Inhibitory Activity Of Compounds Research Articles

Synthesis and docking studies of novel antitumor benzimidazoles

In this work, the benzimidazole-pyrrole conjugates 6a–h and benzimidazole-tetracycles conjugates 12–14 were prepared. The cytotoxicity of the compounds 3, 4a–h, 6a–h, 8, 10 and 12–14 was tested against lung cancer cell line A549. Compound 6b exhibited higher activity than the bis-benzoxazole natural product (UK-1), the standard. The tested 4g,h, 6a–h, 10 and 12–14 exhibited remarkable cytotoxicity activity against breast cancer cell line MCF-7 with higher activity than tamoxifen. Furthermore, compound 4h was found to be also more potent than doxurubicin. The antitumor promotion activity of synthesized compounds 4g,h, 6a–h, 10 and 12–14 has been estimated by studying their possible inhibitory effects on EBV-EA activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Among the studied compounds, the inhibitory activities of compounds 8, 13 and 14 demonstrated strong inhibitory effects on the Epstein–Barr virus early antigen (EBV-EA) activation without showing any cytotoxicity on the Raji cells and their effects being stronger than that of a representative control, oleanolic acid.Moreover, the molecular docking of the new compounds into plasminogen activator (uPA) receptor has been in correlation with the antitumor activity. All synthesized compounds 3, 4a–h, 6a–h, 8, 10 and 12–14 were docked into same groove of the binding site of the native co-crystalized (4-iodobenzo[b]thiophene-2-carboxamidine) ligand (PDB code:1c5x) for activity explaination. Compounds 4h, 6b and 13, giving the best docking results, were further studied to estimate their effect on the level of uPA using AssayMax human urokinase (uPA) ELISA kit. In case of A549 cell line, compound 6 exhibited similar activity to MMC, and for MCF-7 cell line, compound 4h exhibited similar activity to doxorubicin, in inhibiting the expression of uPA.

Chemical constituents from Chirita longgangensis var. hongyao with inhibitory activity against porcine respiratory and reproductive syndrome virus

Two new quinonoids chiritalone A and B, and a new neolignan 7'E-4,9-dihydroxy3,3',5'-trimethoxy-8,4'-oxyneolign-7'-en-9'-al, along with known (-)-8-hydroxy-alpha-dunnione, digiferruginol, 2,5-dimethoxy-1,4-benzoquinone and hederagenin, were isolated from the stems of Chirita longgangensis var. hongyao. The structures of the new compounds were elucidated by detailed analysis from NMR (nuclear magnetic resonance) and MS (mass spectrometry) data, and the absolute configuration of chiritalone A was determined by single crystal X-ray diffraction analysis using the Flack parameter. The inhibitory activity of compounds against porcine respiratory and reproductive syndrome virus (PRRSV) was measured by the cytopathic effect (CPE) method. Digiferruginol and hederagenin showed weak effect on PRRSV with an IC50 value of 80.5 +/- 16.9 mu mol L-1 (SI = 19.9) and 43.2 +/- 7.4 mu mol L-1 (SI = 13.1), respectively.

A new flavan-3-ol lactone and other constituents from Euonymus alatus with inhibitory activities on α-glucosidase and differentiation of 3T3-L1 cells

Bioassay-guided fractionation, based on inhibition of α-glucosidase, of Euonymus alatus led to the isolation of a new compound, catechin lactone A (7), and seven known compounds (1–6 and 8). Their structures were established on the basis of extensive 1D- and 2D-NMR experiments. The absolute configurations of compound 7 have been determined using vibrational circular dichroism spectroscopy. All these compounds were evaluated for their inhibition activities on α-glucosidase and differentiation of 3T3-L1 cells. Compounds 1, 3–5, 7 and 8 showed potent yeast α-glucosidase inhibition with IC50 values of 119.1, 39.6, 31.6, 23.0, 71.8 and 102.5 µM, respectively; compounds 3–5, 7 and 8 can remarkably inhibit the differentiation of 3T3-L1 pre-adipocytes. This is the first report about α-glucosidase and 3T3-L1 inhibitory activities of compounds 3, 7 and 8.

