Chemical Composition and Cytotoxic Activity of Eucalyptus torquata Luehm. and Eucalyptus salmonophloia F.†Muell. Trunk Bark Essential Oils against Human SW620 and MDA-MB-231 Cancer Cell Lines.

In recent years, there has been a growing interest in the screening of natural active ingredients from Eucalyptus essential oils because of their evident importance in practical utility and their undeniable therapeutic properties. Based on this, the aim of the present study was to investigate the chemical profile of the essential oils of the trunk bark of Eucalyptus torquata Luehm. (ETEO), and E. salmonophloia F. Muell. (ESEO), growing in Tunisia. The in vitro cytotoxic properties of the extracted EOs were also evaluated against two human cancer cell lines: breast carcinoma cell lines MDA-MB-231 and colorectal cancer cell lines SW620. The analysis by gas chromatography coupled with mass spectrometry (GC/MS) led to the identification of 32 compounds from the ETEO, with the dominant constituents being the monoterpenes trans-myrtanol (73.4 %) and myrtenol (4.7 %), and the apocarotene (E)-ß-ionone (3.9 %). In the case of ESEO, 29 compounds were identified with trans-myrtanol (25.0 %), decanoic acid (22.1 %), nonanoic acid (9.8 %), γ-elemene (6.5 %), γ-maaliene (5.5 %), and α-terpineol (5.3 %) as the main components. The cytotoxicity of EOs against the two chosen cell lines was tested using Crystal Violet Staining (CVS) assay and 5-fluorouracil as a reference drug. The two EOs exhibited a significant dose-dependent inhibition against the viability of the used cell lines. Their inhibitory effects were particularly observed towards SW620 colon carcinoma cells with IC50 values of 26.71±1.22 and 22.21±0.85 µg/mL, respectively, indicating that both oils were more cytotoxic for SW620 cells compared to MDA-MB-231 one.

Characterization of Polar and Non-Polar Compounds of House Edible Bird's Nest (EBN) from Johor, Malaysia.

This work investigated the polar (PC: protein, amino acid and metabolite) and non-polar (NPC: fatty acid) compounds and bioactivity characteristics of the EBN harvested from the state of Johor in Malaysia. The electrophoretic gels exhibited 15 protein bands (16-173 kD) with unique protein profile. Amino acids analysis by AccQ⋅Tag method revealed 18 types of amino acids in EBN. Metabolite profiling was performed using High-Performance Liquid Chromatography coupled with Quadrupole Time-of-Flight Mass Spectrometer (HPLC-QTOF/MS) technique and a total of 54 compounds belonging to different groups were detected and identified. These findings help to uncover the relation of therapeutic activity of EBN. The EBN was further extracted with AcOEt and BuOH. The AcOEt extract was fractionated into three fractions (F1 -F3 ), and the high triglyceride content in F2 was verified by gC-FID. The three groups of fatty acids discovered in EBN are 48.43 % of poly-unsaturated (PUFA), 25.35 % of saturated fatty acids (SFA) and 24.74 % of mono-unsaturated fat (MUFA). This is the first time to report results ofEBN, BuOH, and AcOEt extracts and of fraction F2 (TEBN) on their analysis for their antioxidant activities by DPPH, ABTS and catalase assay and for their paraoxonase and anti-tyrosinase activities. The results showed that TEBN exhibited the significant bioactivity in all assays. These findings suggest that TEBN is a good source for natural bioactive compounds in promoting body vigor. Current work widened the content of EBN especially on the triglyceride and also marked the content of specific location (Johor, Malaysia) of EBN origin.

Synthesis, molecular properties, anti-inflammatory and anticancer activities of novel 3-hydroxyflavone derivatives.

A new series of 3-hydroxyflavones (1-46) were synthesized according to the Claisen-Schmidt followed by Algar-Flynn-Oyamada reactions (AFO) in one step. The synthesized flavonoids were characterized by 1H NMR, 13C NMR and DCI-HRMS. All the synthesized compounds were tested in vitro for their 15-lipoxygenase inhibitory and cytotoxic activity against the human cell lines HCT-116 (Human colon carcinoma), IGROV-1 and OVCAR-3 (human ovarian carcinoma). It has been found that the derivatives 25, 37 and 45 were the most actives against HCT-116 (IC50 = 8.0, 9.0 and 9.0 µM, respectively) and against IGROV-1 (IC50 = 2.4, 5.0 and 6.0 µM, respectively). The derivatives 14 and 21 exhibited the higher anti-inflammatory activity at 100 µM with PI values of 76.50 and 72.70%, respectively. Molecule description was performed with DFT calculations, the drug likeness and bioactivity scores. The results exhibted that some compounds are in linear correlation with Lipinski's rule of five showing good drug likeness and bioactivity score for drug targets.

