Design, synthesis, docking studies and biological screening of 2-thiazolyl substituted -2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines as potent HIV-1 reverse transcriptase inhibitors.
Identifieur interne : 000A17 ( PubMed/Checkpoint ); précédent : 000A16; suivant : 000A18Design, synthesis, docking studies and biological screening of 2-thiazolyl substituted -2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines as potent HIV-1 reverse transcriptase inhibitors.
Auteurs : Rakhi Gawali [Inde] ; Jay Trivedi [Inde] ; Sujit Bhansali [Inde] ; Raghunath Bhosale [Inde] ; Dhiman Sarkar [Inde] ; Debashis Mitra [Inde]Source :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2018.
Descripteurs français
- KwdFr :
- Agents antiVIH (), Agents antiVIH (pharmacologie), Agents antiVIH (synthèse chimique), Conception de médicament, Inhibiteurs de la transcriptase inverse (), Inhibiteurs de la transcriptase inverse (pharmacologie), Inhibiteurs de la transcriptase inverse (synthèse chimique), Naphtalènes (), Naphtalènes (pharmacologie), Naphtalènes (synthèse chimique), Oxazines (), Oxazines (pharmacologie), Oxazines (synthèse chimique), Relation dose-effet des médicaments, Relation structure-activité, Simulation de docking moléculaire, Structure moléculaire, Tests de sensibilité microbienne, Thiazoles (), Thiazoles (pharmacologie), Thiazoles (synthèse chimique), Transcriptase inverse du VIH (antagonistes et inhibiteurs), Transcriptase inverse du VIH (métabolisme), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (), Évaluation préclinique de médicament.
- MESH :
- antagonistes et inhibiteurs : Transcriptase inverse du VIH.
- métabolisme : Transcriptase inverse du VIH.
- pharmacologie : Agents antiVIH, Inhibiteurs de la transcriptase inverse, Naphtalènes, Oxazines, Thiazoles.
- synthèse chimique : Agents antiVIH, Inhibiteurs de la transcriptase inverse, Naphtalènes, Oxazines, Thiazoles.
- Agents antiVIH, Conception de médicament, Inhibiteurs de la transcriptase inverse, Naphtalènes, Oxazines, Relation dose-effet des médicaments, Relation structure-activité, Simulation de docking moléculaire, Structure moléculaire, Tests de sensibilité microbienne, Thiazoles, VIH-1 (Virus de l'Immunodéficience Humaine de type 1), Évaluation préclinique de médicament.
English descriptors
- KwdEn :
- Anti-HIV Agents (chemical synthesis), Anti-HIV Agents (chemistry), Anti-HIV Agents (pharmacology), Dose-Response Relationship, Drug, Drug Design, Drug Evaluation, Preclinical, HIV Reverse Transcriptase (antagonists & inhibitors), HIV Reverse Transcriptase (metabolism), HIV-1 (drug effects), Microbial Sensitivity Tests, Molecular Docking Simulation, Molecular Structure, Naphthalenes (chemical synthesis), Naphthalenes (chemistry), Naphthalenes (pharmacology), Oxazines (chemical synthesis), Oxazines (chemistry), Oxazines (pharmacology), Reverse Transcriptase Inhibitors (chemical synthesis), Reverse Transcriptase Inhibitors (chemistry), Reverse Transcriptase Inhibitors (pharmacology), Structure-Activity Relationship, Thiazoles (chemical synthesis), Thiazoles (chemistry), Thiazoles (pharmacology).
- MESH :
- chemical , antagonists & inhibitors : HIV Reverse Transcriptase.
- chemical , chemical synthesis : Anti-HIV Agents, Naphthalenes, Oxazines, Reverse Transcriptase Inhibitors, Thiazoles.
- chemical , chemistry : Anti-HIV Agents, Naphthalenes, Oxazines, Reverse Transcriptase Inhibitors, Thiazoles.
- chemical , metabolism : HIV Reverse Transcriptase.
- chemical , pharmacology : Anti-HIV Agents, Naphthalenes, Oxazines, Reverse Transcriptase Inhibitors, Thiazoles.
- drug effects : HIV-1.
- Dose-Response Relationship, Drug, Drug Design, Drug Evaluation, Preclinical, Microbial Sensitivity Tests, Molecular Docking Simulation, Molecular Structure, Structure-Activity Relationship.
