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Herein, we highlight the significance of molecular modeling approaches prior to in vitro and in vivo studies; particularly, in diseases with no recognized treatments such as neurological abnormalities. Alzheimer disease is a neurodegenerative disorder that causes irreversible cognitive decline. Toxicity and ADMET studies were conducted using the Qikprop platform in Maestro software and Discovery Studio 2.0, respectively, to select the promising skeletons from more than 45 reviewed compounds isolated from mushrooms in the last decade. Using rigid and flexible molecular docking approaches such as induced fit docking (IFD) in the binding sites of ß-secretase (BACE1) and acetylcholine esterase (ACHE), promising structures were screened through high precision molecular docking compared with standard drugs donepezil and (2E)-2-imino-3-methyl-5,5-diphenylimidazolidin-4-one (OKK) using Maestro and Cresset Flare platforms. Molecular interactions, binding distances, and RMSD values were measured to reveal key interactions at the binding sites of the two neurodegenerative enzymes. Analysis of IFD results revealed consistent bindings of dictyoquinazol A and gensetin I in the pocket of 4ey7 while inonophenol A, ganomycin, and fornicin fit quite well in 4dju demonstrating binding poses very close to native ligands at ACHE and BACE1. Respective key amino acid contacts manifested the least steric problems according to their Gibbs free binding energies, Glide XP scores, RMSD values, and molecular orientation respect to the key amino acids. Molecular dynamics simulations further confirmed our findings and prospected these compounds to show significant in vitro results in their future pharmacological studies.
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BACKGROUND: Moringa oleifera is a highly nutritious plant widely used in traditional medicine. RESULTS: The aroma constituents present in the fresh flowers of M. oleifera versus the hydrodistilled oil and hexane extract were studied using GC-MS. Aldehydes were the major class detected in the fresh flowers (64.75%) with E-2-hexenal being the predominant component constituting > 50%. Alkane hydrocarbons, monoterpenes, and aldehydes constituted > 50% of the hydrodistilled oil, while alkane hydrocarbons exclusively constitute up to 65.48% of the hexane extract with heptacosane being the major component (46.2%). The cytotoxicity of the hexane extract was assessed on RAW 264.7 macrophages using the MTT assay which revealed no significant cytotoxicity at concentrations of 1 µg/mL and displayed IC50 value at 398.53 µg/mL as compared to celecoxib (anti-inflammatory drug) with IC50 value at 274.55 µg/ml. The hexane extract of Moringa flowers displayed good anti-inflammatory activity through suppression of NO, IL-6, and TNF-α in lipopolysaccharide-induced RAW 264.7 macrophages. The total phenolic and flavonoid content in the hexane extract was found to be 12.51 ± 0.28 mg GAE/g extract and 0.16 ± 0.01 mg RuE/g extract, respectively. It displayed moderate antioxidant activity as indicated by the in vitro DPPH, ABTS, CUPRAC, FRAP, and phosphomolybdenum (PBA) assays. No metal chelating properties were observed for the extract. The enzyme inhibitory potential of the hexane extract was evaluated on acetyl- and butyrylcholinesterases (for neuroprotective assessment), α-amylase and α-glucosidase (for antihyperglycemic assessment), and tyrosinase (for dermoprotective assessment) revealing promising results on cholinesterases, tyrosinase, and α-glucosidase. CONCLUSION: Our findings suggested that M. oleifera leaves can be considered as a multidirectional ingredient for preparing functional applications.
Subject(s)
Anti-Inflammatory Agents , Antioxidants , Flowers , Moringa oleifera , Plant Extracts , Mice , Animals , Flowers/chemistry , Plant Extracts/pharmacology , Plant Extracts/chemistry , Moringa oleifera/chemistry , RAW 264.7 Cells , Antioxidants/pharmacology , Antioxidants/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Odorants/analysisABSTRACT
INTRODUCTION: This study focuses on the development of novel antimicrobial agents. A Schiff base ligand, 6-(2-(4-hydroxy-3-methoxybenzylideneamino)-2-(4-hydroxyphenyl)acetamido)-3,3-dimethyl-7-oxo- 4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid, synthesized through the condensation of amoxicillin and vanillin in methanol, served as the foundation. Polydentate mixed ligand complexes were then formed by reacting the Schiff base with metal ions (Fe(II), Co(II), Ni(II), Cu(II), and Zn(II)) and nicotinamide in specific ratios. METHODS: Characterization involved various techniques, such as 1H-NMR, FT-IR, UV-Vis, and elemental analysis for the ligand, and Atomic Absorption, FT-IR, UV-Vis, magnetic susceptibility, and conductance measurements for the Schiff base-metal ion complexes. RESULTS: Quantum chemical features of both ligands and metal complexes were computed, refining their electronic and molecular structures theoretically. Antimicrobial activity against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Salmonella typhi, Acinetobacter baumannii, and Pseudomonas aeruginosa was assessed for the starting materials, ligands, and synthesized complexes, revealing significant effects on certain species. In-silico binding modes with Escherichia coli (PDB ID: 5iq9) were determined through molecular docking. CONCLUSION: This study underscores the potential applications of the Schiff base ligands and their metal complexes in developing new antimicrobial agents.
