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.
Highlights
Since the discovery of the bacterial ethiology of tuberculosis (TB) by Robert Koch in 1882, various attempts have been devised to treat infections caused by Mycobacterium tuberculosis
We report the synthesis and biological evaluation of N-alkyl4(1H)-quinolones having alkynyls at C-NMR δ: 207.2 (C-2) with the intent of elucidating the role that these groups may play in the in vitro antibacterial profile against fast and slow growing strains of mycobacteria, and methicillin-resistant S. aureus strains keeping in mind potential correlations with the M. tuberculosis
As shown in Scheme 1, our rational design for the synthesis of N-alkyl-2-alkynyl-4(1H)-quinolones was based on the replacement of the double bond with a triple bond, while maintaining the basic quinolone skeleton
Summary
Since the discovery of the bacterial ethiology of tuberculosis (TB) by Robert Koch in 1882, various attempts have been devised to treat infections caused by Mycobacterium tuberculosis. Streptomycin and p-aminosalicylic acid were the first drugs introduced to treat TB, followed by isoniazid, pyrazinamide, rifampicin and ethambutol, which were championed as the first-line agents [1,2]. The emergence of strains that are resistant to these weapons necessitated further drug options that led to the second- and third-generation antibiotics. In the early 1990’s fluoroquinolones were introduced to tackle the ever increasing danger of bacterial resistance and have enjoyed great success against both Gram-positive and Gram-negative bacteria and certain anaerobes. There is increasing concern regarding the paucity of new antimycobacterial therapeutic agents that are coming onto the market in spite of increased mycobacterial resistance. New drugs with new modes of action are required in view of worldwide-emerging multi drug resistant (MDR-) and extensively drug resistant (XDR) M. tuberculosis strains [4]
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