Abstract
1,3-oxazine nucleus and thiazolyl group features prominently in many biologically important natural products as well as bioactive molecules. A series of novel 2-thiazolyl substituted-2,3-dihydro-1H-naphtho [1,2-e][1,3]oxazine derivatives were designed and synthesized based on their structure-activity relationships (SARs) from 2-naphthol, substituted thiazolyl amines and formalin through ring closure by one-pot three component reaction. These derivatives were first evaluated for their inhibitory effect on HIV-1 Reverse Transcriptase (RT) enzyme activity. Out of 14 compounds, 4 showed potent inhibition of HIV-1 RT activity at significantly low concentration. Docking studies of these molecules revealed their high affinity binding to several amino acids of HIV-1 RT which are less sensitive to point mutations. Furthermore, anti-HIV activity of these molecules was analysed in a CD4+ T cell-line, which indicates that Therapeutic Index (TI) of some of these compounds is better than Zidovudine and Efavirenz, known HIV-1 RT inhibitors. Taken together, our studies report for the first time some novel naphthoxazine derivatives with significant TI, which is through inhibition of HIV-1 RT activity.
DOI: 10.1016/j.ejmech.2018.07.067
PubMed: 30099253
Affiliations:
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pubmed:30099253Le document en format XML
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<term>Anti-HIV Agents (chemistry)</term>
<term>Anti-HIV Agents (pharmacology)</term>
<term>Dose-Response Relationship, Drug</term>
<term>Drug Design</term>
<term>Drug Evaluation, Preclinical</term>
<term>HIV Reverse Transcriptase (antagonists & inhibitors)</term>
<term>HIV Reverse Transcriptase (metabolism)</term>
<term>HIV-1 (drug effects)</term>
<term>Microbial Sensitivity Tests</term>
<term>Molecular Docking Simulation</term>
<term>Molecular Structure</term>
<term>Naphthalenes (chemical synthesis)</term>
<term>Naphthalenes (chemistry)</term>
<term>Naphthalenes (pharmacology)</term>
<term>Oxazines (chemical synthesis)</term>
<term>Oxazines (chemistry)</term>
<term>Oxazines (pharmacology)</term>
<term>Reverse Transcriptase Inhibitors (chemical synthesis)</term>
<term>Reverse Transcriptase Inhibitors (chemistry)</term>
<term>Reverse Transcriptase Inhibitors (pharmacology)</term>
<term>Structure-Activity Relationship</term>
<term>Thiazoles (chemical synthesis)</term>
<term>Thiazoles (chemistry)</term>
<term>Thiazoles (pharmacology)</term>
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<keywords scheme="KwdFr" xml:lang="fr"><term>Agents antiVIH ()</term>
<term>Agents antiVIH (pharmacologie)</term>
<term>Agents antiVIH (synthèse chimique)</term>
<term>Conception de médicament</term>
<term>Inhibiteurs de la transcriptase inverse ()</term>
<term>Inhibiteurs de la transcriptase inverse (pharmacologie)</term>
<term>Inhibiteurs de la transcriptase inverse (synthèse chimique)</term>
<term>Naphtalènes ()</term>
<term>Naphtalènes (pharmacologie)</term>
<term>Naphtalènes (synthèse chimique)</term>
<term>Oxazines ()</term>
<term>Oxazines (pharmacologie)</term>
<term>Oxazines (synthèse chimique)</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Simulation de docking moléculaire</term>
<term>Structure moléculaire</term>
<term>Tests de sensibilité microbienne</term>
<term>Thiazoles ()</term>
<term>Thiazoles (pharmacologie)</term>
<term>Thiazoles (synthèse chimique)</term>
<term>Transcriptase inverse du VIH (antagonistes et inhibiteurs)</term>
<term>Transcriptase inverse du VIH (métabolisme)</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term>
<term>Évaluation préclinique de médicament</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>HIV Reverse Transcriptase</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Anti-HIV Agents</term>
<term>Naphthalenes</term>
<term>Oxazines</term>
<term>Reverse Transcriptase Inhibitors</term>
<term>Thiazoles</term>
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<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Anti-HIV Agents</term>
<term>Naphthalenes</term>
<term>Oxazines</term>
<term>Reverse Transcriptase Inhibitors</term>
<term>Thiazoles</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>HIV Reverse Transcriptase</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-HIV Agents</term>
<term>Naphthalenes</term>
<term>Oxazines</term>
<term>Reverse Transcriptase Inhibitors</term>
<term>Thiazoles</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Transcriptase inverse du VIH</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>HIV-1</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Transcriptase inverse du VIH</term>
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<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Agents antiVIH</term>
<term>Inhibiteurs de la transcriptase inverse</term>
<term>Naphtalènes</term>
<term>Oxazines</term>
<term>Thiazoles</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Agents antiVIH</term>