Caryophyllene Sesquiterpenes from Pulicaria vulgaris Gaertn.: Isolation, Structure Determination, Bioactivity and Structure-Activity Relationship.

A new caryophyllene, named pulicaryenne A (1), along with four other known caryophyllene derivatives (2, 3, 4 and 5) were isolated from the ethyl acetate extract of aerial parts of Pulicaria vulgaris Gaertn. (Asteraceae). All compounds were isolated for the first time from this species. Compound 2 was identified as a new epimer of a known caryophyllene derivative isolated previously from P. dysenterica. Their structures were established by spectroscopic means including NMR analysis (1D- and 2D-NMR) and ESI-TOF-MS. All compounds were evaluated for their anticholinesterase, antityrosinase and cytotoxic activities against two human cell lines (A549 and HeLa). Results showed that compound 5 exhibited the highest cytotoxic effect against A549 and anticholinesterase activity with IC50 values of 8.50±0.75 and 6.45±0.09 µg/mL, respectively. Furthermore, compound 5 showed also an interesting antityrosinase activity with percent inhibition value of 79.0±2.5 % at 50 µg/mL. The bioactivity and drug likeness scores of the isolated compounds 1-5 were calculated using Molinspiration software and discussed. These results may suggest that the five caryophyllene derivatives endowed with good biological properties, which could be used as bioactive alternatives in pharmaceutical preparations.

Isocostic Acid, a Promising Bioactive Agent from the Essential Oil of Inula viscosa (L.): Insights from Drug Likeness Properties, Molecular Docking and SAR Analysis.

The chemical composition of the essential oil (LEO) and its volatile fractions (V1 -V10 ) collected during the hydrodistillation process every 15 min from the fresh leaves of I. viscosa (L.), growing in Tunisia, were analyzed by GC-FID and GC/MS. Eighty-two compounds, representing 90.9-99.4 % of the total samples, were identified. The crude essential oil (LEO) and its fractions (V1 -V10 ) were characterized by the presence of a high amount of oxygenated sesquiterpenes (82.7-95.8 %). Isocostic acid (1) was found to be the most abundant component (37.4-83.9 %) and was isolated from the same essential oil over silica gel column chromatography and identified by spectroscopic methods (1 H, 13 C, DEPT 135 NMR and EI-MS) and by comparison with literature data. Furthermore, the fresh leaves essential oil (LEO), its volatile fractions (V1 -V10 ) as well as compound 1 were screened for their antibacterial, antityrosinase, anticholinesterase and anti-5-lipoxygenase activities. It was found that the isolated compound 1 exhibited an interesting antibacterial activity against Staphylococcus aureus ATCC 25923 (MIC=32 µg/mL) and Enterococcus faecalis ATCC 29212 (MIC=32 µg/mL) and the highest antityrosinase activity (IC50 =13.82±0.87 µg/mL). Compound 1 was also found to be able to strongly inhibit 5-lipoxygenase with an IC50 value of 59.21±0.85 µg/mL. The bioactivity and drug likeness scores of compound 1 were calculated using Molinspiration software and interpreted, and the structure-activity relationship (SAR) was discussed with the help of molecular docking analysis.

New cytotoxic sesquiterpene lactones from Achillea cretica L. growing in Tunisia.

The phytochemical study of Achillea cretica growing in Tunisia led to the isolation of two novel sesquiterpene lactones, which have been designated achicretin 1 and achicretin 2. Their chemical structures were further confirmed by mass spectroscopy (ESI-MS) and by extensive application of one- and two-dimensional NMR spectroscopy. The isolated compounds were tested for their cytotoxic activity against four human cancer cell lines, IGROV-1, OVCAR-3, MCF-7, and HCT-116 using the MTT assay. It has been found that achicretin 2 exhibited more potent inhibitory activity with IC50 = values of 14.0 ± 1.0 and 16.0 ± 2.0 µM against OVCAR-3 and HCT-116 cells, respectively.

