Abstract
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.
Graphical Abstract
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