Design, synthesis and evaluation of acridine and fused-quinoline derivatives as potential anti-tuberculosis agents

• We synthesized a series of twelve acridine and fused-quinoline derivatives via MW assisted Friedländer reaction and TFA catalysis.
• Three derivatives were active against Mycobacterium tuberculosis H37Rv (NIAID, USA) and were selected for additional testing.
• Compounds 9 and 13 showed remarkable MIC values against the rifampin resistant strain.
• Compound 9 can be a new leader due to its intracellular activity similar to rifampin.

The synthesis of twelve acridine and polycyclic acridine derivatives prepared via the Friedländer reaction is described. The one-pot reactions of 2-amino-5-chloro or 5-nitro-benzophenones and a variety of cyclanones and indanones were carried out in a MW oven under TFA catalysis in good yields. The products were designed according natural antituberculosis products and were evaluated for growth inhibitory activity towards Mycobacterium tuberculosis H37Rv (Mtb) through the National Institute of Allergy and Infectious Diseases (NIAID, USA). Three of them underwent additional testings. The cyclopenta[b]quinoline derivative 9 and the acridine derivative 13 showed remarkable MIC values against the rifampin resistant strain. The former exhibited bactericidal activity at 50 μg/mL, its intracellular activity is similar to rifampin and it was not cytotoxic at low concentrations so it can be considered a new lead compound.

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