In this paper, cercariae, schistosomula, and adult Schistosoma mansoni worms were incubated in vitro with the essential oil of Piper cubeba (PC-EO) at concentrations from 12.5 to 200 μg/mL, and the viability was evaluated using an inverted microscopy. The effects of PC-EO at 100 and 200 μg/mL on the stages of S. mansoni were similar to those of the positive control (PZQ at 12.5 μg/mL), with total absence of mobility after 120 h. However, at concentrations from 12.5 to 50 μg/mL, PC-EO caused a reduction in the viability of cercariae and schistosomula when compared with the negative control groups (RPMI 1640 or dechlorinated water) or (RPMI 1640 + 0.1% DMSO or dechlorinated water + 0.1% DMSO). On the other hand, adult S. mansoni worms remained normally active when incubated with PC-EO at concentrations of 12.5 and 25 μg/mL, and their viabilities were similar to those of the negative control groups. In addition, at concentrations ranging from 50 to 200 μg/mL, separation of all the coupled adult worms was observed after 24 h of incubation, which is related to the fact of the reduction in egg production at this concentration. The main chemical constituents of PC-EO were identified by gas chromatography-mass spectrometry as being sabinene (19.99%), eucalyptol (11.87%), 4-terpineol (6.36%), β-pinene (5.81%), camphor (5.61%), and δ-3-carene (5.34%). The cytotoxicity of the PC-EO was determined, and a significant cytotoxicity was only obtained in the concentration of 200 μg/mL after 24 h treatment. The results suggest that PC-EO possesses an effect against cercariae, schistosomula, and adult worms of the S. mansoni.

Protozoans of the trypanosomatid family cause the neglected tropical diseases leishmaniasis and trypanosomiasis, for which few drugs are available. In this context our group has recently reported that the essential oil obtained by steam distillation of the fruits of Piper cubeba is active against Schistosoma mansoni. Therefore, we have investigated the in vitro effects of the essential oil against the trypomastigote and amastigote forms of Trypanosoma cruzi isolated from an LLCMK₂ cell line culture and the promastigote forms of Leishmania amazonensis. The in vitro activity of the essential oil against trypomastigotes of T. cruzi increased upon rising concentrations, giving IC₅₀ values of 45.5 and 87.9 µg · mL⁻¹ against trypomastigotes and amastigotes, respectively. The essential oil was not active against L. amazonensis, since it displayed lyses of only 24 % at 400 µg · mL⁻¹, and an IC₅₀ of 326.5 µg · mL⁻¹. Therefore, the essential oil should be further investigated to determine the compounds responsible for the observed activities, as well as its mechanism of action.

(-)-Cubebin (CUB), isolated from seeds of Piper cubeba, was used as starting material to obtain the derivatives (-)-hinokinin (HK) and (-)-O-benzyl cubebin (OBZ). Using paw edema as the experimental model and different chemical mediators (prostaglandin and dextran), it was observed that both derivatives were active in comparison with both negative (5% Tween® 80 in saline) and positive (indomethacin) controls. The highest reduction in the prostaglandin-induced edema was achieved by OBZ (66.0%), while HK caused a 59.2% reduction. Nonetheless, the dextran-induced paw edema was not significantly reduced by either of the derivatives (HK or OBZ), which inhibited edema formation by 18.3% and 3.5%, respectively, in contrast with the positive control, cyproheptadine, which reduced the edema by 56.0%. The docking analysis showed that OBZ presented the most stable ligand-receptor (COX-2 - cyclooxygenase-2) interaction in comparison with CUB and HK.

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Breast cancer incidence rises worldwide and new chemotherapeutical strategies have been investigated to overcome chemoresistance. (-)-Hinokinin is a dibenzylbutyrolactone lignan derived from the partial synthesis of (-)-cubebin extracted from Piper cubeba seeds. Biological effects of dibenzylbutyrolactone lignans include antiviral, antitumor, anti-inflammatory, and trypanocidal activities. In the present study, we evaluated the ability of (-)-hinokinin to modulate the antiproliferative effects of doxorubicin intumoral (MCF-7 and SKBR-3) and normal (MCF-10 A) breast cell lines. Treatment with (-)-hinokinin did not affect the cellular proliferation or contribute to the antitproliferative effects of doxorubicin in MCF-10 A cells. After 24 and 48 hours of treatment with (-)-hinokinin, MCF-7 and SKBR-3 were accumulated in G2/M and, when combined with doxorubicin, (-)-hinokinin contributed to the antiproliferative effects of this chemotherapic by modulation of the cyclin-dependent kinase inhibitor 1. Apoptotic cell death was observed in response to (-)-hinokinin alone in MCF-7, but not in SKBR-3 even 72 hours after treatment. In MCF-7, doxorubicin-induced apoptosis was not increased by (-)-hinokinin. The findings of the present study suggest (-)-hinokinin as an antiproliferative agent that contributes to the effects of doxorubicin. (-)-Hinokinin modulates apoptotic cell death via the molecular regulation of the cell cycle and apoptotic control genes, but the cellular genetic background directly affects the cell fate decision in response to treatment.

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Six dibenzylbutyrolactonic lignans ((−)‐hinokinin (1), (−)‐cubebin (2), (−)‐yatein (3), (−)‐5‐methoxyyatein (4), dihydrocubebin (5) and dihydroclusin (6)) were isolated from Piper cubeba seed extract and evaluated against Schistosoma mansoni. All lignans, except 5, were able to separate the adult worm pairs and reduce the egg numbers during 24 h of incubation. Lignans 1, 3 and 4 (containing a lactone ring) were the most efficient concerning antiparasitary activity. Comparing structures 3 and 4, the presence of the methoxy group at position 5 appears to be important for this activity. Considering 1 and 3, it is possible to see that the substitution pattern change (methylenedioxy or methoxy groups) in positions 3′ and 4′ alter the biological response, with 1 being the second most active compound. Computational calculations suggest that the activity of compound 4 can be correlated with the largest lipophilicity value.