Sulfonyl-polyol N,N-dichloroamines with rapid, broad-spectrum antimicrobial activity
Polyol-solubilized 3-(dichloroamino)-3-methylbutylsulfones 1a–m and sulfonamides 2a–b show fast-acting, broad spectrum antimicrobial activity against bacterial and viral pathogens as tested by 1-h MBC’s against E. coli and S. aureus, and 1-h IC50’s against Ad5 and HSV-1. The discovery and developmen...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2013-10, Vol.23 (20), p.5650-5653 |
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| creator | Shiau, Timothy P. Low, Eddy Kim, Bum Turtle, Eric D. Francavilla, Charles O’Mahony, Donogh J.R. Friedman, Lisa D’Lima, Louisa Jekle, Andreas Debabov, Dmitri Zuck, Meghan Alvarez, Nichole J. Anderson, Mark Najafi, Ramin (Ron) Jain, Rakesh K. |
| description | Polyol-solubilized 3-(dichloroamino)-3-methylbutylsulfones 1a–m and sulfonamides 2a–b show fast-acting, broad spectrum antimicrobial activity against bacterial and viral pathogens as tested by 1-h MBC’s against E. coli and S. aureus, and 1-h IC50’s against Ad5 and HSV-1.
The discovery and development of antimicrobial agents that do not give rise to resistance remains an ongoing challenge. Our efforts in this regard continue to reveal new potential therapeutic agents with differing physicochemical properties while retaining the effective N,N-dichloroamine pharmacophore as the key antimicrobial warhead. In this Letter, we disclose agents containing polyol units as a water solubilizing group. These sulfonyl-polyol agents show broad spectrum bactericidal and virucidal activity. These compounds show 1h MBC’s of 16–512μg/mL against Escherichia coli and 4–256μg/mL against Staphylococcus aureus at neutral pH, and 1-h IC50’s of 4.5–32μM against Adenovirus 5 and 0.7–3.0μM against Herpes simplex virus 1. The lead compounds were tested in a tissue culture irritancy assay and showed only minimal irritation at the highest concentrations tested. |
| doi_str_mv | 10.1016/j.bmcl.2013.08.027 |
| format | Article |
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The discovery and development of antimicrobial agents that do not give rise to resistance remains an ongoing challenge. Our efforts in this regard continue to reveal new potential therapeutic agents with differing physicochemical properties while retaining the effective N,N-dichloroamine pharmacophore as the key antimicrobial warhead. In this Letter, we disclose agents containing polyol units as a water solubilizing group. These sulfonyl-polyol agents show broad spectrum bactericidal and virucidal activity. These compounds show 1h MBC’s of 16–512μg/mL against Escherichia coli and 4–256μg/mL against Staphylococcus aureus at neutral pH, and 1-h IC50’s of 4.5–32μM against Adenovirus 5 and 0.7–3.0μM against Herpes simplex virus 1. The lead compounds were tested in a tissue culture irritancy assay and showed only minimal irritation at the highest concentrations tested.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2013.08.027</identifier><identifier>PMID: 23999044</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adenoviridae - metabolism ; Adenovirus ; Amines - chemical synthesis ; Amines - chemistry ; Amines - pharmacology ; Animals ; anti-infective agents ; Anti-Infective Agents - chemical synthesis ; Anti-Infective Agents - chemistry ; Anti-Infective Agents - pharmacology ; antiviral properties ; Bacteria ; Bactericidal ; Cell Line, Tumor ; Cercopithecus aethiops ; Chloroamines ; Conjunctivitis ; Cytopathogenic Effect, Viral - drug effects ; Escherichia coli ; Escherichia coli - drug effects ; Herpes simplex virus 1 ; Herpesvirus 1, Human - metabolism ; Human herpesvirus 1 ; Humans ; Hydrogen-Ion Concentration ; inhibitory concentration 50 ; Microbial Sensitivity Tests ; pharmacology ; Polymers - chemistry ; polyols ; solubilization ; Staphylococcus aureus ; Staphylococcus aureus - drug effects ; tissue culture ; Vero Cells ; Virucidal ; Virus</subject><ispartof>Bioorganic & medicinal chemistry letters, 2013-10, Vol.23 (20), p.5650-5653</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-46d4718389b4f3789afaf547db83237c7835581b72ffc6733a78bb38b4d9e43c3</citedby><cites>FETCH-LOGICAL-c413t-46d4718389b4f3789afaf547db83237c7835581b72ffc6733a78bb38b4d9e43c3</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.2013.08.027$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23999044$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shiau, Timothy P.</creatorcontrib><creatorcontrib>Low, Eddy</creatorcontrib><creatorcontrib>Kim, Bum</creatorcontrib><creatorcontrib>Turtle, Eric D.</creatorcontrib><creatorcontrib>Francavilla, Charles</creatorcontrib><creatorcontrib>O’Mahony, Donogh J.R.</creatorcontrib><creatorcontrib>Friedman, Lisa</creatorcontrib><creatorcontrib>D’Lima, Louisa</creatorcontrib><creatorcontrib>Jekle, Andreas</creatorcontrib><creatorcontrib>Debabov, Dmitri</creatorcontrib><creatorcontrib>Zuck, Meghan</creatorcontrib><creatorcontrib>Alvarez, Nichole J.</creatorcontrib><creatorcontrib>Anderson, Mark</creatorcontrib><creatorcontrib>Najafi, Ramin (Ron)</creatorcontrib><creatorcontrib>Jain, Rakesh K.</creatorcontrib><title>Sulfonyl-polyol N,N-dichloroamines with rapid, broad-spectrum antimicrobial activity</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Polyol-solubilized 3-(dichloroamino)-3-methylbutylsulfones 1a–m and sulfonamides 2a–b show fast-acting, broad spectrum antimicrobial activity against bacterial and viral pathogens as tested by 1-h MBC’s against E. coli and S. aureus, and 1-h IC50’s against Ad5 and HSV-1.
The discovery and development of antimicrobial agents that do not give rise to resistance remains an ongoing challenge. Our efforts in this regard continue to reveal new potential therapeutic agents with differing physicochemical properties while retaining the effective N,N-dichloroamine pharmacophore as the key antimicrobial warhead. In this Letter, we disclose agents containing polyol units as a water solubilizing group. These sulfonyl-polyol agents show broad spectrum bactericidal and virucidal activity. These compounds show 1h MBC’s of 16–512μg/mL against Escherichia coli and 4–256μg/mL against Staphylococcus aureus at neutral pH, and 1-h IC50’s of 4.5–32μM against Adenovirus 5 and 0.7–3.0μM against Herpes simplex virus 1. The lead compounds were tested in a tissue culture irritancy assay and showed only minimal irritation at the highest concentrations tested.</description><subject>Adenoviridae - metabolism</subject><subject>Adenovirus</subject><subject>Amines - chemical synthesis</subject><subject>Amines - chemistry</subject><subject>Amines - pharmacology</subject><subject>Animals</subject><subject>anti-infective agents</subject><subject>Anti-Infective Agents - chemical synthesis</subject><subject>Anti-Infective Agents - chemistry</subject><subject>Anti-Infective Agents - pharmacology</subject><subject>antiviral properties</subject><subject>Bacteria</subject><subject>Bactericidal</subject><subject>Cell Line, Tumor</subject><subject>Cercopithecus aethiops</subject><subject>Chloroamines</subject><subject>Conjunctivitis</subject><subject>Cytopathogenic Effect, Viral - drug effects</subject><subject>Escherichia coli</subject><subject>Escherichia coli - drug effects</subject><subject>Herpes simplex virus 1</subject><subject>Herpesvirus 1, Human - metabolism</subject><subject>Human herpesvirus 