Mahmoud Fahmi Elsebai

Pan-genotypic Hepatitis C Virus Inhibition by Natural Products Derived from the Wild Egyptian Artichoke.

ABSTRACT Hepatitis C virus (HCV) infection is the leading cause of chronic liver diseases. Water extracts of the leaves of the wild Egyptian artichoke (WEA) [Cynara cardunculus L. var. sylvestris (Lam.) Fiori] have been used for centuries in the Sinai Peninsula to treat hepatitis symptoms. Here we isolated and characterized six compounds from the water extracts of WEA and evaluated their HCV inhibition capacities in vitro. Importantly, two of these compounds, grosheimol and cynaropicrin, inhibited HCV with half-maximal effective concentrations (EC50s) in the low micromolar range. They inhibited HCV entry into target cells and were active against both cell-free infection as well as cell-cell transmission. Furthermore, the antiviral activity of both compounds was pan-genotypic as HCV genotypes 1a, 1b, 2b, 3a, 4a, 5a, 6a, and 7a were inhibited. Thus, grosheimol and cynaropicrin are promising candidates for the development of new pan-genotypic entry inhibitors of HCV infection. IMPORTANCE Because there is no preventive HCV vaccine available today, the discovery of novel anti-HCV cell entry inhibitors could help develop preventive measures against infection. The present study describes two compounds isolated from the wild Egyptian artichoke (WEA) with respect to their structural elucidation, absolute configuration, and quantitative determination. Importantly, both compounds inhibited HCV infection in vitro. The first compound was an unknown molecule, and it was designated “grosheimol,” while the second compound is the known molecule cynaropicrin. Both compounds belong to the group of sesquiterpene lactones. The mode of action of these compounds occurred during the early steps of the HCV life cycle, including cell-free and cell-cell infection inhibition. These natural compounds present promising candidates for further development into anti-HCV therapeutics.

Metabolites profiling reveals for antimicrobial compositional differences and action mechanism in the toothbrushing stick “miswak” Salvadora persica

HIGHLIGHTSSPME‐GC/MS was adopted for the chemical analysis of Salvadora persica.A total of 21 volatile and 75 primary metabolites were identified.PCA and OPLS were used to classify samples.Effect of salivation on S. persica volatiles profile was attempted. ABSTRACT Among many plant species suitable for preparing toothbrushing sticks, miswak (Salvadora persica, family Salvadoraceae) is found the most effective tool for oral hygiene. S. persica possesses antibacterial, antiviral and antifungal effects against oral microbes, mostly due to its benzyl isothiocyanate content. To provide insight into S. persica chemical composition, volatile constituents from roots and stems of S. persica grown in Egypt and Saudi Arabia were profiled using solid‐phase microextraction (SPME) coupled to gas chromatography‐mass spectrometry (GC–MS). A total of 21 volatiles were identified with sulfur compounds amounting for the major volatile class. Orthogonal projection to latent structures‐discriminant analysis (OPLS‐DA) revealed for benzyl isothiocyanate (BITC) enrichment in roots versus stems. Primary metabolites contributing to S. persica taste viz. sugars and organic acids were profiled using GC–MS with silylation. Polyols (sugars) viz. arabitol, meso‐erythritol, and mannitol were found to predominate sugars composition in S. persica stems being most enriched in meso‐erythritol. The impact of saliva on S. persica aroma profile was further assessed and revealing for no enhancement in BITC production with salivation, and further not being detected in toothpaste preparation claimed to contain S. persica extract. This study provides the most complete profile of volatiles, sugars, and organic acids in S. persica organs and more rationalizing its use as a toothbrush.