Synthesis, DNA-PK inhibition, anti-platelet activity studies of 2-(N-substituted-3-aminopyridine)-substituted-1,3-benzoxazines and DNA-PK and PI3K inhibition, homology modelling studies of 2-morpholino-(7,8-di and 8-substituted)-1,3-benzoxazines

A number of new 2-(pyridin-3-ylamino)-4H-(substituted) benz[e]-1,3-oxazin-4-ones were synthesized 10a–g. These were then reacted with the hydro-halogen salt of 2, 3 and 4-(halo-methyl) pyridine in the presence of Cs2CO3 to give eighteen new 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11a–i, 13a–c, and 15a–f). X-ray crystallography was used to confirm that the 2-N-substituted structures 11 and 13 were formed rather than the 3-N-substitution analogues 12 and 14. Eleven of the new compounds were tested for their effect on collagen induced platelet aggregation and it was found that the most active inhibitory compound was 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC50 of 10 ± 2 μM. DNA-dependent protein kinase (DNA-PK) inhibition data for 12 previously prepared 2-morpholino substituted-1,3-benzoxazines (compounds 19–31) were measured and showed high to moderate activity where the most active compound was compound 27 with an IC50 of 0.28 μM. Furthermore DNA-PK inhibition data for six newly prepared 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11b, 13a–b, 15a–b and 15e) and 8-methyl-7-(pyridin-3-ylmethoxy)-3-(pyridin-3-ylmethyl)-2H-benz[e]-1,3-oxazin-2,4(3H)-dione 17d were measured and moderate to low inhibitory activity was observed, with the most active of the compounds in this series being 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC50 of 2.5 μM. PI3K inhibition studies revealed that compound 27 is highly potent (IC50 for PI3Kα = 0.13 μM, PI3Kβ = 0.14 μM, PI3Kγ = 0.72 μM, PI3Kδ = 2.02 μM). Compound 22 with 7-[2-(4-methylpiperazin-1-yl)ethoxy] group shows greater inhibition of DNA-PK over PI3K.Docking of some 2-morpholino-substituted-1,3-benzoxazine compounds 19–31 within the binding pocket and structure–activity relationships (SAR) analyses were performed with results agreeing well with observed activities.

A new sesquiterpene lactone from Hosta ensata

A new monocyclofarnesane-type sesquiterpenoid, hostasolide A (1), along with five known compounds, lyciumide A, feruloyltyramine, dimethyl 4,4'-dihydroxy-3,3'-dimethoxy-beta-truxinate, 4-hydroxy3-methoxybenzaldehyde, and 3,4-dimethoxycinnamic acid, were isolated from the whole plant of Hosta ensata. The structure of compound 1 was determined on the basis of spectroscopic analysis. The inhibitory activities of compound 1 against acetylcholinesterase, human chronic myelogenous leukemia K562 cells, and human breast cancer MCF-7 cells were also evaluated.

Strong Inhibition of Celastrol Towards UDP-Glucuronosyl Transferase (UGT) 1A6 and 2B7 Indicating Potential Risk of UGT-Based Herb-Drug Interaction

Celastrol, a quinone methide triterpene isolated from Tripterygium wilfordii Hook F., has various biochemical and pharmacological activities, and is now being developed as a promising anti-tumor agent. Inhibitory activity of compounds towards UDP-glucuronosyltransferase (UGT) is an important cause of clinical drug-drug interactions and herb-drug interactions. The aim of the present study is to investigate the inhibition of celastrol towards two important UDP-glucuronosyltransferase (UGT) isoforms UGT1A6 and UGT2B7. Recombinant UGT isoforms and non-specific substrate 4-methylumbelliferone (4-MU) were used. The results showed that celastrol strongly inhibited the UGT1A6 and 2B7-mediated 4-MU glucuronidation reaction, with 0.9 ± 0.1% and 1.8 ± 0.2% residual 4-MU glucuronidation activity at 100 μM of celastrol, respectively. Furthermore, inhibition kinetic study (Dixon plot and Lineweaver-Burk plot) demonstrated that celastrol noncompetitively inhibited the UGT1A1-mediated 4-MU glucuronidation, and competitively inhibited UGT2B7-catalyzed 4-MU glucuronidation. The inhibition kinetic parameters (Ki) were calculated to be 0.49 μM and 0.045 μM for UGT1A6 and UGT2B7, respectively. At the therapeutic concentration of celastrol for anti-tumor utilization, the possibility of celastrol-drug interaction and celastrol-containing herbs-drug interaction were strongly indicated. However, given the complicated nature of herbs, these results should be viewed with more caution.

