Structure−Activity Relationships for a Series of Quinoline-Based Compounds Active against Replicating and Nonreplicating Mycobacterium tuberculosis
Tuberculosis (TB) remains as a global pandemic that is aggravated by a lack of health care, the spread of HIV, and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. New anti-TB drugs are urgently required to shorten the long 6−12 month treatment reg...
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| Veröffentlicht in: | Journal of medicinal chemistry 2009-04, Vol.52 (7), p.2109-2118 |
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| container_title | Journal of medicinal chemistry |
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| creator | Lilienkampf, Annamaria Mao, Jialin Wan, Baojie Wang, Yuehong Franzblau, Scott G Kozikowski, Alan P |
| description | Tuberculosis (TB) remains as a global pandemic that is aggravated by a lack of health care, the spread of HIV, and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. New anti-TB drugs are urgently required to shorten the long 6−12 month treatment regimen and to battle drug-resistant Mtb strains. We have identified several potent quinoline-based anti-TB compounds, bearing an isoxazole containing side-chain. The most potent compounds, 7g and 13, exhibited submicromolar activity against the replicating bacteria (R-TB), with minimum inhibitory concentrations (MICs) of 0.77 and 0.95 μM, respectively. In general, these compounds also had micromolar activity against the nonreplicating persistent bacteria (NRP-TB) and did not show toxicity on Vero cells up to 128 μM concentration. Compounds 7g and 13 were shown to retain their anti-TB activity against rifampin, isoniazid, and streptomycin resistant Mtb strains. The results suggest that quinoline−isoxazole-based anti-TB compounds are promising leads for new TB drug development. |
| doi_str_mv | 10.1021/jm900003c |
| format | Article |
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New anti-TB drugs are urgently required to shorten the long 6−12 month treatment regimen and to battle drug-resistant Mtb strains. We have identified several potent quinoline-based anti-TB compounds, bearing an isoxazole containing side-chain. The most potent compounds, 7g and 13, exhibited submicromolar activity against the replicating bacteria (R-TB), with minimum inhibitory concentrations (MICs) of 0.77 and 0.95 μM, respectively. In general, these compounds also had micromolar activity against the nonreplicating persistent bacteria (NRP-TB) and did not show toxicity on Vero cells up to 128 μM concentration. Compounds 7g and 13 were shown to retain their anti-TB activity against rifampin, isoniazid, and streptomycin resistant Mtb strains. The results suggest that quinoline−isoxazole-based anti-TB compounds are promising leads for new TB drug development.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm900003c</identifier><identifier>PMID: 19271749</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject>Animals ; Antibacterial agents ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antitubercular Agents - chemical synthesis ; Antitubercular Agents - chemistry ; Antitubercular Agents - pharmacology ; Biological and medical sciences ; Cercopithecus aethiops ; Drug Resistance, Bacterial ; Drug Resistance, Multiple, Bacterial ; Isoxazoles - chemical synthesis ; Isoxazoles - chemistry ; Isoxazoles - pharmacology ; Medical sciences ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis - drug effects ; Mycobacterium tuberculosis - physiology ; Pharmacology. Drug treatments ; Quinolines - chemical synthesis ; Quinolines - chemistry ; Quinolines - pharmacology ; Structure-Activity Relationship ; Vero Cells</subject><ispartof>Journal of medicinal chemistry, 2009-04, Vol.52 (7), p.2109-2118</ispartof><rights>Copyright © 2009 American Chemical