Ethnobotanical Uses and Pharmacological Activities of Moroccan Ephedra Species.

Ephedra species are among the most popular herbs used in traditional medicine for a long time. The ancient Chinese medical book "Treatise on Febrile Diseases" refers to the classic traditional Chinese medicine prescription Ge Gen decoction, which consists of seven herbs, including an Ephedra species. Ephedra species are utilized all over the world to treat symptoms of the common cold and coughs, and to combat major human diseases, such as asthma, cancers, diabetes, cardiovascular and digestive disorders, and microbial infections. This study aimed at identifying specific Ephedra species used traditionally in Morocco for therapeutic purposes. The plant parts, their preparation process, and the treated pathologies were identified and analyzed. The results revealed five ethnobotanically important species of Ephedra: Ephedra alata Decne, Ephedra altissima Desf., Ephedra distachya L., Ephedra fragilis Desf., and Ephedra nebrodensis Tineo. These species are used traditionally in Morocco for treating people with diabetes, cancer, rheumatism, cold and asthma, hypertension, influenza virus infection, and respiratory ailments. In addition, they are occasionally used as calefacient agents, to regulate weight, or for capillary care. Few studies have underlined the antibacterial and antioxidant activities of some of these Moroccan Ephedra species, but little information is available regarding the natural products at the origin of the bioactivities. Further phytochemical investigations and clinical data are encouraged to better support the use of these plants.

Synthesis, Molecular Electron Density Theory Study, Molecular Docking, and Pharmacological Evaluation of New Coumarin-Sulfonamide-Nitroindazolyl-Triazole Hybrids as Monoamine Oxidase Inhibitors.

Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed by copper azide-alkyne cycloaddition, leading to coumarin-sulfonamide-nitroindazolyl-triazole hybrids. The nitration position on the coumarin moiety was confirmed through nuclear magnetic resonance spectroscopy and molecular electron density theory in order to elucidate the molecular mechanism and selectivity of the electrophilic aromatic substitution reaction. The coumarin derivatives were evaluated for their inhibitory potency against monoamine oxidases and cholinesterases. Molecular docking calculations provided a rational binding mode of the best compounds in the series with MAO A and B. The work identified hybrids 14a-c as novel MAO inhibitors, with a selective action against isoform B, of potential interest to combat neurological diseases.

Towards Alzheimer's disease-related targets: One-pot Cu(I)- mediated synthesis of new nitroindazolyltriazoles.

In this work, we have investigated the one pot strategy for the Cu(I)-mediated synthesis of new triazoles bearing nitroindazole moieties using different copper catalysts. The biological activity of newly synthesized nitroindazolyltriazoles towards Alzheimer's disease-related targets, namely cholinesterases, monoamine oxidases, and amyloid aggregation, were investigated. Predictions of target affinity, physicochemical parameters, gastrointestinal absorption and brain penetration were achieved by means of in silico tools.

Determination of the Phenolic Profile, and Evaluation of Biological Activities of Hydroethanolic Extract from Aerial Parts of Origanum compactum from Morocco.

Origanum compactum belonging to the family Lamiaceae is widely used in food and pharmaceutical fields due to its biologically active substances. We aimed to investigate the total phenol and flavonoid contents and the phenolic composition, and to evaluate the antioxidant and antibacterial properties of hydroethanolic extract from of Origanum compactum. Total phenol and flavonoid contents were evaluated using gallic acid and quercetin as standards, respectively, and the phenolic profile was characterized using high-performance liquid chromatography coupled to a photodiode array and electrospray ionization mass spectrometry (HPLC-PDA-ESI/MS). The antioxidant activity was determined by two methods: ferric reducing power (FRAP) assay and the phosphomolybdate method. The antibacterial effect was evaluated against four bacteria (Escherichia coli, Salmonella typhimurium, Staphylococcus aureus and Listeria monocytogenes) using the broth microdilution method. The findings show that the total phenolic and flavonoid contents were 107.789 ± 5.39 mg GAE/g dm and 14,977 ± 0.79 mg QE/g dm, respectively. A total of sixteen phenolic compounds belonging to phenolic acids and flavonoids were detected. Furthermore, the extract showed strong antioxidant activity, and displayed a bacteriostatic effect against Escherichia coli and Salmonella typhimuriumn, and a bactericidal effect against Staphylococcus aureus and Listeria monocytogenes. Therefore, this study reveals that Origanum compactum extracts display potential as antibacterial and natural antioxidant agents for fighting against pathogenic bacteria and preventing oxidative stress.

