Coumarine Analogues with Antimycobacterial and Immunomodulatory Activity
Thatiana L.B. Ventura,
Diego R.C. Silva,
Edmilson J. Maria,
Michelle F. Muzitano,
Rodrigo R. de Oliveira.
Novels coumarin derivatives containing hydroxyl and alkyl groups on the aromatic ring
were obtained through a hydroarylation reaction (1A-D) or by demethylation of bergapten (2A-C), and
were then evaluated for their immunomodulatory and antimycobacterial activities. The immunomodulatory
activity was evaluated in lipopolysaccharide (LPS)-stimulated mouse macrophage cells (RAW
264.7) by performing inhibition assays of nitric oxide (NO) and tumour necrosis factor (TNF-α) production. The cytotoxic
effect was determined using a commercial lactate dehydrogenase (LDH) kit and MTT assay. The antimycobacterial activity
of the coumarin derivatives was evaluated against Mycobacterium bovis BCG using the MTT method. Coumarin 1D
was able to inhibit almost 80% of NO production, even at 4 µg/mL, exhibiting an IC50 value of 3.08±2.36 µg/mL. Our results
indicate that the brominated substituents, despite their chain length, increased this activity, which is in contrast to the
furan ring that caused a decreased in activity. For all of the tested compounds, the observed activities were not affected by
their cytotoxicity to macrophages. For the TNF-α inhibitory activity, substituents -O(CH2)nBr and -OCH3 seem to be important,
as observed in 1C and 1D (IC50 19.61±1.16 and 10.54±0.86 µg/mL, respectively). Compounds 1C and 2B were
the most potent in the antimycobacterial assay, showing the lowest MIC50 value. All compounds containing bromine
alkoxy significantly reduced NO and TNF-α production, with compounds 1C and 1D being the most promising, and they
also showed antimycobacterial activity.
Keywords: Anti-inflammatory, antimycobacterial, Mycobacterium, nitric oxide, synthetic coumarins, tuberculosis.
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