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Chemical exploration of the total extract derived from Epicoccum nigrum Ann-B-2, an endophyte associated with Annona squamosa fruits, afforded two new metabolites, epicoccofuran A (1) and flavimycin C (2), along with four known compounds namely, epicocconigrone A (3), epicoccolide B (4), epicoccone (5) and 4,5,6-trihydroxy-7-methyl-1,3-dihydroisobenzofuran (6). Structures of the isolated compounds were elucidated using extensive 1D and 2D NMR along with HR-ESI-MS. Flavimycin C (2) was isolated as an epimeric mixture of its two diastereomers 2a and 2b. The new compounds 1 and 2 displayed moderate activity against B. subtilis, whereas compounds (2, 3, 5, and 6) showed significant antiproliferative effects against a panel of seven different cancer cell lines with IC50 values ranging from 1.3 to 12 µM.
Subject(s)
Annona , Antineoplastic Agents , Ascomycota , Benzofurans , Annona/chemistry , Fruit , Benzofurans/pharmacology , Ascomycota/chemistry , Antineoplastic Agents/chemistry , Molecular StructureABSTRACT
Plant species C. majus, which is a very rich source of secondary metabolites, was used to obtain extracts, using a conventional extraction technique. For the extraction of bioactive molecules, three solvents were used: ethyl acetate, methanol and water, which differ from each other based on their polarity. The obtained extracts were examined in terms of chemical composition, antioxidant, enzyme inhibitory activity, and cytotoxic effects. The research results indicate that methanol was a better and more efficient extractant in the process of isolating bioactive compounds than ethyl acetate and water. The chemical composition of this solvent, i.e. its polarity, contributed the most to the extraction of alkaloids and flavonoids. The high content of total phenolic compounds in the methanol extract, as well as individual alkaloids, caused a very strong antioxidant activity, as well as a strong inhibitory power when it comes to inhibiting the excessive activity of cholinesterase and tyrosinase. Methanol and ethyl acetate extracts achieved very good cytotoxic activity against cancerous cells HGC-27 and HT-29 and did not exert a toxic effect on non-cancerous cell lines (HEK293). Extracts of plant species C. majus, especially methanol extract could be characterized as a very good starting plant material for the formulation of products intended for various branches of the food and pharmaceutical industry.
