Synthesis,Antioxidant and Antiproliferative Evaluation,Molecular Docking and DFT Studies of Some Novel Coumarin and Fused Coumarin Derivatives

N′-[(4-Chloro-2-oxo-2H-chromen-3-yl)methylene]-2-cyanoacetohydrazide ( 3 ) was synthesized in excellent yield from the condensation of 4-Chloro-2-oxo-2H-chromene-3-carbaldehyde with cyanoacetohydrazide. Compound 3 was utilized as a building block to synthesize novel coumarin and heterocycle-fused coumarin derivatives. The chemical structures of all the new coumarin compounds were identified by spectral analyses. Some of the new coumarins compounds were screened in human cancer cell lines (HEPG-2, MCF-7, HCT-116 and PC-3) to learn about their cytotoxic effects in addition to the study of their DNA damage and antioxidant activity. Three of these compounds exhibited remarkable antioxidant and anti-proliferative activities. Moreover, they have the capability to protect DNA from damage induced by bleomycin. Molecular docking, DFT and molecular electrostatic potential studies were performed on the compounds in vitro.     

Coumarin, anthroquinone and stilbene derivatives with anticholinesterase activity

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are the key enzymes in pathogenesis of Alzheimer's disease (AD), which is characterized by a deficit in central cholinergic transmission. In the current study, AChE and BChE inhibitory activities of seven coumarin derivatives [umbelliferone (1), 4-methylumbelliferone (2), 4-hydroxycoumarin (3), scopoletin (4), 8-methoxypsoralen (5), bergapten (6), and iso-bergapten (7)], a furanocoumarin mixture obtained from Heracleum crenatifolium Boiss. (Umbelliferae), as well as of two anthroquinone derivatives [rhein (8) and aloe-emodine (9)] and one stilbene, rhapontin (10), were tested by the spectrophotometric method of Ellman using an ELISA microplate-reader at 1 mg mL(-1). Among them, the furanocoumarin mixture [(68.8 +/- 0.76)%], bergapten [(62.4 +/- 0.74)%], aloe-emodine [(57.2 +/- 1.32)%], scopoletin [(53.1 +/- 0.83)%], and 4-methylumbelliferone [(62.3 +/- 1.03)%] showed over 50% inhibition against AchE, while umbelliferone [(54.3 +/- 0.23)%], 4-methylumbelliferone [(80.9 +/- 1.17)%], scopoletin [(73.5 +/- 1.01)%], 8-methoxypsoralen [(67.1 +/- 0.98)%], as well as the furanocoumarin mixture [(76.7 +/- 0.95)%] had a notable anti-BChE effect.     

Coumarin Therapy and Platelet Aggregation

Platelet aggregation has been related to blood coagulation studies in patients on nicoumalone, a coumarin anticoagulant. Aggregation studies were performed by means of Chandler''s tube and the adenosine diphosphate (A.D.P.)-induced optical density method. Platelet aggregation in Chandler''s tube has been shown to be quite different from A.D.P. aggregation and to be dependent on the “intrinsic” (blood) clotting system. When the intrinsic system was depressed by coumarin anticoagulant, aggregation was delayed in Chandler''s tube, but patients with a predominantly “extrinsic” (tissue) system defect gave normal results even when their prothrombin time was excessively prolonged. In contrast there was an increased response to A.D.P. in the anticoagulated patients.The study emphasizes the different mechanisms of platelet aggregation, which we have referred to as coagulation-induced and A.D.P.-induced aggregation. It also shows the limitations of routine control of oral anticoagulants by prothrombin time alone, as the coagulation-induced platelet aggregation appears to be quantitatively related to the overall level of clotting factors in the intrinsic system and independent of the extrinsic system.     

Synthesis of Coumarin Derivatives with Cytotoxic,Antibacterial and Antifungal Activity

The synthesis and selective biological screening of 7-hydroxy-4-methyl-2H-chromen-2-one (2), 7-hydroxy-4,5-dimethyl-2H-chromen-2-one (15) and some of their derivatives were carried out. Compound 13 was found to be most potent cytotoxic agent with LD₅₀ = 126.69 μg/ml. In antibacterial assay the compounds showed a broad spectrum of activities. Compound 11 exhibited a very high degree of plant growth inhibition at three levels of concentration. Compound 4 showed very promising antifungal activity against Candida albicans. Compounds 12 and 13 demonstrated excellent antioxidant activity.     

Coumarin in Chromosome Analysis

Root tips of monocotyledons were soaked 2.5-3.0 hours at 25-27° C. in saturated aqueous coumarin solution and stained in a mixture of N HC 1 and 2% aceto-orcein (1:9 by volume) 3-4 seconds over a flame. They were then squashed in 1% orcein under a cover glass, the excess stain blotted and the cover sealed. Preparations could be kept about one week. Good chromosome morphology was secured.     

