Development of amino-alcohol-quinolines targeting lung diseases caused by non-tuberculous mycobacteria.

The emergence of non-tuberculous mycobacteria (NTM) infections is outstripping that of Mycobacterium tuberculosis. Some species cause opportunistic infections in humans. In people with bronchiectasis or chronic respiratory disease, 80% of infections are related to NTM, and among these, Mycobacterium avium complex (MAC) is the most common. Guidelines-based treatment consists of a combination of a macrolide, a rifamycin and ethambutol. This treatment is prescribed for at least 12 months and its effectiveness is estimated at 52%, due to the development of macrolide resistance in MAC. These drugs can cause inconveniences or serious effects. Drug interactions can also occur, e.g., clarithromycin and rifampicin are strong inducers of cytochrome P450. Consequently, there is an urgent need to develop safer molecules with novel mechanisms of action that also minimize the risk of antibiotic resistance.

The quinoline-based pharmacophore is found in mefloquine (MQ). MQ has moderate anti-NTM activity in vitro (MIC = 4 µg/mL on MAC), high in vitro toxicity (CC₅₀ = 2.6 µg/mL on HepG2 cells) and a low maximum tolerated in vivo dose (40 mg/kg).

Our aim is to develop new amino-alcohol-quinolines (AAQ), analogues of MQ, by modulating the structural positions of the MQ core, particularly the amino-alcohol chain, in order to improve efficacy and reduce toxicity. Two series of AAQ were developed and thirty-one compounds were obtained. One hit was identified, with the highest selectivity index (SI) on M. avium (SI = 5.8). Additionally, checkerboard assay was demonstrated an additive effect with the antibiotics used in the reference treatment. Finally, this hit was evaluated in BALB/c mice and excellent tolerance was revealed (tolerate dose ≥ 500 mg/kg).

The following topics will be presented: i) the design and synthesis of AAQ, ii) their in vitro activity and toxicity, iii) the potential in vitro synergistic effects of one hit compound, and iv) the in vivo toxicity of this promising compound.