Metabolism and antifungal activity of safrole, dillapiole, and derivatives against botryodiplodia theobromae and colletotrichum acutatum / Metabolismo y actividad antifúngica de safrol, dilapiol, y derivados contra botryodiplodia theobromae y colletotrichum acutatum

The direct in vitro fungitoxicity and metabolism of safrole and dillapiole (isolated from Piper auritum and Piper holtonii, respectively) by Botryodiplodia theobromae and Colletotrichum acutatum were investigated. Higher values of mycelial growth inhibition for both fungi were obtained for dillapiole, as compared with safrole. B. theobromae was able to metabolize both compounds to their respective vicinal diols, reaching 65 percent relative abundance during the biotransformation of dillapiole; while C. acutatum only transformed safrole to various metabolites with relative abundances under 5 percent. According to the low antifungal activity of the major metabolic products (< 5 percent for vicinal diols), a detoxification process was implied. Studies on the influence of some substituents in the aromatic ring of safrole and dillapiole on the antifungal activity against B. theobromae were also carried out. As result, the safrole nitrated derivative, 6-nitrosafrole, showed a fungitoxicity level similar to that displayed by the commercial fungicide Carbendazim® under the conditions used. In light of this, safrole and dillapiole could be suggested as feasible structural templates for developing new antifungal agents.

Se investigó la fungitoxicidad directa in vitro y el metabolismo de safrol y dilapiol (obtenidos desde Piper auritum and Piper holtonii, respectivamente) por Botryodiplodia theobromae y Colletotrichum acutatum. Los valores mayores de inhibición del crecimiento micelial de ambos hongos se obtuvieron para dilapiol, en comparación con safrol. B. theobromae metabolizó ambos compuestos a sus respectivos dioles vecinales, alcanzando abundancias relativas del 65 por ciento durante la biotransformación del dilapiol; mientras que C. acutatum solo transformó safrol en varios metabolitos con abundancias relativas menores al 5 por ciento. De acuerdo con la baja actividad antifúngica de los productos metabólicos mayoritarios (< 5 por ciento para los dioles vecinales), se sugiere un proceso de desintoxicación. Adicionalmente, se evaluó la influencia de algunos sustituyentes en el anillo aromático de safrol y dilapiol sobre la actividad antifúngica contra B. theobromae. Como resultado, el derivado nitrado del safrol, el 6–nitro safrol, presentó un nivel de fungitoxicidad similar al exhibido por el fungicida comercial Carbendazim® bajo las condiciones usadas. A la luz de lo anterior, safrol y dilapiol podrían ser sugeridos como plantillas estructurales adecuadas para el desarrollo de nuevos agentes antifúngicos.

Anti-inflammatory preoperties of new bioisosteres of indomethacim synthesized from safrole which are sulindac analogues

The anti-inflammatory activities of new compounds (I, II, II and IV) synthesized in 30% overall yield from the abundant natural product safrole, the principal chemical constituent of the oil of sassafras (Ocotea pretiosa, Lauraceae), were determined in mice. The synthesis of these new indenyl-acetic acids (I and II) and indenyl-propionic acids (III and IV) was based on the minimal structural features of non-steroid anti-inflammatory agents of the aryl- or heteroarylcarboxylic acid group. The compounds exhibited potencies 4- to 10-fold less than that of indometacin in inhibiting carrageenan-induced hindpaw edema. In contrast, like sulindac, all the new compounds were more potent than indomethacin in antagonizing writhing pain and increased vascular permeability caused by acetic acid. The results confirm the anticipated bioisosteric relationship between these synthetic derivatives, designed as sulindac analogues, and the classical non-steroidal anti-inflammatory agent, indomethacin