Molecular docking,ADME/Tox prediction,and in vitro study of the cell growth inhibitory activity of five β-carboline alkaloids

Structural Chemistry - In a continuing effort to find new cytotoxic, antitumor, and less toxic agents from β-carbolines derivatives, using experimental and computational studies, five...     

Quantum chemical properties investigation and molecular docking analysis with DNA topoisomerase II of β-carboline indole alkaloids from Simaba guianensis: a combined experimental and theoretical DFT study

Structural Chemistry - A theoretical and experimental DFT study of the vibrational, structural, and quantum properties of 9-methoxy-canthin-6-one (I) and...     

Two new β-carboline alkaloids from the roots of Gypsophila oldhamiana

Phytochemical investigation of the roots of Gypsophila oldhamiana afforded two new β-carboline alkaloids, oldhamiaines A and B (1 and 2), along with a known analogue (3). Their structures were elucidated by using spectroscopic and chemical methods. This is the first report of β-carboline alkaloids in the genus Gypsophila.     

Synthesis of 1-indolyl substituted β-carboline natural products and discovery of antimalarial and cytotoxic activities

A series of 1-indolyl substituted β-carbolines including the natural products hyrtiosulawesine, pityriacitrin and pityriacitrin B were prepared via Pictet–Spengler condensation—oxidation strategy from the corresponding indolyl-acetaldehydes and substituted tryptamines. Efforts to prepare the C-1 methylene-linked β-carboline analogues for structure–activity relationship studies were unsuccessful. Biological evaluation revealed two analogues (5 and 41) to exhibit weak inhibition of phospholipase A₂ (IC₅₀ 171 and 131 μM, respectively), two to act as antioxidants (3 and 43), and 12 analogues with activity towards a chloroquine-resistant strain (FcB1) of Plasmodium falciparum (IC₅₀ 1.0–23 μM). Testing against a panel of 60 human tumour cell lines revealed a general lack of cytotoxic effect for most of the compounds with the exception of β-carboline 42 exhibiting modest antileukaemic activity towards the HL-60(TB) cell line (LC₅₀ 4.2 μM). In addition, two novel structures (30 and 32) resulting from aldol condensation followed by Pictet–Spengler cyclisation displayed cytotoxicity with pronounced subpanel specificities towards colon cancer (COLO 205 and HCC-2998) cell lines.     

Identification of novel PI3Kδ inhibitors by docking,ADMET prediction and molecular dynamics simulations

BackgroundPhosphoinositide-3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ is confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Virtual screening techniques have been used to discover new molecules for developing novel PI3Kδ inhibitors with little side effects.MethodComputer aided drug design method were used to rapidly screen optimal PI3Kδ inhibitors from the Asinex database. Virtual screening based molecular docking was performed to find novel and potential lead compound targeting PI3Kδ, at first. Subsequently, drug likeness studies were carried out on the retrieved hits to evaluate and analyze their drug like properties such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) for toxicity prediction. Three least toxic compounds were selected for the molecular dynamics (MD) simulations for 30 ns in order to validate its stability inside the active site of PI3Kδ receptor.ResultsBased on the present in silico analysis, two molecules have been identified which occupied the same binding pocket confirming the selection of active site. ASN 16296138 (Glide score: −12.175 kcal/mol, cdocker binding energy: −42.975 kcal/mol and ΔG_bind value: −90.457 kcal/mol) and BAS 00227397 (Glide score: −10.988 kcal/mol, cdocker binding energy: −39.3376 kcal/mol and ΔG_bind value: −81.953 kcal/mol) showed docking affinities comparatively much stronger than those of already reported known inhibitors against PI3Kδ. These two ligand’s behaviors also showed consistency during the simulation of protein-ligand complexes for 30000 ps respectively, which is indicative of its stability in the receptor pocket.ConclusionCompound ASN 16296138 and BAS 00227397 are potential candidates for experimental validation of biological activity against PI3Kδ in future drug discovery studies. This study smoothes the path for the development of novel leads with improved binding properties, high drug likeness, and low toxicity to humans for the treatment of cancer.     

First total synthesis of the β-carboline alkaloids trigonostemine A,trigonostemine B and a new synthesis of pityriacitrin and hyrtiosulawesine

The total synthesis of four natural products, trigonostemine A, trigonostemine B, pityriacitrin, and hyrtiosulawesine was accomplished. The key intermediates, variously substituted 1-formyl-β-carbolines, were prepared in five steps via a novel synthetic approach using readily available starting materials. These formyl derivatives were then further transformed, providing a general route for the synthesis of the four title alkaloids. The method reported herein represents the first total synthesis of the two trigonostemines and a new pathway to pityriacitrin and hyrtiosulawesine.     

