Rational Design, Synthesis, and Biological Evaluation of Heterocyclic Quinolones Targeting the Respiratory Chain of Mycobacterium tuberculosis

In 2014, tuberculosis (TB) globally infected 9.6 million people, resulting in an estimated 1.5 million deaths.(1) With the emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB, the need for new drug treatments targeting the disease has never been greater.(2) Current first line drugs for TB were developed in 1952–1966 (Figure 1). Shortcomings of these drugs include: (i) long treatment regimens (6–9 months), leading to patient noncompliance, (ii) adverse drug–drug interactions with anti HIV drugs (HIV/AIDS is a common coinfection), and (iii) limited or no activity against MDR and XDR Mycobacterium tuberculosis (Mtb).(3) Bedaquiline(4, 5) and delamanid(6, 7) are the only recently FDA approved drugs for the treatment of TB, and their approval is currently only for MDR in cases where established treatments have failed (Figure 1).(8) To find an effective treatment for MDR and XDR, it is believed that a drug with a novel mode of action is required in order to circumvent resistance.