A QSAR Study on a Series of Pyrrole Derivatives Acting as Lymphocyte- Specific Kinase (Lck) Inhibitors

A quantitative structure-activity relationship (QSAR) study has been made on a novel series of pyrrole derivatives acting as lymphocyte-specific kinase (Lck) inhibitors. The Lck inhibition activity of compounds is found to be significantly correlated with their molar volume (MV) and surface tension (ST) and the hydrophobic constant of one of their substituents. Both the molar properties MV and ST of the compounds are found to have the negative effect but the hydrophobic property of R(2)-substituen is found to have the positive effect. This leads to suggest that the bulky molecules and the those with high surface tension will not be advantageous to the Lck inhibition, rather their R(2)-substituent with hydrophobic property will be conducive to the activity.

Synthesis of (2E,3E,10E,12E)-3,11-dimethyl-5,9-dioxa-4,10-diazatrideca-3,10-diene-2,12-dione dioxime and its Cu(II), Ni(II), and Co(II) complexes

A new tetradentate ligand incorporating dioximes has been synthesized. The dioxime, (H2L) was characterized by elemental analysis, 1H-NMR, 13C-NMR, IR, and mass spectral data. In addition, its copper(II), nickel(II), and cobalt(II) complexes have been prepared and characterized by physical and spectral methods. Elemental analyses and spectroscopic data of the metal complexes are consistent with the proposed structures. The crystal structure of the Co(II) complex (7) was determined by single-crystal X-ray diffraction technique. The inhibitory activities of compounds were examined. Biological activities of the ligand and its metal complexes were tested and the ligand and its metal complexes had inhibitory activity against G(–) Staphylococcus aureus and Pseudomonas aeruginosa.

Two new triterpenoid saponins from the husks of Xanthoceras sorbifolia

Two new oleanane triterpenoid saponins, xanthohuskisides A (1) and B (2), were isolated from the husks of Xanthoceras sorbifolia. The structures of these two compounds were established as 3-O-β-D-glucopyranosyl (1→6)-[β-D-glucopyranosyl (1→2)]-β-D-glucopyranosyl, 28-O-β-D-glucopyranosyl (1→6)-[α-L-rhamnopyranosyl (1→2)]-β-D-glucopyranosyl 16-deoxybarringtogenol C (1) and 3-O-β-D-glucopyranosyl (1→6)-[β-D-glucopyranosyl (1→2)]-β-D-glucopyranosyl, 28-O-β-D-glucopyranosyl (1→6)-β-D-glucopyranosyl 16-deoxybarringtogenol C (2), respectively, based on the analysis on their spectral data including NMR and HR-ESI-MS. The growth inhibitory activities of compounds 1 and 2 were assayed, and 2 showed moderate activity against U937 cell line with the IG50 value of 82.85 ± 1.58 µM.

Inhibitory Activities of Compounds from the Twigs of Garcinia hombroniana Pierre on Human Low‐density Lipoprotein (LDL) Oxidation and Platelet Aggregation

The methanol extract of the twigs of Garcinia hombroniana, which showed strong LDL antioxidation and antiplatelet aggregation activities, was subjected to column chromatography to obtain 3,5,3',5'-tetrahydroxy-4-methoxybenzophenone, 1,7-dihydroxyxanthone and eight triterpenoids, garcihombronane B, D, E and F, friedelin, glutin-5-en-3β-ol, stigmasterol and lupeol. The structures of the compounds were elucidated by spectroscopic methods. The compounds were evaluated for their ability to inhibit copper-mediated LDL oxidation and arachidonic acid (AA)-, adenosine diphosphate (ADP)-, collagen-induced platelet aggregation in vitro. Among the compounds tested, 3,5,3',5'-tetrahydroxy-4-methoxybenzophenone and 1,7-dihydroxyxanthone showed strong inhibitory activity on LDL oxidation with half-maximal inhibitory concentration (IC(50)) values of 6.6 and 1.7 µM, respectively. 3,5,3',5'-Tetrahydroxy-4-methoxybenzophenone exhibited strong activity on AA-, ADP- and collagen-induced platelet aggregation with IC(50) values of 53.6, 125.7 and 178.6 µM, respectively, while 1,7 dihydroxyxanthone showed significant and selective inhibitory activity against ADP-induced aggregation with IC(50) value of 5.7 µM. Of the triterpenoids tested, garcihombronane B showed moderate activity against LDL oxidation and garcihombronane D and F showed selective inhibition on ADP-induced platelet aggregation.