In vitro activity of plant extracts and alkaloids against clinical isolates of extended-spectrum β-lactamase (ESBL)-producing strains

The antibacterial activity of 80% ethanol extracts of 10 medicinal plants collected in Yunnan (Southwest China), was tested against clinical isolates of extended-spectrum β-lactamase (ESBL)-producing strains. Their MIC values ranged between 1.56-12.50 mg/mL. The most active plant extract was Chelidonium majus L. (MIC = 1.56 mg/mL). Two potent isoquinoline alkaloids, 8-hydroxydihydrosanguinarine and 8-hydroxydihydrochelerythrine, were identified as the major active principles through bioassay-guided fractionation and identification of the active ethyl acetate fraction from C. majus, with minimum MIC/MBC values of 15.63/62.50 mg/mL.     

In vitro cytotoxic and antiviral activities of Ficus carica latex extracts

The latex of fig fruit (Ficus carica) is used in traditional medicine for the treatment of skin infections such as warts and also diseases of possible viral origin. Five extracts (methanolic, hexanic, ethyl acetate, hexane-ethyl acetate (v/v) and chloroformic) of this species were investigated in?vitro for their antiviral potential activity against herpes simplex type 1 (HSV-1), echovirus type 11 (ECV-11) and adenovirus (ADV). To evaluate the capacity of the extracts to inhibit the replication of viruses, the following assays were performed: adsorption and penetration, intracellular inhibition and virucidal activity. Observation of cytopathic effects was used to determine the antiviral action. The hexanic and hexane-ethyl acetate (v/v) extracts inhibited multiplication of viruses by tested techniques at concentrations of 78 μg mL(-1). These two extracts were possible candidates as herbal medicines for herpes virus, echovirus and adenovirus infectious diseases. All extracts had no cytotoxic effect on Vero cells at all tested concentrations.     

In vitro antioxidant activities of the methanol extract and its different solvent fractions obtained from the fruit pericarp of Terminalia bellerica

Terminalia bellerica has been used as a traditional medicine in a variety of ailments including anaemia, asthma, cancer, inflammation, rheumatism and hypertension. In this study, the free radical scavenging and antioxidant activities of methanol extract (ME) and its different solvent fractions (namely hexane (HE), ethyl acetate (EA), butanol (BL) and water (WA)) of the T. bellerica fruit pericarp were evaluated and compared with standard antioxidant compounds like gallic acid (GA), catechin and ascorbic acid. Among the different fractions tested, the EA fraction exhibited higher antioxidant and radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH), superoxide and hydroxyl radicals than the other fractions, which may be attributed to its higher phenolic and flavonoid content, since a linear relation was observed between the phenolic content and the antioxidant parameters. The HPTLC analysis of the EA fraction revealed that it mainly contains GA and ferulic acid (FA) as major phenolics, and the higher antioxidant activities of EA fraction may be due to the presence of these compounds.     

In vitro antioxidant activity of the water and ethanol extracts of Forsythia koreana flowers

The antioxidant activities of the water and ethanol extracts of F. koreana flowers were evaluated using DPPH, superoxide anion (?O(-2)), and nitric oxide (?NO) radical scavenging activity assays. The SC(50) values of the water extract of F. koreana on DPPH, ?O(-2) and ?NO were 48.39, 24.36 and 100.21 μg mL(-1), respectively. The SC(50) values of the ethanol extract of F. koreana on the aforesaid free radicals were 57.50, 49.00 and 146.08 μg mL(-1), respectively. Further, the total phenolic contents of both extracts were determined and expressed as milligram gallic acid equivalent (GAE) per gram of extract. The water extract exhibited a higher phenolic content (113.78 mg GAE?g(-1)), while the ethanol extract showed 94.53?mg GAE?g(-1). Our findings demonstrate that the water and ethanol extracts of F. koreana flowers might be potential natural sources of antioxidative additives for use in the food and other allied industries.     

In vitro digestibility of soybean β-conglycinin hydrolysates

The in vitro digestibility of alcalase enzymatic hydrolysates ofβ-conglycinin was studied.The results showed that the zeta potentials ofβ-conglycinin hydrolysates decreased and their electronegativity increased when digested with pepsin and trypsin.Furthermore,the content of peptides with molecular weight from 10 kDa to 20 kDa remained stable,while those with higher molecular weight(>20 kDa) decreased,and those with lower molecular weight(<10 kDa) increased.The proportion of highly hydrophobic peptides decreased in the process of the in vitro digestion,but no significant change in the surface hydropliobicity indices of digestion products was observed(P<0.05).These results indicate that theβ-congiycinin hydrolysates were degraded through in vitro digestion,but the degree of degradation was relatively low.Peptides with molecular weight from 10 kDa to 20 kDa in theβ-conglycinin hydrolysates resisted the digestion by pepsin and trypsin and they remained stable during the in vitro digestion processes.     