1</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>inhibitory concentration 50</subject><subject>Microbial Sensitivity Tests</subject><subject>pharmacology</subject><subject>Polymers - chemistry</subject><subject>polyols</subject><subject>solubilization</subject><subject>Staphylococcus aureus</subject><subject>Staphylococcus aureus - drug effects</subject><subject>tissue culture</subject><subject>Vero Cells</subject><subject>Virucidal</subject><subject>Virus</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>eNqFkE1v1DAQhi1ERbctf4AD5MihScexEzsSl6qCglS1h7YSN8uf1CsnDnZStP8er7ZwhNOMRs-8mnkQeoehwYD7i22jRh2aFjBpgDfQsldog2lPa0Khe402MPRQ84F-P0YnOW8BMAVK36DjlgzDUNoNerhfg4vTLtRzDLsYqtvz29p4_RRiinL0k83VL788VUnO3pxXqkxNnWerl7SOlZwWP3qdovIyVFIv_tkvuzN05GTI9u1LPUWPXz4_XH2tb-6uv11d3tSaYrLUtDeUYU74oKgjjA_SSddRZhQnLWGacdJ1HCvWOqd7RohkXCnCFTWDpUSTU_TxkDun-HO1eRGjz9qGICcb1yxwB8AYcE7-j9LiDAOHtqDtAS1v5ZysE3Pyo0w7gUHsxYut2IsXe_ECuCjiy9L7l_xVjdb8XfljugAfDoCTUcgfyWfxeF8SyomYtB0Mhfh0IGxR9uxtEll7O2lrfCq6hYn-Xxf8BkF6nSI</recordid><startdate>20131015</startdate><enddate>20131015</enddate><creator>Shiau, Timothy P.</creator><creator>Low, Eddy</creator><creator>Kim, Bum</creator><creator>Turtle, Eric D.</creator><creator>Francavilla, Charles</creator><creator>O’Mahony, Donogh J.R.</creator><creator>Friedman, Lisa</creator><creator>D’Lima, Louisa</creator><creator>Jekle, Andreas</creator><creator>Debabov, Dmitri</creator><creator>Zuck, Meghan</creator><creator>Alvarez, Nichole J.</creator><creator>Anderson, Mark</creator><creator>Najafi, Ramin (Ron)</creator><creator>Jain, Rakesh K.</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>7T7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20131015</creationdate><title>Sulfonyl-polyol N,N-dichloroamines with rapid, broad-spectrum antimicrobial activity</title><author>Shiau, Timothy P. ; Low, Eddy ; Kim, Bum ; Turtle, Eric D. ; Francavilla, Charles ; O’Mahony, Donogh J.R. ; Friedman, Lisa ; D’Lima, Louisa ; Jekle, Andreas ; Debabov, Dmitri ; Zuck, Meghan ; Alvarez, Nichole J. ; Anderson, Mark ; Najafi, Ramin (Ron) ; Jain, Rakesh K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c413t-46d4718389b4f3789afaf547db83237c7835581b72ffc6733a78bb38b4d9e43c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adenoviridae - metabolism</topic><topic>Adenovirus</topic><topic>Amines - chemical synthesis</topic><topic>Amines - chemistry</topic><topic>Amines - pharmacology</topic><topic>Animals</topic><topic>anti-infective agents</topic><topic>Anti-Infective Agents - chemical synthesis</topic><topic>Anti-Infective Agents - chemistry</topic><topic>Anti-Infective Agents - pharmacology</topic><topic>antiviral properties</topic><topic>Bacteria</topic><topic>Bactericidal</topic><topic>Cell Line, Tumor</topic><topic>Cercopithecus aethiops</topic><topic>Chloroamines</topic><topic>Conjunctivitis</topic><topic>Cytopathogenic Effect, Viral - drug effects</topic><topic>Escherichia coli</topic><topic>Escherichia coli - drug effects</topic><topic>Herpes simplex virus 1</topic><topic>Herpesvirus 1, Human - metabolism</topic><topic>Human herpesvirus 1</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>inhibitory concentration 50</topic><topic>Microbial Sensitivity Tests</topic><topic>pharmacology</topic><topic>Polymers - chemistry</topic><topic>polyols</topic><topic>solubilization</topic><topic>Staphylococcus aureus</topic><topic>Staphylococcus aureus - drug effects</topic><topic>tissue culture</topic><topic>Vero Cells</topic><topic>Virucidal</topic><topic>Virus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shiau, Timothy P.</creatorcontrib><creatorcontrib>Low, Eddy</creatorcontrib><creatorcontrib>Kim, Bum</creatorcontrib><creatorcontrib>Turtle, Eric D.