Antifungal and Cytotoxic Activity of Diterpenes and Bisnorsesquiterpenoides from the Latex of Euphorbia resinifera Berg.

Euphorbia resinifera latex has been extensively utilized in traditional medicine due to its range of bioactivities. Chromatographic separations on silica gel of ethanol extract of E. resinifera latex led to the development of a new procedure for isolating resiniferatoxin (4) via dried E. resinifera latex and the identification of nine compounds. Among these, catechol (7), protocatechuic acid (8) and 3,4-dihydroxyphenylacetic acid (9), known phenolic compounds, were identified for the first time in E. resinifera latex. Herein we investigated the effects of major compounds of the latex of E. resinifera on the yeast Saccharomyces cerevisiae, on the growth of Aspergillus carbonarius, a widespread fungal contaminant, and on the breast cancer cell line MCF7 as well as on MCF10A normal breast cells. 12-deoxyphorbol-13-isobutyrate-20-acetate (2) had an inhibiting effect on the growth of A. carbonarius, and 7-p-metoxyphenylacetate-3,8,12-triacetate ingol (3) showed a negative effect on yeast cell growth and also a cytotoxic effect on breast cancer cell line MCF7, but not on MCF10A cells. Deglucosyl euphorbioside A (5) and euphorbioside A (6) showed a discoloration effect that was possibly related to mitochondrial functionality in yeast, and also cytotoxicity only on the cancer cell line that was tested. Interestingly, treatment of MCF7 cells with 7-p-metoxyphenylacetate-3,8,12-triacetate ingol (3) and deglucosyl euphorbioside A (5) not only led to a specific cytotoxic effect but also to the increase in the level of intracellular ROS.

New nitroindazole-porphyrin conjugates: Synthesis, characterization and antibacterial properties.

The synthesis of new porphyrin-indazole hybrids by a Knoevenagel condensation of 2-formyl-5,10,15,20-tetraphenylporphyrin and N-methyl-nitroindazolylacetonitrile derivatives is reported. The target compounds were isolated in moderate to good yields (32-57%) and some of the isolated porphyrin-indazole conjugates showed good performance in the generation of singlet oxygen when irradiated with visible light. Their efficiency as photosensitizers in the photoinactivation of methicillin resistant Staphylococcus aureus-MRSA was evaluated. All derivatives showed to be able to photoinactivate the MRSA bacteria. Compound 3a appears to be the most promising photosensitiser (PS) in the photoinactivation of these bacteria, despite being the least efficient in singlet oxygen generation. The addition of potassium iodide (KI) significantly potentiated the antimicrobial Photodynamic Therapy (aPDT) process mediated by all the analysed porphyrin-indazole conjugates. The combined action of nitroindazole-porphyrins with potassium iodide (KI) action appears to be promising in the photoinactivation of MRSA.

A Suitable Functionalization of Nitroindazoles with Triazolyl and Pyrazolyl Moieties via Cycloaddition Reactions.