The Effect of Coumarin on Growth, Production of Dry Matter, Protein and Nucleic Acids in Roots of Maize and Wheat and the Interaction of Coumarin with Metabolic Inhibitors

Effects of coumarin on fresh weight, dry matter, protein and nucleic acid content per cell in attached roots of maize and wheat and in whole excised elongation zones of maize were determined. The inhibition in cell length exerted by coumarin did not correspond to an inhibition of the net synthetic capacity. Coumarin treatment increased the cell surface, the production of dry matter and the protein content per cell. The dry matter and the protein content per unit surface was slightly increased or unaffected. The effect of coumann on cell shape seemed to be independent of that on dry matter production and net protein synthesis. The same was found in excised elongation zones. —The net DNA-synthesis per cell was slightly increased in attached roots by coumann treatment, but this effect was probably not correlated with the morphogenetic changes. Inhibition of DNA-synthesis with hydroxyurea did not alter the coumarin induced changes in cell shape. —The net RNA-synthesis per cell was slightly decreased after coumarin treatment, but the net RNA-synthesis per cell and the morphogenetic effects exerted by coumarin were not related with each other. Inhibition of m-RNA-synthesis with actinomycin D did not prevent the effects of coumarin on cell division, cell expansion, dry matter production and net protein synthesis. The same was true for inhibitors of protein synthesis, puromycin and p-fluorophenyl-alanine. The findings are in support of the view that coumarin affects already existing structures or enzymes. —Comparisons between coumarin and the uncouplers, DNP and dicoumarol, showed that the effects of coumarin were not, solely, due to uncoupling. SH-protecting agents, BAL, DTE and glutathione, did, with few exceptions, not reduce the morphogenetic effects of coumarin.     

Coumarin constituents of Selinum tenuifolium

Three furocoumarins, bergapten, heraclenin and heraclenol have been isolated from the roots of Selinum tenuifolium (Umbelliferae). Another coumarin, m.p. 85–86°, isolated from the same source and provisionally designated as ST-1, has been proved to be mixture of imperatorin, and 8-geranyloxypsolaren by analyses of various reaction products and separation by preparative TLC on silica gel G impregnated with silver nitrate.     

Coumarin glucosides from Cruciata taurica

Two new coumarin glycosides (1 and 2) along with two known coumarin glucosides, daphnin (3) and daphnetin glucoside (4) were isolated from the aerial parts of Cruciata taurica. The structures of the new compounds were elucidated by spectral methods and chemical means as 7-O-(6' -acetoxy-beta-D-glucopyranosyl)-8-hydroxycoumarin (1) and 7-O-[6 '-O-(3',4'-dihydroxycinnamoyl)-beta-D-glucopyranosyl]-8-hydroxycoumarin (2). The phylogenetic significance of coumarins in C. taurica was discussed.     

Coumarin glycosides of seseli montanum

Three new coumarin glycosides isolated from roots of Seseli montanum were shown to be the 3′-O-,2′-O-, and the 7-O-β-D-glucopyranosides respectively of 2′(R)-6-(2′,3′-dihydroxy-3′-methylbutyl)-7-hydroxy-coumarin. The structures were elucidated by spectroscopic and chemical methods. (R)-Configuration was assigned to the aglycone, also known as ( + )-peucedanol, and to its 7-methyl ether, ( + )-ulopterol, by chemical correlation. Additionally, apterin was obtained and characterized.     

Design,Synthesis, and Anti-Breast Cancer Activity of Some Hybrid Molecules Containing Coumarin Moiety

Russian Journal of Bioorganic Chemistry - (Benzimidazol-2-yl)-7-hydroxycoumarin and N-(2-hydroxyphenyl)-7-hydroxycoumarin-3-carboxamide have been synthesized by the condensation of ethyl...     

In Vivo Efficacy of a Synthetic Coumarin Derivative in a Murine Model of Aspergillosis

Despite advances in therapeutic modalities, aspergillosis remains a leading cause of mortality. This has necessitated the identification of effective and safe antifungal molecules. In the present study, in vivo safety and antifungal efficacy of a coumarin derivative, N, N, N-Triethyl-11-(4-methyl-2-oxo-2H-benzopyran-7-yloxy)-11-oxoundecan-1-aminium bromide (SCD-1), was investigated. The maximum tolerable dose of compound was determined according to OECD 423 guidelines. The compound could be assigned to category IV of the Globally Harmonized System and its LD₅₀ cut-off was found to be 2000 mg/kg body weight. The survival increased in Aspergillus fumigatus-infected mice treated with a dose of 200 mg/kg, orally or 100 mg/kg body weight, intraperitoneally, of SCD-1 in comparison to infected-untreated animals. The SCD-1 treatment resulted in significant reduction in colony counts in vital organs of the animals. Its protective effect was also observed on day 14 as there was marked reduction in fungal colonies. The treatment with SCD-1 also reduced the levels of serum biochemical parameters with respect to infected-untreated animals. It could be concluded that SCD-1 is a quite safe antifungal compound, which conferred dose dependent protection against experimental aspergillosis. Therefore, SCD-1 holds potential for developing new formulations for aspergillosis.     

