Three new α-pyrone derivatives from the plant endophytic fungus Penicillium ochrochloronthe and their antibacterial,antifungal, and cytotoxic activities

Three new 3,4,6-trisubstituted α-pyrone derivatives, namely 6-(2′R-hydroxy-3′E,5′E-diene-1′-heptyl)-4-hydroxy-3-methyl-2H-pyran-2-one (1), 6-(2′S-hydroxy-5′E-ene-1′-heptyl)-4-hydroxy-3-methyl-2H-pyran-2-one (2), and 6-(2′S-hydroxy-1′-heptyl)-4 -hydroxy-3-methyl-2H-pyran-2-one (3), together with one known compound trichodermic acid (4), were isolated from the solid-substrate fermentation culture of Penicillium ochrochloronthe associated the roots of Taxus media. Compounds 1–4 displayed the antimicrobial activity selectively against tested fungal and bacterial strains with minimum inhibitory concentration (MIC) values ranging from 12.5 to 100 μg/ml. Furthermore, we found that only compound 4 exhibited moderate cytotoxicity against five human cancer cells (A549, LN229, MGC, LOVO, and MDA231) with IC₅₀ values of 51.45, 23.43, 39.16, 46.97, and 42.85 μg/ml, respectively.     

Synthesis,antibacterial and antifungal activities of naphthoquinone derivatives: a structure–activity relationship study

The synthesis of 1,4-naphthoquinone derivatives is of great interest since these compounds exhibit strong activity as antimalarial, antibacterial, antifungal and anticancer agents. A series of 50 naphthoquinone derivatives was synthesized and evaluated for antibacterial and antifungal activity against Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus, Candida krusei, Candida parapsilosis and Cryptococcus neoformans using the broth microdilution method. The Candida species were the most susceptible microorganisms. Halogen derivatives of 1,4-naphthoquinone presented strong activity, e.g., 2-bromo-5-hydroxy-1,4-naphthoquinone, which exhibited inhibition at an MIC of 16 µg/mL in S. aureus, and 2-chloro-5,8-dihydroxy-1,4-naphthoquinone, with an MIC of 2 µg/mL in C. krusei. These compounds showed higher activity against fungi, but the antibacterial activities were very low. The study of structure–activity relationships is very important in the search for new antimicrobial drugs due to the limited therapeutic arsenal.     

Crystal structures,absolute configurations and molecular docking studies of naftopidil enantiomers as α1D-adrenoceptor antagonists

Chiral drug naftopidil (NAF), a specific α_1D-adrenoceptor (AR) antagonist for the treatment of benign prostatic hyperplasia, was used in racemic form for several decades. Our recent work declared that NAF enantiomers showed the same antagonistic effects on the α_1D-AR, but the binding mechanism of these two stereochemical NAF isomers to the α_1D receptor remained unclear. Herein, we reported the crystallographic structures of optically pure NAF stereoisomers for the first time and unambiguously determined their absolute configurations. The crystal data of R and S enantiomers matched satisfactorily the pharmacophore model for α_1D-selective antagonists. Based on the constructed α_1D homology model, molecular docking studies shed light on the molecular mechanism of NAF enantiomers binding to α_1D-AR. The results indicated that NAF enantiomers exhibited the very similar binding poses and occupied the same binding pocket.     

Synthesis,characterization, molecular docking,and biological activities of coumarin–1,2,3-triazole-acetamide hybrid derivatives

