Infectious diseases are the second most frequent cause of death worldwide. Among them, tuberculosis and nosocomial infections are particularly worrying. Tuberculosis is a bacterial infection caused by some bacteria from the genus Mycobacterium, such as Mycobacterium tuberculosis. The majority of the nosocomial infections involves the ESKAPE pathogens. Mycobacteria and ESKAPE bacteria can become resistant to most current antibiotic treatments. In the case of tuberculosis, the treatment of drug-resistant or multi drug-resistant mycobacteria is more complex and requires combination chemotherapy. Since 1970, only five antibiotics with new mechanism of action were marketed. Consequently, there is a necessity to set up new strategies to prevent the spread of antibiotic resistant bacteria. The quinoline core is found in anti-infectious drugs such as mefloquine (MQ) or bedaquiline (BQ). MQ is an aminoquinolinemethanol antimalarial drug that possesses also antibacterial activity against Gram-positive bacteria and most mycobacterial strains. Bedaquiline (BQ) is a diarylquinoline, recently marketed as antitubercular compound, which acts against latent mycobacteria by binding selectively to the mycobacterial F0F1-ATP synthase, a novel bacterial target. Some studies reported also that MQ was able to inhibit the F0F1-ATP synthase of Streptococcus pneumonia. During the antibacterial screening of new aminoquinolinemethanols synthesized in the AGIR’s team, we have identified a promising compound with good activities against S. aureus (MIC = 8 µg/mL), E. faecalis (MIC = 8 µg/mL) and E. coli (MIC = 16 µg/mL) and a very strong activity against M. tuberculosis (MIC = 1 µM). The objectives of this work are to design, to synthesize and to evaluate the antibacterial activity of new enantiopure aminoquinolinemethanols expecting to target the F0F1-ATP synthase. Currently, more than twenty compounds have been synthesized through an asymmetric synthetic route in 5 steps with a yield ranging from 14 and 47%. This synthesis and the antibacterial evaluation against two strains of mycobacteria and four ESKAPE pathogens will be presented.

Synthesis and study of new aminoquinolinemethanols as potential antibacterial drugs

2019 Fall National Meeting

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