Bioactive flavones isolated from Tunisian Artemisia campestris L. Leaves.

Four flavones were isolated from dried leaves of Artemisia campestris L. 2',4',5,7-tetrahydroxy-5',6-dimethoxyflavone, eupatilin and dimethoxycentaureidin were reported for the first time in this species whereas cirsiliol was previously identified but it was isolated for the first time. Their structures were elucidated by spectroscopic methods, including 1D and 2D NMR experiments and mass spectrometry analysis. In addition, all isolated flavones were evaluated for their antioxidant, anti-inflammatory, anti-superoxide dismutase, anti-xanthine oxidase and cytotoxic activities. The results showed that all isolated compounds exhibited potent anti-xanthine oxidase activity with IC50 ranging from 3.3 to 6.8 µM, which was higher than that of the control compound allopurinol (8.2 ± 0.6 µM). In addition, cirsiliol was found to be the most cytotoxic against OVCAR-3, IGROV-1and HCT-116 cell lines at 15µM, with inhibition percentage values of 53.7, 48.8 and 40.9%, respectively. All compounds also showed weak to moderate anti-inflammatory and anti-superoxide dismutase activities.

Chemical Composition and In Vitro Evaluation of Antimicrobial, Antioxidant and Antigerminative Properties of the Seed Oil from the Tunisian Endemic Ferula tunetana Pomel ex Batt.

Essential oil of the seeds from the endemic Tunisian plant Ferula tunetana Pomel ex Batt. was analyzed for its chemical composition and screened for its antimicrobial, antioxidant and antigerminative properties. The chemical composition of the isolated oil is reported for the first time. According to the GC/FID, GC/MS and 13 C-NMR analysis results; 18 compounds were identified accounting for 84.6% of the total oil. The chemical composition of this essential oil was characterized by the presence of a high proportion of monoterpene hydrocarbons (77.3%) followed by oxygenated sesquiterpenes (4.1%) and sesquiterpene hydrocarbons (3.2%). α-Pinene (39.8%), ß-pinene (11.5%) and (Z)-ß-ocimene (7.5%) were the predominant compounds. Moreover, the isolated oil was tested for its antimicrobial activity using the disc-diffusion and the microdilution assays against six Gram-positive and five Gram-negative bacteria as well as towards two Candida species. The isolated oil was tested also for its antioxidant activity against DPPH, ABTS, O2∙ and hydrogen peroxide (H2 O2 ), and for its antigerminative potential. It was found that it exhibited interesting antimicrobial activity against Salmonella typhimurium LT2 DT104 (inhibition zone (IZ) 16.2 ± 1.0 mm) and Bacillus cereus ATCC 14579 (IZ 15.8 ± 1.0 mm). However, it exerted a moderate antioxidant activity against H2 O2 (IC50 78.2 ± 2.98 µg/ml) and towards O2∙ (IC50 89.2 ± 3.82 µg/ml). The antigerminative effect of this oil was also evaluated in this work. Results showed a toxic effect.

Synthesis of new isoxazoline derivatives from harmine and evaluation of their anti-Alzheimer, anti-cancer and anti-inflammatory activities.

In our study, a series of new harmine derivatives has been prepared by cycloaddition reaction using various arylnitrile oxides and evaluated in vitro against acetylcholinesterase and 5-lipoxygenase enzymes, MCF7 and HCT116 cancer cell lines. Some of these molecules have been shown to be potent inhibitors of acetylcholinesterase and MCF7 cell line. The greatest activity against acetylcholinesterase (IC50 = 10.4 µM) was obtained for harmine 1 and cytotoxic activities (IC50 = 0.2 µM) for compound 3a. Two derivatives 3e and 3f with the thiophene and furan systems, respectively, showed good activity against 5- lipoxygenase enzyme (IC50 = 29.2 and 55.5 µM, respectively).

Chemical composition, biological and cytotoxic activities of plant extracts and compounds isolated from Ferula lutea.

