Antifungal piperolides, coumarins, pyrones and amides from Piper species and synthetic analogs

Bioguided chromatographic fractionation of extracts from Piper species from Brazilian Atlantic forest, yielded the piperolides 4,6-dimethoxy-5-E-phenylbutenolide and 4,6-dimethoxy-5-Z-phenylbutenolide, and the known amides piperine, piperovatine, piperlonguminine, corcovadine and the aristolactam piperolactam C from leaves of P. malacophyllum and P. scutifolium, respectively. These compounds showed antifungal activity against Cladosporium cladosporioides and C. sphaerospermum [1, 2] in preliminary assays and based on such results, several analogs were synthesized looking at preliminary structure-activity relationship. Due to structural similarities between pyrones and coumarins to piperolides available compounds were also assayed. Butenolides were synthesized by treating 4-methoxyfuran-2(5H)-one with several benzaldehydes in presence of TBDMSOTf and di-isopropylethylamine, followed by β-elimination mediated by DBU, to yield (5Z)-5-(3-bromobenzylidene)-4-methoxyfuran-2(5H)-one, 5-[{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-4-methoxyfuran-2(5H)-one and 5-(3-bromophenyl){[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methoxyfuran-2(5H)-one. Dienamides have been synthesized by extension of substituted benzaldehydes using the Wadsworth-Emmons reaction for side chain extension, followed by hydrolysis and reaction with oxalyl chloride, and finally reaction with the desired amines to yield the dienamides ((2E,4E)-N,N-diethyl-5-(4-methoxyphenyl)penta-2,4-dienamide, (2E, 4E)-N,N-diethyl-5-phenylpenta-2,4-dienamide, (2E, 4E)-N-isobutyl-5-phenylpenta-2,4-dienamide, (2E,4E)-N-isobutyl-5-(4-methoxyphenyl)penta-2,4-dienamide, (2E,4E)-N-isobutyl-5-(3-methoxyphenyl)penta-2,4-dienamide and (2E,4E)-N,N-diethyl-5-(3-methoxyphenyl)penta-2,4-dienamide. The synthetic and natural compounds were assayed against C. cladosporioides and C. sphaerospermum by bioautography which indicated their strong potential as antifungal agents, with similar detection limit as standard nystatin. The synthetic N,N-diethylamides were more effective against C. sphaerospermum than isobutyl amides, indicating a differential mode of action or susceptibility.

Acknowledgements: CNPQ, CAPES and FAPESP.

References: 1. Lago, J. H.G. et al. (2005)J. Braz. Chem. Soc. 16: 153. 2. Marques J.V.et al. (2007)J. Nat. Prod. 70: 2036