Novel Trisubstituted Benzimidazoles, Targeting Mtb FtsZ, as a New Class of Antitubercular Agents
Libraries of novel trisubstituted benzimidazoles were created through rational drug design. A good number of these benzimidazoles exhibited promising MIC values in the range of 0.5−6 μg/mL (2−15 μM) for their antibacterial activity against Mtb H37Rv strain. Moreover, five of the lead compounds also...
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| Veröffentlicht in: | Journal of medicinal chemistry 2011-01, Vol.54 (1), p.374-381 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 54 |
| creator | Kumar, Kunal Awasthi, Divya Lee, Seung-Yub Zanardi, Ilaria Ruzsicska, Bela Knudson, Susan Tonge, Peter J Slayden, Richard A Ojima, Iwao |
| description | Libraries of novel trisubstituted benzimidazoles were created through rational drug design. A good number of these benzimidazoles exhibited promising MIC values in the range of 0.5−6 μg/mL (2−15 μM) for their antibacterial activity against Mtb H37Rv strain. Moreover, five of the lead compounds also exhibited excellent activity against clinical Mtb strains with different drug-resistance profiles. All lead compounds did not show appreciable cytotoxicity (IC50 > 200 μM) against Vero cells, which inhibited Mtb FtsZ assembly in a dose dependent manner. The two lead compounds unexpectedly showed enhancement of the GTPase activity of Mtb FtsZ. The result strongly suggests that the increased GTPase activity destabilizes FtsZ assembly, leading to efficient inhibition of FtsZ polymerization and filament formation. The TEM and SEM analyses of Mtb FtsZ and Mtb cells, respectively, treated with a lead compound strongly suggest that lead benzimidazoles have a novel mechanism of action on the inhibition of Mtb FtsZ assembly and Z-ring formation. |
| doi_str_mv | 10.1021/jm1012006 |
| format | Article |
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A good number of these benzimidazoles exhibited promising MIC values in the range of 0.5−6 μg/mL (2−15 μM) for their antibacterial activity against Mtb H37Rv strain. Moreover, five of the lead compounds also exhibited excellent activity against clinical Mtb strains with different drug-resistance profiles. All lead compounds did not show appreciable cytotoxicity (IC50 > 200 μM) against Vero cells, which inhibited Mtb FtsZ assembly in a dose dependent manner. The two lead compounds unexpectedly showed enhancement of the GTPase activity of Mtb FtsZ. The result strongly suggests that the increased GTPase activity destabilizes FtsZ assembly, leading to efficient inhibition of FtsZ polymerization and filament formation. The TEM and SEM analyses of Mtb FtsZ and Mtb cells, respectively, treated with a lead compound strongly suggest that lead benzimidazoles have a novel mechanism of action on the inhibition of Mtb FtsZ assembly and Z-ring formation.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm1012006</identifier><identifier>PMID: 21126020</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antitubercular Agents - chemical synthesis ; Antitubercular Agents - chemistry ; Antitubercular Agents - pharmacology ; Bacterial Proteins - metabolism ; Benzimidazoles - chemical synthesis ; Benzimidazoles - chemistry ; Benzimidazoles - pharmacology ; Cercopithecus aethiops ; Cytoskeletal Proteins - metabolism ; GTP Phosphohydrolases - metabolism ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis - drug effects ; Mycobacterium tuberculosis - metabolism ; Structure-Activity Relationship ; Vero Cells</subject><ispartof>Journal of medicinal chemistry, 2011-01, Vol.54 (1), p.374-381</ispartof><rights>Copyright © 2010 