Subject(s)
Acetates , Alkaloids , Chelidonium , Humans , Plant Extracts/chemistry , Chelidonium majus , Methanol , HEK293 Cells , Molecular Structure , Alkaloids/pharmacology , Alkaloids/chemistry , Solvents/chemistry , Antioxidants , Water , Chelidonium/chemistryABSTRACT
BACKGROUND: Inhibition of NF-κB activity represents a strategy to treat acute myeloid leukemia, one of the most lethal leukemia types. Naphthylisoquinolines (NIQs) are cytotoxic alkaloids from lianas of the families Ancistrocladaceae and Dioncophyllaceae, which are indigenous to tropical rainforests. PURPOSE: Uncovering therapeutic possibilities and underlying molecular mechanisms of dioncophylline A and its derivatives towards NF-κB related cellular processes. METHODS: Resazurin-based cell viability assay was performed for dioncophylline A and three derivatives on wild-type CCRF-CEM and multidrug-resistant CEM/ADR5000 cells. Transcriptome analysis was executed to discover cellular functions and molecular networks associated with dioncophylline A treatment. Expression changes obtained by mRNA microarray hybridization were confirmed using qRT-PCR. Molecular docking was applied to predict the affinity of the NIQs with NF-κB. To validate the in silico approach, NF-κB reporter assays were conducted on HEK-Blue™ Null1 cells. Cell death mechanisms and cell cycle arrest were studied using flow cytometry. The potential activity on angiogenesis was evaluated with the endothelial cell tube formation assay on HUVECs using fluorescence microscopy. Intracellular NF-κB location in HEK-Blue™ Null1 cells was visualized with immunofluorescence. Finally, the anti-tumor activity of dioncophylline A was studied by a xenograft zebrafish model in vivo. RESULTS: Our study demonstrated that dioncophylline A and its derivatives exerted potent cytotoxicity on leukemia cells. Using Ingenuity Pathway Analysis, we identified the NF-κB network as the top network, and docking experiments predicted dioncophylline A and two of its derivatives sharing the same binding pocket with the positive control compound, triptolide. Dioncophylline A showed the best inhibitory activity in NF-κB reporter assays compared to its derivatives, caused autophagy rather than apoptosis, and induced G2/M arrest. It also prevented NF-κB translocation from the cytoplasm to the nucleus. Tube formation as an angiogenesis marker was significantly suppressed by dioncophylline A treatment. Finally, the remarkable anti-tumor activity of dioncophylline A was proven in zebrafish in vivo. CONCLUSION: Taken together, we report for the first time the molecular mechanism behind the cytotoxic effect of dioncophylline A on leukemia cells. Dioncophylline A showed strong cytotoxic activity, inhibited NF-κB translocation, significantly affected the NF-κB in silico and in vitro, subdued tube formation, induced autophagy, and exerted antitumor activity in vivo. Our findings enlighten both the cellular functions including the NF-κB signaling pathway and the cytotoxic mechanism affected by dioncophylline A.
Subject(s)
Antineoplastic Agents , Isoquinolines , Leukemia , Animals , Humans , NF-kappa B/metabolism , Zebrafish/metabolism , Apoptosis , Molecular Docking Simulation , Angiogenesis , G2 Phase Cell Cycle Checkpoints , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints , AutophagyABSTRACT
Phytolacca americana L. is of great interest as a traditional additive in various folk remedies in several countries, including Turkey. We aimed to determine the chemical profile (assisted by high-Performance liquid chromatography-electrospray ionization-tandem mass apectrometry (HPLC-ESI-MS/MS) experiments of three extracts obtained by different polarity solvents viz. ethyl acetate (to extract semipolar compounds), methanol and water (to extract highly polar metabolites) from P. americana leaves. Their anti-diabetic effects were investigated in vitro by assessing their inhibition toα-amylase and α-glucosidase. Assessment of the neuroprotective potential of the three extracts was carried out against acetyl-(AChE) and butyryl-(BChE) cholinesterase enzymes. HPLC-ESI-MS/MS experiments showed a total of 17 chromatographic peaks primarily classified to six flavonoids, two saponins, and six fatty acids. Antioxidant assays revealed remarkable activity for the ethyl acetate and methanol extracts. The BChE inhibition was considerably more significant (4.08 mg galantamine equivalent (GALAE)/g) for the ethyl acetate extract, whereas the methanol extract had good inhibitory efficacy for AChE (2.05 mg GALAE/g). Through network pharmacology, the compounds' mechanism of action of targeted key gene in their associated diseases were identified. The hubb gene signal transducer and activator of transcription 3 (STAT3) and tumour necrosis factor (TNFα) where the P. americana compound's site of action in inflammation bowel disease. The results offer possibilities for the prospective application of P. americana in metabolic regulation, blood glucose control, and as a source of bioactive compounds with cholinesterase enzyme inhibitory characteristics which could be of relevance in the cosmetic or pharmaceutical industry for combating melanogenesis.Communicated by Ramaswamy H. Sarma.
