New cytotoxic and antifungal amides from the fruit of Piper retrofractum

Piper retrofractum is an economically and medicinally important species in the genus Piper (Piperaceae). The fruit extract has been reported to possess various bioactivities such as antifungal, insecticidal, antibacterial, anticancer, antileishmanial, antidiabetic and antiobesity activity [1,2]. In search of new natural products with respect to pharmaceutical lead discovery of antifungal and anticancer agents, bioassay-guided fractionation and chemical investigation of the methanol extract of the dried fruit of Piper retrofractum led to the isolation of three new amides, namely (2E,14Z)-N-isobutyleicosa-2,14-dienamide (1), dipiperamides F and G (2 and 3), together with 30 known compounds. Their structures were elucidated by extensive spectroscopic analyses including 1D and 2D NMR as well as MS, and by comparison with the literature. All isolated compounds were screened for their antifungal and cytotoxic activities. Piperanine (9) showed potent activity against the plant pathogenic fungus, Cladosporium cladosporioides, compared to nystatin (positive control). Dipiperamides F and G (2 and 3), chabamide (30), nigramide R (31), dehydropipernonaline (24), pipernonaline (25), guineensine (22), brachystamide B (23), retrofractamide C (20), pellitorine (13) and pipericine (14) exhibited cytotoxicity against L5178Y mouse lymphoma cells with IC₅₀ values of 10.0, 13.9, 11.6, 9.3, 8.9, 17.0, 17.0, 16.4, 13.4, 28.3 and 24.2 µM, respectively. The presence of a methylenedioxyphenyl moiety in the amides structure tends to increase the cytotoxicity.

References:

[1] Lim TK. Edible Medicinal and Non-medicinal Plants, vol. 4. Netherlands: Springer Science & Business; 2012: 351 – 357.

[2] Luyen BTT, Tai BH, Thao NP, Yang SY, Cuong NM, Kwon IY, Jang HD, Kim YH. A new phenylpropanoid and an alkylglycoside from Piper retrofractum leaves with their antioxidant and α-glucosidase inhibitory activity. Bioorg Med Chem Lett 2014: 4120 – 4124.