The present work describes the phytochemical study on Ferula lutea flowers. Total phenolics and flavonoids of the n-butanol and ethyl acetate extracts were quantified (phenolics [40.68-52.29 mg gallic acid equivalent/g of dry weight], flavonoids [12.38-14.72 mg quercitin/g dry weight]). Two diastereoisomers were isolated and identified using spectroscopic techniques (1D, 2D NMR and GC-MS). The extracts and diastereoisomers were tested for antioxidant, antiacetylcholinesterase, antimicrobial, antidiabectic, cytotoxic (leukemia cell line) activities and allelopathic potentialities. The strongest antioxidant activity was obtained for the ethyl acetate extract (IC50 = 12.8 ± 1.29 µg/mL). The two extracts exhibited high antidiabetic activity (54.1 and 52.1% at 40 µg/mL).

Antioxidant, 5-lipoxygenase inhibitory and cytotoxic activities of compounds isolated from the Ferula lutea flowers.

A phytochemical investigation of the Ferula lutea (Poir.) Maire flowers has led to the isolation of a new compound, (E)-5-ethylidenefuran-2(5H)-one-5-O-ß-d-glucopyranoside (1), designated ferunide, 4-hydroxy-3-methylbut-2-enoic acid (2), reported for the first time as a natural product, together with nine known compounds, verbenone-5-O-ß-d-glucopyranoside (3), 5-O-caffeoylquinic acid (4), methyl caffeate (5), methyl 3,5-O-dicaffeoylquinate (6), 3,5-O-dicaffeoylquinic acid (7), isorhamnetin-3-O-α-l-rhamnopyranosyl(1→6)-ß-d-glucopyranoside, narcissin (8), (-)-marmesin (9), isoimperatorin (10) and 2,3,6-trimethylbenzaldehyde (11). Compounds 3-10 were identified for the first time in Ferula genus. Their structures were elucidated by spectroscopic methods, including 1D and 2D NMR experiments, mass spectroscopy and X-ray diffraction analysis (compound 2), as well as by comparison with literature data. The antioxidant, anti-inflammatory and cytotoxic activities of isolated compounds were evaluated. Results showed that compound 7 exhibited the highest antioxidant activity with IC50 values of 18 ± 0.5 µmol/L and 19.7 ± 0.7 µmol/L by DPPH radical and ABTS radical cation, respectively. The compound 6 exhibited the highest anti-inflammatory activity with an IC50 value of 5.3 ± 0.1 µmol/L against 5-lipoxygenase. In addition, compound 5 was found to be the most cytotoxic, with IC50 values of 22.5 ± 2.4 µmol/L, 17.8 ± 1.1 µmol/L and 25 ± 1.1 µmol/L against the HCT-116, IGROV-1 and OVCAR-3 cell lines, respectively.

Semi-synthesis, α-amylase inhibition, and kinetic and molecular docking studies of arylidene-based sesquiterpene coumarins isolated from Ferula tunetana Pomel ex Batt.

Despite all the significant progresses made to enhance the efficacy of the existing bank of drugs used to manage and cure type II diabetes mellitus, there is still a need to search and develop novel bioactive compounds with superior efficacy and minimal adverse effects. This study describes the valorization of the natural bioactive sesquiterpene coumarin via the semi-synthesis of new analogs and the study of their α-amylase inhibition activity. The sesquiterpene coumarin named coladonin (1) was quantitatively isolated from the chloroform extract of endemic Ferula tunetana roots. Subsequently, the oxidation of 1via the Jones oxidation reaction, used as a key reaction, afforded precursor 2. The condensation of oxidized coladonin (2) with various aryl aldehydes provided a series of new arylidene-based sesquiterpene coumarin derivatives (3a-m), which were characterized by NMR and ESI-HRMS experiments. All derivatives evaluated in vitro for their α-amylase inhibitory potential showed interesting α-amylase inhibition with IC50 values ranging from 7.24 to 28.98 µM. Notably, compounds 3k and 3m exhibited lower IC50 values (7.24 µM and 8.38 µM, respectively) compared to the standard (acarbose: IC50 = 9.83 µM). In addition, the structure-activity relationship (SAR) for all the compounds was studied. The most active compounds were found to be mixed-type inhibitors, which was revealed by kinetic studies. Furthermore, molecular in silico docking studies were established for all synthesized analogs with the binding site for the α-amylase enzyme.