ABSTRACT
The Lamiaceae family, encompassing diverse plant species, holds significant value in food, medicine, and cosmetics. Within this family, Pentapleura subulifera and Cyclotrichium glabrescens, relatively unexplored species, were investigated for their chemical composition, antioxidant capacity, and enzyme-inhibiting effects. The chemical composition of hexane, methanolic, and aqueous extracts from P.â subulifera and C.â glabrescens were analyzed using LC-ESI-MS/MS and the non-polar hexane fraction was investigated via GC-MS. The antioxidant potential of the extracts was determined through radical scavenging, reducing power and metal chelating assays. Additionally, inhibitory activity against six enzymes - acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, amylase, and glucosidase - was examined. The aqueous extract of P.â subulifera and the methanolic extract of C.â glabrescens exhibited elevated phenolic content at 129.47â mg gallic acid equivalent (GAE)/g and 55.97â mg GAE/g, respectively. Chemical profiling of the constituents of the two plant species resulted in the identification of a total of twenty compounds. The majority of which belonged to flavonoids and quinic acid derivatives, primarily concentrated in the methanol and aqueous extracts. Among all antioxidant assays, the aqueous extracts of P.â subulifera demonstrated superior antioxidant activity, with the highest recorded activity of 404.93â mg trolox equivalent (TE)/g in the cupric reducing antioxidant capacity (CUPRAC) test. Meanwhile, the hexane extract of C.â glabrescens exhibited the highest AChE inhibitory activity at 2.71â mg galanthamine equivalent (GALAE)/g, followed by the methanol extract of P.â subulifera at 2.41â mg GALAE/g. These findings unequivocally establish the notable antioxidant and enzyme inhibitory activity of P.â subulifera and C.â glabrescens extracts, underscoring their potential as a source of valuable natural antioxidants.
Subject(s)
Antioxidants , Lamiaceae , Antioxidants/pharmacology , Antioxidants/chemistry , Butyrylcholinesterase , Hexanes , Acetylcholinesterase , Methanol , Tandem Mass Spectrometry , Plant Extracts/pharmacology , Plant Extracts/chemistry , Phytochemicals , Flavonoids/chemistryABSTRACT
The Eucalyptus tree, belonging to the myrtle family, grows all over the world for its pharmaceutical and industrial benefits. In this article, we present a comparative analysis of the chemical composition of the hydrodistilled oils obtained from three different Eucalyptus species growing in Egypt viz. E. citriodora, E. camaldulensis, and E. ficifolia. Gas Chromatography-Mass Spectrometric guided analysis resulted in the identification of a total of 20 metabolites in E. citriodora oil with citronellal (54.9%) and citronellol (25.4%) being the most dominant components. ß-cymene (12.7%) and 1,8-cineole (11.7%) were the major volatile constituents identified in E. camaldulensis oil, while trans-ß-ocimene (22.4%), 1,8-cineole (13.5%), and L-trans-pinocarveol (12.5%) were the dominating components in the oil of E. ficifolia. The essential oils of the studied species were evaluated for their in vitro anti-inflammatory, antiviral including anti-SARS-CoV-2 (severe acute respiratory syndrome corona virus 2), antibacterial, and antifungal activities. E. citriodora oil displayed the highest inhibitory activity on the release of the superoxide radical (32%) and elastase enzyme (31%) in human neutrophils, while E. ficifolia oil had enhancing effects on elastase. The latter showed significant antiviral effects against hepatitis A, herpes simplex, and coxsackie viruses with IC50 values at 2.1, 2.5, and 5.6 µg/mL, respectively. Moderate antibacterial and antifungal activities were observed for Eucalyptus oils with Staphylococcus aureus being the most susceptible bacterial strain. E. ficifolia oil, similarly, displayed the best antibacterial activity with minimum inhibitory concentration (MIC) value at ca. 25 µg/mL (for S. aureus). On the contrary, E. camaldulensis oil was the most active against Candida albicans with an MIC value at 45 µg/mL. In silico studies were performed with a number of macromolecular drug targets for confirming the biological activities of the identified compounds and for interpreting their ADME (absorption-distribution-metabolism-elimination) parameters.
