Discovery of quinolone derivatives as antimycobacterial agents

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis ( M. tuberculosis ), is an important public health issue. Current first-line drugs administered to TB patients have been in use for over 40 years, whereas second-line drugs display strong side effects and poor compliance. Additionally, designing effective regimens to treat patients infected with multi- and extremely-drug-resistant (MDR and XDR) strains of TB is challenging. In this report, we screened our compound library and identified compound 1 with antituberculosis activity and a minimal inhibitory concentration (MIC) against M. tuberculosis of 20 μg mL −1 . Structure optimization and the structure-activity relationship of 1 as the lead compound enabled the design and synthesis of a series of quinolone derivatives, 6a1-6a2 , 6b1-6b36 , 6c1 , 6d1-6d14 , 7a1-7a2 , 7b1-7b2 , 7c1 , 8a1-8a5 , 9a1-9a4 and 10a1-10a6 . These compounds were evaluated in vitro for anti-tubercular activity against the M. tuberculosis H 37 Rv strain. Among them, compounds 6b6 , 6b12 and 6b21 exhibited MIC values in the range of 1.2-3 μg mL −1 and showed excellent activity against the tested MDR-TB strain (MIC: 3, 2.9 and 0.9 μg mL −1 , respectively). All three compounds were non-toxic toward A549 and Vero cells (>100 and >50 μg mL −1 , respectively). In addition, an antibacterial spectrum test carried out using compound 6b21 showed that this compound specifically inhibits M. tuberculosis . These can serve as a new starting point for the development of anti-TB agents with therapeutic potential. 6b21 : MIC against M. tb H 37 Rv = 1.2 μg mL −1 , MIC against drug-resistant strains = 0.9 μg mL −1 , solubility = 132 μg mL −1 , non-cytotoxicity.