Iván Montenegro

Structural Requirements for the Antifungal Activities of Natural Drimane Sesquiterpenes and Analogues, Supported by Conformational and Electronic Studies

Seventeen drimanes including polygodial (1), isopolygodial (2), drimenol (3) and confertifolin (4) obtained from natural sources and the semi-synthetic derivatives 5–17 obtained from 1–3, were evaluated in vitro for antifungal properties against a unique panel of fungi with standardized procedures by using two end-points, MIC100 and MIC50. A SAR analysis of the whole series, supported by conformational and electronic studies, allowed us to show that the Δ7,8 -double bond would be one of the key structural features related to the antifungal activity. The MEPs obtained for active compounds exhibit a clear negative minimum value (deep red zone) in the vicinity of the Δ7,8 -double bond, which is not present in the inactive ones. Apart of this negative zone, a positive region (deep blue) appears in 1, which is not observed either in its epimer 2 nor in the rest of the active compounds. The LogP of active compounds varies between 2.33 and 3.84, but differences in MICs are not correlated with concomitant variations in LogP values.

Study on the cytotoxic activity of drimane sesquiterpenes and nordrimane compounds against cancer cell lines

Twelve drimanes, including polygodial (1), isopolygodial (2), drimenol (3), confertifolin (4), and isodrimenin (5), were obtained from natural sources. Semi-synthetic derivatives 6–12 were obtained from 1 and 2, and cytotoxic activity was evaluated in vitro against cancer cell lines (HT-29, MDA-MB231, DHF, MCF-7, PC-3, DU-145, and CoN). IC50 values were determined at concentrations of 12.5–100 µM of each compound for 72 h. In addition, it was found that polygodial (1), 8, and 12 induced changes in mitochondrial membrane permeability in CoN, MCF-7, and PC-3 cells.

Diterpenylhydroquinones from natural ent-labdanes induce apoptosis through decreased mitochondrial membrane potential.

In this study, we examined the cytotoxic effects of seven ent-labdane derivatives 1–7 (0–100 μM) in different human cancer cell lines. Our results showed that compounds 1–3 exhibited significant dose-dependent inhibition on the growth of the three different human cell lines, according to the sulphorhodamine B assay and produced morphological changes consistent with apoptosis, as confirmed by Hoestch 3342 staining analysis. They induced apoptosis in various cancer cell lines, as shown by nuclear condensation and fragmentation and caspase 3 activation. Such induction was associated with the depletion of mitochondrial membrane potential. These activities led to the cleavage of caspases and the trigger of cell death process. Overall, the compounds showed potent proapoptotic effects on the two different cancer cell lines, suggesting that the compounds deserve more extensive investigation of their potential medicinal applications.

Antifungal study of the resinous exudate and of meroterpenoids isolated from Psoralea glandulosa (Fabaceae)

ETHNOPHARMACOLOGICAL RELEVANCE Psoralea glandulosa L. (Fabaceae) is a medicinal resinous shrub used in Chilean folk medicine as antiseptic in treatment of infections and skin diseases caused by bacteria and fungus. AIM OF THE STUDY To evaluate the in vitro antifungal activity of the resin and the active components from P. glandulosa against clinical yeast isolates. MATERIALS AND METHODS Active compounds were obtained of the resinous exudate from aerial parts of P. glandulosa. Eight species of yeast were exposed to the resin and two major compounds. Minimum inhibitory concentration (MIC(80)) was determined according to the standard broth microdilution method. RESULTS Bakuchiol and 3-hydroxy-bakuchiol demonstrated potent activity with the MIC(80) ranging from 4 to >16 and 0.125 to 16 μg/mL, respectively. The resin had some degree of antifungal activity. CONCLUSIONS The overall results provided important information for the potential application of the 3-hydroxy-bakuchiol from P. glandulosa in the therapy of serious infection and skin diseases caused by clinical yeast.

Psoralea glandulosa as a Potential Source of Anticancer Agents for Melanoma Treatment

With the aim of identifying novel agents with antigrowth and pro-apoptotic activity on melanoma cancer, the present study was undertaken to investigate the biological activity of the resinous exudate of aerial parts from Psoralea glandulosa, and its active components (bakuchiol (1), 3-hydroxy-bakuchiol (2) and 12-hydroxy-iso-bakuchiol (3)) against melanoma cells (A2058). In addition, the effect in cancer cells of bakuchiol acetate (4), a semi-synthetic derivative of bakuchiol, was examined. The results obtained show that the resinous exudate inhibited the growth of cancer cells with IC50 value of 10.5 μg/mL after 48 h of treatment, while, for pure compounds, the most active was the semi-synthetic compound 4. Our data also demonstrate that resin is able to induce apoptotic cell death, which could be related to an overall action of the meroterpenes present. In addition, our data seem to indicate that the apoptosis correlated to the tested products appears, at least in part, to be associated with an increase of reactive oxygen species (ROS) production. In summary, our study provides the first evidence that P. glandulosa may be considered a source of useful molecules in the development of analogues with more potent efficacy against melanoma cells.

Synthesis and Evaluation of Novel Oxyalkylated Derivatives of 2′,4′-Dihydroxychalcone as Anti-Oomycete Agents against Bronopol Resistant Strains of Saprolegnia sp.