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The chemical composition as well as antioxidant, antiproliferative, and enzyme inhibition activities of extracts from aerial parts of Thymus leucostomus H ausskn. & V elen. obtained with hexane, methanol, and water were evaluated. Results showed that the methanol extract had significantly (p < 0.05) the highest total phenolic content (TPC; 107.80 mg GAE/g) and total flavonoids content (TFC; 25.21 mg RE/g) followed by the aqueous extract (102.72 mg GAE/g and 20.88 mg RE/g, respectively). LC-MS/MS-guided profiling of the three extracts revealed that rosmarinic acid (34.8%), hesperetin (42.9%), and linoleic acid (18%) were the dominant compounds in the methanol, aqueous and hexane extracts, respectively. GC-MS analysis of the hexane extract showed that É£-sitosterol (29.9%) was the major constituent. The methanol extract displayed significantly (p < 0.05) the highest Cu++ , Fe+++ , and Mo(VI) ions scavenging and reducing properties while the aqueous extract exerted significantly (p < 0.05) the highest metal chelating power (42.51 mg EDTAE/g). Both the hexane and methanol extracts effectively inhibited the acetylcholinesterase enzyme (2.63 and 2.65 mg GALAE/g, respectively) while the former extract exerted significantly (p < 0.05) the highest butyrylcholinesterase (2.32 mg GALAE/g), tyrosinase (19.73 mg KAE/g), and amylase (1.16 mmol ACAE/g) inhibition capacity. The aqueous extract exhibited the best glucosidase inhibition property (0.49 mmol ACAE/g). The methanol and hexane extracts exerted a higher cytotoxic effect on HT-29 (IC50 : 8.12 µg/mL) and HeLa (IC50 = 8.08 µg/mL) cells, respectively. In conclusion, these results provide valuable insight into the potential use of T. leucostomus bioactive extracts in different pharmaceutical applications.
Subject(s)
Antioxidants , Hexanes , Antioxidants/pharmacology , Antioxidants/chemistry , Chromatography, Liquid , Gas Chromatography-Mass Spectrometry , Hexanes/analysis , Methanol/analysis , Butyrylcholinesterase , Acetylcholinesterase , Tandem Mass Spectrometry , Plant Extracts/chemistry , Structure-Activity RelationshipABSTRACT
Geldanamycin is an ansamycin-derivative of a benzoquinone isolated from Streptomyces hygroscopicus. It inhibits tyrosine kinases and heat shock protein 90 (HSP90). Geldanamycin and 11 derivatives were subjected to molecular docking to HSP90, and 17-desmethoxy-17-N,N-dimethylamino-geldanamycin (17-DMAG) was the compound with the highest binding affinity (-7.73 ± 0.12 kcal/mol) and the lowest inhibition constant (2.16 ± 0.49 µM). Therefore, 17-DMAG was selected for further experiments in comparison to geldanamycin. Multidrug resistance (MDR) represents a major problem for successful cancer therapy. We tested geldanamycin and 17-DMAG against various drug-resistant cancer cell lines. Although geldanamycin and 17-DMAG inhibited the proliferation in all cell lines tested, multidrug-resistant P-glycoprotein-overexpressing CEM/ADR5000 cells were cross-resistant, ΔEGFR-overexpressing tumor cells and p53 knockout cells were sensitive to these two compounds. COMPARE and hierarchical cluster analyses were performed, and 60 genes were identified to predict the sensitivity or resistance of 59 NCI tumor cell lines towards geldanamycin and 17-DMAG. The distribution of cell lines according to their mRNA expression profiles indicated sensitivity or resistance to both compounds with statistical significance. Moreover, bioinformatic tools were used to study possible mechanisms of action of geldanamycin and 17-DMAG. Galaxy Cistrome analyses were carried out to predict transcription factor binding motifs in the promoter regions of the candidate genes. Interestingly, the NF-ĸB DNA binding motif (Rel) was identified as the top transcription factor. Furthermore, these 60 genes were subjected to Ingenuity Pathway Analysis (IPA) to study the signaling pathway interactions of these genes. Interestingly, IPA also revealed the NF-ĸB pathway as the top network among these genes. Finally, NF-ĸB reporter assays confirmed the bioinformatic prediction, and both geldanamycin and 17-DMAG significantly inhibited NF-κB activity after exposure for 24 h. In conclusion, geldanamycin and 17-DMAG exhibited cytotoxic activity against different tumor cell lines. Their activity was not restricted to HSP90 but indicated an involvement of the NF-KB pathway.
