Semisynthesis, ex vivo evaluation, and SAR studies of coumarin derivatives as potential antiasthmatic drugs

• Eighteen coumarin derivatives were semisynthesized with potential antiasthmatic properties.
• Results indicate that ether derivatives 1–3, 7–9 and 13–15 showed the best relaxant activity.
• Compound 2 (42 μM) was the most potent of the entire series, being 4-times more active than theophylline (positive control).

Asthma is a chronic inflammatory disorder that causes contraction in the smooth muscle of the airway and blocking of airflow. Reversal the contractile process is a strategy for the search of new drugs that could be used for the treatment of asthma. This work reports the semisynthesis, ex vivo relaxing evaluation and SAR studies of a series of 18 coumarins. The results pointed that the ether derivatives 1–3, 7–9 and 13–15 showed the best activity (Emax = 100%), where compound 2 (42 μM) was the most potent, being 4-times more active than theophylline (positive control). The ether homologation (methyl, ethyl and propyl) in position 7 or positions 6 and 7 of coumarins lead to relaxing effect, meanwhile formation of esters generated less active compounds than ethers. The SAR analysis showed that it is necessary the presence of two small ether groups and the methyl group at position 4 (site 3) encourage biological activity through soft hydrophobic changes in the molecule, without drastically affecting the cLogP.

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