New Alpha-Amylase Inhibitory Metabolites from Pericarps of Garcinia mangostana.

Two new benzophenones: garcimangophenones A (6) and B (7) and five formerly reported metabolites were purified from the pericarps EtOAc fraction of Garcinia mangostana ((GM) Clusiaceae). Their structures were characterized by various spectral techniques and by comparing with the literature. The α-amylase inhibitory (AAI) potential of the isolated metabolites was assessed. Compounds 7 and 6 had significant AAI activity (IC50 9.3 and 12.2 µM, respectively) compared with acarbose (IC50 6.4 µM, reference α-amylase inhibitor). On the other hand, 5 had a moderate activity. Additionally, their activity towards the α-amylase was assessed utilizing docking studies and molecular dynamics (MD) simulations. The docking and predictive binding energy estimations were accomplished using reported crystal structure of the α-amylase (PDB ID: 5TD4). Compounds 7 and 6 possessed highly negative docking scores of -11.3 and -8.2 kcal/mol, when complexed with 5TD4, respectively while acarbose had a docking score of -16.1 kcal/mol, when complexed with 5TD4. By using molecular dynamics simulations, the compounds stability in the complexes with the α-amylase was analyzed, and it was found to be stable over the course of 50 ns. The results suggested that the benzophenone derivative 7 may be potential α-amylase inhibitors. However, further investigations to support these findings are required.

Fusaroxazin, a novel cytotoxic and antimicrobial xanthone derivative from Fusarium oxysporum.

Oxazines and their derivatives are an uncommon natural heterocyclic compounds, which contain oxygen and nitrogen atoms and possess various bioactivities. A novel 1,4-oxazine-xanthone derivative, fusarioxazin (4) and three known sterols (1-3) were separated from Fusarium oxysporum EtOAc extract associated with Vicia faba L. (broad bean, Fabaceae) roots. Their structural assignment was accomplished using various spectroscopic tools and comparing with literature data. The cytotoxic and antimicrobial potentials of the novel metabolite (4) were evaluated. It possessed a significant antibacterial activity towards S. aureus (IZD 14.8 mm and MIC 5.3 µg/mL) and B. cereus (IZD 18.9 mm and MIC 3.7 µg/mL), in comparison to ciprofloxacin (IZDs 16.9 and 20.5 mm; MICs 3.9 and 2.3 µg/mL, respectively). Furthermore, it displayed a promising cytotoxic effect toward HCT-116 (IC50 2.1 µM), MCF-7 (IC50 1.8 µM), and A549 (IC50 3.2 µM) comparable to doxorubicin (IC50s 0.68, 0.54, and 0.39 µM, respectively).

Anti-inflammatory ergosterol derivatives from the endophytic fungus Fusarium chlamydosporum.

Two new ergosterol derivatives namely, chlamydosterols A [(22E,24R)-ergosta-7,22-diene-3ß,5α,6ß-triol 6-decanoate] (1) and B [5α,6ß,25-trihydroxy-(22E,24R)-ergosta-7,22-dien-3-one] (5) and three known ergosterols: ergosta-7,22-dien-3ß-ol (2), ergosta-5,7,22-triene-3ß-ol (3), and ergosta-7,22-diene-3ß,5α,6ß-triol (4) were separated from the EtOAc extract of the endophytic fungus Fusarium chlamydosporum isolated from Anvillea garcinii (Asteraceae) leaves growing in Saudi Arabia. Their structural assignment was accomplished by various spectroscopic analyses, as well as comparing with the published data. The 5-lipoxygenase (5-LOX) inhibitory potential of the isolated metabolites was assessed. Compounds 1 and 3 displayed moderate 5-LOX inhibitory potential with IC50s 3.06 and 3.57 µM, respectively compared to indomethacin (IC50 1.13 µM).

Naturally Occurring Isocoumarins Derivatives from Endophytic Fungi: Sources, Isolation, Structural Characterization, Biosynthesis, and Biological Activities.

Recently, the metabolites separated from endophytes have attracted significant attention, as many of them have a unique structure and appealing pharmacological and biological potentials. Isocoumarins represent one of the most interesting classes of metabolites, which are coumarins isomers with a reversed lactone moiety. They are produced by plants, microbes, marine organisms, bacteria, insects, liverworts, and fungi and possessed a wide array of bioactivities. This review gives an overview of isocoumarins derivatives from endophytic fungi and their source, isolation, structural characterization, biosynthesis, and bioactivities, concentrating on the period from 2000 to 2019. Overall, 307 metabolites and more than 120 references are conferred. This is the first review on these multi-facetted metabolites from endophytic fungi.

