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Molecules 2012, 17(7), 8217-8240; doi:10.3390/molecules17078217

Synthesis and Antibacterial Evaluation of a New Series of N-Alkyl-2-alkynyl/(E)-alkenyl-4-(1H)-quinolones

1 Department of Pharmacognosy, Institute of Pharmaceutical Sciences, Karl-Franzens-University Graz, Universitätsplatz 4, A-8010 Graz, Austria 2 Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK 3 Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK 4 Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Karl-Franzens-University Graz, Universitätsplatz 1, A-8010 Graz, Austria
* Author to whom correspondence should be addressed.
Received: 10 April 2012 / Revised: 12 June 2012 / Accepted: 15 June 2012 / Published: 9 July 2012
(This article belongs to the Section Medicinal Chemistry)
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To gain further insight into the structural requirements of the aliphatic group at position 2 for their antimycobacterial activity, some N-alkyl-4-(1H)-quinolones bearing position 2 alkynyls with various chain length and triple bond positions were prepared and tested for in vitro antibacterial activity against rapidly-growing strains of mycobacteria, the vaccine strain Mycobacterium bovis BCG, and methicillin-resistant Staphylococcus aureus strains, EMRSA-15 and -16. The compounds were also evaluated for inhibition of ATP-dependent MurE ligase of Mycobacterium tuberculosis. The lowest MIC value of 0.5 mg/L (1.2–1.5 µM) was found against M. fortuitum and M. smegmatis. 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 M. bovis BCG with an MIC value of 25 mg/L (66.0–77.4 µM). In addition, the compounds inhibited the MurE ligase of M. tuberculosis with moderate to weak activity showing IC50 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 N-alkyl-2-(E)-alkenyl-4-(1H)-quinolones showed improved antimycobacterial activity whereas a cyclopropyl residue at N-1 was suggested to be detrimental to antibacterial activity.
Keywords: N-alkyl-2-alkynyl/(E)-alkenyl-4(1H)-quinolone; antimycobacterial; MRSA; cytotoxicity N-alkyl-2-alkynyl/(E)-alkenyl-4(1H)-quinolone; antimycobacterial; MRSA; cytotoxicity
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Wube, A.; Guzman, J.-D.; Hüfner, A.; Hochfellner, C.; Blunder, M.; Bauer, R.; Gibbons, S.; Bhakta, S.; Bucar, F. Synthesis and Antibacterial Evaluation of a New Series of N-Alkyl-2-alkynyl/(E)-alkenyl-4-(1H)-quinolones. Molecules 2012, 17, 8217-8240.

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