Coumarinic Derivatives Research Articles

English

Gymnema sylvestre (Retz.) R. Br. ex Schult (Asclepiadaceae) and Sclerocarya birrea (A. Rich) Hochst (Anacardiaceae) are two plants used in Burkina Faso in traditional medicine and in the form of phytomedicine in the treatment of diabetes. This study evaluated the effect of aqueous ethanolic extracts of leaves of Gymnema sylvestre and Sclerocarya birrea on glycemia. A phytochemical screening of the extracts obtained by successive exhaustion after maceration of the leaves was carried out. The effect of these extracts was tested on basal plasma glucose and oral tolerance glucose in mice. Saponosides, tannins, flavonoids, sterol and triterpene glycosides, reducing compounds and coumarinic derivatives were found in the leaves of both plants. Alkaloids were also detected in the leaves of G. sylvestre and anthocyanosides in the leaves of S. birrea. The aqueous ethanolic extracts from leaves of G. sylvestre, S. birrea or both in combination at 100 mg/kg body per weight did not have a significant hypoglycemic effect on basal plasma glucose but significantly reduced (p<0.05; p<0.001) peak of hyperglycemia. The effect of the combination of the aqueous ethanolic extracts of the two plants on hyperglycemia is greater (47% reduction) than the effect of the aqueous ethanolic extracts of G. sylvestre (21% reduction) or S. birrea (36% reduction) alone. These results show that the combined use of G. sylvestre and S. birrea aqueous ethanolic extracts would be an asset in the treatment of diabetes. Key words: Gymnema sylvestre, Sclerocarya birrea, oral glucose tolerance test, hypoglycemia, Antihyperglycemia.

Polyester-based nanoparticles for the controlled release of bioactive coumarinic derivatives

Event Abstract Back to Event Polyester-based nanoparticles for the controlled release of bioactive coumarinic derivatives Ines Msolli1, 2, Frederic Chaubet1, Raoui Mounir Maaroufi2 and Christel Barbaud1 1 Galilee institute, LVTS, France 2 ISBM, LGBBV, Tunisia Introduction: Advancement in polymer science and engineering led to new polymers for controlled delivery of therapeutic drugs [1]. Poly([R,S]-3,3-dimethylmalic acid) (PDMMLA) and its hydrophobic derivatives can be considered as a family of promising polymers. PDMMLA is polyester synthesized for temporary therapeutic applications. Bioactive coumarinic derivatives, such as warfarin, present biological activities related to the cardiovascular field [2]. The encapsulation of a coumarinic derivative and its controlled delivery would be a relevant application of PDMMLA. Thus we first tried to encapsulate warfarin as a coumarinic model drug to optimize the controlled release settings. Experimental Part: A series of amphiphilic statistical and block copolyesters with different carboxylic acid/hexylic ester proportion: 70/30, 50/50 and 30/70 (mol/mol) belonging to the poly([R,S]-3,3-dimethylmalic acid) (PDMMLA) family have been synthesized [2],[3]. Polymer nanoparticles were further prepared by a nanoprecipitation solvent-evaporation method, and characterized by Transmission Electronic Microscopy (TEM) for nanoparticles morphology and dynamic light scattering for size and zeta potential studies.Controlled release of warfarin as a coumarinic drug model was followed by reversed-phase HPLC. Results: Statistical polymer with 30% of carboxylic acid and 70% of hexylic ester was choosen to investigate warfarin encapsulation by nanoprecipitation method and controlled release efficiency. TEM analysis evidenced spherical nanoparticles (Figure 2), which present an average size in physiological medium of about 80 nm (with a slight evolution of the size distribution over the study (28 days). The release of warfarin in a phosphate buffer saline at pH 7.4 and 37°C was monitored with reversed-phase HPLC over 28 days. The release followed a zero-order kinetics. Conclusion: We prepared a copolyester PDMMLAH30-co-Hex70 able to steadily release warfarin under simulated physiological conditions over 28 days. First results evidenced this polymer as a promising candidate for the delivery of bioactive coumarinic derivatives.

Coumarinic chalcone derivatives as chemosensors for cyanide anions and copper ions

Four coumarinic chalcone derivatives were synthesized via typical condensation reaction between 4-(hydroxyl)coumarinketone and 4-(diethylamino)-benzaldehyde or 7-(diethylamino)coumarinaldehyde in good yields. Their crystal structures and recognition properties for cyanide and copper ions were investigated. The results indicate that the compounds exhibit quick and obvious color and fluorescence response to the ions with high sensitivity and selectivity in acetonitrile. Mechanism studies suggest that cyanide group is possibly bonded to 4-position of coumarin group or the α carbon atom of CC bridge. Coordinate between the compounds and copper ions forms.