Spectroscopic study of molecular associations between riboflavin and some (dihydro) β-carboline derivatives

The spectrophotometric and thermodynamic properties of molecular complexes of riboflavin (RFN) with some dihydro β-carboline derivatives have been investigated by using electronic absorption and fluorescence spectroscopic methods in aqueous solution. The molecular associations have been examined by means of eletronic absorption spectra, since in each, a new charge transfer-like band has been located, and also by observing the variation of the fluorescence emission of RFN on the solutions. The formation constants for the molecular complexes were determined from absorption data, using the Forster—Hammick—Wardley method. The quenching phenomenon observed in RFN fluorescence is related to the concentration of the dihydro β-carboline derivatives, allowing the calculation of the quenching constants for RFN—β-carboline complexes. Thermodynamic parameters have been determined from the values of association constants for the molecular complexes at various temperatures. The influence of substituents in the dihydro β-carboline molecule on the stability of the complexes formed was also investigated.     

Green synthesis,antibacterial, antiviral and molecular docking studies of α-aminophosphonates

Abstract

An efficient method for the synthesis of α-aminophosphonate derivatives has been developed with different functional groups under catalyst and solvent free conditions at room temperature in both conventional and ultrasonication methods. Ultrasonication method offers excellent yields within shorter reaction times. All the title compounds 4a–l were tested for their antibacterial, antiviral activity using Gram-positive bacteria (Staphylococcus aureus, and Bacillus subtilis), Gram-negative bacteria (Klebsiella pneumoniae and Escherichia coli) and NDV infected embryonated eggs (in ovo) and NDV infected BHK-21 cell lines (in vitro) respectively. Besides, molecular docking studies were also carried out to the title compounds against Hemagglutinin-neuramidase enzyme to determine the therapeutic binding efficacy of the ligands synthesized. The results indicated that, among the title compounds, compounds such as 4f, 4l, 4k, 4b, 4i and 4h have shown high content of antibacterial and antiviral activity than the rest of the compounds and the level activity was high when compared to the standard, ribavirin. Based on the results, it is concluded that, the reported α-aminophosphonates will open new vistas and stands as a new generation of antiviral and antibacterial drug candidates in future.     

Design, synthesis and molecular docking studies of novel triazole antifungal compounds

Based on the active site of Candida albicans lanosterol 14α-demethylase (CACYP51), novel triazole compounds structurally different from the current triazole drugs were designed and synthesized. In vitro antifungal activities showed that compounds 10,11, 16 and 20 exhibited strong activities. In addition, compounds 10,11 and 16 also displayed certain activities against fluconazole-resistant fungi.     

A meglumine catalyst–based synthesis,molecular docking,and antioxidant studies of dihydropyrano[3, 2-b]chromenedione derivatives

A simple method was employed for the synthesis of dihydropyrano[3, 2-b]chromenedione derivatives ( 4a-o) in high yields by condensation of 5, 5-dimethylcyclohexane-1, 3-dione( 1 ), different aromatic aldehydes ( 2a-o ), and 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one( 3 ), using meglumine as a stable and reusable catalyst. Meglumine, an amino sugar, was employed as an environmentally benign catalyst, due to its splendid properties such as being inexpensive, recyclable, and biodegradable. The accomplished protocol employs low catalyst loading and easy work-up for the synthesis of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one derivatives. A great asset is that without any significant loss, the catalyst could be recovered and reused for extended synthetic steps. This offer huge advantage to overcome recyclability issues. Our synthesized compounds were analyzed by IR, ¹H, ¹³C NMR, mass spectra and evaluated for their antioxidant properties by 1, 1-diphenyl-2-picryl hydrazyl radical (DPPH), hydrogen peroxide(H₂O₂), and nitric oxide (NO) scavenging methods. The correlation in exhibition of antioxidant activity was effective at all doses. The binding interactions and molecular docking studies for entitled compounds were studied against 3MNG protein; 4k exhibited marked binding affinity with excellent docking score of −7.6 Kcal/mol and emerged as a lead compound.     

