinal chemistry letters</Title><ISOAbbreviation>Bioorg. Med. Chem. Lett.</ISOAbbreviation></Journal><ArticleTitle>Development of 2-substituted-N-(naphth-1-ylmethyl) and N-benzhydrylpyrimidin-4-amines as dual cholinesterase and Aβ-aggregation inhibitors: Synthesis and biological evaluation.</ArticleTitle><Pagination><MedlinePgn>5881-7</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.bmcl.2011.07.091</ELocationID><Abstract><AbstractText>A group of 2-substituted N-(naphth-1-ylmethyl)pyrimidin-4-amines (6a-k) and N-benzhydrylpyrimidin-4-amines (7a-k) in conjunction with varying steric and electronic properties at the C-2 position were designed, synthesized and evaluated as dual cholinesterase and amyloid-β (Aβ)-aggregation inhibitors. The naphth-1-ylmethyl compound 6f (2-(4-cyclohexylpiperazin-1-yl)-N-(naphth-1-ylmethyl)pyrimidin-4-amine) exhibited optimum dual ChE (AChE IC(50)=8.0 μM, BuChE IC(50)=3.9 μM) and hAChE-promoted Aβ-aggregation inhibition (30.8% at 100 μM), whereas in the N-benzhydryl series, compound 7f (N-benzhydryl-2-(4-cyclohexylpiperazin-1-yl)pyrimidin-4-amine) exhibited optimum combination of dual ChE (AChE IC(50)=10.0 μM, BuChE IC(50)=7.6μM) and hAChE-promoted Aβ-aggregation inhibition (32% at 100 μM). These results demonstrate that a 2,4-disubstituted pyrimidine ring serves as a suitable template to target multiple pathological routes in AD, with a C-2 cyclohexylpiperazine substituent providing dual ChE inhibition and potency whereas a C-4 diphenylmethane substituent provides Aβ-aggregation inhibition.</AbstractText><CopyrightInformation>Copyright © 2011 Elsevier Ltd. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Mohamed</LastName><ForeName>Tarek</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Department of Biology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yeung</LastName><ForeName>Jacky C K</ForeName><Initials>JC</Initials></Author><Author ValidYN="Y"><LastName>Rao</LastName><ForeName>Praveen P N</ForeName><Initials>PP</Initials></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>2011</Year><Month>07</Month><Day>30</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Bioorg Med Chem Lett</MedlineTA><NlmUniqueID>9107377</NlmUniqueID><ISSNLinking>0960-894X</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D016229">Amyloid beta-Peptides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D001559">Benzhydryl Compounds</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D002800">Cholinesterase Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011743">Pyrimidines</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.1.1.-</RegistryNumber><NameOfSubstance UI="D002091">Butyrylcholinesterase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.1.1.7</RegistryNumber><NameOfSubstance UI="D000110">Acetylcholinesterase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000110" MajorTopicYN="N">Acetylcholinesterase</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016229" MajorTopicYN="N">Amyloid beta-Peptides</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001559" MajorTopicYN="N">Benzhydryl Compounds</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002091" MajorTopicYN="N">Butyrylcholinesterase</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002800" MajorTopicYN="N">Cholinesterase Inhibitors</DescriptorName><QualifierName UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004305" MajorTopicYN="N">Dose-Response Relationship, Drug</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015195" MajorTopicYN="N">Drug Design</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004353" MajorTopicYN="N">Drug Evaluation, Preclinical</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008958" MajorTopicYN="N">Models, Molecular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015394" MajorTopicYN="N">Molecular 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UI="Q000138" MajorTopicYN="Y">chemical synthesis</QualifierName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2011</Year><Month>07</Month><Day>04</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2011</Year><Month>07</Month><Day>22</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2011</Year><Month>07</Month><Day>25</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2011</Year><Month>8</Month><Day>30</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2011</Year><Month>8</Month><Day>30</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2012</Year><Month>4</Month><Day>17</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">21873056</ArticleId><ArticleId IdType="pii">S0960-894X(11)01037-7</ArticleId><ArticleId IdType="doi">10.1016/j.bmcl.2011.07.091</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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