New diaminoether coumarinic derivatives with anti-inflammatory activity.

Four coumarinyl-oxy-diamines were synthesized and tested as anti-inflammatory agents. pKa and log P were theoretically calculated. These compounds were tested for their ability to interact with 1,1-diphenyl-2-picrylhydrazyl stable free radical (DPPH), to inhibit proteolysis and soybean lipoxygenase (LOX) in vitro. They were found to inhibit proteolysis (82-90%) and soybean lipoxygenase activity (52-79%) very significant. On the contrary, their reducing ability was found to be low (8-22%). The effect of the synthesised compounds on inflammation using the carageenan-induced rat paw oedema model was studied. They showed a potent inhibitory effect on inflammation (37-55%). Both anti-inflammatory and antioxidant activities depended on some structural characteristics of the synthesised compounds.

Fluindione and drug reaction with eosinophilia and systemic symptoms: an unrecognised adverse effect?

Fluindione is an oral vitamin K antagonist (indanedione derivative) exclusively marketed in France and Luxembourg, known to have immuno-allergic adverse effects such as hepatitis, fever or interstitial nephritis. A few cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with fluindione. The aim of the present study was to investigate fluindione-induced DRESS cases reported in France and to describe their characteristics. We searched for potential cases of DRESS with fluindione reported in the French pharmacovigilance database since 2000. Thirty-six cases of DRESS were included and concerned 17 women and 19 men. The mean age was 65years (median: 68years, range: 28-95years). Kidneys and liver were the most frequent organs involved. Thirty-five cases were serious. In 5 cases, the effect was life-threatening. Most of the patients recovered. Fluindione was the only medicine suspected in 26 cases. Skin patch tests, performed in 10 cases, were positive with fluindione in 9 cases. Fluindione is not known to be a frequent cause of DRESS. However, the number of reports found is probably underestimated. The seriousness of DRESS, as all immuno-allergic adverse effects, contraindicates fluindione reintroduction. Coumarinic derivatives are the alternatives in patients who need oral anticoagulant treatment.

Coumarinic derivatives show anti-inflammatory effects on alveolar macrophages, but their anti-elastase activity is essential to reduce lung inflammation in vivo

We have previously demonstrated the potency of coumarinic derivatives to inhibit human leukocyte elastase. Given the anti-inflammatory activities of some coumarins, we investigated the capacity of our coumarinic derivatives to inhibit inflammation and whether their anti-elastase activity was essential for their anti-inflammatory functions. All compounds studied were coumarinic derivatives displaying differential anti-proteinase activity. Coumarinic derivatives 1, 2, and 3 efficiently inhibited human leukocyte elastase in vitro, whereas the coumarinic derivative 4 did not show inhibitory activity. The anti-inflammatory effect of these compounds and a coumarin control, scopoletin, on interleukin-6 (IL-6), tumor necrosis factor (TNF), and macrophage chemotactic protein-1 (MCP-1) release was studied using lipopolysaccharide (LPS)-stimulated alveolar macrophages. The in vivo effect of compound 2, that inhibits elastase, and compound 4, that does not show proteinase inhibition, was investigated using a mouse model of LPS-induced lung inflammation and elastase-induced acute lung injury. All investigated coumarinic derivatives, regardless of their anti-proteinase activity, significantly inhibited IL-6 and TNF production by LPS-stimulated alveolar macrophages. However, only compounds 2, 3, and 4 significantly reduced MCP-1 release. Compound 2 attenuated LPS-induced leukocyte recruitment in bronchoalveolar lavage, whereas no inhibition was observed with compound 4 devoid of elastase inhibitory capacity. Interestingly, MCP-1 level was reduced in bronchoalveolar lavage of compound 4 treated mice, whereas TNF and IL-6 levels were not modulated by coumarins. Furthermore, compound 2, but not 4, reduced elastase induced lung injury. Our data suggest that although coumarinic derivatives have anti-inflammatory properties, their anti-elastase activity is essential to reduce lung inflammation in vivo.