<term>Inhibiteurs de la transcriptase inverse</term>
<term>Naphtalènes</term>
<term>Oxazines</term>
<term>Thiazoles</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Dose-Response Relationship, Drug</term>
<term>Drug Design</term>
<term>Drug Evaluation, Preclinical</term>
<term>Microbial Sensitivity Tests</term>
<term>Molecular Docking Simulation</term>
<term>Molecular Structure</term>
<term>Structure-Activity Relationship</term>
</keywords>
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<term>Conception de médicament</term>
<term>Inhibiteurs de la transcriptase inverse</term>
<term>Naphtalènes</term>
<term>Oxazines</term>
<term>Relation dose-effet des médicaments</term>
<term>Relation structure-activité</term>
<term>Simulation de docking moléculaire</term>
<term>Structure moléculaire</term>
<term>Tests de sensibilité microbienne</term>
<term>Thiazoles</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
<term>Évaluation préclinique de médicament</term>
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<front><div type="abstract" xml:lang="en">1,3-oxazine nucleus and thiazolyl group features prominently in many biologically important natural products as well as bioactive molecules. A series of novel 2-thiazolyl substituted-2,3-dihydro-1H-naphtho [1,2-e][1,3]oxazine derivatives were designed and synthesized based on their structure-activity relationships (SARs) from 2-naphthol, substituted thiazolyl amines and formalin through ring closure by one-pot three component reaction. These derivatives were first evaluated for their inhibitory effect on HIV-1 Reverse Transcriptase (RT) enzyme activity. Out of 14 compounds, 4 showed potent inhibition of HIV-1 RT activity at significantly low concentration. Docking studies of these molecules revealed their high affinity binding to several amino acids of HIV-1 RT which are less sensitive to point mutations. Furthermore, anti-HIV activity of these molecules was analysed in a CD4<sup>+</sup>
T cell-line, which indicates that Therapeutic Index (TI) of some of these compounds is better than Zidovudine and Efavirenz, known HIV-1 RT inhibitors. Taken together, our studies report for the first time some novel naphthoxazine derivatives with significant TI, which is through inhibition of HIV-1 RT activity.</div>
</front>
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<Abstract><AbstractText>1,3-oxazine nucleus and thiazolyl group features prominently in many biologically important natural products as well as bioactive molecules. A series of novel 2-thiazolyl substituted-2,3-dihydro-1H-naphtho [1,2-e][1,3]oxazine derivatives were designed and synthesized based on their structure-activity relationships (SARs) from 2-naphthol, substituted thiazolyl amines and formalin through ring closure by one-pot three component reaction. These derivatives were first evaluated for their inhibitory effect on HIV-1 Reverse Transcriptase (RT) enzyme activity. Out of 14 compounds, 4 showed potent inhibition of HIV-1 RT activity at significantly low concentration. Docking studies of these molecules revealed their high affinity binding to several amino acids of HIV-1 RT which are less sensitive to point mutations. Furthermore, anti-HIV activity of these molecules was analysed in a CD4<sup>+</sup>
T cell-line, which indicates that Therapeutic Index (TI) of some of these compounds is better than Zidovudine and Efavirenz, known HIV-1 RT inhibitors. Taken together, our studies report for the first time some novel naphthoxazine derivatives with significant TI, which is through inhibition of HIV-1 RT activity.</AbstractText>
<CopyrightInformation>Copyright © 2018 Elsevier Masson SAS. All rights reserved.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Gawali</LastName>
<ForeName>Rakhi</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Organic Chemistry Research Laboratory, School of Chemical Sciences, Solapur University, Solapur, 413255, Maharashtra, India. Electronic address: rggjknk@gmail.com.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Trivedi</LastName>
<ForeName>Jay</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>National Centre of Cell Science, Savitribai Phule Pune University Campus, Pune, 411007, Maharashtra, India. Electronic address: jay@nccs.res.in.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Bhansali</LastName>
<ForeName>Sujit</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Combichem Bioresource Centre, National Chemical Laboratory, Pune, 411008, Maharashtra, India. Electronic address: sg.bhansali@ncl.res.in.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Bhosale</LastName>
<ForeName>Raghunath</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Organic Chemistry Research Laboratory, School of Chemical Sciences, Solapur University, Solapur, 413255, Maharashtra, India. Electronic address: bhosale62@yahoo.com.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Sarkar</LastName>