Subject(s)
NF-kappa B , Neoplasms , Lactams, Macrocyclic/pharmacology , Molecular Docking Simulation , Benzoquinones/pharmacology , Cell Line, Tumor , HSP90 Heat-Shock Proteins/metabolismABSTRACT
Brown algae comprise up to 2000 species with wide dissemination in temperate zones. A comprehensive untargeted metabolic profiling guided by molecular networking of three uninvestigated Red-Sea-derived brown algae, namely Sirophysalis trinodis, Polycladia myrica, and Turbinaria triquetra, led to the identification of over 115 metabolites categorized as glycerolipids, fatty acids, sterol lipids, sphingolipids, and phospholipids. The three algae exhibited low-to-moderate antioxidant capacity using DPPH and ABTS assays. Preliminary in vitro antiproliferative studies showed that the algal extracts displayed high cytotoxic activity against a panel of cancer cell lines. The most potent activity was recorded against MCF-7 with IC50 values of 51.37 ± 1.19, 63.44 ± 1.13, and 59.70 ± 1.22 µg/mL for S. trinodis, P. myrica, and T. triquetra, respectively. The cytotoxicity of the algae was selective to MCF-7 without showing notable effects on the proliferation of normal human WISH cells. Morphological studies revealed that the algae caused cell shrinkage, increased cellular debris, triggered detachment, cell rounding, and cytoplasmic condensation in MCF-7 cancer cells. Mechanistic investigations using flow cytometry, qPCR, and Western blot showed that the algae induced apoptosis, initiated cell cycle arrest in the sub-G0/G1 phase, and inhibited the proliferation of cancer cells via increasing mRNA and protein expression of p53, while reducing the expression of PI3K, Akt, and mTOR.
Subject(s)
Proto-Oncogene Proteins c-akt , Signal Transduction , Humans , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Tumor Suppressor Protein p53/metabolism , Chromatography, Liquid , Indian Ocean , Cell Proliferation , Tandem Mass Spectrometry , TOR Serine-Threonine Kinases/metabolism , MCF-7 Cells , Apoptosis , Cell Line, TumorABSTRACT
Species belonging to the Zingiberaceae family are of high nutritional, industrial, and medicinal values. In this study, we investigated the effect of processing steps (fresh vs. dried milled rhizomes) and extraction methodologies (hydrodistillation vs. hexane extraction) of curcuma essential oil on its chemical content (using GC-MS analysis), its antioxidant behavior (using in vitro assays such as DPPH, ABTS, CUPRAC, FRAP, phosphomolybdenum, and metal chelation), and its enzyme inhibitory activities (on tyrosinase, acetylcholinesterase, butylcholinesterase, α-amylase, and α-glucosidase) supported by multivariate analysis, in silico studies, and molecular dynamics. The GC-MS investigations revealed a high degree of similarity in the chemical profile of fresh hydrodistilled and hexane-extracted essential oils with tumerone and curlone being the major metabolites. The extraction techniques affected the concentrations of other minor constituents such as terpinolene, caryophylla-4(12), 8(13)-dien-5α-ol, and neo-intermedeol, which were almost exclusively detected in the hydrodistilled fresh essential oil; however, zingiberene and ß-sesquiphellandrene were predominant in the hexane-extracted fresh essential oil. In the dried curcuma rhizomes, tumerone and curlone contents were significantly reduced, with the former being detected only in the hydrodistilled essential oil while the latter was doubly concentrated in the hexane-derived oil. Constituents such as D-limonene and caryophyllene oxide represented ca. 29% of the dried hydrodistilled essential oil, while ar-turmerone was detected only in the dried hydrodistilled and hexane-extracted essential oils, representing ca. 16% and 26% of the essential oil composition, respectively. These variations in the essential oil chemical content have subsequently affected its antioxidant properties and enzyme inhibitory activities. In silico investigations showed that hydrophobic interactions and hydrogen bonding were the characteristic binding modes of the bioactive metabolites to their respective targets. Molecular dynamics revealed the stability of the ligand-target complex over time. From the current study we conclude that fresh hexane-extracted essential oil showed the best radical scavenging properties, and fresh rhizomes in general display better enzyme inhibitory activity regardless of the extraction technique.
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The discovery of a new naphthylisoquinoline alkaloid, dioncophyllidine E (4), from the tropical liana Ancistrocladus abbreviatus (Ancistrocladaceae) is described. Due to its rare 7,3'-coupling type, combined with the lack of an oxygen function at C-6, it is configurationally semi-stable at the biaryl axis, and thus occurs as a pair of slowly interconverting atropo-diastereomers, 4a and 4b. Its constitution was assigned mainly by 1D and 2D NMR. The absolute configuration at the stereocenter, C-3, was elucidated by oxidative degradation. The absolute axial configuration of the individual atropo-diastereomers was established by their HPLC resolution, combined with online electronic circular dichroism (ECD) investigations, providing nearly mirror-imaged LC-ECD spectra. These were assigned to the respective atropisomers by ECD comparison with a related, but configurationally stable alkaloid, ancistrocladidine (5). Dioncophyllidine E (4a/4b) exhibits a strong preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrient-deprived conditions, with a PC50 value of 7.4 µM, suggesting its potential as an agent against pancreatic cancer.