Synthesis and protective effects of coumarin derivatives against oxidative stress induced by doxorubicin

The use of doxorubicin (DOX) in the treatment of solid tumors is limited by cardiotoxicity essentially due to oxidative stress generation. The aim of this study was to identify coumarin derivatives displaying a protective antioxidant activity without affecting DOX antitumoral efficiency. A set of eighteen coumarinic derivatives was synthesized. Their antioxidant power was evaluated in vitro with the FRAP (ferric reducing ability of plasma) method and in human breast adenocarcinoma MCF7 cells using H(2)DCFDA (2',7'-dichlorodihydrofluorescein diacetate) in a cytometric analysis. 4-Methyl-7,8-dihydroxycoumarin was found to exhibit an important antioxidant strength, a low cytotoxicity, and could decrease ROS (reactive oxygen species) production generated by DOX treatment without affecting DOX cytotoxicity in MCF7 cells.

Enantioselectivity of structurally modified poly(sodium undecenoyl‐L‐leucinate) by insertionof Triton X‐102 surfactant molecules

The effectiveness of Triton X-102 (TX-102), as a structural modifier of the polymeric surfactant sodium undecanoyl-L-leucinate (L-SUL) was investigated for enhanced enantiomeric recognition of various chiral compounds in micellar electrokinetic chromatography (MEKC). Increasing concentrations of TX-102 were separately added into the micellar solutions of L-SUL and then polymerized to form poly-L-SUL. The resulting polymers were purified by use of 3500 molecular-weight-cutoff (MWCO) dialysis membranes. Fluorescence and pulsed field gradient-nuclear magnetic resonance (PFG-NMR) techniques were used to elucidate the structural effects of TX-102 on poly-L-SUL. Evaluation of data from fluorescence measurements suggested an increase in polarity with increasing concentration of TX-102. However, the polarity decreased at higher concentrations of TX-102. Evaluation of data from PFG-NMR suggested an increase in hydrodynamic radius upon increasing the concentration of TX-102. The racemates of coumarinic and phenythiohydantoin amino acid derivatives, and pindolol were used as test analytes in MEKC. A notable increase in resolution and capacity factors of the test analytes was observed when the modified poly-L-SUL was used in MEKC measurements. Examination of the data obtained from fluorescence, PFG-NMR, and MEKC suggests a strong correlation between the polarity and the hydrodynamic radii of TX-102 modified micelles and the enantiomeric resolution of the test analytes.

Influence of the polydispersity of polymeric surfactants on the enantioselectivity of chiral compounds in micellar electrokinetic chromatography.

Poly(sodium undecenoyl-L-leucinate) (poly-L-SUL) was fractionated by the use of different molecular weight cutoff (MWCO) filters to narrow the polydispersity of the macromolecular sizes of the polymeric surfactant. The resulting polymeric surfactant fractions were characterized by the use of three techniques: (1) pulsed field gradient nuclear magnetic resonance (PFG-NMR) was used to determine the hydrodynamic radii, (2) analytical ultracentrifugation (AUC) was used to determine the molecular weights, and (3) steady-state fluorescence was used to determine the polarity of the nonfractionated and fractionated polymeric surfactants. From the data acquired from PFG-NMR, AUC, and fluorescence, it was noted that the hydrodynamic radii and molecular weight of the fractionated poly-L-SUL increased, while the polarity decreased with the increase in the size of the MWCO filter. However, a similarity in physical properties was observed between the nonfractionated and 10-30K fractionated poly-L-SUL except for the hydrodynamic radius and diffusion coefficients. The influence of different macromolecular sizes of poly-L-SUL on the chiral separation of phenylthiohydantion (PTH)-amino acids and coumarinic derivatives, as test analytes, was elucidated by the use of micellar electrokinetic chromatography (MEKC). The size of polymeric surfactants as a prerequisite for chiral separation was demonstrated by comparing the separation properties of fractionated versus nonfractionated polymeric surfactants. Fractionated poly-L-SUL resulted in enhanced resolution and separation efficiency of the test analytes as compared to the case of the nonfractionated poly-L-SUL. This observation indicates that minimizing polydispersity of polymeric surfactants may be important for some chiral separation applications.

The effect of substitution patterns on the release rates of opioid peptides DADLE and [Leu 5]-enkephalin from coumarin prodrug moieties

A coumarin-based prodrug system has been developed in our laboratory for the preparation of esterase-sensitive prodrugs of amines, peptides, and peptidomimetics. The drug release rates from this prodrug system were found to be dependent on the structural features of the drug moiety. The effect of the phenyl ring substitutions on the release kinetics of such prodrugs of model amines was examined recently and it was found that appropriately positioned alkyl substituents on the phenyl ring could help to facilitate the release. Aimed at further understanding the structure–release rate relationship of the coumarin-based cyclic prodrugs, we synthesized and examined a series of substituted coumarinic acid derivatives of opioid peptides, DADLE, and [Leu 5]-enkephalin.