Inhibitory activity of eudesmane sesquiterpenes from Alpinia oxyphylla on production of nitric oxide

Sixteen eudesmane-type sesquiterpenes including seven new compounds oxyphyllanene A-G (1-2 and 5-9) were isolated from the fruits of Alpinia oxyphylla. Among them, compounds 1-2 are novel trinoreudesmane sesquiterpenes, and 5 is a noreudesmane one. Their structures were established by spectroscopic analysis, including 2D-NMR techniques. Inhibitory activity of compounds 3-8 and 10-16 were tested against nitric oxide production in LPS and IFN-γ-induced RAW 264.7 murine macrophages, and their IC(50) values ranged from 9.85 to 13.95 μg/ml.

Synthesis, antimicrobial activity and possible mechanism of action of 9-bromo-substituted indolizinoquinoline-5,12-dione derivatives

A series of 9-bromo-substituted indolizinoquinoline-5,12-dione derivatives was synthesized. Antimicrobial activity assessment indicates that compounds 1, 26, 27 and 28 exhibit strong activity against gram-positive bacterial strains, including Beta-hemolytic streptococcus CMCC32210, Staphylococcus aureus ATCC25923, Staphylococcus epidermidis ATCC12228, Enterococcus faecalis ATCC29212 and methicillin-resistant S. aureus ATCC43300 (MRSA). Compound 27 shows the best anti-MRSA activity with an MIC value of 0.031 μg/ml. To assess the mechanism of action, the inhibitory activities of compound 1 against DNA gyrase and DNA topoisomerase IV were also measured. The results indicate that compound 1 has strong inhibitory effects on the Escherichia coli DNA gyrase supercoiling activity and S. aureus Topo IV relaxing activity.

Stereoselective Biotransformation of Timosaponin A-III by Saccharomyces cerevisiae

Bioconversion of timosaponin A-III (TA-III), one of the major steroidal saponins isolated from the rhizomes of Anemarrhenae asphodeloides Bunge (Liliaceae), was investigated in Saccharomyces cerevisiae. Five bioconversion products, denoted compounds 2-6, were obtained. Biotransformation metabolite 2 was a stereoisomer of TAIII with a specific isotype F-ring and beta-ranged CH3-21, which rarely occurs in nature. The structure of 2 was elucidated by extensive spectroscopic analysis (H-H COSY, HSQC, HMBC), as well as by high-resolution mass spectral analysis. The growth inhibitory activity of compounds 1-6 was assayed against four human cancer cell lines, HepG2, H-1299, HT-29, and HCT-116. Compounds 1 and 2 obviously inhibited the growth of the four types of cancer cells with IC50 values being less than 19 micrometer. A structure-activity relationship is discussed, and the spirostane-ring F in compounds 1 and 2 appears to be the critical bioactive moiety for the cell growth inhibitory property.

The preparation and the antibacterial and antifungal properties of some substituted benzyl alcohols.

Abstract A number of substituted benzyl alcohols have been prepared and together with some related, commercially available, compounds have been tested for antibacterial and antifungal properties. The most active inhibitory compound was 3:4:5-trichlorobenzyl alcohol followed by 4-chloro-3:5-dimethyl-, 3:4-dichloro- and 2:4-dichlorobenzyl alcohols, but saturated aqueus solutions of the last three compounds were more rapidly bactericidal. Pharmacological tests have shown that 2:4-dichlorobenzyl alcohol has low toxicity.

A yeast cell-based system for screening Candida glabrata multidrug resistance reversal agents and selection of loss-of-function pdr1 mutants

In the pathogenic yeast Candida glabrata, multidrug resistance is associated with the overexpression of drug efflux pumps caused by gain-of-function mutations in the CgPDR1 gene. CgPdr1p transcription factor, which activates the expression of several drug efflux transporter genes, is considered to be a promising target for compounds sensitizing the multidrug-resistant yeast cells. Here, we describe a cell-based screening system for detecting the inhibitory activity of compounds interfering with the CgPdr1p function in a heterologous genetic background of the hypersensitive Saccharomyces cerevisiae mutant strain. The screening is based on the ability to abrogate the growth defect of cells suffering from the galactose-induced and CgPdr1p-driven overexpression of a dominant lethal pma1(D378N) allele placed under the control of the ScPDR5 promoter. The system allows rapid identification of multidrug resistance reversal agents inhibiting the CgPdr1p activity or loss-of-function Cgpdr1 mutations, and is amenable to high-throughput screening on solid or liquid media.

Effect of NO Inhibitors on Hypovolemic Shock-Induced Hypotension

In vivo effect of isothiourea derivatives on NO production was studied by the method of electron paramagnetic resonance spectroscopy with a spin trap. We evaluated the influence of these compounds on hemodynamic parameters in anesthetized rats with hypovolemic shock. A correlation was found between the size of S,N-substituents in isothiourea derivatives (methyl, ethyl, and isopropyl) and NO inhibitory activity of compounds. The antihypotensive effect was more pronounced in compounds with high NO inhibitory activity containing the isopropyl radical.