Subject(s)
Alkaloids , Antineoplastic Agents, Phytogenic , Antineoplastic Agents , Pancreatic Neoplasms , Humans , Molecular Structure , Alkaloids/pharmacology , Alkaloids/chemistry , Antineoplastic Agents/therapeutic use , Magnetic Resonance Spectroscopy , Pancreatic Neoplasms/drug therapy , Antineoplastic Agents, Phytogenic/chemistryABSTRACT
Ancistrobrevinium A (1) is the first N-methylated and non-hydrogenated, and thus cationic naphthylisoquinoline alkaloid. It was discovered in the root bark extract of the phytochemically productive West African liana Ancistrocladus abbreviatus (Ancistrocladaceae). Its constitution was elucidated by HR-ESI-MS and 1D and 2D NMR. Due to the steric hindrance in the proximity of the linkage between the naphthalene and isoquinoline parts, the biaryl axis is rotationally hindered. It thus constitutes a stable element of chirality - the only one in the new alkaloid since, different from most other naphthylisoquinoline alkaloids, it has no stereogenic centers. The axial configuration of 1 was assigned by electronic circular dichroism (ECD) investigations, which gave a positive couplet, indicating a 'positive chirality', here corresponding to a P-configuration. Ancistrobrevinium A (1) showed a weak cytotoxic activity against A549 lung cancer cells (IC50 = 50.6 µM).
ABSTRACT
The antimicrobial resistance (AMR) has opened a new market for functional foods with antibacterial activities. More than ever before, people are interested in the natural foods that offer a pathogen fighting benefits due to their obvious advantages over management of diseases. Consumers who are health aware are continually using functional foods in their dietary regimens both for their nutritious, associated health benefits values and convenience. Examples include plant-based essential oils, garlic, and mushrooms. Many studies were conducted on mushrooms crude extracts as functional food with antimicrobial properties, yet the bioactive compounds isolated are few or even rare. Because antimicrobial resistance and biofilm formation are exacerbating the severity of infectious diseases worldwide, this review summarized the antimicrobial molecules compared to the number of extracts as well as the biofilm acting compounds and extracts from edible mushrooms in the last seven years to facilitate drawing the roadmap of anti-infectious agent's discovery from functional foods in the future. 156 compounds and more than 100 edible mushroom extracts with antibacterial, antifungal or biofilm inhibiting activities through the period from 2015 to 2022 were reviewed. Pubmed, Web of Science, and Scopus were thoroughly searched with relevant search words, and data reviewed indicated ninety active compounds against Gram (-ve), hundred and twenty active compounds against Gram (+ve), sixty-eight active compounds against fungi. The biofilm inhibition was revealed by nineteen compounds. Effective combinations active in biofilm inhibition were represented by quinic acid with uridine/inosine or adenine/oxalic mixtures. Activities against multi-resistant strains, represented by ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), MRSA (Methicillin Resistant Staphylococcus aureus), VRSA (Vancomycin Resistant Staphylococcus aureus) and multi-resistant tuberculosis were shown by 39 compounds and extracts. Terpenoid compounds revealed the most potent antimicrobial action; for instance, cyathanes, cerevisterol, psathyrins and grifolaone. Because variation in cultural media is accompanied by a different response in fungal growth and mass yield as well as the variation of compounds of interest from one strain to another, the methods of isolation, cultures and media used are highlighted together with structure activity relationships when available.
Subject(s)
Agaricales , Anti-Infective Agents , Garlic , Methicillin-Resistant Staphylococcus aureus , Humans , Anti-Infective Agents/pharmacology , Anti-Bacterial Agents/pharmacology , BiofilmsABSTRACT
[This corrects the article DOI: 10.1039/D2RA05758A.].