Coumarins and their derivatives are receiving increasing attention due to numerous biochemical and pharmacological applications. In this study, a series of novel coumarin–1,2,3-triazole-acetamide hybrids was tested against some metabolic enzymes including α-glycosidase (α-Gly), α-amylase (α-Amy), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), human carbonic anhydrase I (hCA I), and hCA II. The new coumarin–1,2,3-triazole-acetamide hybrids showed K_i values in the range of 483.50–1,243.04 nM against hCA I, 508.55–1,284.36 nM against hCA II, 24.85–132.85 nM against AChE, 27.17–1,104.36 nM against BChE, 590.42–1,104.36 nM against α-Gly, and 55.38–128.63 nM against α-Amy. The novel coumarin–1,2,3-triazole-acetamide hybrids had effective inhibition profiles against all tested metabolic enzymes. Also, due to the enzyme inhibitory effects of the new hybrids, they are potential drug candidates to treat diseases such as epilepsy, glaucoma, type-2 diabetes mellitus (T2DM), Alzheimer's disease (AD), and leukemia. Additionally, these inhibition effects were compared with standard enzyme inhibitors like acetazolamide (for hCA I and II), tacrine (for AChE and BChE), and acarbose (for α-Gly and α-Amy). Also, those coumarin–1,2,3-triazole-acetamide hybrids with the best inhibition score were docked into the active site of the indicated metabolic enzymes.     

The discovery of novel β-secretase inhibitors: pharmacophore modeling, virtual screening, and docking studies

This article describes the identification of two small molecular inhibitors for β-secretase by integrating virtual screening with fluorescence resonance energy transfer bioassay. A ligand-based pharmacophore model was developed, and the sequential virtual screening of ZINC database was performed using the acquired pharmacophore model and molecular docking. Biological evaluation of 10 virtual hits led to the identification of two novel inhibitors with IC(50) values of 4.76 and 0.31 μm, respectively. These two moderate inhibitors could represent new potentials for the development of anti-Alzheimer's disease agents.     

Xanthones as potential α-glucosidase non-competition inhibitors: Synthesis,inhibitory activities,and in silico studies

α-glucosidase inhibitors (AGIs) were commonly used in clinical for the treatment of type 2 diabetes. Xanthones were naturally occurring antioxidants, and they may also be potential AGIs. In this study, eleven 1,6- and 1,3-substituted xanthone compounds were designed and synthesized, of which four were new compounds. Their α-glucosidase inhibitory activities in vitro and in silico were evaluated. Five xanthone compounds with higher activity than acarbose were screened out, and the xanthones substituted at the 1,6-positions were more likely to be potential α-glucosidase non-competitive inhibitors. The binding mode of xanthones with α-glucosidase was further studied by molecular docking method, and the results showed that the inhibitory effect of non-competitive inhibitors on site 1 of α-glucosidase may be related to the hydrogen bonds formed by the compounds with amino acid residues ASN165, HIS209, TRY207, ASP243, and SER104. This study provided a theoretical basis of the rapid discovery and structural modification of non-competitive xanthone inhibitors of α-glucosidase.     

Molecular docking studies of potent inhibitors of tyrosinase and α-glucosidase

Copper containing tyrosinase enzyme is responsible for melanin biosynthesis in human. Anomalous growth of this enzyme causes hyper-pigmentation related disorders. Melanoma-specific anticarcinogenic activity has also been associated with this enzyme. Recently reported metabolites of tibolone exhibited significant inhibitory activities against both tyrosinase and α-glucosidase enzymes. Molecular docking studies of these enzymes with those metabolites have been the focus of this study. It is comprehensively studied that the inhibition of α-glucosidase is crucial for glycemic control. The active site similarity between tyrosinase and α-glucosidase has also been observed. GOLD is utilized to investigate the conformation and binding affinities of newly discovered inhibitors. In both enzymes, metal ions seem to play an important role in establishing the interaction within the cavity of active sites. Results obtained by recent study are not only consistent with the experimental findings but also provide a deeper insight into the structural attributes and overall molecular interactions.     

