| Summary: | 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.
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