Society</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a409t-78242f2bd04a69ee0ebf3a718ca465fb04f46f32ef88223910c135459a8f42fc3</citedby><cites>FETCH-LOGICAL-a409t-78242f2bd04a69ee0ebf3a718ca465fb04f46f32ef88223910c135459a8f42fc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm900003c$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm900003c$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2756,27067,27915,27916,56729,56779</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21324356$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19271749$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lilienkampf, Annamaria</creatorcontrib><creatorcontrib>Mao, Jialin</creatorcontrib><creatorcontrib>Wan, Baojie</creatorcontrib><creatorcontrib>Wang, Yuehong</creatorcontrib><creatorcontrib>Franzblau, Scott G</creatorcontrib><creatorcontrib>Kozikowski, Alan P</creatorcontrib><title>Structure−Activity Relationships for a Series of Quinoline-Based Compounds Active against Replicating and Nonreplicating Mycobacterium tuberculosis</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Tuberculosis (TB) remains as a global pandemic that is aggravated by a lack of health care, the spread of HIV, and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. New anti-TB drugs are urgently required to shorten the long 6−12 month treatment regimen and to battle drug-resistant Mtb strains. We have identified several potent quinoline-based anti-TB compounds, bearing an isoxazole containing side-chain. The most potent compounds, 7g and 13, exhibited submicromolar activity against the replicating bacteria (R-TB), with minimum inhibitory concentrations (MICs) of 0.77 and 0.95 μM, respectively. In general, these compounds also had micromolar activity against the nonreplicating persistent bacteria (NRP-TB) and did not show toxicity on Vero cells up to 128 μM concentration. Compounds 7g and 13 were shown to retain their anti-TB activity against rifampin, isoniazid, and streptomycin resistant Mtb strains. The results suggest that quinoline−isoxazole-based anti-TB compounds are promising leads for new TB drug development.</description><subject>Animals</subject><subject>Antibacterial agents</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antitubercular Agents - chemical synthesis</subject><subject>Antitubercular Agents - chemistry</subject><subject>Antitubercular Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cercopithecus aethiops</subject><subject>Drug Resistance, Bacterial</subject><subject>Drug Resistance, Multiple, Bacterial</subject><subject>Isoxazoles - chemical synthesis</subject><subject>Isoxazoles - chemistry</subject><subject>Isoxazoles - pharmacology</subject><subject>Medical sciences</subject><subject>Microbial Sensitivity Tests</subject><subject>Mycobacterium tuberculosis - drug effects</subject><subject>Mycobacterium tuberculosis - physiology</subject><subject>Pharmacology. Drug treatments</subject><subject>Quinolines - chemical synthesis</subject><subject>Quinolines - chemistry</subject><subject>Quinolines - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Vero Cells</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM2O0zAQxy3EipbCgRdAvnDgkF1_JU2OpeJjpQKCwjmaOHZxldiRP5D6BnteiRfcJ1kvW7UcmMtIo9_8RvNH6BUll5QwerUfG5KLyydoTktGClET8RTNCWGsYBXjM_Q8hP0DQhl_hma0YUu6FM0c_dlGn2RMXt3d3K5kNL9NPODvaoBonA2_zBSwdh4D3ipvVMBO42_JWDcYq4p3EFSP126cXLJ9wH8FCsMOjA0xa6bByGyyOwy2x1-c9f-MPh-k60DGLE4jjqlTXqbBBRNeoAsNQ1Avj32Bfn54_2P9qdh8_Xi9Xm0KEKSJxbJmgmnW9URA1ShFVKc5LGktQVSl7ojQotKcKV3XjPGGEkl5KcoGap0XJV-gt49e6V0IXul28mYEf2gpaR-ibU_RZvb1IzulblT9mTxmmYE3RwCChEF7sNKEE8coZ4KX1ZkDGdq9S97mF_9z8B4gZ5GB</recordid><startdate>20090409</startdate><enddate>20090409</enddate><creator>Lilienkampf, Annamaria</creator><creator>Mao, Jialin</creator><creator>Wan, Baojie</creator><creator>Wang, Yuehong</creator><creator>Franzblau, Scott G</creator><creator>Kozikowski, Alan P</creator><general>American Chemical Society</general><scope>IQODW</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></search><sort><creationdate>20090409</creationdate><title>Structure−Activity Relationships for a Series of Quinoline-Based Compounds Active against Replicating and Nonreplicating Mycobacterium tuberculosis</title><author>Lilienkampf, Annamaria ; Mao, Jialin ; Wan, Baojie ; Wang, Yuehong ; Franzblau, Scott G ; Kozikowski, Alan