The depsidones from marine sponge-derived fungus Aspergillus unguis IB151 as an anti-MRSA agent: Molecular docking, pharmacokinetics analysis, and molecular dynamic simulation studies.

Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging nosocomial pathogen among hospitalized patients, with high morbidity and mortality rates. The discovery of a novel antibacterial is urgently needed to address this resistance problem. The present study aims to explore the antibacterial potential of three depsidone compounds: 2-clorounguinol (1), unguinol (2), and nidulin (3), isolated from the marine sponge-derived fungus Aspergillus unguis IB1, both in vitro and in silico. The antibacterial activity of all compounds was evaluated by calculating the Minimum inhibitory concentration (MIC) and Minimum bactericidal concentration (MBC) against MRSA using agar diffusion and total plate count methods, respectively. Bacterial cell morphology changes were  studied for the first time using scanning electron microscopy (SEM). Molecular docking, pharmacokinetics analysis, and molecular dynamics simulation were performed to determine possible protein-ligand interactions and the stability of the targeting penicillin-binding protein 2a (PBP2a) against 2-clorounguinol (1). The research findings indicated that compounds 1 to 3 exhibited MIC and MBC values of 2 µg/mL and 16 µg/mL against MRSA, respectively. MRSA cells displayed a distinct shape after the addition of the depsidone compound, as observed in SEM. According to the in silico study, 2-chlorounguinol exhibited the highest binding-free energy (BFE) with PBP2a (-6.7 kcal/mol). For comparison, (E)-3-(2-(4-cyanostyryl)-4-oxoquinazolin-3(4H)-yl) benzoic acid inhibits PBP2a with a BFE less than -6.6 kcal/mol. Based on the Lipinski's rule of 5, depsidone compounds constitute a class of compounds with good pharmacokinetic properties, being easily absorbed and permeable. These findings suggest that 2-chlorounguinol possesses potential antibacterial activity and could be developed as an antibiotic adjuvant to reduce antimicrobial resistance.

Comparative Study of Phytochemical, Antioxidant, and Cytotoxic Activities and Phenolic Content of Syzygium aqueum (Burm. f. Alston f.) Extracts Growing in West Sumatera Indonesia.

Syzygium aqueum, consisting of various fruit colors, is one of the plants that have been used as traditional medicine. This study aims to evaluate and compare phytochemical, antioxidant, and cytotoxic activities and total phenolic content of leaves and stem bark extracts of S. aqueum with pink and red fruits, in order to identify the best extract that can be used as a natural antioxidant. Phytochemical constituents were evaluated qualitatively using chemicals, while cytotoxic activities were identified using the brine shrimp lethality test. Total phenolic content was determined via the Folin-Ciocalteu method. Leaves and stem bark of S. aqueum contained flavonoids, phenolics, and triterpenoids, but the stem bark also contained saponins and alkaloids. Methanol and ethyl acetate extracts of leaves and stem bark were categorized as very powerful antioxidants to DPPH (IC50 9.71-38.69 µg/mL) and hydrogen peroxide (IC50 16.44-44.02 µg/mL), while hexane extracts were inactive. Methanol, ethyl acetate, and hexane extracts of leaves and stem bark were categorized as moderately cytotoxic to A. salina larvae (LC50 104.04-440.65 µg/mL). Comparing leaves and stem barks, antioxidant and cytotoxic activities of stem bark extracts were higher than those of leaves extracts. Total phenolic content of leaves extracts was higher than that of stem bark extracts where the order of total phenolic content progressed from methanol extracts > ethyl acetate extracts > hexane extracts. Therefore, the stem bark of S. aqueum was identified as the better source of natural antioxidant compared with the leaves.

Sentulic acid isolated from Sandoricum koetjape Merr attenuates lipopolysaccharide and interferon gamma co-stimulated nitric oxide production in murine macrophage RAW264 cells.

A seco-triterpenoid, sentulic acid (SA) isolated from Sandoricum koetjape Merr attenuated nitric oxide (NO) production following co-stimulation with lipopolysaccharide (LPS) and interferon-gamma (IFNγ) in RAW264.7 macrophage cells. The mRNA expression levels of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), IFNγ, interleukin (IL)-6, and IL-12 in LPS/IFNγ co-stimulated RAW264.7 cells also decreased upon SA treatment. To determine the molecular mechanisms underlying the inhibitory effect of SA on LPS/IFNγ-induced NO production in RAW264.7 cells, we further analyzed Toll-like receptor (TLR) signaling by western blotting. The expression of TLR4 and IFN signaling molecules in cells treated with SA was significantly suppressed compared to that in cells not treated with SA. Additionally, SA inhibited the binding of LPS to the TLR4 receptor in RAW264.7 cells stimulated with Alexa Fluor 488-conjugated LPS. These results demonstrate that SA attenuates NO production after LPS/IFNγ co-stimulation in RAW264.7 cells by inhibiting the binding of LPS to TLR4. Our findings suggest that SA is beneficial for the treatment of inflammatory diseases.