The alkylation of a series of nitroindazole derivatives with 1,2-dibromoethane afforded the corresponding N-(2-bromoethyl)- and N-vinyl-nitro-1H-indazoles. The Cu(I)-catalysed azide- alkyne 1,3-dipolar cycloaddition was selected to substitute the nitroindazole core with 1,4-disubstituted triazole units after converting one of the N-(2-bromoethyl)nitroindazoles into the corresponding azide. The reactivity in 1,3-dipolar cycloaddition reactions with nitrile imines generated in situ from ethyl hydrazono-α-bromoglyoxylates was studied with nitroindazoles bearing a vinyl unit. The corresponding nitroindazole-pyrazoline derivatives were obtained in good to excellent yields.

Synthesis and antitumor activity of some substituted indazole derivatives.

Some new N-[6-indazolyl]arylsulfonamides and N-[alkoxy-6-indazolyl]arylsulfonamides were prepared by the reduction of 2-alkyl-6-nitroindazoles with SnCl2 in different alcohols, followed by coupling the corresponding amine with arylsulfonyl chlorides in pyridine. The newly synthesized compounds were evaluated for their antiproliferative and apoptotic activities against two human tumor cell lines: A2780 (ovarian carcinoma) and A549 (lung adenocarcinoma). Preliminary in vitro pharmacological studies revealed that N-(2-allyl-2H-indazol-6-yl)-4-methoxybenzenesulfonamide 4 and N-[7-ethoxy-2-(4-methyl-benzyl)-2H-indazol-6-yl]-4-methyl-benzenesulfonamide 9 exhibited significant antiproliferative activity against the A2780 and A549 cell lines with IC50 values in the range from 4.21 to 18.6 µM, and also that they trigger apoptosis in a dose-dependent manner. Furthermore, both active compounds were able to cause an arrest of cells in the G2/M phase of the cell cycle, typical but not exclusive of tubulin interacting agents, although only infrequent interactions with the microtubule network were observed by immunofluorescence microscopy, while docking analysis showed a possible different behavior between the two active compounds.

Crystal structure of N-(1-allyl-3-chloro-4-eth-oxy-1H-indazol-5-yl)-4-meth-oxybenzene-sulfonamide.

In the title compound, C19H20ClN3O4S, the benzene ring is inclined to the indazole ring system (r.m.s. deviation = 0.014 Å) by 65.07 (8)°. The allyl and eth-oxy groups are almost normal to the indazole ring, as indicated by the respective torsion angles [N-N-C-C = 111.6 (2) and C-C-O-C = -88.1 (2)°]. In the crystal, mol-ecules are connected by N-H⋯N hydrogen bonds, forming helical chains propagating along [010]. The chains are linked by C-H⋯O hydrogen bonds, forming a three-dimensional network.

N-(1-Allyl-3-chloro-4-eth-oxy-1H-indazol-5-yl)-4-methyl-benzene-sulfonamide.

In the title compound, C19H20ClN3O3S, the benzene ring is inclined to the indazole ring system by 51.23 (8)°. In the crystal, mol-ecules are linked by pairs of N-H⋯O hydrogen bonds, forming inversion dimers which stack in columns parallel to [011]. The atoms in the allyl group are disordered over two sets of sites with an occupancy ratio of 0.624 (8):0.376 (8).

N-(2-Allyl-4-eth-oxy-2H-indazol-5-yl)-4-methyl-benzene-sulfonamide.

The indazole ring system of the title compound, C19H21N3O3S, is almost planar (r.m.s. deviation = 0.0192 Å) and forms dihedral angles of 77.99 (15) and 83.9 (3)° with the benzene ring and allyl group, respectively. In the crystal, centrosymmetrically related mol-ecules are connected by pairs of N-H⋯O hydrogen bonds into dimers, which are further linked by C-H⋯O hydrogen bonds, forming columns parallel to the b axis.

Withania frutescens (L.) Pauquy, a valuable Mediterranean shrub containing bioactive withanolides.

