Synthesis and structure–activity relationships evaluation of benzothiazinone derivatives as potential anti-tubercular agents
The synthesis and SAR profile of N-alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives are described. The most potent compound 8o exhibits a MIC of 0.0001μM against Mycobacterium tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. N-Alkyl and heterocycle substituted...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2013-09, Vol.23 (17), p.4919-4922 |
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| creator | Gao, Chao Ye, Ting-Hong Wang, Ning-Yu Zeng, Xiu-Xiu Zhang, Li-Dan Xiong, Ying You, Xin-Yu Xia, Yong Xu, Ying Peng, Cui-Ting Zuo, Wei-Qiong Wei, Yuquan Yu, Luo-Ting |
| description | The synthesis and SAR profile of N-alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives are described. The most potent compound 8o exhibits a MIC of 0.0001μM against Mycobacterium tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate.
N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds were evaluated by determination of minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, and activities of N-alkyl substituted BTZs were not affected by either nitro or trifluoromethyl at 6-position. Trifluoromethyl plays an important role in maintaining anti-tubercular activity in the piperazine or piperidine analogs. Compound 8o, which contains an azaspirodithiolane group, showed a MIC of 0.0001μM against M. tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested that the volume and lipophilicity of the substituents were important in maintaining activity. In addition, compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study. |
| doi_str_mv | 10.1016/j.bmcl.2013.06.069 |
| format | Article |
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N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds were evaluated by determination of minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, and activities of N-alkyl substituted BTZs were not affected by either nitro or trifluoromethyl at 6-position. Trifluoromethyl plays an important role in maintaining anti-tubercular activity in the piperazine or piperidine analogs. Compound 8o, which contains an azaspirodithiolane group, showed a MIC of 0.0001μM against M. tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested that the volume and lipophilicity of the substituents were important in maintaining activity. In addition, compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2013.06.069</identifier><identifier>PMID: 23886691</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Antitubercular Agents - chemical synthesis ; Antitubercular Agents - chemistry ; Antitubercular Agents - pharmacokinetics ; Antitubercular Agents - pharmacology ; Benzothiazinone ; Cercopithecus aethiops ; DprE1 ; Humans ; hydrophobicity ; minimum inhibitory concentration ; Mycobacterium tuberculosis ; Mycobacterium tuberculosis - drug effects ; pharmacokinetics ; piperazine ; piperidines ; Rats ; Rats, Sprague-Dawley ; Spiro Compounds - chemical synthesis ; Spiro Compounds - chemistry ; Spiro Compounds - pharmacokinetics ; Spiro Compounds - pharmacology ; Structure-Activity Relationship ; structure-activity relationships ; Structure–activity relationships (SAR) ; Thiazines - chemical synthesis ; Thiazines - chemistry ; Thiazines - pharmacokinetics ; Thiazines - pharmacology ; Tuberculosis ; Tuberculosis - drug therapy ; Vero Cells</subject><ispartof>Bioorganic & medicinal chemistry letters, 2013-09, Vol.23 (17), p.4919-4922</ispartof><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c413t-e7611334d3b0a66a3cbc903b44cb088fefd19bcab203b0c60c6e3680a9a5593e3</citedby><cites>FETCH-LOGICAL-c413t-e7611334d3b0a66a3cbc903b44cb088fefd19bcab203b0c60c6e3680a9a5593e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2013.06.069$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3549,27923,27924,45994</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23886691$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gao, Chao</creatorcontrib><creatorcontrib>Ye, Ting-Hong</creatorcontrib><creatorcontrib>Wang, Ning-Yu</creatorcontrib><creatorcontrib>Zeng, Xiu-Xiu</creatorcontrib><creatorcontrib>Zhang, Li-Dan</creatorcontrib><creatorcontrib>Xiong, Ying</creatorcontrib><creatorcontrib>You, Xin-Yu</creatorcontrib><creatorcontrib>Xia, Yong</creatorcontrib><creatorcontrib>Xu, Ying</creatorcontrib><creatorcontrib>Peng, Cui-Ting</creatorcontrib><creatorcontrib>Zuo, Wei-Qiong</creatorcontrib><creatorcontrib>Wei, Yuquan</creatorcontrib><creatorcontrib>Yu, Luo-Ting</creatorcontrib><title>Synthesis and structure–activity relationships evaluation of benzothiazinone derivatives as potential anti-tubercular agents</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The synthesis and SAR profile of N-alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives are described. The most potent compound 8o exhibits a MIC of 0.0001μM against Mycobacterium tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate.
