Synthesis and study of new antitubercular compounds

Abstract

Tuberculosis is regarded as one of the deadliest diseases in the world. It is a bacterial infection caused by some bacteria from the genus Mycobacterium, such as Mycobacterium tuberculosis. Some bacterial strains are multi-resistant or extensively-resistant against classical antibiotics. Consequently, there is a necessity to set up new strategies to prevent the spread of antibiotic resistant mycobacteria. Quinoline core is present in some antitubercular compounds. Indeed, bedaquiline (one of the last commercialized antitubercular compounds) is a diarylquinoline, which acts by inhibiting selectively the mycobacterial ATP synthase. This enzyme is required for the energetic metabolism of the cell and is a critical target to kill dormant strains. Mefloquine is a quinoline used as antimalarial compound but this molecule shows also antimycobacterial properties. Mefloquine can inhibit ATP synthase of Streptococcus pneumoniae, this inhibition may explain it antimycobacterial activity. The objectives of this work are designing, synthesizing, and evaluating new antitubercular compounds as quinoline derivatives (AQM). These molecules are expected to inhibit mycobacterial ATP synthase in order to fight latent forms of mycobacteria. The previous works of the research team have allowed to identify a lead compound which shows an MIC of 1 μM against M. tuberculosis MtbH37Rv strain. A pharmacomodulation of this lead compound will be shown here.