The bushy plant Withania frutescens (L.) Pauquy is well distributed in the West-Mediterranean area, notably in the south of Spain, Algeria and Morocco where is it is used traditionally for the treatment of various human diseases, including diabetes. Unlike the two major species W. somnifera and W. coagulans extensively studied, the genomically close species W. frutescens has been much less investigated. Nevertheless, this shrub species displays a comparable phytochemical profile and marked antioxidant and anti-inflammatory properties, at the origin of reported pharmacological effects and its traditional uses. Here we have analyzed the diversity of biological effects reported with leaves and root extracts of W. frutescens. Hydroalcoholic extracts prepared from the aerial parts of the plant have revealed antihyperglycemic and cell-protective activities along with antimicrobial and anticorrosive effects. The extracts contained diverse polyphenolic compounds and a few alkaloids (calystegines) but most of the observed effects have been attributed to the presence of withanolides which are modified C28 ergostane-type steroids. Our analysis focused in part on specific withanolides found in W. frutescens, in particular an unusual 3-O-sulfated withanolide considered as a potential pro-drug of the major active compound withaferin A (WA) and a lead compound for the development of a potential drug candidate. The mechanism of action of this sulfated WA analogue is discussed. Altogether, our unprecedented extensive analysis of W. frutescens highlighted the pharmacological potential of this atypical medicinal plant. By analogy with the major cultivated Withania species, the market potential of little-known plant is underlined.

Carvacrol and Thymol Content Affects the Antioxidant and Antibacterial Activity of Origanum compactum and Thymus zygis Essential Oils.

Essential oils are of great interest due to their potent pharmaceutical and biological activities. In this study, essential oils extracted from Origanum compactum and Thymus zygis originating from the Middle Atlas of Morocco were investigated. Their chemical compositions were analyzed using gas chromatography and mass spectrometry, while the assessment of the trapping power of the radical (DPPH: 1,1-diphenyl-2-picrylhydrazyl) and the reducing antioxidant potential of ferric ions (FRAP: Ferric Reducing Antioxidant Power) were performed in order to evaluate the antioxidant activity. Their antibacterial potency was tested against six bacterial strains through the disk diffusion method. The chromatography analyses of the extracted essential oils highlighted the presence of two main components, namely carvacrol at 75.70% in O. compactum and thymol at 40.67% in T. zygis. The antioxidant activity tests showed that both essential oils demonstrated a significant antioxidant activity comparable to the positive control (e.g., ascorbic acid). The antibacterial activity results showed a strong antimicrobial effect for both essential oils, compared to synthetic antibiotics. This study affirms the presence of bioactive components with interesting antioxidant and antibacterial activities in the essential oils extracted from Origanum compactum and Thymus zygis, which could find several applications in the food and pharmaceutical industries through the substitution of synthetic antioxidants and antibiotics.

Tetraclinis articulata (Vahl) Mast.: Volatile constituents, antioxidant, antidiabetic and wound healing activities of its essential oil.

Type 2 diabetes mellitus (T2DM) is a metabolic syndrome known to contribute to impaired wound healing. This condition can be further worsened by excessive melanin production, elastin degradation, and chronic infections at the wound site, potentially leading to melasma and diabetic dermopathy. The purpose of this study was to investigate the phytochemical profile and inhibitory effects of Tetraclinis articulata essential oil (TAEO) on target enzymes involved in diabetes pathogenesis and chronic wound remodeling, namely α-amylase, α-glucosidase, tyrosinase, and elastase, as well as its in vitro antibacterial activity. Gas chromatography and mass spectrometry (GC-MS) analysis of TAEO led to the identification of 46 volatile compounds, representing 96.61 % of TAEO. The major metabolites were bornyl acetate (29.48 %), α-pinene (8.96 %), germacrene D (7.70 %), and d-limonene (5.90 %). TAEO exhibited limited scavenging activity against DPPH free radicals, whereas the FRAP and ABTS assays indicated a relatively higher antioxidant activity. Remarkably, TAEO disclosed a promising in vitro antidiabetic activity against α-glucosidase with an IC50 value of 178 ± 1.6 µg/mL, which is comparable to the standard inhibitor acarbose (IC50 = 143 ± 1.1 µg/mL). In silico, molecular docking analysis against α-glucosidase identified 15 compounds that interacted with the enzyme's active site, whereas skin permeability and sensitization assessments indicated that 26 out of the 44 identified volatile compounds were predicted to be free from any skin sensitivity risk. On the other hand, moderate inhibitory activity was recorded against α-amylase, tyrosinase, and elastase. Notably, TAEO at 5 % significantly suppressed biofilm formation by P. aeruginosa, S. aureus, and E. faecalis, common skin pathogens associated with wound infections, and reduced their swarming motility. Our findings suggest that TAEO may hold the potential as a natural remedy for type 2 diabetes and its associated co-morbidities, especially chronic wounds.