Coumarin metabolic routes in Aspergillus spp

Coumarin metabolism by several Aspergillus strains was studied. Aspergillus ochraceus and Aspergillus niger carried out the reduction of the C3-C4 double bond to yield dihydrocoumarin in 24h. Meanwhile, the first strain did not transform dihydrocoumarin after 7d, A. niger demonstrated to have two divergent catabolic pathways: (a) the lactone moiety?opening and further reduction of the carboxylic acid furnishing the primary alcohol 2-(3-hydroxypropyl)phenol and, (b) the hydroxylation of the aromatic ring of dihydrocoumarin at a specific position to give 6-hydroxy-3,4-dihydrochromen-2-one. Aspergillus flavus did not perform double bond reductions, and only produced oxygenated metabolites, mainly 5-hydroxycoumarin. Enzyme-specific inhibitors and a coumarin analogous were useful to confirm the A. niger catabolic route.     

Coumarin and Euponin,Two Inhibitors for Insect Development from Leaves of Eupatorium japonicum

An ovicide and a larval growth inhibitor against Drosophila melanogaster were isolated from leaves of Eupatorium japonicum. The ovicide was identified as coumarin. The structure of the larval growth inhibitor, a new naturally occurring guaianolide named euponin, was elucidated on the basis of spectral and chemical evidence. The inhibitory effects of these agents on the egg and larva were also described.     

Coumarin hybrids as novel therapeutic agents

Naturally occurring coumarins, having wide spectrum of activities such as antioxidant, anti-inflammatory, anticancer, MAO-B inhibitory and antimicrobial, are frequently used by the researchers to develop novel synthetic and semisynthetic coumarin based therapeutic agents. Many of these agents are hybrid molecules, which are designed through concept of molecular hybridization and have shown multiple pharmacological activities. This multifunctional attribute of these hybrid compounds makes them potential drug candidates for the treatment of multifactorial diseases such as cancer, Alzheimer’s disease, metabolic syndromes, AIDS, malaria, and cardiovascular diseases. The present review compiles research reports on development of different coumarin hybrids, classify these on the basis of their therapeutic uses and propose structure–activity relationships. It is intended to help medicinal chemist in designing and synthesizing novel and potent hybrid compounds for the treatment of different disorders.     

On the Co-occurrence of Coumarin, o-Coumaric Acid, and Melilotic Acid in Gliricidia sepium and Dipteryx odorata

The presence of coumarin, o-coumaric acid, and melilotic acidhas been shown in leaf tissue of Gliricidia sepium and Dipteryxodorata. The formation of these compounds in relation to leafmaturation is described and their possible bio-synthetic interrelationshipsdiscussed. Qualitative and quantitative chromato-graphic methodsfor their determination are described.     

Coumarin derivatives as potential inhibitors of acetylcholinesterase: Synthesis,molecular docking and biological studies

A series of novel hybrids has been synthesized by linking coumarin moiety through an appropriate spacer to various substituted heterocyclic amines and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of cognitive dysfunction caused by increased hydrolysis of acetylcholine and scopolamine induced oxidative stress. Anti-amnesic activity of the compounds was evaluated using Morris water maze model at a dose of 1 mg/kg with reference to the standard, donepezil. Biochemical estimation of oxidative stress markers (lipid peroxidation, superoxide dismutase, and plasma nitrite) was carried out to assess the antioxidant potential of the synthesized molecules. Among all the synthesized compounds (15a–i, 16a–d, 17a–b), compound 15a [4-[3-(4-phenylpiperazin-1-yl)propoxy]-2H-chromen-2-one] displayed significant antiamnesic activity, AChE inhibitory activity (IC₅₀ = 2.42 μM) and antioxidant activity in comparison to donepezil (IC₅₀ = 1.82 μM). Molecular docking study of 15a indicated that it interacts with all the crucial amino acids present at the CAS, mid-gorge and PAS of TcAChE resulting in increased inhibition of AChE enzyme.     

Coumarin sulphates of Seseli libanotis

Three new sulphate ester salts derived from known coumarin alcohols–one of them tertiary–have been obtained from roots of Seseli libanotis subsp. eu-libanotis. Their structures were established as (2′S)-rutaretin-1″-sulphate, (3′R)-lomatin-3′-sulphate and (3′R,4′R)-khellactone-3′-sulphate. They were together with their parent alcohols characterized by ¹³C NMR spectroscopy. It is the first report on coumarin sulphates in plants.     

Coumarin content and physicochemical profile of Mikania laevigata extracts

The 'guaco' lianous herb Mikania laevigata, which is widespread in Southern Brazil, is traditionally used to treat bronchitis, asthma and cough. This work investigates the influence of the extraction method, solvent:drug ratio, ethanol proportion, harvest season (summer or winter) and solvent heating on the physicochemical profile of the extracts (dry weight, density, pH) and the coumarin (1,2-benzopyrone) content determined by LC. Among the results obtained, it is observed that higher ethanol content increases the amount of coumarin in the extract. Leaves harvested in summer also produce an extract with a high coumarin yield. The most efficient method of extraction is percolation, independent of the solvent used.