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Synthesis and study of new antitubercular compounds
* 1 , 2 , 2
1  AGIR, EA 4294, UFR of Pharmacy, Jules Verne University of Picardie, 80037 Amiens, France;
2  Université de Picardie

Published: 31 October 2018 by MDPI in 4th International Electronic Conference on Medicinal Chemistry session ECMC-4

Tuberculosis is regarded as one of the deadliest diseases in the world. In 2017, 10 million people were affected by tuberculosis and 1.7 million died because of it1.
Tuberculosis 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.
Only two antitubercular compounds have been commercialized during the last 40 years: bedaquiline in 20122 and delamanid in 2014. That emphasizes the lack of therapeutic options available to cure tuberculosis.

Quinoline core is present in some antitubercular compounds.
Indeed, bedaquiline is a diarylquinoline, which acts by inhibiting selectively the mycobacterial ATP synthase, an enzyme required for the energetic metabolism of the cell. The stereochemistry is particularly important in this selectivity as the (1R, 2S) enantiomer is 630 times more active than the (1S, 2R) enantiomer.
Mefloquine is a quinoline used as antimalarial compound but this molecule shows also antimycobacterial properties. Indeed, mefloquine can inhibit ATP synthase of Streptococcus pneumoniae3.
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 team4 have allowed to identify a lead compound which shows an MIC of 2 µM against M. tuberculosis MtbH37Rv strain. A pharmacomodulation of this lead compound will be shown here.
Twenty two molecules have been synthesized through an asymmetric synthetic route in 5 steps with an average yield from 14 to 47 %. These molecules have been tested in vitro, against M. avium and M. xenopi and have shown interesting biological activity with a MIC between 18 µM and more than 72 µM.

  1. WHO, Global tuberculosis report 2017.
  2. Haagsma AC, Abdillahi-Ibrahim R, et al. Antimicrob Agents Chemother. 2009, 53, 1290-1292.
  3. Martin-Galiano AJ, Gorgojo B, Kunin CM, de la Campa AG. Antimicrob Agents Chemother. 2002, 46, 1680-1697.
  4. Jonet, A. Dassonville-Klimpt, P. Sonnet, C. Mullié. J. of Antibiotics, 2013, 66, 683-686.

Keywords: Tuberculosis; Antitubercular; Quinoline