Substituted Coumarin Derivatives Research Articles

Biochemical and biological evaluation of novel potent coumarin inhibitor of 17β-HSD type 1

Human 17β-hydroxysteroid dehydrogenase (17β-HSD) type 1 is an enzyme that acts at the pre-receptor level. It catalyzes the NADPH-dependent reduction of the weak estrogen estrone into the most potent estrogen 17β-estradiol, which exerts proliferative effects via estrogen receptors. Overexpression of 17β-HSD type 1 in estrogen-responsive tissues is related to the development of hormone-dependent diseases, such as breast cancer and endometriosis. 17β-HSD type 1 thus represents an attractive target for development of new drugs. Recently, we discovered that substituted coumarin derivatives potently and selectively inhibit 17β-HSD type 1. In the present study, we have performed additional biochemical and biological evaluation of the most promising coumarin derivative. First, we used an efficient method for isolation and purification of the active, soluble recombinant human 17β-HSD type 1 from Escherichia coli. This 17β-HSD type 1 showed a specific activity of 0.64 ± 0.08 μmol min −1 mg −1 for estrone reduction in the presence of NADPH at pH 6.5, and a K m of 62 nM for estrone. Next, we evaluated the best of the coumarin-derivative inhibitors, showing its reversible and competitive inhibition of 17β-HSD type 1 reductive activity with a K i of 53 nM. We confirmed that this coumarin inhibitor acts not only in a cell-free assay, but also decreases endogenous 17β-HSD type 1 activity in human T-47D breast cancer cells. This inhibitor also reduced estrone dependent growth of T-47D cells after 48 h of incubation.

Pharmacophores modeling in terms of prediction of theoretical physico-chemical properties and verification by experimental correlations of novel coumarin derivatives produced via Betti’s protocol

A general, simple and straight forward approach to new substituted coumarin derivatives via Betti’s condensation reaction of aromatic aldehydes, coumarin and ammonia precursors has been demonstrated successfully under mild reaction conditions. All the synthesized molecules were characterized on the basis of IR, 1H NMR, 13C NMR, Mass spectrometry and Elemental data. We have reported the design and calculated molecular properties of some coumarin derivatives on the basis of hypothetical antibacterial pharmacophores, structures which were designed to interact with both of Gram positive and Gram negative bacteria. A correlation of structure and activities relationship of these compounds with respect to molecular modeling, Lipinski rule of five, drug likeness, toxicity profiles and other physico-chemical properties of drugs are described and verified experimentally.

Photophysical investigation of 3-substituted 4-alkyl and/or 7-acetoxy coumarin derivatives—A study of the effect of substituents on fluorescence

In the present work an array of novel substituted 2H-chromen-2-one (coumarin) derivatives has been subjected to photophysical analysis. Though the influence of the electron-donating groups such as amino, substituted amino, hydroxyl, alkoxy groups, etc. at position 7 of the coumarin ring system has been extensively studied, the luminescent properties of the coumarin moieties with an acetoxy substituent have not been explored. Herein it is attempted to study the variation of fluorescence behavior of substituted coumarin derivatives with change of nature and position of the substituents on the 2H-chromen-2-one skeleton. Effect of a methyl substituent at position 4 which imposes abnormal photophysical behavior to the chromenone unit has also been briefly described.

Dually Activated Organo- and Nano-cocatalyzed Synthesis of Coumarin Derivatives

A wide range of substituted coumarin derivatives were synthesized by refluxing in acetonitrile, ethyl acetoacetate, and ethyl benzoyl acetate with a wide range of structurally diverse phenol derivatives within a short reaction time with a catalytic combination of pyridine dicarboxylic acid as organocatalyst and nanocrystalline ZnO.

