Synthesis and evaluation of novel dapsone–thalidomide hybrids for the treatment of type 2 leprosy reactions
[Display omitted] We synthesized a series of novel dapsone–thalidomide hybrids (3a–i) by molecular hybridization and evaluated their potential for the treatment of type 2 leprosy reactions. All of the compounds had analgesic properties. Compounds 3c and 3h were the most active antinociceptive compou...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2014-07, Vol.24 (14), p.3084-3087 |
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| creator | Yamasaki, Paulo Renato do Nascimento, Dejair Caetano Chelucci, Rafael Consolin de Faria Fernandes Belone, Andréa Rosa, Patrícia Sammarco Diório, Suzana Madeira de Melo, Thais Regina Ferreira Barbieri, Karina Pereira Placeres, Marisa Campos Polési Carlos, Iracilda Zepone Chung, Man Chin dos Santos, Jean Leandro |
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We synthesized a series of novel dapsone–thalidomide hybrids (3a–i) by molecular hybridization and evaluated their potential for the treatment of type 2 leprosy reactions. All of the compounds had analgesic properties. Compounds 3c and 3h were the most active antinociceptive compounds and reduced acetic acid-induced abdominal constrictions by 49.8% and 39.1%, respectively. The hybrid compounds also reduced tumor necrosis factor-α levels in lipopolysaccharide-stimulated L929 cells. Compound 3i was the most active compound; at concentrations of 15.62 and 125μM, compound 3i decreased tumor necrosis factor-α levels by 86.33% and 87.80%, respectively. In nude mice infected with Mycobacterium leprae in vivo, compound 3i did not reduce the number of bacilli compared with controls. Compound 3i did not have mutagenic effects in Salmonella typhimurium strains TA100 and TA102, with or without metabolic activation (S9 mixture). Our results indicate that compound 3i is a novel lead compound for the treatment of type 2 leprosy reactions. |
| doi_str_mv | 10.1016/j.bmcl.2014.05.017 |
| format | Article |
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We synthesized a series of novel dapsone–thalidomide hybrids (3a–i) by molecular hybridization and evaluated their potential for the treatment of type 2 leprosy reactions. All of the compounds had analgesic properties. Compounds 3c and 3h were the most active antinociceptive compounds and reduced acetic acid-induced abdominal constrictions by 49.8% and 39.1%, respectively. The hybrid compounds also reduced tumor necrosis factor-α levels in lipopolysaccharide-stimulated L929 cells. Compound 3i was the most active compound; at concentrations of 15.62 and 125μM, compound 3i decreased tumor necrosis factor-α levels by 86.33% and 87.80%, respectively. In nude mice infected with Mycobacterium leprae in vivo, compound 3i did not reduce the number of bacilli compared with controls. Compound 3i did not have mutagenic effects in Salmonella typhimurium strains TA100 and TA102, with or without metabolic activation (S9 mixture). Our results indicate that compound 3i is a novel lead compound for the treatment of type 2 leprosy reactions.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2014.05.017</identifier><identifier>PMID: 24907144</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Analgesic ; Animals ; Anti-Bacterial Agents - chemical synthesis ; Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - pharmacology ; Anti-inflammatory ; Cell Line ; Dapsone ; Dapsone - chemistry ; Dapsone - pharmacology ; Dose-Response Relationship, Drug ; Erythema nodosum leprosum ; Humans ; Leprosy ; Leprosy - drug therapy ; M. leprae ; Mice ; Mice, Nude ; Microbial Sensitivity Tests ; Molecular hybridization ; Molecular Structure ; Mycobacterium leprae ; Mycobacterium leprae - drug effects ; Salmonella typhimurium ; Structure-Activity Relationship ; Thalidomide ; Thalidomide - chemistry ; Thalidomide - pharmacology ; TNFα</subject><ispartof>Bioorganic & medicinal chemistry letters, 2014-07, Vol.24 (14), p.3084-3087</ispartof><rights>2014 Elsevier Ltd</rights><rights>Copyright © 2014 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-c6fd2e1dc8f2da5acf9d75ab75f14f2339b4c13f813fca02c5f7d89aa8e53ca23</citedby><cites>FETCH-LOGICAL-c389t-c6fd2e1dc8f2da5acf9d75ab75f14f2339b4c13f813fca02c5f7d89aa8e53ca23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X14005046$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24907144$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yamasaki, Paulo Renato</creatorcontrib><creatorcontrib>do Nascimento, Dejair Caetano</creatorcontrib><creatorcontrib>Chelucci, Rafael Consolin</creatorcontrib><creatorcontrib>de Faria Fernandes Belone, Andréa</creatorcontrib><creatorcontrib>Rosa, Patrícia Sammarco</creatorcontrib><creatorcontrib>Diório, Suzana Madeira</creatorcontrib><creatorcontrib>de Melo, Thais Regina Ferreira</creatorcontrib><creatorcontrib>Barbieri, Karina Pereira</creatorcontrib><creatorcontrib>Placeres, Marisa Campos Polési</creatorcontrib><creatorcontrib>Carlos, Iracilda Zepone</creatorcontrib><creatorcontrib>Chung, Man Chin</creatorcontrib><creatorcontrib>dos Santos, Jean Leandro</creatorcontrib><title>Synthesis and evaluation of novel dapsone–thalidomide hybrids for the treatment of type 2 leprosy reactions</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
