Synthesis and Antibacterial Evaluation of a New Series of <em>N</em>-Alkyl-2-alkynyl/(<em>E</em>)-alkenyl-4-(1<em>H</em>)-quinolones
To gain further insight into the structural requirements of the aliphatic group at position 2 for their antimycobacterial activity, some <em>N</em>-alkyl-4-(1<em>H</em>)-quinolones bearing position 2 alkynyls with various chain length and tripl...
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| Format: | Article |
| Language: | English |
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MDPI AG
2012-07-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/17/7/8217 |
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| author | Abraham Wube Juan-David Guzman Antje Hüfner Christina Hochfellner Martina Blunder Rudolf Bauer Simon Gibbons Sanjib Bhakta Franz Bucar |
| author_facet | Abraham Wube Juan-David Guzman Antje Hüfner Christina Hochfellner Martina Blunder Rudolf Bauer Simon Gibbons Sanjib Bhakta Franz Bucar |
| author_sort | Abraham Wube |
| collection | DOAJ |
| description | To gain further insight into the structural requirements of the aliphatic group at position 2 for their antimycobacterial activity, some <em>N</em>-alkyl-4-(1<em>H</em>)-quinolones bearing position 2 alkynyls with various chain length and triple bond positions were prepared and tested for<em> in vitro</em> antibacterial activity against rapidly-growing strains of mycobacteria, the vaccine strain <em>Mycobacterium bovis</em> BCG, and methicillin-resistant <em>Staphylococcus aureus</em> strains, EMRSA-15 and -16. The compounds were also evaluated for inhibition of ATP-dependent MurE ligase<em> </em>of <em>Mycobacterium tuberculosis</em>. The lowest MIC value of 0.5 mg/L (1.2–1.5 µM) was found against <em>M. fortuitum</em> and <em>M. smegmatis</em>. These compounds displayed no or only weak toxicity to the human lung fibroblast cell line MRC-5 at 100 µM concentration. The quinolone derivatives exhibited pronounced activity against the epidemic MRSA strains (EMRSA-15 and -16) with MIC values of 2–128 mg/L (5.3–364.7 µM), and <em>M. bovis</em> BCG with an MIC value of 25 mg/L (66.0–77.4 µM). In addition, the compounds inhibited the MurE ligase of <em>M. tuberculosis</em> with moderate to weak activity showing IC<sub>50</sub> values of 200–774 µM. The increased selectivity towards mycobacterial bacilli with reference to MRC-5 cells observed for 2-alkynyl quinolones compared to their corresponding 2-alkenyl analogues serves to highlight the mycobacterial specific effect of the triple bond. Exploration of a terminal bromine atom at the side chain of <em>N</em>-alkyl-2-(<em>E</em>)-alkenyl-4-(1<em>H</em>)-quinolones showed improved antimycobacterial activity whereas a cyclopropyl residue at N-1 was suggested to be detrimental to antibacterial activity. |
| first_indexed | 2024-04-14T07:26:43Z |
| format | Article |
| id | doaj.art-b3ee9ed3339d4a4ba4ec7d2058c8805f |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-14T07:26:43Z |
| publishDate | 2012-07-01 |
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| series | Molecules |
