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Abstract
New derivatives of 7-hydroxy-4-methylcoumarin were synthesized using a chemical method
and a microwave-assisted method to compare the feasibility, reaction times, and yields
of the product. The newly synthesized coumarins were characterized by different spectroscopic
techniques (FT-IR and NMR) and micro-elemental analysis (CHNS). In vitro antioxidant
activities of these compounds were evaluated against hydrogen peroxide and were compared
with standard natural antioxidant, vitamin C. Our results reveal that these compounds
exhibit excellent radical scavenging activities.
1. More than 300 coumarins have been identified from natural sources, especially green plants. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. More complex related compounds based on the coumarin nucleus include the dicoumarol/warfarin anticoagulants, aflatoxins and the psoralens (photosensitizing agents). 2. Coumarin itself (1,2-benzopyrone) has long-established efficacy in slow-onset long-term reduction of lymphoedema in man, as confirmed in recent double-blind trials against elephantiasis and postmastectomy swelling of the arm. The mechanism of action is uncertain, but may involve macrophage-induced proteolysis of oedema protein. However, coumarin has low absolute bioavailability in man (< 5%), due to extensive first-pass hepatic conversion to 7-hydroxycoumarin followed by glucuronidation. It may, therefore, be a prodrug. 3. Scoparone (6,7-dimethoxycoumarin) has been purified from the hypolipidaemic Chinese herb Artemisia scoparia and shown to reduce the proliferative responses of human peripheral mononuclear cells, to relax smooth muscle, to reduce total cholesterol and triglycerides and to retard the characteristic pathomorphological changes in hypercholesterolaemic diabetic rabbits. Various properties of scoparone were suggested to account for these findings, including ability to scavenge reactive oxygen species, inhibition of tyrosine kinases and potentiation of prostaglandin generation. 4. Osthole (7-methoxy-8-[3-methylpent-2-enyl]coumarin) from Angelica pubescens, used also in Chinese medicine, causes hypotension in vivo, and inhibits platelet aggregation and smooth muscle contraction in vitro. It may interfere with calcium influx and with cyclic nucleotide phosphodiesterases. 5. Cloricromene, a synthetic coumarin derivative, also possesses antithrombotic antiplatelet actions, inhibits PMN neutrophil function and causes vasodilatation. Some of these properties of cloricromene have been ascribed to inhibition of arachidonate release from membrane phospholipids. 6. Simple coumarins possessing ortho-dihydroxy functions, such as fraxetin and 4-methyldaphnetin, are potent inhibitors (low micromolar) of lipid peroxidation and scavengers of superoxide anion radicals and of aqueous alkylperoxyl radicals, but may be pro-oxidant (enhancing generation of hydroxyl radicals) in the presence of free iron ions. These coumarins also inhibit the proinflammatory 5-lipoxygenase enzyme at micromolar concentrations. Another related coumarin, 5,7-dihydroxy-4-methylcoumarin, is of special interest as it inhibits lipid peroxidation, and scavenges alkylperoxyl and superoxide radicals. Unlike most other simple coumarins studied, 5,7-dihydroxy-4-methylcoumarin also scavenges hypochlorous acid, and is a potent inhibitor of cyclo-oxygenase, but is not pro-oxidant. 7. 5,7- and 6,7-dihydroxy-4-methylcoumarin both reduced the duration of ventricular fibrillation in postischaemic reperfused isolated perfused rat hearts (in which oxygen-derived free radicals are implicated), showing that these antioxidant coumarins possess beneficial properties in this pathophysiological model. 8. In view of the established low toxicity, relative cheapness, presence in the diet and occurrence in various herbal remedies of coumarins, it appears prudent to evaluate their properties and applications further.
An activity-directed fractionation and purification process was used to identify the antioxidative components of Polygonum multiflorum Thunb. (PM). Dried root of PM was extracted with 95% ethanol and then separated into water, ethyl acetate, and hexane fractions. Among these only the ethyl acetate phase showed strong antioxidant activity by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) test when compared with water and hexane phases. The ethyl acetate fraction was then subjected to separation and purification using silica gel column chromatography and Sephadex LH-20 chromatography. Three compounds showing strong antioxidant activity were identified by spectral methods ((1)H NMR, (13)C NMR, and MS) and by comparison with authentic samples to be gallic acid, catechin, and 2,3,5, 4'-tetrahydroxystilbene 2-O-beta-D-glucopyranoside.
The antioxidant activity of two synthesized coumarins namely, N-(4,7-dioxo-2- phenyl-1,3-oxazepin-3(2H,4H,7H)-yl)-2-(2-oxo-2H-chromen-4-yloxy)acetamide 5 and N-(4-oxo-2-phenylthiazolidin-3-yl)-2-(2-oxo-2H-chromen-4-yloxy)acetamide 6 were studied with the DPPH, hydrogen peroxide and nitric oxide radical methods and compared with the known antioxidant ascorbic acid. Compounds 5 and 6 were synthesized in a good yield from the addition reaction of maleic anhydride or mercaptoacetic acid to compound 4, namely N′-benzylidene-2-(2-oxo-2H-chromen-4-yloxy)acetohydrazide. Compound 4 was synthesized by the condensation of compound 3, namely 2-(2-oxo-2H-chromen-4-yloxy) acetohydrazide, with benzaldehyde. Compound 3, however, was synthesized from the addition of hydrazine to compound 2, namely ethyl 2-(2-oxo-2H-chromen-4-yloxy)acetate, which was synthesized from the reaction of ethyl bromoacetate with 4-hydroxycoumarin 1. Structures for the synthesized coumarins 2–6 are proposed on the basis of spectroscopic evidence.
Publisher:
Public Library of Science
(San Francisco, CA USA
)
ISSN
(Electronic):
1932-6203
Publication date
(Electronic):
6
July
2015
Publication date Collection: 2015
Volume: 10
Issue: 7
Electronic Location Identifier: e0132175
Affiliations
[1
]Department of Chemical and Process Engineering, University Kebangsaan Malaysia (UKM),
Bangi, Selangor, 43000, Malaysia
[2
]Environmental Research Center, University of Technology (UOT), Baghdad, 10001, Iraq
[3
]Fuel Cell Institute, University Kebangsaan Malaysia (UKM), Bangi, Selangor, 43000,
Malaysia
The University of Iowa, UNITED STATES
Author notes
Competing Interests: The authors have declared that no competing interests exist.
Conceived and designed the experiments: AAA ABM AHK. Performed the experiments: YKA.
Analyzed the data: AAA ABM AHK. Contributed reagents/materials/analysis tools: AAA
ABM YKA AHK. Wrote the paper: AAA.
This is an open access article distributed under the terms of the
Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided
the original author and source are credited
History
Date
received
: 23
February
2015
Date
accepted
: 10
June
2015
Page count
Figures: 4,
Tables: 1,
Pages: 9
Funding
This study was supported by the Universiti Kebangsaan Malaysia under the DIP-2012-02
grant.
Categories
Subject:
Research Article
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