We synthesized a series of novel dapsone–thalidomide hybrids (3a–i) by molecular hybridization and evaluated their potential for the treatment of type 2 leprosy reactions. All of the compounds had analgesic properties. Compounds 3c and 3h were the most active antinociceptive compounds and reduced acetic acid-induced abdominal constrictions by 49.8% and 39.1%, respectively. The hybrid compounds also reduced tumor necrosis factor-α levels in lipopolysaccharide-stimulated L929 cells. Compound 3i was the most active compound; at concentrations of 15.62 and 125μM, compound 3i decreased tumor necrosis factor-α levels by 86.33% and 87.80%, respectively. In nude mice infected with Mycobacterium leprae in vivo, compound 3i did not reduce the number of bacilli compared with controls. Compound 3i did not have mutagenic effects in Salmonella typhimurium strains TA100 and TA102, with or without metabolic activation (S9 mixture). Our results indicate that compound 3i is a novel lead compound for the treatment of type 2 leprosy reactions.</description><subject>Analgesic</subject><subject>Animals</subject><subject>Anti-Bacterial Agents - chemical synthesis</subject><subject>Anti-Bacterial Agents - chemistry</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Anti-inflammatory</subject><subject>Cell Line</subject><subject>Dapsone</subject><subject>Dapsone - chemistry</subject><subject>Dapsone - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Erythema nodosum leprosum</subject><subject>Humans</subject><subject>Leprosy</subject><subject>Leprosy - drug therapy</subject><subject>M. leprae</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Microbial Sensitivity Tests</subject><subject>Molecular hybridization</subject><subject>Molecular Structure</subject><subject>Mycobacterium leprae</subject><subject>Mycobacterium leprae - drug effects</subject><subject>Salmonella typhimurium</subject><subject>Structure-Activity Relationship</subject><subject>Thalidomide</subject><subject>Thalidomide - chemistry</subject><subject>Thalidomide - pharmacology</subject><subject>TNFα</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kL1uHCEURlEUK7ve5AVSWJRpZgIMzI-UxrKcxJIlF7aldIiBi5bVzLAGdqXp_A5-wzyJGa3jMgW6Bef7LhyEvlJSUkLr77uyH_VQMkJ5SURJaPMBrSmveVFxIj6iNelqUrQd_7NC5zHuSAYJ55_QivGONJTzNRrv5yltIbqI1WQwHNVwUMn5CXuLJ3-EARu1j36Cv88vaasGZ_zoDODt3AdnIrY-4FyAUwCVRpjSEkzzHjDDA-yDjzPOV3rpjJ_RmVVDhC9vc4Mef14_XP0ubu9-3Vxd3ha6artU6NoaBtTo1jKjhNK2M41QfSMs5ZZVVddzTSvb5qMVYVrYxrSdUi2ISitWbdC3U2_e_3SAmOToooZhUBP4Q5RUcE6ygbrNKDuhOj81BrByH9yowiwpkYtmuZOLZrlolkTIrDmHLt76D_0I5j3yz2sGfpwAyL88OggyageTBuMC6CSNd__rfwVOCZJa</recordid><startdate>20140715</startdate><enddate>20140715</enddate><creator>Yamasaki, Paulo Renato</creator><creator>do Nascimento, Dejair Caetano</creator><creator>Chelucci, Rafael Consolin</creator><creator>de Faria Fernandes Belone, Andréa</creator><creator>Rosa, Patrícia Sammarco</creator><creator>Diório, Suzana Madeira</creator><creator>de Melo, Thais Regina Ferreira</creator><creator>Barbieri, Karina Pereira</creator><creator>Placeres, Marisa Campos Polési</creator><creator>Carlos, Iracilda Zepone</creator><creator>Chung, Man Chin</creator><creator>dos Santos, Jean Leandro</creator><general>Elsevier Ltd</general><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>7QL</scope><scope>7QO</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20140715</creationdate><title>Synthesis and evaluation of novel dapsone–thalidomide hybrids for the treatment of type 2 leprosy reactions</title><author>Yamasaki, Paulo Renato ; do Nascimento, Dejair Caetano ; Chelucci, Rafael Consolin ; de Faria Fernandes Belone, Andréa ; Rosa, Patrícia Sammarco ; Diório, Suzana Madeira ; de Melo, Thais Regina Ferreira ; Barbieri, Karina Pereira ; Placeres, Marisa Campos Polési ; Carlos, Iracilda Zepone ; Chung, Man Chin ; dos Santos, Jean