Enantioselectivity of alcohol-modified polymeric surfactants in micellar electrokinetic chromatography.

A novel method of modifying sodium undecanoyl-L-leucinate (SUL) micelles employed in chiral separation of analytes in micellar electrokinetic chromatography (MEKC) to enhance selectivity toward specific analytes is discussed. The current study aimed at modifying the SUL micelles by introducing different alcohols into the mono-SUL micelles. The micellar solutions were then polymerized in the presence of alcohols followed by postpolymerization extraction of the alcohols to yield alcohol-free polymeric surfactants (poly-L-SUL). The effects of hexanol (C(6)OH) and undecylenyl alcohol (C(11)OH) on micellar properties of this surfactant were investigated by use of surface tensiometry, fluorescence spectroscopy, pulsed field gradient-nuclear magnetic resonance (PFG-NMR), and MEKC. The surface tension and PFG-NMR studies indicated an increase in the critical micelle concentration (cmc) and micellar size upon increasing the alcohol concentration. Fluorescence measurements suggested that alcohols induce closely packed micellar structures. Coumarinic and benzoin derivatives, as well as (+/-)-1, 1'-binaphthyl-2,2'-dihydrogen phosphate (BNP) were used as test analytes for MEKC experiments. Examination of MEKC data showed remarkable resolutions and capacity factors of coumarinic derivatives obtained with modified poly-L-SUL as compared to the unmodified poly-L-SUL. Evaluation of fluorescence, PFG-NMR, and MEKC data suggest a strong correlation between the polarity and hydrodynamic radii of alcohol-modified micelles and the resolution of the test analytes.

Coumarinic derivatives as mechanism-based inhibitors of α-chymotrypsin and human leukocyte elastase

Novel coumarinic derivatives were synthesized and tested for their inhibitory potency toward α-CT and HLE. Cycloalkyl esters and amides were found to be essentially inactive on both enzymes. On the opposite, aromatic esters strongly inactivated α-CT whereas HLE was less efficiently inhibited with dichlorophenyl ester derivatives (kinact/KI=4000M−1 s−1 for 36). Representative examples of amide, ester, thioester and ketone derivatives were prepared in order to evaluate the influence of the link between the coumarinic ring and the phenyl side chain. The irreversible inactivation of α-CT by 6-chloromethyl derivatives should be due to alkylation of a histidine residue as suggested by the amino acid analysis of the modified chymotrypsin. Conversely the inhibition of HLE was transient. Intrinsic reactivity of coumarins has been calculated using a model of a nucleophilic reaction between the ligand and the couple methanol–water. From this calculation, it appears that differences in the inhibitory potency expressed by these molecules cannot only be explained by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack.

Molluscicidal constituents of Calophyllum from Madagascar: activity of some natural and synthetic neoflavonoids and khellactones.

Crude extracts of seeds, leaves and barks of four Madagascan Calophyllum species: C. inophyllum, C. recedens, C. chapelieri, and C. verticullatum, have been tested for molluscicidal activity against Biomphalaria glabrata. All seed extracts showed significant activity. The major constituents of the most active Calophyllum species were examined. Some related coumarinic derivatives were synthesized in order to improve the biological activity. Among the compounds prepared, 5,7-dihydroxy-6-(2-methylbutyryl)-4-phenyl-coumarin presented an interesting molluscicidal activity.

Synthesis and properties of some new 3-substituted hexestrol derivatives

A series of new monosubstituted hexestrol derivatives were synthesized and the estrogenic and cytotoxic properties of some of them were studied. 3-Acetoxymethyl-hexestrol 8 has a binding affinity for the cytoplasmic estrogen receptor as high as estradiol. It is 100–1000 times lower for the coumarinic derivatives 13, 14 and 15. None of these compounds becomes covalently bound to the receptor. They display a 20–1000 times lower affinity for the estrogen receptor in the whole cell test on the MCF-7 mammary tumor cell culture. At low concentrations (10 −8 M) the three coumarinic derivatives stimulate the growth of these cells (estrogenic effect) as strongly as estradiol does.