Determination of the inhibition profiles of pyrazolyl–thiazole derivatives against aldose reductase and α-glycosidase and molecular docking studies

Aldose reductase (AR) is the first and rate-limiting enzyme of the polyol pathway, which converts glucose to sorbitol in an NADPH-dependent reaction. α-Glycosidase breaks down starch and disaccharides to glucose. Hence, inhibition of these enzymes can be regarded a considerable approach in the treatment of diabetic complications. AR was purified from sheep liver using simple chromatographic methods. The inhibitory effects of pyrazolyl–thiazoles ((3aR,4S,7R,7aS)-2-(4-{1-[4-(4-bromophenyl)thiazol-2-yl]-5-(aryl)-4,5-dihydro-1H-pyrazol-3-yl}phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione derivatives; 3a – i ) on AR and α-glycosidase enzymes were investigated. All compounds showed a good inhibitory action against AR and α-glycosidase. Among these compounds, compound 3d exhibited the best inhibition profiles against AR, with a K_i value of 7.09 ± 0.19 µM, whereas compound 3e showed the lowest inhibition effects, with a K_i value of 21.89 ± 1.87 µM. Also, all compounds showed efficient inhibition profiles against α-glycosidase, with K_i values in the range of 0.43 ± 0.06 to 2.30 ± 0.48 µM, whereas the K_i value of acarbose was 12.60 ± 0.78 µM. Lastly, molecular modeling approaches were implemented to predict the binding affinities of compounds against AR and α-glycosidase. In addition, the ADME analysis of the molecules was performed.     

QSAR and docking studies of novel β-carboline derivatives as anticancer

Quantitative structure–activity relationship (QSAR) studies were performed on β-carboline derivatives for prediction of anticancer activity. The statistically significant 2D-QSAR model having r ² = 0.726 and q ² = 0.654 with pred_r ² = 0.763 was developed by stepwise multiple linear regression method. In order to understand the structural requirement of these β-carboline derivatives, a ligand-based pharmacophore 3D-QSAR model was developed. The five-point pharmacophore hypothesis yielded a 3D-QSAR model with good partial least-square statistics results (r ² = 0.73, Q _ext ²  = 0.755, F = 67.5, SD = 0.245, RMSE = 0.241, Pearson-R = 0.883). A docking study revealed the binding orientations of these derivatives at the active site amino residues of DNA intercalate (PDB ID: 1D12). The results of 2D-QSAR, atom-based 3D-QSAR, and docking studies gave detailed structural insights as well as highlighted important binding features of β-carboline derivatives as anticancer agent which provided guidance for the rational design of novel potent anticancer agents.     

Synthesis and biological evaluation of α, β-unsaturated ketone as potential antifungal agents

Abstract  With the aim of developing potential antifungals, a series of chalcones incorporating sulfur either as part of a heteroaromatic ring (thiophene) or as a side chain (thiomethyl group) were synthesized and tested for their in vitro activity. Some of the compounds showed appreciable activity against a fluconazole-resistant strain, and could act as new hits for the design of better analogs. Graphical Abstract  Synthesis and biological evaluation of α,β-unsaturated ketone as potential antifungal agentsSeema Bag, S.Ramar, Mariam S. Degani*With an aim to develop new chemical entities with potent antifungal activity against Candida albicans strains, a series of chalcones incorporating sulfur either as part of a heteroaromatic ring (thiophene) or as a side chain (thiomethyl group) were synthesized. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Identification of highly potent α-glucosidase inhibitory and antioxidant constituents from Zizyphus rugosa bark: enzyme kinetic and molecular docking studies with active metabolites

Context: Previous studies have shown that extracts of Zizyphus rugosa Lam. (Rhamnaceae) bark contained phytoconstituents with antidiabetic potential to lower blood glucose levels in diabetic rats. However, there has been no report on the active compounds in this plant as potential antidiabetic inhibitors.

Objective: We evaluated the α-glucosidase inhibitory and antioxidant activities of Z. rugosa extract. Moreover, the active phytochemical constituents were isolated and characterized.

Materials and methods: The α-glucosidase inhibition of crude ethanol extract obtained from the bark of Z. rugosa was assayed as well as the antioxidant activity. Active compounds (1–6) were isolated, the structures were determined, and derivatives (2a–2?l) were prepared. All compounds were tested for their α-glucosidase inhibitory (yeast and rat intestine) and antioxidant (DPPH) activities.