P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a409t-78242f2bd04a69ee0ebf3a718ca465fb04f46f32ef88223910c135459a8f42fc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Antibacterial agents</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antitubercular Agents - chemical synthesis</topic><topic>Antitubercular Agents - chemistry</topic><topic>Antitubercular Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cercopithecus aethiops</topic><topic>Drug Resistance, Bacterial</topic><topic>Drug Resistance, Multiple, Bacterial</topic><topic>Isoxazoles - chemical synthesis</topic><topic>Isoxazoles - chemistry</topic><topic>Isoxazoles - pharmacology</topic><topic>Medical sciences</topic><topic>Microbial Sensitivity Tests</topic><topic>Mycobacterium tuberculosis - drug effects</topic><topic>Mycobacterium tuberculosis - physiology</topic><topic>Pharmacology. Drug treatments</topic><topic>Quinolines - chemical synthesis</topic><topic>Quinolines - chemistry</topic><topic>Quinolines - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Vero Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lilienkampf, Annamaria</creatorcontrib><creatorcontrib>Mao, Jialin</creatorcontrib><creatorcontrib>Wan, Baojie</creatorcontrib><creatorcontrib>Wang, Yuehong</creatorcontrib><creatorcontrib>Franzblau, Scott G</creatorcontrib><creatorcontrib>Kozikowski, Alan P</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lilienkampf, Annamaria</au><au>Mao, Jialin</au><au>Wan, Baojie</au><au>Wang, Yuehong</au><au>Franzblau, Scott G</au><au>Kozikowski, Alan P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure−Activity Relationships for a Series of Quinoline-Based Compounds Active against Replicating and Nonreplicating Mycobacterium tuberculosis</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2009-04-09</date><risdate>2009</risdate><volume>52</volume><issue>7</issue><spage>2109</spage><epage>2118</epage><pages>2109-2118</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Tuberculosis (TB) remains as a global pandemic that is aggravated by a lack of health care, the spread of HIV, and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. New anti-TB drugs are urgently required to shorten the long 6−12 month treatment regimen and to battle drug-resistant Mtb strains. We have identified several potent quinoline-based anti-TB compounds, bearing an isoxazole containing side-chain. The most potent compounds, 7g and 13, exhibited submicromolar activity against the replicating bacteria (R-TB), with minimum inhibitory concentrations (MICs) of 0.77 and 0.95 μM, respectively. In general, these compounds also had micromolar activity against the nonreplicating persistent bacteria (NRP-TB) and did not show toxicity on Vero cells up to 128 μM concentration. Compounds 7g and 13 were shown to retain their anti-TB activity against rifampin, isoniazid, and streptomycin resistant Mtb strains. The results suggest that quinoline−isoxazole-based anti-TB compounds are promising leads for new TB drug development.</abstract><cop>Columbus, OH</cop><pub>American Chemical Society</pub><pmid>19271749</pmid><doi>10.1021/jm900003c</doi><tpages>10</tpages></addata></record> |
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| subjects | Animals Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents Antitubercular Agents - chemical synthesis Antitubercular Agents - chemistry Antitubercular Agents - pharmacology Biological and medical sciences Cercopithecus aethiops Drug Resistance, Bacterial Drug Resistance, Multiple, Bacterial Isoxazoles - chemical synthesis Isoxazoles - chemistry Isoxazoles - pharmacology Medical sciences Microbial Sensitivity Tests Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - physiology Pharmacology. Drug treatments Quinolines - chemical synthesis Quinolines - chemistry Quinolines - pharmacology Structure-Activity Relationship Vero Cells |
| title | Structure−Activity Relationships for a Series of Quinoline-Based Compounds Active against Replicating and Nonreplicating Mycobacterium tuberculosis |
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