Suppression of LPS-Induced Hepato- and Cardiotoxic Effects by Pulicaria petiolaris via NF-κB Dependent Mechanism.

Recently, there is an increasing interest in searching for harmless natural products isolated from plant materials that can be used as beneficial dietary supplements and/or therapeutic drug candidates. The present study aimed to test the potential protective role of Pulicaria petiolaris (PP, Asteraceae) against hepatic and cardiotoxic effects associated with lipopolysaccharide (LPS) injection. PP was given orally for 5 days at two different doses before LPS injection. Results have shown that LPS induced remarkable hepatic and cardiac injurious effects in mice. Hepatic damage was evident through increased serum transaminases, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and activity. Estimation of high levels of serum creatine kinase-MB (CK-MB) and cardiac troponin I indicated cardiac damage. Histopathological examination of liver and heart confirmed the biochemical results. Increase in oxidative stress along with a depressed antioxidant status of liver and heart were observed in LPS-intoxicated animals. Furthermore, LPS induced activation of nuclear factor-κB (NF-κB) and subsequent elevation of inflammatory cytokines (TNF-α, IL-6). On the other hand, PP treatment successfully safeguards both organs against LPS-induced injury as indicated by the improvement of the biochemical and histopathological parameters. These results suggest that PP ameliorates LPS-induced hepatic and cardiac oxidative injurious effects via antioxidant and anti-inflammatory effects.

α-Amylase inhibition of xanthones from Garcinia mangostana pericarps and their possible use for the treatment of diabetes with molecular docking studies.

Chromatographic separation of the methanol extract of Garcinia mangostana (mangosteen, Guttiferae) dried pericarps led to the isolation and structural characterization of a new xanthone, namely garcimangostin A (5), together with garcixanthone A (1), gartanin (2), normangostin (3), and garcinone C (4). Their structural characterization was achieved using various NMR spectroscopic tools as well as HRMS. Their α-amylase inhibitory (AAI) potential was assessed. It is noteworthy that 5 had the most potent inhibitory effect with % inhibition 94.1 compared to acarbose (96.7%). Moreover, the molecular modeling studies were estimated. The observed scoring results correlated to those results of the AAI assay. Interestingly, 5 was completely fitting with acarbose structure and a superimposition of acarbose complexed structure with 5 in the enzyme binding site was observed. The AAI activity of 5 could be attributed to the xanthone moiety insertion in the active site of the enzyme via H-bonds network and pi-pi interactions. PRACTICAL APPLICATIONS: Garcinia mangostana is a widely consumed fruit for its unique pleasant aroma and sweet taste. Also, it contains valuable nutritious compounds that are advantageous for human body. It is used as various traditional medicines for treating several ailments such as skin infection, hyperkeratosis, eczema, wounds, psoriasis, amebic dysentery, cholera, diarrhea, and suppuration. The findings of this work can demonstrate the significant AAI potential of G. mangostana xanthones. Therefore, mangosteen as a functional food could help in lowering the postprandial glucose absorption and identifying lead compounds from α-amylase inhibition for the treatment and/or prevention of diabetes and obesity.

Vitex agnus-castus safeguards the lung against lipopolysaccharide-induced toxicity in mice.

Vitex agnus-castus (VAC, Verbenaceae) is widely used in Chinese traditional medicine as an antiinflammatory agent. This study aimed to explore the efficacy of the VAC extract to protect against lipopolysaccharide (LPS)-induced acute lung injury. The results have shown that VAC had a potent protective activity against LPS-induced acute lung damage. It significantly decreased pulmonary edema as there was a significant decrease in lung wet/dry ratio and in protein content. VAC also decreased the lactate dehydrogenase's activity in the bronchoalveolar fluid. VAC ameliorated LPS-induced inflammatory cells infiltration into the lung tissue and reversed the histopathological lesions of the lung. Furthermore, VAC counteracted LPS-induced oxidative stress as it attenuated the lipid peroxidation marker, malondialdehyde, in the lung. VAC increased the antioxidant activity as evident by elevated superoxide dismutase activity and increased reduced glutathione content in the lung tissue. Collectively, VAC has a protective activity against LPS-induced acute lung damage through its antioxidant potential. PRACTICAL APPLICATIONS: Vitex agnus-castus has been used in various traditional medicines for treating various ailments as digestive complains, acne, rheumatic pains, menstrual irregularities, premenstrual syndrome, infertility, and hyperprolactinemia. Its leaves are used as a spice and the fruits are used as a substitute for pepper. VAC food supplements are used by women against psychic and somatic premenstrual symptoms. The findings of this study can demonstrate the potent protective activity of the VAC extract against LPS-induced acute lung damage due to its antioxidative effects. Therefore, VAC could be developed as a health functional food to improve acute lung damage and many diseases caused by oxidative damage.