Synthesis and electronic spectra of 3‐hetaryl substituted coumarin derivatives 7‐hydroxy‐2H‐chromen‐2‐on and 9‐hydroxy‐2H‐benzo(f)chromen‐2‐on

The synthesis of 3‐hetaryl substituted coumarin derivatives [7‐hydroxy‐2H‐chromen‐2‐on and 9‐hydroxy‐2H‐benzo(f)chromen‐2‐on] containing a hydroxyl group by reacting 2,4‐dihydroxybenzaldehyde and 2,4‐dihydroxynaphtaldehydes with 2‐cyanomethylbenzothiazole, 2‐cyanomethylbenzimidazole, 1‐methyl‐2‐cyanomethylbenzimidazole and 2‐cyanomethyl‐4‐phenylthiazole is presented. The absorption and steady‐state fluorescence characteristics of the synthesised 3‐hetaryl substituted 7‐hydroxy‐2H‐chromen‐2‐on and 9‐hydroxy‐2H‐benzo(f)chromen‐2‐on in a solution of ethanol and at different pH values are studied to assess their possible application as fluorescent probes for use in molecular biology and medicine.

Substituted coumarins as potent 5-lipoxygenase inhibitors

Leukotriene biosynthesis inhibitors have potential as therapeutic agents for asthma and inflammatory diseases. A novel series of substituted coumarin derivatives has been synthesized and the structure–activity relationship was evaluated with respect to their ability to inhibit the formation of leukotrienes via the human 5-lipoxygenase enzyme.

Design, Synthesis, and 3D QSAR of Novel Potent and Selective Aromatase Inhibitors

The design, synthesis, and biological evaluation of a series of new aromatase inhibitors bearing an imidazole or triazole ring linked to a fluorene (A), indenodiazine (B), or coumarin scaffold (C) are reported. Properly substituted coumarin derivatives displayed the highest aromatase inhibitory potency and selectivity over 17-alpha-hydroxylase/17-20 lyase. The modeling of the aromatase inhibition data by Comparative Molecular Field Analysis (CoMFA/GOLPE 3D QSAR approach) led to the development of a PLS model with good fitting and predictive powers (n = 22, ONC = 3, r(2) = 0.949, s = 0.216, and q(2) = 0.715). The relationship between aromatase inhibition and the steric and electrostatic fields generated by the examined azole inhibitors enables a clear understanding of the nature and spatial location of the main interactions modulating the aromatase inhibitory potency.

Analysis of the interaction of substituted coumarins with the DPPH free radical by means of multivariate statistics.

The interaction of some substituted coumarin derivatives with the stable 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical was analysed by means of multivariate statistics using a variety of molecular descriptors. The compounds contain a conjugated double bond system, which was considered to be an essential structural characteristic for the free-radical scavenging activity. Partial least-square analysis led to an adequate two-component model based on bulk descriptors and the electronic properties concerning atoms involved or next to the double-bond system.

Characteristics of the excited states of 3-substituted coumarin derivatives and transfer of electronic energy to N-oxyl radicals

Photophysical properties and characteristics of electronic energy transfer of coumarin derivatives substituted by bulky group in position 3 and 7-diethylamino-4-methyl coumarin (Coumarin 1) were investigated in solution and polymer matrices. The bulky electron donating groups were: phenyl-, phenylthio-, 2-methylphenylthio-, 2,6-dimethylphenylthio-, dimethylamino- and benzoylamino- in position 3. Fluorescence of coumarin derivatives was quenched by polar methanol with bimolecular rate constant ( k q) larger than the diffusion controlled limit indicating static quenching. The increased polarity of mixed solvent prefers processes leading to intramolecular charge transfer (ICT) or twisted intramolecular charge transfer (TICT) which effectively compete with fluorescence. The experimental and theoretical values for the rate constants of the electronic energy transfer ( k ET) and critical radius ( R 0) were determined for derivatives of coumarin as donors and N-oxyl radical as acceptor. For selected pairs, the experimental and theoretical values of the electronic energy transfer for k ET and R 0 were compared in various solvents like cyclohexane, heptadecane and methanol in order to determine the type of the electronic energy transfer, influence of the solvent and number of paramagnetic centers on this process. The resonance transfer seems to be the prevailing mechanism of energy transfer. In non-polar glassy polystyrene matrix at temperature lower than T g, the energy transfer from coumarin donor to N-oxyl acceptor follows the Perrin’s model for static quenching in solid phase. There is strong indication that resonance energy transfer is operative as well.

