Abstract
Twenty six α-substituted N4-acetamide derivatives of ciprofloxacin (CIPRO) and norfloxacin (NOR) were synthesized and assayed for antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus and Bacillus subtilis. The derivatives were primarily more active against Gram-positive bacteria. The CIPRO derivatives, CD-7 (Ar = 3-chlorophenyl), CD-9 (Ar = 2-pyrimidyl) and CD-10 (α-phenyl, Ar = 2-pyrimidyl), exhibited lower MIC values, 0.4–0.9 μM, against Staphylococcus aureus than CIPRO, while only compound CD-10 exhibited better activity, 0.1 μM, against Bacillus subtilis than CIPRO. In addition, compounds CD-5 (Ar = 2-methoxyphenyl), CD-6 (α-phenyl, Ar = 2-methoxyphenyl), CD-7 (Ar = 3-Chlorophenyl), CD-8 (α-phenyl, Ar = 3-chlorophenyl) and CD-9 (Ar = 2-pyrimidyl) showed MIC values below 1.0 μM against this strain. The NOR derivatives showed lower activity than NOR itself against Staphylococcus aureus, although ND-6 (α-phenyl, Ar = 2-methoxyphenyl) and ND-7 (Ar = 3-chlorophenyl) showed MIC values less than 2 μM. Two NOR derivatives, ND-7 and ND-6, exhibited MIC values of 0.7 and 0.6, respectively, which were comparable to that of NOR against Bacillus subtilis, while compounds ND-8 (α-phenyl, Ar = 3-chlorophenyl) and ND-10 (α-phenyl, Ar = 2-pyrimidyl) exhibited MIC values less than 1.0 μM against the same strain. QSAR revealed that while polarity is the major contributing factor in the potency against Staphylococcus aureus, it is balanced by lipophilicity and electron density around the acetamide group. On the other hand, electron density around the introduced acetamide group is the major determining factor in the activity against Bacillus subtilis, with a lesser and variable effect for lipophilicity.
Highlights
Ciprofloxacin (CIPRO) and norfloxacin (NOR), Figure 1, are two simple and broad-spectrum fluoroquinolones
4-Benzylpiperidine and dibenzylamine were coupled to CD-1 and ND-1 only, as the substitution reaction failed with bulkier CD-2 and ND-2, even when the reaction was maintained at reflux for several days, which might be due to the increased bulk of the nucleophile, at least in the case of dibenzylamine
From a spectral point of view, the well-known characteristic splitting of the signals corresponding to C5, C6 and C7 of the fluoroquinolone nucleus with C–F coupling constants (J) of about 22, 246 and 10 Hz, respectively, was evident in all of the 13C-NMR spectra [24]
Summary
Ciprofloxacin (CIPRO) and norfloxacin (NOR), Figure 1, are two simple and broad-spectrum fluoroquinolones. Fluoroquinolones are synthetic antibacterial agents that exhibit activity against, but not limited to, Enterobacteria, Mycobacteria, Pseudomonas spp., Streptococci (including pneumococci) and Staphylococci [1,2] This group of compounds exert their antibacterial action by inhibiting bacterial DNA gyrase (topoisomerase II), which is the primary target in Gram-negative bacteria (e.g., E. coli and Neisseria gonorrhoeae), and topoisomerase IV, which is their primary site of action in. Gram-positive bacteria (e.g., S. aureus and S. pneumonia) [3] Structural modifications of this ubiquitous class of antibacterial agents have afforded compounds with reduced adverse effects, enhanced potency and/or better efficacy in resistant bacterial strains [4]. This is important, because the fast spread of resistant bacterial strains is a major challenge in treating bacterial infections [12,13]
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