Antimicrobial, antiquorum sensing, and antiproliferative activities of sesquiterpenes from Costus speciosus rhizomes.

The quorum sensing inhibitory (QSI) and antimicrobial potentials of the total methanol extract (TME) and different extractives as well as the sesquiterpenes: dehydrodihydrocostus lactone (1), dehydrocostus lactone (2), arbusculin A (3), santamarine (4), reynosin (5), and specioic acid (6) isolated from Costus speciosus rhizomes were evaluated. The CHCl3:EtOAc (1:1), EtOAc, and TME fractions exhibited potent antibacterial activity toward B. cereus with inhibition zone diameter 13 mm. While the CHCl3 fraction showed strong activity towards S. aureus and B. cereus with inhibition zone diameter 11 and 19 mm, respectively. Moreover, the TME and CHCl3 fractions have strong activity towards C. albicans with inhibition zone diameter 15 and 12 mm, respectively. Compound 5 showed prominent activity towards B. cereus (MIC 385 µg/mL). However, 6 exhibited significant activity with MIC values of 150, 400, and 550 µg/mL towards S. aureus, E. coli, and B. cereus, respectively. Moreover, it showed potent antifungal effect towards C. albicans (MIC 320 µg/mL). Most of the tested fractions had QSI activity against C. violaceum. Only compound 6 exhibited moderate QSI effect with disappearance of violet pigment. In addition, compounds 1-6 were evaluated for their in vitro antiproliferative activity towards KB, BT-549, SK-MEL, and SKOV-3 cancer cell lines.

Garcixanthone A, a new cytotoxic xanthone from the pericarps of Garcinia mangostana.

A new prenylated xanthone, garcixanthone A (5), together with eight known compounds, mangostanaxanthones I (1) and II (2), garcinone E (3), ß-mangostin (4), 8-hydroxycudraxanthone G (6), garcinone C (7), cudraxanthone G (8), and (-)-epicatechin (9) were isolated from the EtOAc-soluble fraction of the air-dried pericarps of Garcinia mangostana (family Clusiaceae). Their structures were verified on the basis of spectroscopic data interpretation as well as comparison with the literature. The cytotoxic and antimicrobial activities of the new compound were assessed using sulforhodamine B (SRB) and agar disk diffusion assays, respectively. Compound 5 showed significant cytotoxic potential against epithelial lung carcinoma (A549) and breast carcinoma (MCF7) cell lines with IC50s 3.0 and 4.2 µM, respectively, compared to doxorubicin (0.74 and 0.41 µM, respectively).

Cucumol B, a new triterpene benzoate from Cucumis melo seeds with cytotoxic effect toward ovarian and human breast adenocarcinoma.

Phytochemical investigation of the methanolic extract of Cucumis melo L. (Cucurbitaceae) seeds furnished a new triterpene benzoate derivative: cucumol B (1) and four known flavonoids: quercetin-3-O-ß-D-glucopyranosyl-(1→6)-α-L-rhamnopyranoside (2), quercetin-3-O-ß-D-glucopyranoside (3), quercetin (4), and luteolin (5). Their structures were identified by UV, IR, 1D (13C and 1H), 2D (HSQC, 1H-1H COSY, HMBC, and NOESY) NMR, and HRESIMS spectral as well as comparing with literature data. Compound 1 has been assessed for the in vitro cytotoxic effect against SKOV-3, MCF-7, and HCT-116 cell lines. It had selective and potent effect toward SKOV-3 and MCF-7 cell lines with IC50s 2.05 and 0.41 µM, respectively, in comparison to doxorubicin (IC50s 0.32 and 0.05 µM). However, it showed moderate activity toward HCT-116 cell line with IC50 8.27 µM.