Chemical composition, antioxidant and anti-tyrosinase potentials of Acacia cyclops trunk bark using in vitro and in silico approaches.

The purpose of this paper was to evaluate the phytochemical profile of Acacia cyclops trunk bark methanol extract using LC-MS/MS, as well as to assess its antioxidant and anti-tyrosinase activities. Thus, total phenolic and flavonoid contents of the studied extract were established and 19 compounds were detected and quantified. In addition of their antioxidant potential against DPPH and ABTS assays, in vitro and in silico studies were adopted to evaluate tyrosinase inhibitory property of A. cyclops extract. Methanol trunk bark extract showed significant total phenolic content, antioxidant potential in terms of free radical scavenging, as well as an interesting tyrosinase inhibitory action (IC50= 05.12 ± 0.41 µg/mL). The molecular docking analysis and the drug-likeness prediction of the major selected compounds supported the significant anti-tyrosinase activity of the studied extract. The obtained results suggest that A. cyclops extract could be a promising candidate in the treatment of skin hyperpigmentation disorders.

Synthesis of new anticancer and anti-inflammatory isoxazolines and aziridines from the natural (-)-deltoin.

OBJECTIVES: This work describes the synthesis, the bioactivity and the structure-activity relationship of new derivatives from a natural coumarin. METHODS: (-)-Deltoin 1 and the corresponding isoxazolines and aziridines were characterized by spectroscopic means. The cytotoxic (HTC-116, IGROV-1 and OVCAR-3 cancer cell lines) and 5-lipoxygenase activity of (-)-deltoin 1 and its structural analogues have been evaluated. KEY FINDINGS: The phytochemical investigation of the ethyl acetate extract of the flowers of Ferula lutea (Poir.) Maire has led to the isolation of (-)-deltoin 1. A series of new isoxazoline 2a,a'-2f,f' and aziridine 3a,a'-3e,e' derivatives have been prepared by 1,3-dipolar cycloaddition. It has been found that the derivatives 2a (IC50 = 3.3 ± 0.1 µm), 3a,a' (IC50 = 5.9 ± 0.1 µm), 3b,b' (IC50 = 6.1 ± 0.7 µm) and 3c,c' (IC50 = 7.3 ± 0.9 µm) bearing a phenyl isoxazoline, a phenylaziridine, a 4-methlphenylaziridine and a 4-methoxyphenylaziridine, respectively, are more cytotoxic than (-)-deltoin 1 (IC50 = 14.3 ± 0.2 µm). The diastereoisomers in mixture (2f,f') with a 6-chloropyridin-2-yl system have shown the best anti-5-lipoxygenase activity (% inhibition = 53.1 ± 4.8% at 200 µm). CONCLUSIONS: Some analogues have been found more bioactive than deltoin 1. Their activity has been related to the nature of the added heterocycles. It would be interesting to evaluate their in-vivo activity.

Design and semisynthesis of new herbicide as 1,2,3-triazole derivatives of the natural maslinic acid.

Interesting biological activities (anti-inflammatory, anticancer, antiviral, antioxidant, antidiabetic…) have been reported for maslinic acid (MA) and MA-based compounds. In continuation of our previous work on MA, herbicide potential of Tunisian plant extracts and 1,4-triazolyl derivatives of MA, we now wish to report semisynthesis of new MA-based triazole hybrid compounds with herbicide potential. These compounds were synthesized through Cu-catalyzed azide-alkyne cycloaddition (CuAAC) under microwave irradiation conditions between propargylated MA and a series of phthalimide azides. Here, the first partner of CuAAC reaction (propargylated MA) resulted from propargylation of C-28 carboxylic acid group of isolated MA from the well-known Mediterranean plant Olea europaea L. (Oleaceae). So far, phthalimide azide derivatives were achieved by trapping of N-acyliminium ion, in-situ generated under catalytic condition of Bi(OTf)3, by aromatic nucleophiles. The cycloaddition reaction afforded regiospecifically 1,4-disubstituted triazoles in good yields. The latter hybrid compounds were shown to exhibit a high inhibition potential of seed germination. This constitutes the first step in development of potent herbicides since one of the final semisynthesized structures can serve as a promising lead candidate for further studies.

