Analogues of natural products yaequinolones as potential inflammatory inhibitors: Design, synthesis and biological evaluation

Inflammation is connected with a variety of diseases and there is still a need to develop more effective and safer anti-inflammatory drugs. Herein, we synthesized, resolved, and characterized eight enantiopure isomers of yaequinolone J1 (1), yaequinolone J2 (2), 4′-desmethoxyyaequinolone J1 (3), and 4′-desmethoxyyaequinolone J2 (4). The key synthetic steps were extended and 34 racemic analogues modified at the 4-aryl, the N-position, and the pyran ring were designed and synthesized. All the synthesized compounds were evaluated for their anti-inflammatory activities in RAW 264.7 cells of which 13 compounds showed significant inhibition of nitric oxide (NO) production at a concentration of 0.1 μM, which was more potent than that of indomethacin. Furthermore, compounds (−)-3, (−)-4, 5h, and 6g reduced the production of IL-6 in LPS-stimulated RAW 264.7 cells at a concentration of 50 nM. A preliminary SAR indicated that 3′-Br (5h), 4′-NO2 (6g) on 4-phenyl and 3-bromobenzyl (7f) on the N-position were the most effective substituents. This is the first report of the anti-inflammatory yaequinolone alkaloids and the present study provided evidence for exploiting this series of highly efficacious derivatives for new anti-inflammatory agents. [Display omitted] •Yaequinolone fused with an isoprenyl pyran ring reported as a novel chemotype for development of inflammatory inhibitors.•SynThesized eight chiral non-racemic yaequinolones and 34 racemic yaequinolone analogues to establish valuable SARs.•A total of 13 chiral, non-racemic and racemic compounds showed inhibition of NO production at a concentration of 0.1 μM.•Four compounds reduced the production of IL-6 at a concentration of 50 nM.