N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds were evaluated by determination of minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, and activities of N-alkyl substituted BTZs were not affected by either nitro or trifluoromethyl at 6-position. Trifluoromethyl plays an important role in maintaining anti-tubercular activity in the piperazine or piperidine analogs. Compound 8o, which contains an azaspirodithiolane group, showed a MIC of 0.0001μM against M. tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested that the volume and lipophilicity of the substituents were important in maintaining activity. In addition, compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study.</description><subject>Animals</subject><subject>Antitubercular Agents - chemical synthesis</subject><subject>Antitubercular Agents - chemistry</subject><subject>Antitubercular Agents - pharmacokinetics</subject><subject>Antitubercular Agents - pharmacology</subject><subject>Benzothiazinone</subject><subject>Cercopithecus aethiops</subject><subject>DprE1</subject><subject>Humans</subject><subject>hydrophobicity</subject><subject>minimum inhibitory concentration</subject><subject>Mycobacterium tuberculosis</subject><subject>Mycobacterium tuberculosis - drug effects</subject><subject>pharmacokinetics</subject><subject>piperazine</subject><subject>piperidines</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Spiro Compounds - chemical synthesis</subject><subject>Spiro Compounds - chemistry</subject><subject>Spiro Compounds - pharmacokinetics</subject><subject>Spiro Compounds - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>structure-activity relationships</subject><subject>Structure–activity relationships (SAR)</subject><subject>Thiazines - chemical synthesis</subject><subject>Thiazines - chemistry</subject><subject>Thiazines - pharmacokinetics</subject><subject>Thiazines - pharmacology</subject><subject>Tuberculosis</subject><subject>Tuberculosis - drug therapy</subject><subject>Vero Cells</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcGKFDEQhoO4uOPqC3jQPnrp2UonnemAF1lWV1jwsC54C0m6eidDTzIm6YbZg_gOvqFPshln9ajwQ1Gpr36K_IS8orCkQMX5Zmm2dlw2QNkSRJF8QhaUC14zDu1TsgApoO4k_3pKnqe0AaAcOH9GThvWdUJIuiDfb_Y-rzG5VGnfVynHyeYp4q8fP7XNbnZ5X0UcdXbBp7XbpQpnPU6_-yoMlUF_H_La6Xvng8eqx-jmMp2xGKZqFzL67PRY3LOr82Qw2mnUsdJ3ZZBekJNBjwlfPtYzcvvh8svFVX39-eOni_fXteWU5RpXglLGeM8MaCE0s8ZKYIZza6DrBhx6Ko3VpimPYEURMtGBlrptJUN2Rt4efXcxfJswZbV1yeI4ao9hSoq2AKtOtB37P8qpZJw1tCloc0RtDClFHNQuuq2Oe0VBHSJSG3WISB0iUiCKZFl6_eg_mS32f1f-ZFKAN0dg0EHpu-iSur0pDuVEyhq2agvx7khg-bLZYVTJOvQWexfRZtUH968LHgAlWrBx</recordid><startdate>20130901</startdate><enddate>20130901</enddate><creator>Gao, Chao</creator><creator>Ye, Ting-Hong</creator><creator>Wang, Ning-Yu</creator><creator>Zeng, Xiu-Xiu</creator><creator>Zhang, Li-Dan</creator><creator>Xiong, Ying</creator><creator>You, Xin-Yu</creator><creator>Xia, Yong</creator><creator>Xu, Ying</creator><creator>Peng, Cui-Ting</creator><creator>Zuo, Wei-Qiong</creator><creator>Wei, Yuquan</creator><creator>Yu, Luo-Ting</creator><general>Elsevier Ltd</general><scope>FBQ</scope><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><scope>7QL</scope><scope>7QO</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20130901</creationdate><title>Synthesis and structure–activity relationships evaluation of benzothiazinone derivatives as potential anti-tubercular agents</title><author>Gao, Chao ; Ye, Ting-Hong ; Wang, Ning-Yu ; Zeng, Xiu-Xiu ; Zhang, Li-Dan ; Xiong, Ying ; You, Xin-Yu ; Xia, Yong ; Xu, Ying ; Peng, Cui-Ting ; Zuo, Wei-Qiong ; Wei, Yuquan ; Yu, Luo-Ting</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c413t-e7611334d3b0a66a3cbc903b44cb088fefd19bcab203b0c60c6e3680a9a5593e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Antitubercular Agents - chemical synthesis</topic><topic>Antitubercular Agents - chemistry</topic><topic>Antitubercular Agents - pharmacokinetics</topic><topic>Antitubercular Agents - pharmacology</topic><topic>Benzothiazinone</topic><topic>Cercopithecus aethiops</topic><topic>DprE1</topic><topic>Humans</topic><topic>hydrophobicity</topic><topic>minimum inhibitory concentration</topic><topic>Mycobacterium tuberculosis</topic><topic>Mycobacterium