<ForeName>Dhiman</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>Combichem Bioresource Centre, National Chemical Laboratory, Pune, 411008, Maharashtra, India. Electronic address: d.sarkar@ncl.res.in.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Mitra</LastName>
<ForeName>Debashis</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>National Centre of Cell Science, Savitribai Phule Pune University Campus, Pune, 411007, Maharashtra, India; Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India. Electronic address: dmitra@nccs.res.in.</Affiliation>
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<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C000628713">2,3-dihydro-1H-naphtho(1,2-e)(1,3)oxazine</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D019380">Anti-HIV Agents</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D009281">Naphthalenes</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D010078">Oxazines</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D018894">Reverse Transcriptase Inhibitors</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D013844">Thiazoles</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.7.-</RegistryNumber>
<NameOfSubstance UI="C514824">reverse transcriptase, Human immunodeficiency virus 1</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.7.49</RegistryNumber>
<NameOfSubstance UI="D054303">HIV Reverse Transcriptase</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D019380" MajorTopicYN="N">Anti-HIV 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="D004305" MajorTopicYN="N">Dose-Response Relationship, Drug</DescriptorName>
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</MeshHeading>
<MeshHeading><DescriptorName UI="D004353" MajorTopicYN="N">Drug Evaluation, Preclinical</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D054303" MajorTopicYN="N">HIV Reverse Transcriptase</DescriptorName>
<QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D015497" MajorTopicYN="N">HIV-1</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008826" MajorTopicYN="N">Microbial Sensitivity Tests</DescriptorName>
</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="D009281" MajorTopicYN="N">Naphthalenes</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="D010078" MajorTopicYN="N">Oxazines</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="D018894" MajorTopicYN="N">Reverse Transcriptase 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="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D013844" MajorTopicYN="N">Thiazoles</DescriptorName>
<QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
</MeshHeadingList>
<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Anti-HIV</Keyword>
<Keyword MajorTopicYN="N">CD4+ T cell-line</Keyword>
<Keyword MajorTopicYN="N">Efavirenz</Keyword>
<Keyword MajorTopicYN="N">Naphthoxazine derivatives</Keyword>
</KeywordList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2018</Year>
<Month>03</Month>
<Day>26</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="revised"><Year>2018</Year>
<Month>07</Month>
<Day>27</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted"><Year>2018</Year>
<Month>07</Month>
<Day>29</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="pubmed"><Year>2018</Year>
<Month>8</Month>
<Day>14</Day>
<Hour>6</Hour>
<Minute>0</Minute>
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<PubMedPubDate PubStatus="medline"><Year>2018</Year>
<Month>10</Month>
<Day>23</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>2018</Year>
<Month>8</Month>
<Day>13</Day>
<Hour>6</Hour>
<Minute>0</Minute>
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</History>
<PublicationStatus>ppublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="pubmed">30099253</ArticleId>
<ArticleId IdType="pii">S0223-5234(18)30632-9</ArticleId>
<ArticleId IdType="doi">10.1016/j.ejmech.2018.07.067</ArticleId>
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<affiliations><list><country><li>Inde</li>
</country>
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<tree><country name="Inde"><noRegion><name sortKey="Gawali, Rakhi" sort="Gawali, Rakhi" uniqKey="Gawali R" first="Rakhi" last="Gawali">Rakhi Gawali</name>
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<name sortKey="Bhansali, Sujit" sort="Bhansali, Sujit" uniqKey="Bhansali S" first="Sujit" last="Bhansali">Sujit Bhansali</name>
<name sortKey="Bhosale, Raghunath" sort="Bhosale, Raghunath" uniqKey="Bhosale R" first="Raghunath" last="Bhosale">Raghunath Bhosale</name>
<name sortKey="Mitra, Debashis" sort="Mitra, Debashis" uniqKey="Mitra D" first="Debashis" last="Mitra">Debashis Mitra</name>
<name sortKey="Sarkar, Dhiman" sort="Sarkar, Dhiman" uniqKey="Sarkar D" first="Dhiman" last="Sarkar">Dhiman Sarkar</name>
<name sortKey="Trivedi, Jay" sort="Trivedi, Jay" uniqKey="Trivedi J" first="Jay" last="Trivedi">Jay Trivedi</name>
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