Tuberculosis (TB) is an old and re-emerging disease that spreads at alarming rate. Mycobacterium tuberculosis (Mtb) is responsible for 8.8 million new active cases and 1.5 million deaths in 2010, and one-third of the world’s population is estimated to be latently infected with TB. About 95% of the tuberculosis cases and deaths occur in the developing countries, but there has also been a recent, highly publicized, resurgence of TB also in developed ones.a This pandemic is complicated by the co-infection with HIV (15% of new cases worldwide are HIV positive) and the emergence of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) Mtb strains.b The current recommended therapeutic strategy, namely Directly Observed Therapy, Short-course (DOTS) is based on the co-administration of four drugs, namely rifampin (RMP), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) for 2 months, followed by a prolonged treatment with INH and RMP for an additional 4–7 months.c The cause of the long-period treatment is the peculiar ability of Mtb to survive in a non-replicating persistent (NRP-TB) state while withstanding chemotherapy. These features highlight the need to develop well-tolerated drugs able to shorten the anti-TB treatment by targeting bacteria in a NRP state and effective also in the treatment of MDR-TB and XDR-TB strains.
After 40 years of neglect, because of a combination of medical and marketing evaluations, novel therapeutics are fuelling the anti-TB pipeline, with ten compounds in clinical trials and about the same number in preclinical development (1,2). Some of these molecules are New Chemical Entities (NCEs), while others are drugs already marketed for purposes other than the antimycobacterial chemotherapy. Belonging to the latter class, the 8-methoxyfluoroquinolones, moxifloxacin (3) and gatifloxacin (4), have earned a place in the antitubercular chemotherapy as second-line drugs, in the case of intolerance or resistance to the first-line drugs (5,6).d In addition, because of the high oral bioavailability, generally good tolerability, and low-to-moderate cost, they are currently in phase III of clinical trials for an evaluation of their potential to shorten TB treatment when in combination with other anti-TB agents (7). If successful, these drugs could shift from second-line antituberculars to first-line (8–10). However, mainly because of the recurrent use of quinolones for infections in patients where TB initially was not suspected, resistance to these two agents is a matter of concern (11,12). Cross-resistance is likely to occur because all the fluoroquinolones (FQs) target gyrA (13,14). However, an analysis of the gyrA mutations has shown that about a half of the isolated strains resistant to ofloxacin are susceptible to moxifloxacin (15,16) and to high doses of levofloxacin (16). So it is not unlikely that novel quinolones might be active also against FQ-resistant TB strains.
Challenging the C-6 fluorine dogma, our group has synthesized a relevant number of 6-amino- and 6-hydrogenquinolone derivatives, collectively referred as 6-desfluoroquinolones (6-DFQs) (17–22), with potent broad antibacterial spectra, including multidrug-resistant Gram-positive pathogens, such as methicillin-resistant and ciprofloxacin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae.
The encouraging evidences obtained with regard to the antibacterial activity and the availability of a large series of variously substituted 6-DFQs prompted us to evaluate their capability to inhibit the growth of Mtb, with the aim of contributing to the enrichment of the SAR regarding their antitubercular activity.
In particular, in this study, we report the inhibitory activity against Mtb strain H37Rv of about 60 selected 6-DFQs (1–14, Figure 1). The results obtained from the primary screening guided the design of new analogues (11ah, 11ai, and 11aj) for which the synthesis and antimycobacterial activity are also herein reported. To provide a comprehensive profile of their antimycobacterial properties, the activity against single-drug-resistant strains (SDR-TB), the minimum bactericidal concentration (MBC), and the apparent cytotoxicity to Vero cells have been also evaluated for selected molecules. In addition, a low oxygen recovery assay (LORA) was used to test their activity against NRP-TB.