Unusual Nitrogenous Phenalenone Derivatives from the Marine-Derived Fungus Coniothyrium cereale

The new phenalenone metabolites 1, 2, 4, and 6 were isolated from the marine-derived endophytic fungus Coniothyrium cereale, in addition to the ergostane-type sterol (3) and entatrovenetinone (5). Compounds 1 and 2 represent two unusual nitrogen-containing compounds, which are composed of a sterol portion condensed via two bonds to phenalenone derivatives. Compound 6, which contains unprecedented imine functionality between two carbonyl groups to form a oxepane -imine-dione ring, exhibited a moderate cytotoxicity against K562, U266, and SKM1 cancer cell lines. Moreover, molecular docking studies were done on estrogen receptor α-ligand binding domain (ERα-LBD) to compounds 1 and 2 to correlate with binding energies and affinities calculated from molecular docking to the anti-proliferative activity.

Cynaropicrin: A Comprehensive Research Review and Therapeutic Potential As an Anti-Hepatitis C Virus Agent.

The different pharmacologic properties of plants-containing cynaropicrin, especially artichokes, have been known for many centuries. More recently, cynaropicrin exhibited a potential activity against all genotypes of hepatitis C virus (HCV). Cynaropicrin has also shown a wide range of other pharmacologic properties such as anti-hyperlipidemic, anti-trypanosomal, anti-malarial, antifeedant, antispasmodic, anti-photoaging, and anti-tumor action, as well as activation of bitter sensory receptors, and anti-inflammatory properties (e.g., associated with the suppression of the key pro-inflammatory NF-κB pathway). These pharmacological effects are very supportive factors to its outstanding activity against HCV. Structurally, cynaropicrin might be considered as a potential drug candidate, since it has no violations for the rule of five and its water-solubility could allow formulation as therapeutic injections. Moreover, cynaropicrin is a small molecule that can be easily synthesized and as the major constituent of the edible plant artichoke, which has a history of safe dietary use. In summary, cynaropicrin is a promising bioactive natural product that, with minor hit-to-lead optimization, might be developed as a drug for HCV.

Endophytes as a Novel Source of Bioactive New Structures

Fighting the existing and emerging diseases is one of the big challenges of this age, as the appearance of drug-resistant pathogens is an alarming phenomenon, globally. To address this matter of urgency, researchers and pharmaceutical companies have to revive efforts to develop completely new classes of pharmaceuticals. Natural products have proved a fascinating resource in the continued search for new drug candidates. Among various natural sources, microorganisms represent a sustainable and reproductive source of bioactive compounds, where endophytes are considered a hidden component. Endophytes have fascinating potential for a source of new drug leads as they have capacity to synthesize organic compound of diverse structural features. Most of the promising natural products are available only in extremely small quantities, which necessitate substantial efforts to produce required amounts for pharmacological testing. In addition, many natural products have highly complex structures, complicating commercial production through chemical synthesis. The majority of such drug candidates remains pharmacologically undeveloped due to the perceived supply problem and anticipated higher production costs. Therefore, new methods and techniques such as metagenomics and metatranscriptomics are needed to facilitate production of such compounds for pharmaceutical industry.

New pregnane glycoside derivative from Caralluma retrospiciens (Ehrenb)

Retrospinoside (1) is a new polyoxy pregnane glycoside which was isolated and characterised from the aerial parts of Caralluma retrospiciens (Ehrenb.) N. E. Br., family Apocynaceae. The structure was established as 3-O-[β-D-glucopyranosyl-(1 → 4)-β-D-(3-O-methyl-6-desoxygalactopyranosy)]-14,15,20-trihydroxy-4β-pregnane. Its structural elucidation was performed through extensive spectroscopic measurements including 1D- and 2D-NMR, and HRMS, in addition to chemical methods.