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a404t-d065b953d1bd7bb5ac103c5227515ad249db6086a489b61ebc72ef13b81d4b73</citedby><cites>FETCH-LOGICAL-a404t-d065b953d1bd7bb5ac103c5227515ad249db6086a489b61ebc72ef13b81d4b73</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/jm1012006$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm1012006$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21126020$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kumar, Kunal</creatorcontrib><creatorcontrib>Awasthi, Divya</creatorcontrib><creatorcontrib>Lee, Seung-Yub</creatorcontrib><creatorcontrib>Zanardi, Ilaria</creatorcontrib><creatorcontrib>Ruzsicska, Bela</creatorcontrib><creatorcontrib>Knudson, Susan</creatorcontrib><creatorcontrib>Tonge, Peter J</creatorcontrib><creatorcontrib>Slayden, Richard A</creatorcontrib><creatorcontrib>Ojima, Iwao</creatorcontrib><title>Novel Trisubstituted Benzimidazoles, Targeting Mtb FtsZ, as a New Class of Antitubercular Agents</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Libraries of novel trisubstituted benzimidazoles were created through rational drug design. A good number of these benzimidazoles exhibited promising MIC values in the range of 0.5−6 μg/mL (2−15 μM) for their antibacterial activity against Mtb H37Rv strain. Moreover, five of the lead compounds also exhibited excellent activity against clinical Mtb strains with different drug-resistance profiles. All lead compounds did not show appreciable cytotoxicity (IC50 > 200 μM) against Vero cells, which inhibited Mtb FtsZ assembly in a dose dependent manner. The two lead compounds unexpectedly showed enhancement of the GTPase activity of Mtb FtsZ. The result strongly suggests that the increased GTPase activity destabilizes FtsZ assembly, leading to efficient inhibition of FtsZ polymerization and filament formation. The TEM and SEM analyses of Mtb FtsZ and Mtb cells, respectively, treated with a lead compound strongly suggest that lead benzimidazoles have a novel mechanism of action on the inhibition of Mtb FtsZ assembly and Z-ring formation.</description><subject>Animals</subject><subject>Antitubercular Agents - chemical synthesis</subject><subject>Antitubercular Agents - chemistry</subject><subject>Antitubercular Agents - pharmacology</subject><subject>Bacterial Proteins - metabolism</subject><subject>Benzimidazoles - chemical synthesis</subject><subject>Benzimidazoles - chemistry</subject><subject>Benzimidazoles - pharmacology</subject><subject>Cercopithecus aethiops</subject><subject>Cytoskeletal Proteins - metabolism</subject><subject>GTP Phosphohydrolases - metabolism</subject><subject>Microbial Sensitivity Tests</subject><subject>Mycobacterium tuberculosis - drug effects</subject><subject>Mycobacterium tuberculosis - metabolism</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>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkcFu1DAQhi0EokvhwAsgXxBCamDGdpzsBWlZUUAq5bInLsaOvYtXSdx6nCL69KTasgKJ0xzmm29G8zP2HOENgsC3-wEBBYB-wBZYC6hUC-ohWwAIUQkt5Al7QrQHAIlCPmYnAlFoELBg3y_TTej5JkeaHJVYphI8fx_G2zhEb29TH-iMb2zehRLHHf9SHD8v9O2MW-KWX4affN1bIp62fDXezbuQu6m3ma92YSz0lD3a2p7Cs_t6yjbnHzbrT9XF14-f16uLyipQpfKga7espUfnG-dq2yHIrhaiqbG2XqildxpabVW7dBqD6xoRtihdi165Rp6ydwft1eSG4Lt5dba9ucpxsPmXSTaafztj_GF26cZIaFAJPQte3Qtyup4CFTNE6kLf2zGkiUy7BN0oiXImXx_ILieiHLbHLQjmLg9zzGNmX_x91pH8E8AMvDwAtiOzT1Me5yf9R_QbsKuR7A</recordid><startdate>20110113</startdate><enddate>20110113</enddate><creator>Kumar, Kunal</creator><creator>Awasthi, Divya</creator><creator>Lee, Seung-Yub</creator><creator>Zanardi, Ilaria</creator><creator>Ruzsicska, Bela</creator><creator>Knudson, Susan</creator><creator>Tonge, Peter J</creator><creator>Slayden, Richard A</creator><creator>Ojima, Iwao</creator><general>American Chemical Society</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20110113</creationdate><title>Novel Trisubstituted Benzimidazoles, Targeting Mtb FtsZ, as a New Class of Antitubercular Agents</title><author>Kumar, Kunal ; Awasthi, Divya ; Lee, Seung-Yub ; Zanardi, Ilaria ; Ruzsicska, Bela ; Knudson, Susan ; Tonge, Peter J ; Slayden, Richard A ; Ojima, Iwao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a404t-d065b953d1bd7bb5ac103c5227515ad249db6086a489b61ebc72ef13b81d4b73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Antitubercular Agents - chemical synthesis</topic><topic>Antitubercular Agents - chemistry</topic><topic>Antitubercular Agents - pharmacology</topic><topic>Bacterial Proteins - metabolism</topic><topic>Benzimidazoles - chemical synthesis</topic><topic>Benzimidazoles - chemistry</topic><topic>Benzimidazoles - pharmacology</topic><topic>Cercopithecus aethiops</topic><topic>Cytoskeletal Proteins - metabolism</topic><topic>GTP Phosphohydrolases - metabolism</topic><topic>Microbial Sensitivity Tests</topic><topic>Mycobacterium tuberculosis - drug effects</topic><topic>Mycobacterium tuberculosis - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Vero Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kumar, Kunal</creatorcontrib><creatorcontrib>Awasthi, Divya</creatorcontrib><creatorcontrib>Lee, Seung-Yub</creatorcontrib><creatorcontrib>Zanardi, Ilaria</creatorcontrib><creatorcontrib>Ruzsicska, Bela</creatorcontrib><creatorcontrib>Knudson, Susan</creatorcontrib><creatorcontrib>Tonge, Peter J</creatorcontrib><creatorcontrib>Slayden, Richard A</creatorcontrib><creatorcontrib>Ojima, Iwao</creatorcontrib><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>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kumar, Kunal</au><au>Awasthi, Divya</au><au>Lee, Seung-Yub</au><au>Zanardi, Ilaria</au><au>Ruzsicska, Bela</au><au>Knudson, Susan</au><au>Tonge, Peter J</au><au>Slayden, Richard A</au><au>Ojima, Iwao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel Trisubstituted Benzimidazoles, Targeting Mtb FtsZ, as a New Class of Antitubercular Agents</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2011-01-13</date><risdate>2011</risdate><volume>54</volume><issue>1</issue><spage>374</spage><epage>381</epage><pages>374-381</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Libraries of novel trisubstituted benzimidazoles were created through rational drug design. A good number of these benzimidazoles exhibited promising MIC values in the range of 0.5−6 μg/mL (2−15 μM) for their antibacterial activity against Mtb H37Rv strain. Moreover, five of the lead compounds also exhibited excellent activity against clinical Mtb strains with different drug-resistance profiles. All lead compounds did not show appreciable cytotoxicity (IC50 > 200 μM) against Vero cells, which inhibited Mtb FtsZ assembly in a dose dependent manner. The two lead compounds unexpectedly showed enhancement of the GTPase activity of Mtb FtsZ. The result strongly suggests that the increased GTPase activity destabilizes FtsZ assembly, leading to efficient inhibition of FtsZ polymerization and filament formation. The TEM and SEM analyses of Mtb FtsZ and Mtb cells, respectively, treated with a lead compound strongly suggest that lead benzimidazoles have a novel mechanism of action on the inhibition of Mtb FtsZ assembly and Z-ring formation.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>21126020</pmid><doi>10.1021/jm1012006</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2011-01, Vol.54 (1), p.374-381 |
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| source | MEDLINE; American Chemical Society (ACS) Journals |
| subjects | Animals Antitubercular Agents - chemical synthesis Antitubercular Agents - chemistry Antitubercular Agents - pharmacology Bacterial Proteins - metabolism Benzimidazoles - chemical synthesis Benzimidazoles - chemistry Benzimidazoles - pharmacology Cercopithecus aethiops Cytoskeletal Proteins - metabolism GTP Phosphohydrolases - metabolism Microbial Sensitivity Tests Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - metabolism Structure-Activity Relationship Vero Cells |
| title | Novel Trisubstituted Benzimidazoles, Targeting Mtb FtsZ, as a New Class of Antitubercular Agents |
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