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The global epidemic of tuberculosis (TB) imposes a sustained epidemiologic vigilance and investments in research by governments. Mycobacterium tuberculosis, the main causative agent of TB in human beings, is a very successful pathogen, being the main cause of death in the population among infectious agents. In 2018, ∼10 million individuals were contaminated with this bacillus and became ill with TB, and about 1.2 million succumbed to the disease. Most of the success of the M. tuberculosis to linger in the population comes from its ability to persist in an asymptomatic latent state into the host and, in fact, the majority of the individuals are unaware of being contaminated. Even though TB is a treatable disease and is curable in most cases, the treatment is lengthy and laborious. In addition, the rise of resistance to first-line anti-TB drugs elicits a response from TB research groups to discover new chemical entities, preferably with novel mechanisms of action. The pathway to find a new TB drug, however, is arduous and has many barriers that are difficult to overcome. Fortunately, several approaches are available today to be pursued by scientists interested in anti-TB drug development, which goes from massively testing chemical compounds against mycobacteria, to discovering new molecular targets by genetic manipulation. This review presents some difficulties found along the TB drug development process and illustrates different approaches that might be used to try to identify new molecules or targets that are able to impair M. tuberculosis survival.

Using cycloalkyl and electron-donating groups to decrease the carbonyl electrophilicity, a novel series of 2-(quinoline-4-yloxy)­acetamides was synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Structure–activity relationship studies led to selective and potent antitubercular agents with minimum inhibitory concentrations in the submicromolar range against drug-sensitive and drug-resistant Mtb strains. An evaluation of the activity of the lead compounds against a spontaneous qcrB mutant strain indicated that the structures targeted the cytochrome bc 1 complex. In addition, selected molecules inhibited Mtb growth in a macrophage model of tuberculosis infection. Furthermore, the leading compound was chemically stable depending on the context and showed good kinetic solubility, high permeability, and a low rate of in vitro metabolism. Finally, the pharmacokinetic profile of the compound was assessed after oral administration to mice. To the best of our knowledge, for the first time, a 2-(quinoline-4-yloxy)­acetamide was obtained with a sufficient exposure, which may enable in vivo effectiveness and its further development as an antituberculosis drug candidate.

Tuberculosis remains a global health problem that affects millions of people around the world. Despite recent efforts in drug development, new alternatives are required. Herein, a series of 27 N-(4-(benzyloxy)benzyl)-4-aminoquinolines were synthesized and evaluated for their ability to inhibit the M. tuberculosis H37Rv strain. Two of these compounds exhibited minimal inhibitory concentrations (MICs) similar to the first-line drug isoniazid. In addition, these hit compounds were selective for the bacillus with no significant change in viability of Vero and HepG2 cells. Finally, chemical stability, permeability and metabolic stability were also evaluated. The obtained data show that the molecular hits can be optimized aiming at the development of drug candidates for tuberculosis treatment.