1,3‐cycloaddition reactions of 2‐oxo‐2H‐[1]benzopyran‐4‐carbonitrile N‐oxide. Synthesis of several new 4‐substituted coumarins

Abstract1,3‐Cycloaddition reactions of new 2‐oxo‐2H‐[1]benzopyran‐4‐carbonitrile N‐oxide 2 with dipolarophiles, o‐aminophenols and o‐phenylenediamine resulted in 4‐heterocyclic substituted coumarin derivatives. These derivatives are screened for antiinflammatory activity in vitro through their antiproteolytic activity, the interaction with 1,1‐diphenyl‐2‐picrylhydrazyl and the ability to affect superoxide anion and to inhibit β‐glucuronidase and soybean lipoxygenase.

Effect of functional groups on the solubilities of coumarin derivatives in supercritical carbon dioxide

Solubilities in supercritical CO2 of coumarin, four monosubstituted coumarin derivatives (4-hydroxycoumarin, 7-hydroxycoumarin, 7-methoxycoumarin, and 7-methylcoumarin) and four disubstituted derivatives, (6,7-dihydroxycoumarin, 7-hydroxycoumarin-4-acetic acid, 7-methoxycoumarin-4-acetic acid, and 7-hydroxy-4-methylcoumarin) were measured in the temperature range 35–50 °C and the pressure range 8.5–25 MPa. In general, the substituted coumarin derivatives were less soluble than simple coumarin. It was also found that substitution at the C-4 position of coumarin tended to reduce the solubility more than substitution at the C-7 position. These solubility data are essential for the systematic application of SFE and SFC of coumarin derivatives from plant sources.

ChemInform Abstract: Activated Nitriles in Heterocyclic Synthesis: Novel Synthesis of Substituted Coumarin Derivatives.

AbstractThe coumarin derivatives (IV), (VII), (VIII), and (X) are synthesized as shown in the reaction scheme.

Electron structures and 13C NMR spectra of 3-substituted coumarin derivatives

Quantum-chemical calculation of the electron densities on the atoms and the Wiberg indexes in coumarin and 3-amino-3-hydroxy-, and 3-carboxycoumarin molecules within the CNDO/2 approximation was accomplished. The 13C NMR spectra of the indicated compounds were recorded. The effect of the nature of the substituent in the pyrone ring on the electron structures of 3-substituted coumarin derivatives was evaluated on the basis of the data obtained. The character and degree of the relationship between the chemical shifts and the electron densities on the carbon atoms were established by means of regression analysis.

The auxochromic group in the triplet manifold

The spectral locations of the low energy triplet-triplet ( T-T) and singlet-singlet ( S-S) maxima of coumarin, 6-methyl, 7-methoxy, 7-hydroxy, 7-hydroxy-4-methyl, 7-amino-4-methyl, 7-ethylamino-4,6-dimethyl, 7-dimethylamino-4-methyl, 7-diethylamino-4-methyl coumarin, coumarin 339 and LD 490 were measured. The spectral location of the fluorescence maxima of all the auxochromic group substituted coumarin derivatives were also determined. In addition, the low energy S-S absorption and T-T absorption and polarization spectra of coumarin and 7-diethylamino-4-methyl coumarin were recorded. The importance of polarization of S-S and T-T absorption bands as related to substitution effects is briefly reviewed. T-T laser photoselection spectroscopy is employed to furnish experimental data on the arrangement of singlet and triplet dipoles relative to each other within the molecular frame of a molecule. It was found that the order of effectiveness of the auxochromic group in causing spectral red shifts in the singlet manifold is the same as in the triplet manifold. Using wavelength units the spectral red shifts (bathochromic effect) in the triplet manifold are much larger when compared to the red shift as a result of the auxochromic group substitution in the singlet manifold. When expressed in wavenumbers (energy), however, the red shifts appear to be about the same. The importance of these red shifts, as related to the laser action properties of laser dyes, are discussed. It is concluded that laser dyes superior to the coumarin laser dyes could be synthesized.