Tuberculosis (TB) is currently one of the leading causes of death due to infective agents, and the growing rate of
multidrug-resistant tuberculosis (MDR TB) cases poses an emergent public health threat.
Fluoroquinolones are commonly used in the treatment of both MDR TB and
drug-sensitive
tuberculosis patients who are intolerant to first-line
antitubercular agents. Unfortunately, these drugs have mild side effects, relevant to the prolonged treatment regimens and diminished bioavailability due to binding of
metal ions. Moreover, the resistance to
fluoroquinolones is also on the rise, a characteristic of extensively
drug-resistant TB (
XDR TB). Here, we developed
esters as
prodrugs of the
fluoroquinolones levofloxacin and
ciprofloxacin, with long-chain
fatty alcohols. Both the
alcohols and the
quinolone have previously shown antimycobacterial activity and the aim was to develop
esters with improved lipophilicity and capable of delivering the free
acid inside mycobacterial cells. The
carboxylic acid group of
fluoroquinolones is essential to the mode of action but is also responsible for many of its side effects and
metal-chelating properties. The synthesis, stability in
biological media, and antibacterial activity were evaluated, the latter not only against Mycobacterium tuberculosis but also against other clinically relevant bacterial species, since the parent compounds display a broad spectrum of activity. The
biological results show a reduction in the antitubercular activity of the synthesized derivatives, probably due to deficient activation of the
ester prodrug. Despite this, it was found that the derivatives exhibit bioactivity against other
fluoroquinolone-resistant bacteria, indicating a different mode of action and suggesting that it may be worthwhile to research further modifications to the
carboxylic acid group. This might lead to new compounds that are efficient against resistant strains. This idea that the compounds may act by a different mechanism of action was further supported by a brief computer investigation that demonstrated the potential lack of selectivity of the
esters to the
fluoroquinolone target.