A series of novel oxyalkylchalcones substituted with alkyl groups were designed and synthesized, and the antioomycete activity of the series was evaluated in vitro against Saprolegnia strains. All tested O-alkylchalcones were synthesized by means of nucleophilic substitution from the natural compound 2′,4′-dihydroxychalcone (1) and the respective alkyl bromide. The natural chalcone (1) and 10 synthetic oxyalkylchalcones (2–11) were tested against Saprolegnia parasitica and Saprolegnia australis. Among synthetic analogs, 2-hydroxy,4-farnesyloxychalcone (11) showed the most potent activity against Saprolegnia sp., with MIC and MOC values of 125 µg/mL (similar to bronopol at 150 µg/mL) and 175 µg/mL, respectively; however, 2′,4′-dihydroxychalcone (1) was the strongest and most active molecule, with MIC and MOC values of 6.25 µg/mL and 12.5 µg/mL.

Chemical Characterization and Anti-Oomycete Activity of Laureliopsis philippianna Essential Oils against Saprolegnia parasitica and S. australis

Laureliopsis philippiana (Looser) R. Schodde (Monimiaceae) is a native tree widespread in the forest areas in the south of Chile and Argentina, known for its medicinal properties and excellent wood. The aim of this study was to evaluate the chemical composition of L. philippiana leaf and bark essential oils (EOs) using gas chromatography-mass spectrometry (GC-MS), and to quantify its anti-oomycete activity, specifically against Saprolegnia parasitica and S. australis. Only six components were identified in leaf EO, 96.92% of which are phenylpropanoids and 3.08% are terpenes. As for bark EO, 29 components were identified, representing 67.61% for phenylpropanoids and 32.39% for terpenes. Leaf EO was characterized mainly by safrole (96.92%) and β-phellandrene (1.80%). Bark EO was characterized mainly by isosafrole (30.07%), safrole (24.41%), eucalyptol (13.89%), methyleugenol (7.12%), and eugenol (6.01%). Bark EO has the most promising anti-Saprolegnia activity, with a minimum inhibition concentration (MIC) value of 30.0 µg/mL against mycelia growth and a minimum fungicidal concentration (MFC) value of 50.0 μg/mL against spores; for leaf EO, the MIC and MFC values are 100 and 125 µg/mL, respectively. These findings demonstrate that bark EO has potential to be developed as a remedy for the control of Saprolegnia spp. in aquaculture.

EVALUATION OF THE ANTIOXIDANT CAPACITY OF Psoralea glandulosa L. (Fabaceae) EXTRACTS

The antioxidant properties of different extracts of culen (Psoralea glandulosa L., Fabaceae) herb from Gran Valparaiso location in Chile were evaluated. Antioxidant capacity was assessed in four different model systems. Antioxidant models were examined by measuring the scavenging activity of extracts on 2,2-diphenyl-1-pycrylhydrazil (DPPH●) as well as on hydrogen peroxide (H 2 O 2 ), the oxidant species. In addition, extracts were evaluated by ferric reducing antioxidant power (FRAP) and the total peroxyl radical-trapping potential (TRAP). The amount of dried extract, the content of total phenolics, flavonoids and hydrolyzed sugar were also determined. The leaves extracts from culen expressed very strong scavenging activity, reducing the DPPH● (IC 50 = 1.00 mg/mL to 1.61 mg/mL) and neutralizing H 2 O 2 (IC 50 = 34.29 mg/mL to 64.87 mg/mL). Also, dichloromethane extract of the leaves showed notable index of FRAP (2.71 mM) and TRAP (1.19 mM). The results suggest strong antioxidant potential of dichloromethane and ethyl acetate extracts of leaves of P. glandulosa that could be partially explained by the levels of phenolics (1.65 mg GAE/g dry extract) and flavonoids (55.34 mg QE/g dry extract) respectively.

Antifeedant effect of polygodial and drimenol derivatives against Spodoptera frugiperda and Epilachna paenulata and quantitative structure-activity analysis: Antifeedant effect of polygodial and drimenol derivatives

BACKGROUND The antifeedant activity of 18 sesquiterpenoids of the drimane family (polygodial, drimenol and derivatives) was investigated. RESULTS Polygodial, drimanic and nordrimanic derivatives were found to exert antifeedant effects against two insect species, Spodoptera frugiperda and Epilachna paenulata, which are pests of agronomic interest, indicating that they have potential as biopesticide agents. Among the 18 compounds tested, the epoxynordrimane compound (11) and isonordrimenone (4) showed the highest activity [50% effective concentration (EC50 ) = 23.28 and 25.63 nmol cm-2 , respectively, against S. frugiperda, and 50.50 and 59.00 nmol/cm2 , respectively, against E. paenulata]. CONCLUSION The results suggest that drimanic compounds have potential as new agents against S. frugiperda and E. paenulata. A quantitative structure-activity relationship (QSAR) analysis of the whole series, supported by electronic studies, suggested that drimanic compounds have structural features necessary for increasing antifeedant activity, namely a C-9 carbonyl group and an epoxide at C-8 and C-9.

Hemi-Synthesis and Anti-Oomycete Activity of Analogues of Isocordoin

An efficient synthesis of a series of 4′-oxyalkyl-isocordoin analogues (2–8) is reported for the first time. Their structures were confirmed by 1H-NMR, 13C-NMR, and HRMS. Their anti-oomycete activity was evaluated by mycelium and spores inhibition assay against two selected pathogenic oomycetes strains: Saprolegnia parasitica and Saprolegnia australis. The entire series of isocordoin derivatives (except compound 7) showed high inhibitory activity against these oomycete strains. Among them, compound 2 exhibited strong activity, with minimum inhibitory concentration (MIC) and minimum oomyceticidal concentration (MOC) values of 50 µg/mL and 75 µg/mL, respectively. The results showed that 4′-oxyalkylated analogues of isocordoin could be potential anti-oomycete agents.