Phytochemical analysis and antileukemic activity of polyphenolic constituents of Toona sinensis.

Toona sinensis is a traditional Chinese medicine belonging to the Meliaceae family. The aim of this study was to identify the potential compounds responsible for anticancer activity of T. sinensis. The EtOAc extracts of leaves and woods of T. sinensis inhibited cell proliferation and induced apoptosis in human leukemia HL-60 cells. Our phytochemical research of these extracts led to the isolation of various polyphenolic constituents. The chemical structures were determined by spectroscopic analyses. Among isolates, gallic acid and loropetalin D showed inhibition of cell proliferation and possible induction of apoptosis in these cells. Overall, our results revealed the importance of T. sinensis as a chemopreventive medicinal plant. In addition, an analysis of structure-activity relationship indicated that the number of galloyl groups affects their antileukemic potency.

Clerodane diterpenes isolated from Polyalthia longifolia induce apoptosis in human leukemia HL-60 cells.

Polyalthia is a versatile genus of shrubs and trees found in tropic and sub-tropic regions. In this study, three clerodane diterpenes, kolavenic acid (1), polyalthialdoic acid (2), and 16α-hydroxy-cleroda-3,13(14)Z-dien-15,16-olide (3) isolated from Polyalthia longifolia leaves were evaluated for their apoptotic potential against human leukemia HL-60 cells. Compounds 2 and 3 inhibited cell proliferation with IC50 values of 21.8 and 13.7 µM, respectively. Morphological changes and DNA fragmentation analysis indicated that these diterpenes induce apoptotic cell death in the HL-60 cells. Our results revealed the importance of P. longifolia as a chemopreventive medicinal plant.

Sentulic acid: a cytotoxic ring A-seco triterpenoid from Sandoricum koetjape Merr.

A new ring A-seco triterpenoid, sentulic acid, along with a known oleanane-type triterpenoid, 3-oxoolean-12-en-27-oic acid, were isolated from the Indonesian plant Sandoricum koetjape Merr. Their chemical structures were elucidated by spectroscopic analysis. In addition, the cytotoxic effects of these compounds on human promyelocytic leukemia HL-60 cells were studied. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and trypan blue dye exclusion tests showed that sentulic acid and 3-oxoolean-12-en-27-oic acid were able to induce cytotoxicity in these cells. Furthermore, morphological examination and DNA fragmentation analysis indicated that these cytotoxic effects were mediated by apoptosis.

Isolation of chemical constituents from Enicosanthum cupulare (King) Airy-Shaw.

Six chemical constituents were isolated from Enicosanthum cupulare (King) Airy-Shaw. The structures of the isolated compounds were determined using 1D, 2D-NMR and were found to be identical to those previously reported for these compounds. Three aporphine alkaloids, O-methylmoschatoline, liriodenine and oxostephanine were isolated from this plant for the first time. In addition, we examined the effects of these compounds on melanogenesis in murine B16 melanoma cells; O-methylmoschatoline increased melanin content in these cells.

Chemical studies on Goniothalamus tapis Miq.

Ten secondary metabolites were identified from Goniothalamus tapis Miq. The structures of these compounds were elucidated using spectroscopic analyses. It was revealed for the first time that 3-methyl-1H-benz[f]indole-4,9-dione was produced by the organism.

N-trans-feruloyltyramine as a melanin biosynthesis inhibitor.

In this study, we examined the effect of N-trans-feruloyltyramine (FA) on melanogenesis in mouse B16 melanoma cells. Melanogenesis was inhibited by FA in a dose-dependent manner. FA exhibited a greater potency than kojic acid as a standard inhibitor of melanogenesis. Moreover, treatment of B16 melanoma cells with FA was found to cause marked decreases in the expression levels of tyrosinase. FA-induced downregulation of tyrosinase resulted in suppression of melanin biosynthesis in murine B16 melanoma cells.

The isolation of secondary metabolites and in vitro potent anti-cancer activity of clerodermic acid from Enicosanthum membranifolium.

Four compounds were isolated from Enicosanthum membranifolium. The structures of the compounds were confirmed by spectroscopic data. Their structures were determined as N-trans-feruloyltyramine, R-(-)-mellein, clerodermic acid, and salicifoline chloride as a quaternary alkaloid compound. The structures of R-(-)-mellein and salicifoline chloride were confirmed by using X-ray diffraction. Clerodermic acid was shown to induce potent apoptosis against human leukemia HL60 cells.