Cyclodextrin-based nanosponge for improvement of solubility and oral bioavailability of Ellagic acid.

Ellagic acid (EA) is a polyphenolic compound, naturally occurring in various fruits. It has antioxidant, anticancer and antimutagenic properties. Its low aqueous solubility and permeability in GIT, permanent binding to DNA and proteins of cells and first pass metabolism are considered as the reasons for its low oral bioavailability and consequently its low therapeutic potential. Cyclodextrin-based nanosponges (NS) have been utilized to improve the solubilization efficiency of Ellagic acid and to control its release. The scope of the work was to prepare EA nanosponges (EA-NS) using cyclodextrin (ß-CD) and cross-linked by dimethyl carbonate (DMC). It was found that the particle size of the prepared EA-NS was 423.2 nm with low polydispersity index (0.409) and high zeta potential (-34 mV) which manifests the construction of a stabilized colloidal nanoformulation. Moreover, high solubilization efficiency of the loaded EA-NS (49.79µg/ml) compared with the free EA (9.73µg/ml) was spotted. The prepared EA-NS was characterized by XRD, FTIR, and DSC studies and it elucidated a definite interaction of EA with NS. EA-NS successively improved its solubility and provided a controlled in vitro release for 24 hours. EA-NS produced about 69.17% drug content which indicates a good drug loading of the prepared nanosponges. Dissolution of EA-NS was higher than the drug alone. Animal study displayed an improvement in the oral bioavailability of EA indicated by an increase in AUC (1345.49 ng.hr.ml-1) of the EA -NS compared with (598.94 ng.hr.ml-1) for EA.

Tagetones A and B, new cytotoxic monocyclic diterpenoids from flowers of Tagetes minuta.

Tagetones A (1) and B (2), two new monocyclic diterpenoids were isolated from the n-hexane fraction of fresh flowers of Tagetes minuta L. (Asteraceae). Their structures were established by multiple spectroscopic methods (IR, HR-ESI-MS, and 1D-, and 2D-NMR), in addition to comparison with literature data. Compound 1 showed cytotoxic activity towards MCF7 and A549 cancer cells with IC50 values being 4.68 and 4.24 µmol·L-1, respectively, compared to doxorubicin (IC50 0.13 and 1.12 µmol·L-1, respectively). Compound 2 also exhibited significant activity against HCT116 cancer cells (IC50, 6.30 µmol·L-1).

Fusarithioamide A, a new antimicrobial and cytotoxic benzamide derivative from the endophytic fungus Fusarium chlamydosporium.

Four secondary metabolites (1-4), including a new benzamide derivative, namely fusarithioamide A (2-(2-aminopropanamido)-N-(1-hydroxy-3-mercaptopropyl) benzamide, 4) and three known compounds; 1-O-acetylglycerol (1), 8-acetylneosolaniol (2), and ergosta-7,22-diene-3ß,5α,6ß-triol (3) were characterized from the EtOAc extract of Fusarium chlamydosporium isolated from the leaves of Anvillea garcinii (Burm.f.) DC. (Asteraceae). The structures of the isolated metabolites were verified by using 1D and 2D NMR experiments as well as HRESIMS spectral data. Compounds 1-3 were firstly separated from this fungus. Compound 4 has been tested for their antibacterial and antifungal activity against different microorganisms using disc diffusion assay. It showed antibacterial potential towards B. cereus, S. aureus, and E. coli with inhibition zone diameters (IZDs) of 19.0, 14.1, and 22.7 mm, respectively and MICs values of 3.1, 4.4, and 6.9 µg ml-1, respectively. Also, it exhibited the most potent antifungal activity towards C. albicans (IZD 16.2 mm) comparable to clotrimazole (IZD 18.5 mm, positive control). Furthermore, compounds 1-4 were evaluated for their in vitro cytotoxic effect against KB, BT-549, SK-MEL, and SKOV-3 cell lines. Compounds 4 possessed potent and selective activity towards BT-549 and SKOV-3 cell lines with IC50 values of 0.4 and 0.8 µM, respectively compared to doxorubicin (IC50 0.046 and 0.313 µM, respectively). Moreover, 3 exhibited significant activity towards all tested cell lines. Fusarithioamide A may provide new promising candidates for potential antimicrobial and cytotoxic agent.