Results: The active α-glucosidase inhibitors (1–6) were isolated from Z. rugosa bark and 12 derivatives (2a–2?l) were prepared. Compound 2 showed the most powerful yeast α-glucosidase inhibitory activity (IC₅₀ 16.3?μM), while compounds 3 and 4 display only weak inhibition toward rat intestinal α-glucosidase. Moreover, compound 6 showed the most potent antioxidant activity (IC₅₀ 42.8?μM). The molecular docking results highlighted the role of the carboxyl moiety of 2 for yeast α-glucosidase inhibition through H-bonding.

Discussion and conclusions: These results suggest the potential of Z. rugosa bark for future application in the treatment of diabetes and active compounds 1 and 2 have emerged as promising molecules for therapy.     

QSAR,docking, and Molecular dynamic studies on the polyphenolic as inhibitors of β-amyloid aggregation

Alzheimer’s disease is causally linked to the aggregation of amyloid-β peptide and is one of the main causes of death in developed countries. Consumption of foods rich in polyphenolics is strongly correlated to reduced occurrence rate of Alzheimer’s disease. This paper compares the inhibition effect of amyloid-β aggregation in the presence of 25 polyphenolic compounds by quantitative structure–activity relationship (QSAR), molecular docking, and molecular dynamics simulation. The structure information such as solvent accessible surface area and radial distribution function was obtained at 300?K. The results showed that three compounds, luteolin, transilitin, and maritimetin, were identified as potent inhibitors of Aβ aggregation. Interaction energies between polyphenolic derivatives and β-amyloid were obtained using docking calculation. Computational docking studies offer a rational discussion for the observed inhibitory activity. Multiple linear regression method and principal component analysis were used to set up QSAR models for predicting anti-Alzheimer activity of 25 polyphenolics derivatives. These computational studies may facilitate in understanding the action mechanism and development of improved inhibitors of Aβ aggregation or modification of this series of the anti-Alzheimer agents.     

Tubulin inhibitors： pharmacophore modeling,virtua screening and molecular docking

Aim： To construct a quantitative pharmacophore model of tubulin inhibitors and to discovery new leads with potent antitumor activities. Methods： Ligand-based pharmacophore modeling was used to identify the chemical features responsible for inhibiting tubulin polymerization. A set of 26 training compounds was used to generate hypothetical pharmacophores using the HypoGen algorithm. The structures were further validated using the test set, Fischer randomization method, leave-one-out method and a decoy set, and the best model was chosen to screen the Specs database. Hit compounds were subjected to molecular docking study using a Molecular Operating Environment （MOE） software and to biological evaluation in vitro. Results： Hypol was demonstrated to be the best pharmacophore model that exhibited the highest correlation coefficient （0.9582）, largest cost difference （70.905） and lowest RMSD value （0.6977）. Hypol consisted of one hydrogen-bond acceptor, a hydrogen-bond donor, a hydrophobic feature, a ring aromatic feature and three excluded volumes. Hypol was validated with four different methods and had a goodness-of-hit score of 0.81. When Hypol was used in virtual screening of the Specs database, 952 drug-like compounds were revealed. After docking into the colchicine-binding site of tubulin, 5 drug-like compounds with the required interaction with the critical amino acid residues and the binding free energies 〈-4 kcal/mol were selected as representative leads. Compounds 1 and 3 exhibited inhibitory activity against MCF-7 human breast cancer cells in vitro. Conclusion： Hypol is a quantitative pharmacophore model for tubulin inhibitors, which not only provides a better understanding of their interaction with tubulin, but also assists in discovering new potential leads with antitumor activities.     