</creatorcontrib><creatorcontrib>Francavilla, Charles</creatorcontrib><creatorcontrib>O’Mahony, Donogh J.R.</creatorcontrib><creatorcontrib>Friedman, Lisa</creatorcontrib><creatorcontrib>D’Lima, Louisa</creatorcontrib><creatorcontrib>Jekle, Andreas</creatorcontrib><creatorcontrib>Debabov, Dmitri</creatorcontrib><creatorcontrib>Zuck, Meghan</creatorcontrib><creatorcontrib>Alvarez, Nichole J.</creatorcontrib><creatorcontrib>Anderson, Mark</creatorcontrib><creatorcontrib>Najafi, Ramin (Ron)</creatorcontrib><creatorcontrib>Jain, Rakesh K.</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>Industrial and Applied Microbiology Abstracts (Microbiology A)</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>Shiau, Timothy P.</au><au>Low, Eddy</au><au>Kim, Bum</au><au>Turtle, Eric D.</au><au>Francavilla, Charles</au><au>O’Mahony, Donogh J.R.</au><au>Friedman, Lisa</au><au>D’Lima, Louisa</au><au>Jekle, Andreas</au><au>Debabov, Dmitri</au><au>Zuck, Meghan</au><au>Alvarez, Nichole J.</au><au>Anderson, Mark</au><au>Najafi, Ramin (Ron)</au><au>Jain, Rakesh K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sulfonyl-polyol N,N-dichloroamines with rapid, broad-spectrum antimicrobial activity</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2013-10-15</date><risdate>2013</risdate><volume>23</volume><issue>20</issue><spage>5650</spage><epage>5653</epage><pages>5650-5653</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Polyol-solubilized 3-(dichloroamino)-3-methylbutylsulfones 1a–m and sulfonamides 2a–b show fast-acting, broad spectrum antimicrobial activity against bacterial and viral pathogens as tested by 1-h MBC’s against E. coli and S. aureus, and 1-h IC50’s against Ad5 and HSV-1.
The discovery and development of antimicrobial agents that do not give rise to resistance remains an ongoing challenge. Our efforts in this regard continue to reveal new potential therapeutic agents with differing physicochemical properties while retaining the effective N,N-dichloroamine pharmacophore as the key antimicrobial warhead. In this Letter, we disclose agents containing polyol units as a water solubilizing group. These sulfonyl-polyol agents show broad spectrum bactericidal and virucidal activity. These compounds show 1h MBC’s of 16–512μg/mL against Escherichia coli and 4–256μg/mL against Staphylococcus aureus at neutral pH, and 1-h IC50’s of 4.5–32μM against Adenovirus 5 and 0.7–3.0μM against Herpes simplex virus 1. The lead compounds were tested in a tissue culture irritancy assay and showed only minimal irritation at the highest concentrations tested.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>23999044</pmid><doi>10.1016/j.bmcl.2013.08.027</doi><tpages>4</tpages></addata></record> |
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| subjects | Adenoviridae - metabolism Adenovirus Amines - chemical synthesis Amines - chemistry Amines - pharmacology Animals anti-infective agents Anti-Infective Agents - chemical synthesis Anti-Infective Agents - chemistry Anti-Infective Agents - pharmacology antiviral properties Bacteria Bactericidal Cell Line, Tumor Cercopithecus aethiops Chloroamines Conjunctivitis Cytopathogenic Effect, Viral - drug effects Escherichia coli Escherichia coli - drug effects Herpes simplex virus 1 Herpesvirus 1, Human - metabolism Human herpesvirus 1 Humans Hydrogen-Ion Concentration inhibitory concentration 50 Microbial Sensitivity Tests pharmacology Polymers - chemistry polyols solubilization Staphylococcus aureus Staphylococcus aureus - drug effects tissue culture Vero Cells Virucidal Virus |
| title | Sulfonyl-polyol N,N-dichloroamines with rapid, broad-spectrum antimicrobial activity |
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