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

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

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Received: 10 April 2012; in revised form: 12 June 2012 / Accepted: 15 June 2012 / Published: 9 July 2012
(This article belongs to the Section Medicinal Chemistry)
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Abstract: 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 which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

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.

AMA Style

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(7):8217-8240.

Chicago/Turabian Style

Wube, Abraham; Guzman, Juan-David; Hüfner, Antje; Hochfellner, Christina; Blunder, Martina; Bauer, Rudolf; Gibbons, Simon; Bhakta, Sanjib; Bucar, Franz. 2012. "Synthesis and Antibacterial Evaluation of a New Series of N-Alkyl-2-alkynyl/(E)-alkenyl-4-(1H)-quinolones." Molecules 17, no. 7: 8217-8240.


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