Design, synthesis and in vitro antibacterial and antifungal activities of some novel spiro[azetidine-2,3��-indole]-2,4(1��H)-dione

The present study deals with the synthesis of novel spiro[azetidine-2,3′-indole]-2′,4(1′H)-dione derivative from the reactions of 3-(phenylimino)-1,3-dihydro-2H-indol-2-one derivatives with chloracetyl chloride in the presence of triethylamine (TEA). All the compounds were characterized using IR, ¹H-NMR, MS, and elemental analysis. They were screened for their antibacterial and antifungal activities. The bacterial strains used were Gram-positive Staphylococcus aureus (MTCC-96) and Gram-negative Escherichia coli (MTCC-521) and Pseudomonas aeruginosa (MTCC-647). The antifungal screening was done on Candida albicans (MTCC-183) and Asperigillus niger (MTCC-343) fungal strains. Results revealed that, compounds (7a), (7b), (7c), (7d), and (7e) showed very good activity with MIC value of 6.25–12.5 μg/ml against three evaluated bacterial strains and the remaining compounds showed good to moderate activity comparable to standard drugs as antibacterial agents. Compounds (7c) and (7h) displayed equipotent antifungal activity in comparison to standard drugs. Amoxicillin, gentamycin, and streptomycin were used as standard drugs for antibacterial activity while fluconazole and itraconazole were used as standard drugs for antifungal activity. Structure–activity relationship study of the compounds showed that the presence of electron withdrawing group substitution at 5′ and 7′ positions of indoline ring and on ortho or para position of phenyl ring increases both antibacterial and antifungal activity of the compound. Henceforth, our findings will have a good impact on chemists and biochemists for further investigations in search of spiro-fused antimicrobial agents.     

Synthesis, biological evaluation, and docking studies of tetrahydrofuran- cyclopentanone- and cyclopentanol-based ligands acting at adrenergic α₁- and serotonine 5-HT1A receptors

A series of aralkylphenoxyethylamine and aralkylmethoxyphenylpiperazine compounds was synthesized and their in vitro pharmacological profile at both 5-HT(1A) receptors and α(1)-adrenoceptor subtypes was measured by binding assay and functional studies. The results showed that the replacement of the 1,3-dioxolane ring by a tetrahydrofuran, cyclopentanone, or cyclopentanol moiety leads to an overall reduction of in vitro affinity at the α(1)-adrenoceptor while both potency and efficacy were increased at the 5-HT(1A) receptor. A significant improvement of 5-HT(1A)/α(1) selectivity was observed in some of the cyclopentanol derivatives synthesized (4acis, 4ccis and trans). Compounds 2a and 4ccis emerged as novel and interesting 5-HT(1A) receptor antagonist (pK(i) = 8.70) and a 5-HT(1A) receptor partial agonist (pK(i) = 9.25, pD(2) = 9.03, E(max) = 47%, 5-HT(1A)/α(1a) = 69), respectively. Docking studies were performed at support of the biological data and to elucidate the molecular basis for 5-HT(1A) agonism/antagonism activity.     

Synthesis,biological evaluation,and molecular docking studies of N-(α-acetamido cinnamoyl) aryl hydrazone derivatives as antiinflammatory and analgesic agents

A series of acyl hydrazone derivatives were synthesized and screened for antiinflammatory and analgesic activities. The N-acylarylhydrazone compounds described herein were designed by combining the pharmacophoric features of hydrazones and styryl ketones in order to identify the pharmacophoric contribution of the N-acylarylhydrazone moiety and to study the structure–activity relationships. In carrageenan-induced paw edema test, N′-(4-hydroxy benzylidene)-2-acetamido-3-phenyl propenohydrazide (6j) reduced edema by 74 % which is comparable to the standard reference drug, phenylbutazone at equidose. N′-(4-methoxy benzylidene)-2-acetamido-3-phenyl propenohydrazide (6g) showed analgesic activity (68 %) which is equipotent to the standard drug, aspirin (64 %). Molecular docking studies further confirmed that 6j showed better binding affinity with COX-2 and LOX-5 with reduced gastric ulcerogenic effect when compared to phenylbutazone.