In vitro wound healing properties,antioxidant activities,HPLC–ESI–MS/MS profile and phytoconstituents of the stem aqueous methanolic extract of Dracaena reflexa Lam

Column chromatography of the stem aqueous methanolic extract of Dracaena reflexa Lam. (DRSE) led to the isolation of five flavonoids, one phenolic glycoside, one triterpenoid and two steroidal saponins. Furthermore, 44 compounds were tentatively identified in the phytoconstituent profile of DRSE using HPLC–ESI–MS/MS. The antioxidant activity of DRSE was evaluated. In a DPPH radical scavenging assay, DRSE exhibited an IC₅₀ value of 311.6 ± 10.10 μg/ml compared with the IC₅₀ value of the standard Trolox (24.42 ± 0.87 μg/ml). The antioxidant activities of DRSE using ABTS assay and ferric reducing antioxidant power assay were 326.63 μm Trolox equivalents/mg extract and 208.67 μm Trolox equivalents/mg extract, respectively. The wound-healing activity of DRSE was studied by the scratch assay using Human Skin Fibroblast cells. After 24 h DRSE (at 10 and 20 μg/ml) decreased the wound width to 0.55 ± 0.37 and 0.47 ± 0.55 mm, respectively, compared with the wound width in the control cells (0.77 ± 0.17 mm). This result suggested that DRSE improved the wound-healing process by inducing the migration of fibroblasts. Moreover, a docking study was performed to evaluate the binding affinity of the identified phytoconstituents toward GSK-3β relative to the co-crystalized inhibitor and curcumin with the possible involvement of this pathway in the wound-healing activity of the extract.     

Identification of novel PPARα/γ dual agonists by pharmacophore screening,docking analysis,ADMET prediction and molecular dynamics simulations

PPARα and PPARγ play an important role in regulating glucose and lipid metabolism. The single and selective PPARα or PPARγ agonists have caused several side effects such as edema, weight gain and cardiac failure. In the recent years, the dual PPARs agonist development has become a hot topic in the antidiabetic medicinal chemistry field. In this paper, the compound CHEMBL230490 were gained from CHEMBL database, by means of complex-based pharmacophore (CBP) virtual screening, molecular docking, ADMET prediction and molecular dynamics (MD) simulations. The compound CHEMBL230490 not only displayed higher binding scores and better binding modes with the active site of PPARα a/γ, but also had more favorable the pharmacokinetic properties and toxicity evaluated by ADMET prediction. The representative compound CHEMBL230490 was performed to MDs for studying a stable binding conformation. The results indicated that the CHEMBL230490 might be a potential antidiabetic lead compound. The research provided a valuable approach in developing novel PPARα/γ dual agonists for the treatment of type 2 diabetes mellitus (T2DM).     

Concordance between antioxidant activities in vitro and chemical components of Radix Astragali (Huangqi)

Five Radix Astragali (RA) extracts were prepared and their antioxidant activities were measured in vitro using ABTS [2, 2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid diammonium salt)], DPPH?·?(1,1-diphenyl-2-picrylhydrazyl radical), reducing power, ?O?? and ?OH assays. Their chemical contents were then determined, including total phenolics, total flavonoids, total saponins and total sugars. The 1/IC?? values of the various antioxidant assays were used to evaluate the level of antioxidant activity of the RA extracts (plot showing 1/IC?? values vs. chemical contents), and the average R values (correlation coefficients) of total phenolics and total flavonoids were 0.762 and 0.638. In contrast, the average R values of the total saponins and total sugars were -0.0386 and -0.132, respectively. This large difference clearly demonstrates that the antioxidant effects of RA in vitro might be generally considered to be a result of the presence of phenolic compounds (including flavonoids) but not astragalosides and polysaccharides.     

Chemical composition of essential oil and in vitro antioxidant activities of the essential oil and methanol extracts of Eucalyptus loxophleba

This study was designed to examine the chemical composition of the essential oil and the antioxidant activity of the essential oil and methanol extracts of Eucalyptus loxophleba Benth. subsp. The chemical composition of the essential oil of the leaves of E. loxophleba was analysed by GC and GC/MS. The main constituents of the oil were found to be 1,8-cineole (39.4%), methyl amyl acetate (19.8%) and aromadendrene (10%). Antioxidant activities of the samples were determined by two different test systems namely DPPH and β-carotene/linoleic acid. In the DPPH system, the highest radical-scavenging activity was shown by the polar subfraction of the methanol extract (15.2?±?1.7?μg?mL?1). Also, in the second case, the inhibition capacity (%) of the polar subfraction (94.1?±?1.3) was found to be stronger. In addition, the amounts of total phenol components in the polar subfraction (273.0?±?2.6?μg?mg?1) and nonpolar subfraction (146.3?±?2.5?μg?mg?1) were determined.