tuberculosis - drug effects</topic><topic>pharmacokinetics</topic><topic>piperazine</topic><topic>piperidines</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Spiro Compounds - chemical synthesis</topic><topic>Spiro Compounds - chemistry</topic><topic>Spiro Compounds - pharmacokinetics</topic><topic>Spiro Compounds - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>structure-activity relationships</topic><topic>Structure–activity relationships (SAR)</topic><topic>Thiazines - chemical synthesis</topic><topic>Thiazines - chemistry</topic><topic>Thiazines - pharmacokinetics</topic><topic>Thiazines - pharmacology</topic><topic>Tuberculosis</topic><topic>Tuberculosis - drug therapy</topic><topic>Vero Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gao, Chao</creatorcontrib><creatorcontrib>Ye, Ting-Hong</creatorcontrib><creatorcontrib>Wang, Ning-Yu</creatorcontrib><creatorcontrib>Zeng, Xiu-Xiu</creatorcontrib><creatorcontrib>Zhang, Li-Dan</creatorcontrib><creatorcontrib>Xiong, Ying</creatorcontrib><creatorcontrib>You, Xin-Yu</creatorcontrib><creatorcontrib>Xia, Yong</creatorcontrib><creatorcontrib>Xu, Ying</creatorcontrib><creatorcontrib>Peng, Cui-Ting</creatorcontrib><creatorcontrib>Zuo, Wei-Qiong</creatorcontrib><creatorcontrib>Wei, Yuquan</creatorcontrib><creatorcontrib>Yu, Luo-Ting</creatorcontrib><collection>AGRIS</collection><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><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gao, Chao</au><au>Ye, Ting-Hong</au><au>Wang, Ning-Yu</au><au>Zeng, Xiu-Xiu</au><au>Zhang, Li-Dan</au><au>Xiong, Ying</au><au>You, Xin-Yu</au><au>Xia, Yong</au><au>Xu, Ying</au><au>Peng, Cui-Ting</au><au>Zuo, Wei-Qiong</au><au>Wei, Yuquan</au><au>Yu, Luo-Ting</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and structure–activity relationships evaluation of benzothiazinone derivatives as potential anti-tubercular agents</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2013-09-01</date><risdate>2013</risdate><volume>23</volume><issue>17</issue><spage>4919</spage><epage>4922</epage><pages>4919-4922</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The synthesis and SAR profile of N-alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives are described. The most potent compound 8o exhibits a MIC of 0.0001μM against Mycobacterium tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate.
N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds were evaluated by determination of minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, and activities of N-alkyl substituted BTZs were not affected by either nitro or trifluoromethyl at 6-position. Trifluoromethyl plays an important role in maintaining anti-tubercular activity in the piperazine or piperidine analogs. Compound 8o, which contains an azaspirodithiolane group, showed a MIC of 0.0001μM against M. tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested that the volume and lipophilicity of the substituents were important in maintaining activity. In addition, compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>23886691</pmid><doi>10.1016/j.bmcl.2013.06.069</doi><tpages>4</tpages></addata></record> |
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| subjects | Animals Antitubercular Agents - chemical synthesis Antitubercular Agents - chemistry Antitubercular Agents - pharmacokinetics Antitubercular Agents - pharmacology Benzothiazinone Cercopithecus aethiops DprE1 Humans hydrophobicity minimum inhibitory concentration Mycobacterium tuberculosis Mycobacterium tuberculosis - drug effects pharmacokinetics piperazine piperidines Rats Rats, Sprague-Dawley Spiro Compounds - chemical synthesis Spiro Compounds - chemistry Spiro Compounds - pharmacokinetics Spiro Compounds - pharmacology Structure-Activity Relationship structure-activity relationships Structure–activity relationships (SAR) Thiazines - chemical synthesis Thiazines - chemistry Thiazines - pharmacokinetics Thiazines - pharmacology Tuberculosis Tuberculosis - drug therapy Vero Cells |
| title | Synthesis and structure–activity relationships evaluation of benzothiazinone derivatives as potential anti-tubercular agents |
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