Phytochemical and biological studies of Atriplex inflata f. Muell.: isolation of secondary bioactive metabolites.

OBJECTIVES: This work describes the phytochemical and biological investigation of the Tunisian Atriplex inflata F. Muell (Chenopodiaceae). METHODS: Their chemical structures were elucidated on the basis of extensive spectroscopic methods, including 1D NMR and 2D NMR, ESI-HRMS and comparison with available literature data. The isolates were evaluated for their antioxidant activity by the DPPH• , ABTS+• , Fe3+ and catalase assays and also for their antibacterial and anticholinesterase activity. KEY FINDINGS: The chemical study of Atriplex inflata F. Muell led to the isolation of two fatty acids (9E)-methyl-8,11,12-trihydroxyoctadec-9-enoate 1 and (9E)-8,11,12-trihydroxyoctadecenoic acid 2 together with (Z)-litchiol B 3 and 20-hydroxyecdysone 4. Three of which are reported here for the first time in Atriplex genus. Based on the biosynthesis of hydroxylated arachidonic acid and derivatives, a plausible biogenesis pathway of the two fatty acids (1 and 2) was proposed. (Z)-litchiol B (3) was found to be the most active against Staphylococcus aureus. According to the literature, this is the first time that compounds 1, 2 and 3 were tested for their eventual biological activity. CONCLUSIONS: In the results of the present work, we have proposed the biogenesis pathway of unsaturated fatty acid and described the structure-activity relationship.

Synthesis of New Harmine Isoxazoles and Evaluation of their Potential Anti-Alzheimer, Anti-inflammatory, and Anticancer Activities.

Harmine 1 was extracted from the seeds of Peganum harmala. From this natural molecule, a new series of isoxazole derivatives with complete regiospecificity were prepared using 1,3-dipolar cycloaddition reactions with various arylnitrile oxides. Harmine and its derivatives were characterized by (1)H NMR, (13)C NMR and HRMS. The evaluation of their anti-acetylcholinesterase (AChE), anti-5-lipoxygenase (5-LOX), anti-xanthine oxidase (XOD) and anticancer activities were studied in vitro against AChE, 5-LOX and XOD enzymes, respectively, and in HTC-116, MCF7 and OVCAR-3 cancer cell lines. The prepared derivatives were shown to be inactive against the XOD enzyme (0-38.3 ± 1.9% at 100 µM). Compound 2 exhibited the best anti-AChE activity (IC50=1.9 ± 1.5 µM). Derivatives 3a, 3b and 3d had moderate cytotoxic activities (IC50=5.0 ± 0.3 µM (3a) and IC50=6.3 ± 0.4 µM (3b) against HCT 116 cells, IC50=5.0 ± 1.0 µM (3d) against MCF7 cells).

Chemical composition and in vitro evaluation of antimicrobial and anti-acetylcholinesterase properties of the flower oil of Ferula lutea.

The present work describes the chemical composition and evaluates the antimicrobial and the anti-acetylcholinesterase properties of the flower oil from the Tunisian Ferula lutea obtained by hydrodistillation and analyzed by combination of GC/FID and GC/MS. The chemical composition of the flower oil of this species is reported for the first time. Seventeen compounds were identified accounting for 94.3% of the total oil. The chemical composition of this essential oil was characterized by a high proportion of monoterpene hydrocarbons (80.4%) among which delta-3-carene (31.2%) and alpha-pinene (25.8%) were the predominant compounds. The oxygenated monoterpenes represent the second major fraction (12.0%), 2,3,6-trimethylbenzaldehyde (10.9%) being the predominant one. Furthermore, the isolated oil was tested for its antimicrobial activity using the disc-diffusion and the microdilution assays against six Gram-positive and five Gram-negative bacteria as well as towards eight Candida species. It was found that flower oil of F. lutea exhibited interesting antibacterial and anticandidal activity (MIC = 39 mcirog/mL against Escherichia coli, Staphylococcus aureus and S. epidermidis and MIC = 156 microg/mL against Candida albicans). The anti-acetylcholinesterase effect of this oil was also evaluated in this work. Results showed that this oil exhibits significant activity (IC50 =70.25 +/- 5.41 microg/mL).