Cubeb (Piper cubeba L.): nutritional value, phytochemical profiling and dermacosmeceutical properties.

Introduction: Cubeb, Piper cubeba L., has been used for centuries in traditional medicine and culinary practices, with a wide range of biological and pharmacological activities. Objective: Herein, we determined the phytochemical profile, mineral, fatty acids, and amino acid contents of P. cubeba berries and assessed the dermacosmeceutical properties of their water extract and essential oil (EO). These included assessing their antioxidant and antibacterial activities as well as their in vitro inhibitory activities against tyrosinase and elastase enzymes. In addition, molecular docking and molecular dynamics studies were performed on the major identified compounds of the EO. Results and discussion: A total of forty-three compounds belonging to organic acids, phenolic acids and flavonoids were found in the water extract, while 36 volatile compounds were identified in the EO with Z-isoeugenol, dihydroeugenol, ß-pinene, E-caryophyllene, and 1,8-cineole as major constituents. The berries were found to be rich in sodium and iron, have moderate zinc content along with low contents of total nitrogen, phosphorus, and potassium. Amino acid analysis revealed a considerable concentration of isoleucine and phenylalanine, whereas 11,14,17-eicosatrienoic acid and linoleic acid were identified as the major fatty acids. In the DPPH and FRAP assays, the water extract elicited considerable antioxidant activity compared to the reference compounds. Enzyme inhibitory assays revealed that the EO had a potential to inhibit tyrosinase and elastase enzymes with IC50 values of 340.56 and 86.04 µg/mL, respectively. The water extract and EO completely inhibited the bacterial growth at MIC of 50 mg/mL and 20%, respectively. At sub-MIC concentrations, the extract and the EO substantially reduced the biofilm formation by up to 26.63 and 77.77%, respectively, as well as the swimming and swarming motilities in a dose-dependent manner. Molecular docking and molecular dynamics showed that the five main components of P. cubeba EO could be the major contributors to the elastase and tyrosinase inhibitory effect. Conclusion: This study emphasizes the promising potential of P. cubeba as a valuable source of natural compounds that can be utilized for the development of innovative pharmaceuticals, dietary supplements, and dermacosmeceutical agents.

N-(3-Chloro-1H-indazol-5-yl)-4-meth-oxy-benzene-sulfonamide.

In the title compound, C14H12ClN3O3S, the fused five- and six-membered rings are folded slightly along the common edge, forming a dihedral angle of 3.2 (1)°. The mean plane through the indazole system makes a dihedral angle of 30.75 (7)° with the distant benzene ring. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules, forming a two-dimensional network parallel to (001).

N-(1H-Indazol-5-yl)-4-meth-oxy-benzene-sulfonamide.

In the title compound, C14H13N3O3S, the fused ring system is almost planar, the largest deviation from the mean plane being 0.023 (2) Å, and makes a dihedral angle of 47.92 (10)° with the benzene ring of the benzene-sulfonamide moiety. In the crystal, mol-ecules are connected through N-H⋯O hydrogen bonds and weak C-H⋯O contacts, forming a two-dimensional network which is parallel to (010).