ABSTRACT
The West African liana Ancistrocladus abbreviatus is a rich source of structurally most diverse naphthylisoquinoline alkaloids. From its roots, a series of four novel representatives, named ancistrobrevolines A-D (14-17) have now been isolated, displaying an unprecedented heterocyclic ring system, where the usual isoquinoline entity is replaced by a ring-contracted isoindolinone part. Their constitutions were elucidated by 1D and 2D NMR and HR-ESI-MS. The absolute configurations at the chiral axis and at the stereogenic center were assigned by using experimental and computational electronic circular dichroism (ECD) investigations and a ruthenium-mediated oxidative degradation, respectively. For the biosynthetic origin of the isoindolinones from 'normal' naphthyltetrahydroisoquinolines, a hypothetic pathway is presented. It involves oxidative decarboxylation steps leading to a ring contraction by a benzilic acid rearrangement. Ancistrobrevolines A (14) and B (15) were found to display moderate cytotoxic effects (up to 72%) against MCF-7 breast and A549 lung cancer cells and to reduce the formation of spheroids (mammospheres) in the breast cancer cell line.
ABSTRACT
Duranta erecta Linn. has a longstanding history for use in folk remedy for several disorders. Its hydroalcoholic extract has been investigated intensely in the treatment of many ailments, but to date very few data are presented to explain the pharmacological use of its oil. In this study, the chemical profiles of the leaf oils extracted from three Egyptian Duranta erecta cultivars, namely 'Green', 'Golden edge', and 'Variegata' are traced using GC-MS analysis. D. erecta 'Green' showed predominance of vitamin E (22.7%) and thunbergol (15%) whereas D. erecta 'Golden edge' and 'Variegata' contained tetratetracontane as a major component in their oils. The highest phenolic and flavonoid contents, displayed as gallic acid and rutin equivalents per gram oil, respectively, were observed in the 'Golden edge' and 'Variegata' cultivars, which was reflected by their strong DPPH and ABTS scavenging activities as well as the highest reducing power in both CUPRAC and FRAP assays. D. erecta 'Green' displayed better metal chelating potential, which may be attributed to its content of vitamin E. All cultivars showed similar enzyme inhibitory profiles. The best inhibition of α-glucosidase and α-amylase was observed by D. erecta 'Green'. In silico studies of the major constituents docked on the active sites of the target enzymes NADPH oxidase, amylase, glucosidase, butyrylcholinesterase, and tyrosinase revealed high binding scores, which justified the biological activities of the tested oils.
ABSTRACT
Hepatic encephalopathy (HE) is a deterioration of brain function in patients suffering from chronic liver disease, cirrhosis as a result of elevated blood ammonia and the production of pseudo-neurotransmitters. Herein, we investigated the chemical composition of hexane extract from Origanum vulgare (O. vulgare) leaves as well as its possible protective effects against thioacetamide (TAA)-induced HE in rats. GC-MS analysis of the extract revealed tentative identification of twenty-five compounds (82.93%), predominated by cholesten-3-one (27.30%), followed by γ-tocopherol (13.52%), α-tocopherol (5.01%), ß-amyrin (5.24%) and α-amyrin (4.89%). Albino rats were distributed into seven groups (n = 7). G1 served as negative control; G2 and G3 served as controls treated with O. vulgare (100 and 200 mg/kg/p.o b.w, respectively); G4 served as TAA-positive control group (100 mg/kg/day/i.p., three alternative days per week for six weeks); G5, G6, and G7 served as TAA -induced HE rat model that received O. vulgare 100, O. vulgare 200, and silymarin (100 mg/kg of SILY, as standard drug), respectively. TAA showed depressive and anxiety-like behaviors in forced swimming test (FST) and reduction of cognitive score in elevated plus-maze test (EPMT) as well as impairment of locomotor and exploratory activities in open-field test (OFT). TAA caused a significant decline in body weight gain; however, the relative liver weight and brain water content were statistically increased. TAA-intoxicated rats showed significant increase of serum biomarker enzymes, proinflammatory cytokines, blood ammonia levels, brain serotonin, acetyl cholinesterase and cellular lipid peroxidation with significant decrease of brain dopamine, norepinephrine, antioxidant status. The hepatoprotective/neuro-protective activities of O. vulgare was found to be comparable with that of SILY in HE rats model. Where, treatment of TAA-intoxicated rats with O. vulgare attenuated anxiety, depressive-related behaviors, and reduced the biochemical changes in HE-induced by TAA. Therefore, O. vulgare could be an excellent hepato-/neuroprotective against hepatic injury and HE via improving the oxidative/inflammatory status through its antioxidant and neuro-modulatory properties and its effect is equal to that of SILY.