Synthesis and Ligand Based 3D-QSAR of 2,3-Bis-benzylidenesuccinaldehyde Derivatives as New Class Potent FPTase Inhibitor, and Prediction of Active Molecules

‡In order to search new inhibitors against farnesyl protein transferase (FPTase), a series of 2,3-bis-benzylidenesuccinaldehyde derivatives (1-29) were synthesized and their inhibition activities (pI50) against FPTase were measured. From based on the reported results that the inhibitory activities of dimers 2,3-bis-benzylidenesuccinaldehydes were higher than those of monomers cinnamaldehydes, 3D-QSARs on FPTase inhibitory activities of the dimers (1-29) were studied quantitatively using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. The statistical qualities of the optimized CoMFA model II (r 2 cv .= 0.693 and r 2 ncv .= 0.974) was higher than those of the CoMSIA model II (r 2 cv. = 0.484 and r 2 ncv. = 0.928). The dependence of CoMFA models on chance correlations was evaluated with progressive scrambling analyses. And the inhibitory activity exhibited a strong correlation with steric factors of the substrate molecules. Therefore, from the results of graphical analyses on the contour maps and of predicted higher inhibitory active compounds, it is suggested that the structural distinctions and descriptors that contribute to inhibitory activities (pI50) against FPTase will be able to applied new inhibitor design.

Globostelletins A–I, cytotoxic isomalabaricane derivatives from the marine sponge Rhabdastrella globostellata

Nine new isomalabaricane-derived natural products, globostelletins A–I ( 1– 9), were isolated from the marine sponge Rhabdastrella globostellata, together with jaspolides F ( 10), rhabdastrellic acid-A ( 11), (−)-stellettin E ( 12), stellettins C ( 13) and D ( 14). The structures of these compounds were determined on the basis of extensive spectroscopic analyses and by comparison with the reported data in the literature. The inhibitory activities of compounds 1– 12 against human tumor cell lines were evaluated, and their structure–activity relationships were discussed. In addition, rhabdastrellic acid-A ( 11) showed potent inhibition against HL-60 cells, and it induced the apoptosis of HL-60 cells in M/G2 phase. The mechanism of 11 targeting the ubiquitin-proteasome system, including the regulation of ChT-L and T-L target proteins is discussed.

Tyrosinase inhibitors isolated from the roots of Paeonia suffruticosa

The inhibition of mushroom tyrosinase by Paeonia suffruticosa root-derived materials was evaluated. Six tyrosinase inhibitors were isolated by ethanol extraction, n-hexane, ethyl acetate, n-BuOH, and water partition, silica gel column chromatography, Sephadex LH-20, Lobar PR-8, and high-performance liquid chromatography methods, and they were identified as kaempferol (I), quercetin (II), mudanpioside B (III), benzoyloxypaeoniflorin (IV), mudanpioside H (V), and pentagalloyl-beta-(D)-glucose (VI) on the basis of spectroscopic evidence. The inhibitory activities of compounds I to VI against mushroom tyrosinase were determined with IC(50) values of 0.120, 0.108, 0.368, 0.453, 0.324, and 0.063 mM, respectively. The kinetic study indicated that all purified inhibitors acted competitively for the L-dopa binding site of the enzyme, with an exception of compound VI, which acted non-competitively.

Structure-activity relationship determination within a group of substituted phenyl sulfamate based compounds against the enzyme oestrone sulfatase.

The enzyme oestrone sulfatase (ES) is responsible for the conversion of the stored (sulfated) form of oestrogens to the active form, namely oestrone. In our continuing quest to synthesize potent inhibitors of oestrone sulfatase and to determine the structural requirements for such inhibition, we have synthesized and evaluated several derivatives of phenyl sulfamate. We report the results of the synthesis and biochemical evaluation of a series of 3- and 4-aminosulfonated derivatives of phenol in an effort to investigate the role of the acid dissociation constant (pK(a)), and therefore the stability of the phenoxide ion, on the inhibitory activity of compounds against this enzyme. The results showed that there was a strong correlation between the observed pK(a) and inhibitory activity within the aminosulfonated compounds considered. This suggested that in the inhibition of oestrone sulfatase by these compounds, pK(a) was an important physicochemical property, and as such, the stability of the O(-) ion was a crucial factor in the inhibition, and therefore the drug design process.