Anti-inflammatory activity of piperlotines

In the present study we evaluated six α,β-unsaturated amides named piperlotines (for being isolated originally from Piper species) as new in vivo anti-inflammatory agents. In addition, we report the mechanosynthesis of two of them by mechanochemical activation of a Horner-Wadsworth-Emmons reaction. The reaction of β-amidophosphonate 4, an aromatic aldehyde and K₂CO₃ under grinding in a mortar and pestle afforded piperlotines 5-6 in good yields (70-88%) in short reaction times, obtaining only (E)-diastereomer. Piperlotines previously prepared were tested as anti-inflammatory and antibacterial agents. In this respect, derivatives 2 and 6 exhibited excellent in vivo anti-inflammatory activity on mice, especially trough topical administration (TPA acute inflammation model). Furthermore, piperlotine A, and compounds 2 and 6 had slight antimycobacterial activity against Mycobacterium tuberculosis (MIC = 50 µg/mL). In conclusion, the solvent-free mechanosynthesis of piperlotines produced valuable compounds that could serve as templates for further investigation in the search of better drug-like compounds for the treatment of inflammatory diseases.