Anti-inflammatory Activity of Piperlotines

Abstract. 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.   Resumen. En la presente investigacion se evaluo la actividad anti-inflamatoria in vivo de seis amidas α,β-insaturadas, identificadas en la literatura como piperlotinas debido a su inicial aislamiento a partir de especies vegetales del genero Piper (como las pimientas). La reaccion del β-amidofosfonato 4 con un aldehido aromatico y K2CO3 en molienda con mortero y pistilo produjo las piperlotinas 5-6 con buenos rendimientos (70-80%) en tiempos cortos de reaccion, obteniendo solamente el diastereoisomero (E). Las piperlotinas preparadas se evaluaron como agentes anti-inflamatorios y antibacterianos, observando excelente actividad anti-inflamatoria para los derivados 2 y 6, especialmente cuando se probaron mediante administracion topica (modelo de inflamacion aguda por TPA). Ademas, la piperlotina A y los derivados 2 y 6 mostraron actividad antibacteriana contra Mycobacterium tuberculosis (MIC = 50 µg/mL). En conclusion, la sintesis de piperlotinas a traves de molienda en condiciones libres de disolvente genero importantes productos que pueden ser utilizados como punto de partida para generar nuevos compuestos bioactivos para el tratamiento de padecimientos relacionados con la inflamacion.