Sydnone: Synthesis, Reactivity and Biological Activities.

Sydnones are among the most well-known mesoionic compounds. Since their synthesis in 1935 by Earl and Mecknay, numerous researches have shown that the chemical behavior, physical and biological properties of sydnones make them the most useful compounds in organic chemistry. Sydnones undergo thermal 1,3-dipolar cycloaddition reaction with dipolarophiles (alkynes or alkenes) to give exclusively derivatives containing a pyrazole moiety exhibiting numerous applications, such as pharmaceuticals and agrochemicals. However, the sydnone cycloaddition reaction with alkynes requires harsh conditions, like high temperatures and long reaction times, giving poor regioselectivity to the resulting products. To overcome these constraints, new reactions named CuSAC (Copper- Catalyzed Sydnone-Alkyne Cycloaddition) and SPSAC (Strain-Promoted Sydnone- Alkyne Cycloaddition) have been developed, leading to pyrazoles with interesting constant kinetics.

Tanacetum species: Bridging empirical knowledge, phytochemistry, nutritional value, health benefits and clinical evidence.

Introduction: The Tanacetum genus consists of 160 accepted flowering species thriving throughout temperate regions, mainly in the Mediterranean Basin, Northern America, and southwestern and eastern Asia. Tanacetum species bear a long-standing record of use in the folk medicine of indigenous tribes and communities worldwide, along with multitudinous applications in traditional cuisines, cosmeceuticals, and agricultural fields. Methods: Up-to-date data related to traditional uses, phytochemistry, biological activities, toxicity and clinical trials of the genus Tanacetum were systematically reviewed from several online scientific engines, including PubMed, Web of Science, Scopus, SciFinder, Wiley Online, Science Direct, and Cochrane library. Results and discussion: Over the past three decades, 241 metabolites have been isolated from nearly twenty species, including phenolic acids, flavonoids, coumarins, fatty acids and alkanes, aldehydes, volatile compounds, and naphthoquinones. Some unique metabolites have also been identified, such as the ceramides tanacetamide (A-D) from T. artemisioides, pyrethrins from T. cinerariifolium, and sesquiterpene lactones from several species. However, these secondary metabolites are still poorly studied despite in vitro clues highlighting their colossal pharmacological properties, especially as hypotensive, neuroprotective, anticancer, and antimicrobial agents. Scientific studies have validated some traditional claims of the plant, such as antidiabetic, anticancer, anthelmintic, insecticide, antioxidant, and hepatoprotective activities, as well as against festering wounds, skin ulcers, urinary tract infections, and sexually transmitted diseases. Other ethnomedicinal uses for arthritis, gout, rheumatism, anemia, and as a litholytic, antivenom and diaphoretic have not yet been supported and would constitute the subject of further research.

New and promising type of leukotriene B4 (LTB4) antagonists based on the 1,4-benzodioxine structure.

New leukotriene B4 (LTB4) antagonists have been synthesized that can be considered as potential anti-inflammatory drugs. Structures containing the dioxygenated nucleus of 1,4-benzodioxine constitute a potential group of leukotriene B4 (LTB4) antagonists. The objective of this study was to access efficient and selective LTB4 antagonists as a way to elucidate the role of LTB4 in inflammatory processes and therefore allow the development of new types of structures based on 1,4-benzodioxine. Forty-one new 1,4-benzodioxine molecules substituted at different positions of the heterocyclic nucleus were synthesized to determine the minimum structural requirements by studying structure-activity relationships. Eighteen of them were tested in vitro and in vivo for their anti-inflammatory activity related to the antagonist character of LTB4. Pharmacological tests have shown satisfactory in vitro activity for compounds 24b, 24c and 24e with IC50's of 288, 439, 477 nM respectively. The results of the in vivo tests, carried out with the compound that presented greater activity in the in vitro tests 24b, have shown significant anti-inflammatory properties.