New bioactive chlorinated cyclopentene derivatives from the marine-derived Fungus Phoma sp

AbstractThe new halogenated metabolites cryptophomic acid (1), cryptodiol (2), and cryptotriol (3) and the known dihydro-isocoumarin derivative 4, were isolated from the marine-derived fungus Phoma sp.135. The structural elucidation of these compounds was achieved by extensive analysis of spectroscopic data including 1D- and 2D-NMR, HRMS, optical rotation, UV, and IR. The absolute configuration of cryptophomic acid (1) was determined by using circular dichroism and TD-DFT ECD calculations of the solution conformers. The relative configurations of cryptodiol (2) and cryptotriol (3) were elucidated by a detailed analysis of the spectroscopic data and quantum mechanical calculation of NMR chemical shifts, based also on the newly reported + approach. The dihydro-isocoumarin derivative 4 was also produced by the same fungus and its structure was established as (R)-8-hydroxy-6-methoxy-3-methy-3,4-dihydro-isocoumarin (4), often referred to 6-methoxymellein and its chemical structure and absolute configuration were further confirmed through X-ray diffraction analysis. We report here the new compounds 1–3 and the crystallographic data of compound 4 for the first time. Additionally, we report significant antimicrobial activity of compounds 1–3 against Escherichia coli, Bacillus subtilis, Mycobacterium phlei, and Staphylococcus aureus and they showed no lethality against brine shrimp.

Metabolome based classification of artichoke leaf: A prospect for phyto-equivalency of its different leaf origins and commercial preparations

ABSTRACT The growing interest in assuring phytomedicines efficacy and moreover the increase in requirements for its safety drive the development of analytical methods for its quality control assurance. Herein, we present a nuclear magnetic resonance (NMR) fingerprinting approach of artichoke leaf material from different origins and in its commercial preparations. Under optimized conditions, we were able to simultaneously identify 23 metabolites including sugars, amino and organic acids, sesquiterpene lactones, flavones, cinnamates, inulin, fatty acids and nitrogenous bases. Principal component analysis (PCA) was used to reveal for differences among artichoke specimens. PCA score plot derived from the aromatic region (5–10ppm) provided better classification model than that of full scan (0–10ppm), and revealing for enrichment of wild Egyptian and Tanzanian artichoke in sesquiterpene viz. aguerin B versus O‐caffeoylquinic acid and luteolin abundance in cultivated leaf. PCA analysis of 3 commercial artichoke preparations showed discrimination of a silymarin‐containing capsule suggesting that NMR can distinguish liver‐aid herbal preparations based on its different chemical composition. Quantitative 1H NMR (qHNMR) was further employed to assess major metabolites levels and revealing for the enrichment of cultivated plants in cinnamates viz. (E)‐cinnamaldehyde (1.1mg/g) and O‐caffeoyl quinic acid (15.09mg/g,). To the best of our knowledge, this study provides the first approach utilizing NMR fingerprinting to assess for phytoequivalency among artichoke leaf and in its preparations. HIGHLIGHTSNMR was employed to assess phyto‐equivalency of wild versus cultivated artichoke leaf.23 Metabolites including sugars, amino/organic acids, sesquiterpenes, alkaloids and polyphenols were detected.PCA revealed for sesquiterpene versus cinnamates enrichment in wild and cultivated leaf.Quantitative NMR of major artichoke metabolites in specimens was presented.

Natural Phenolics as Inhibitors of the Human Neutrophil Elastase (HNE) Release: An Overview of Natural Anti-inflammatory Discoveries during Recent Years

Serine protease, Human Neutrophil Elastase (HNE), has been shown to be useful in medical science, however, its over production and malfunctioning may produce devastating effects and cause serious damage to the host. Unfortunately, the present approved drug, sivelestat, only alleviates the symptoms of the diseases caused by malfunction of HNE but not the disease progression. Therefore, there is a crucial need to search potent and safer molecules as elastase inhibitors and to develop better anti-inflammatory drugs in future. In addition, nature is the best architect that may provide a safer future drug candidate as HNEproduction/ activity inhibitor. Since phenolic natural products are already known as antiinflammatory compounds, either by acting as antioxidants or by any other mechanism, thus, this review article summarizes the discovery and elastase inhibitory activity of ∼180 phenolics isolated from diverse natural sources during more than one decade, i.e. 2005-2017.