Leandro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-c6fd2e1dc8f2da5acf9d75ab75f14f2339b4c13f813fca02c5f7d89aa8e53ca23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Analgesic</topic><topic>Animals</topic><topic>Anti-Bacterial Agents - chemical synthesis</topic><topic>Anti-Bacterial Agents - chemistry</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Anti-inflammatory</topic><topic>Cell Line</topic><topic>Dapsone</topic><topic>Dapsone - chemistry</topic><topic>Dapsone - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Erythema nodosum leprosum</topic><topic>Humans</topic><topic>Leprosy</topic><topic>Leprosy - drug therapy</topic><topic>M. leprae</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Microbial Sensitivity Tests</topic><topic>Molecular hybridization</topic><topic>Molecular Structure</topic><topic>Mycobacterium leprae</topic><topic>Mycobacterium leprae - drug effects</topic><topic>Salmonella typhimurium</topic><topic>Structure-Activity Relationship</topic><topic>Thalidomide</topic><topic>Thalidomide - chemistry</topic><topic>Thalidomide - pharmacology</topic><topic>TNFα</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yamasaki, Paulo Renato</creatorcontrib><creatorcontrib>do Nascimento, Dejair Caetano</creatorcontrib><creatorcontrib>Chelucci, Rafael Consolin</creatorcontrib><creatorcontrib>de Faria Fernandes Belone, Andréa</creatorcontrib><creatorcontrib>Rosa, Patrícia Sammarco</creatorcontrib><creatorcontrib>Diório, Suzana Madeira</creatorcontrib><creatorcontrib>de Melo, Thais Regina Ferreira</creatorcontrib><creatorcontrib>Barbieri, Karina Pereira</creatorcontrib><creatorcontrib>Placeres, Marisa Campos Polési</creatorcontrib><creatorcontrib>Carlos, Iracilda Zepone</creatorcontrib><creatorcontrib>Chung, Man Chin</creatorcontrib><creatorcontrib>dos Santos, Jean Leandro</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</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>Yamasaki, Paulo Renato</au><au>do Nascimento, Dejair Caetano</au><au>Chelucci, Rafael Consolin</au><au>de Faria Fernandes Belone, Andréa</au><au>Rosa, Patrícia Sammarco</au><au>Diório, Suzana Madeira</au><au>de Melo, Thais Regina Ferreira</au><au>Barbieri, Karina Pereira</au><au>Placeres, Marisa Campos Polési</au><au>Carlos, Iracilda Zepone</au><au>Chung, Man Chin</au><au>dos Santos, Jean Leandro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and evaluation of novel dapsone–thalidomide hybrids for the treatment of type 2 leprosy reactions</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2014-07-15</date><risdate>2014</risdate><volume>24</volume><issue>14</issue><spage>3084</spage><epage>3087</epage><pages>3084-3087</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
We synthesized a series of novel dapsone–thalidomide hybrids (3a–i) by molecular hybridization and evaluated their potential for the treatment of type 2 leprosy reactions. All of the compounds had analgesic properties. Compounds 3c and 3h were the most active antinociceptive compounds and reduced acetic acid-induced abdominal constrictions by 49.8% and 39.1%, respectively. The hybrid compounds also reduced tumor necrosis factor-α levels in lipopolysaccharide-stimulated L929 cells. Compound 3i was the most active compound; at concentrations of 15.62 and 125μM, compound 3i decreased tumor necrosis factor-α levels by 86.33% and 87.80%, respectively. In nude mice infected with Mycobacterium leprae in vivo, compound 3i did not reduce the number of bacilli compared with controls. Compound 3i did not have mutagenic effects in Salmonella typhimurium strains TA100 and TA102, with or without metabolic activation (S9 mixture). Our results indicate that compound 3i is a novel lead compound for the treatment of type 2 leprosy reactions.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>24907144</pmid><doi>10.1016/j.bmcl.2014.05.017</doi><tpages>4</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2014-07, Vol.24 (14), p.3084-3087 |
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| subjects | Analgesic Animals Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Anti-inflammatory Cell Line Dapsone Dapsone - chemistry Dapsone - pharmacology Dose-Response Relationship, Drug Erythema nodosum leprosum Humans Leprosy Leprosy - drug therapy M. leprae Mice Mice, Nude Microbial Sensitivity Tests Molecular hybridization Molecular Structure Mycobacterium leprae Mycobacterium leprae - drug effects Salmonella typhimurium Structure-Activity Relationship Thalidomide Thalidomide - chemistry Thalidomide - pharmacology TNFα |
| title | Synthesis and evaluation of novel dapsone–thalidomide hybrids for the treatment of type 2 leprosy reactions |
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