| spelling | doaj.art-b3ee9ed3339d4a4ba4ec7d2058c8805f2022-12-22T02:05:59ZengMDPI AGMolecules1420-30492012-07-011778217824010.3390/molecules17078217Synthesis and Antibacterial Evaluation of a New Series of <em>N</em>-Alkyl-2-alkynyl/(<em>E</em>)-alkenyl-4-(1<em>H</em>)-quinolonesAbraham WubeJuan-David GuzmanAntje HüfnerChristina HochfellnerMartina BlunderRudolf BauerSimon GibbonsSanjib BhaktaFranz BucarTo gain further insight into the structural requirements of the aliphatic group at position 2 for their antimycobacterial activity, some <em>N</em>-alkyl-4-(1<em>H</em>)-quinolones bearing position 2 alkynyls with various chain length and triple bond positions were prepared and tested for<em> in vitro</em> antibacterial activity against rapidly-growing strains of mycobacteria, the vaccine strain <em>Mycobacterium bovis</em> BCG, and methicillin-resistant <em>Staphylococcus aureus</em> strains, EMRSA-15 and -16. The compounds were also evaluated for inhibition of ATP-dependent MurE ligase<em> </em>of <em>Mycobacterium tuberculosis</em>. The lowest MIC value of 0.5 mg/L (1.2–1.5 µM) was found against <em>M. fortuitum</em> and <em>M. smegmatis</em>. These compounds displayed no or only weak toxicity to the human lung fibroblast cell line MRC-5 at 100 µM concentration. The quinolone derivatives exhibited pronounced activity against the epidemic MRSA strains (EMRSA-15 and -16) with MIC values of 2–128 mg/L (5.3–364.7 µM), and <em>M. bovis</em> BCG with an MIC value of 25 mg/L (66.0–77.4 µM). In addition, the compounds inhibited the MurE ligase of <em>M. tuberculosis</em> with moderate to weak activity showing IC<sub>50</sub> values of 200–774 µM. The increased selectivity towards mycobacterial bacilli with reference to MRC-5 cells observed for 2-alkynyl quinolones compared to their corresponding 2-alkenyl analogues serves to highlight the mycobacterial specific effect of the triple bond. Exploration of a terminal bromine atom at the side chain of <em>N</em>-alkyl-2-(<em>E</em>)-alkenyl-4-(1<em>H</em>)-quinolones showed improved antimycobacterial activity whereas a cyclopropyl residue at N-1 was suggested to be detrimental to antibacterial activity.http://www.mdpi.com/1420-3049/17/7/8217<em>N</em>-alkyl-2-alkynyl/(<em>E</em>)-alkenyl-4(1<em>H</em>)-quinoloneantimycobacterialMRSAcytotoxicity |
| spellingShingle | Abraham Wube Juan-David Guzman Antje Hüfner Christina Hochfellner Martina Blunder Rudolf Bauer Simon Gibbons Sanjib Bhakta Franz Bucar Synthesis and Antibacterial Evaluation of a New Series of <em>N</em>-Alkyl-2-alkynyl/(<em>E</em>)-alkenyl-4-(1<em>H</em>)-quinolones Molecules <em>N</em>-alkyl-2-alkynyl/(<em>E</em>)-alkenyl-4(1<em>H</em>)-quinolone antimycobacterial MRSA cytotoxicity |
| title | Synthesis and Antibacterial Evaluation of a New Series of <em>N</em>-Alkyl-2-alkynyl/(<em>E</em>)-alkenyl-4-(1<em>H</em>)-quinolones |
| title_full | Synthesis and Antibacterial Evaluation of a New Series of <em>N</em>-Alkyl-2-alkynyl/(<em>E</em>)-alkenyl-4-(1<em>H</em>)-quinolones |
| title_fullStr | Synthesis and Antibacterial Evaluation of a New Series of <em>N</em>-Alkyl-2-alkynyl/(<em>E</em>)-alkenyl-4-(1<em>H</em>)-quinolones |
| title_full_unstemmed | Synthesis and Antibacterial Evaluation of a New Series of <em>N</em>-Alkyl-2-alkynyl/(<em>E</em>)-alkenyl-4-(1<em>H</em>)-quinolones |
| title_short | Synthesis and Antibacterial Evaluation of a New Series of <em>N</em>-Alkyl-2-alkynyl/(<em>E</em>)-alkenyl-4-(1<em>H</em>)-quinolones |
| title_sort | synthesis and antibacterial evaluation of a new series of lt em gt n lt em gt alkyl 2 alkynyl lt em gt e lt em gt alkenyl 4 1 lt em gt h lt em gt quinolones |
| topic | <em>N</em>-alkyl-2-alkynyl/(<em>E</em>)-alkenyl-4(1<em>H</em>)-quinolone antimycobacterial MRSA cytotoxicity |
| url | http://www.mdpi.com/1420-3049/17/7/8217 |
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