Synthesis of novel amino and acetyl amino-4-methylcoumarins and evaluation of their antioxidant activity
Introduction
Coumarins and their derivatives have been found to exhibit different biological and pharmacological activities [1]. The 4-methylcoumarins have been found to possess anti-inflammatory [2], cholesretic [3], analgesic [4], antispermatogenic [5] and diuretic [6] properties. Apart from the medicinal applications coumarins are also used as sweetener, fixative of perfumes [7], enhancer of natural oils such as lavender, a food additive in combination with vanillin, a flavour/odour stabilizer in tobacco [7], an odour masker in paints and rubber. Owning to the widespread applications, synthetic and biological activity evaluation of coumarins and their derivatives has been a subject of intense investigations.
The importance of free radicals, especially reactive oxygen species (ROS) in the pathogenicity of various diseases [8], [9], including hepatic and vascular diseases [10] has of late received greater attention. Antioxidants are now forged as the drug candidates to combat these diseases. Minor dietary constituents have been seriously considered to counter the ill effects of the oxygen radicals. The 4-methyl coumarins are known to be less toxic compared to coumarins. In this report, we have examined 4-methyl coumarin possessing dihydroxy, diacetoxy and hydroxy-amino groups in the benzenoid ring at positions ortho to each other, they have shown very good antioxidant and radical scavenging properties, also comparatively better than those of α-tocopherol.
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Chemicals
Nicotinamide dinucleotide phosphate (NADPH), adenosine diphosphate (ADP), acetic anhydride, pyridine and trichloroacetic acid (TCA) were obtained from Sisco Research Laboratory (Mumbai, India), tris, FeCl3, thiobarbituric acid (TBA), dimethyl sulfoxide (DMSO), ammonium hydroxide and sodium hydrosulfite of high purity were purchased from local suppliers. Diphenyl picryl hydrazyl (DPPH) was procured from Sigma Chemical Co., St. Louis, MO, USA.
Animals
Male albino rats of wistar strain weighing around
Results and discussion
The coumarins (2–15) were synthesized by the well-known Pechmann condensation [11] in quantitative yield. The compounds 8-N-acetyl-7-acetoxy-4-methylcoumarin (8), 5-N-acetyl-6-acetoxy-4-methylcoumarin (9), 5,7-dinitro-6-acetoxy-4-methylcoumarin (11), 5,7-diamino-6-hydroxy-4-methylcoumarin (12), 5,7-N-diacetyl-6-acetoxy-4-methylcoumarin (13), and 7,8-diacetoxy-6-nitro-4-methylcoumarin (15) have been synthesized and reported for the first time (Scheme 1). Structural confirmation was done using 1H
Conclusions
Six novel compounds have been synthesized and characterized with the help of spectroscopic techniques and were screened for their ability to inhibit NADPH dependent lipid peroxidation of rat liver microsomes. Ortho hydroxy-amino coumarins 6, 7 and 12 were identified as potent inhibitors of lipid peroxidation, better than those of α-tocopherol. It is conceivable from these studies that the amino group can substitute for the hydroxyl group of coumarin to be effective as the inhibitor of membrane
Acknowledgements
The financial support of Danish International Development Agency (DANIDA) is gratefully acknowledged.
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