Synthesis of novel amino and acetyl amino-4-methylcoumarins and evaluation of their antioxidant activity

https://doi.org/10.1016/j.ejmech.2004.09.002Get rights and content

Abstract

The six novel 4-methylcoumarins bearing different functionalities such as amino, hydroxy, N-acetyl, acetoxy and nitro have been synthesized and confirmed on the basis of their spectral data (1H-, 13C-NMR, UV, IR and EI mass). They were examined for the first time for their effect on NADPH dependent liver microsomal lipid peroxidation in vitro, and the results were compared with other model 4-methylcoumarin derivatives to establish the structure–activity relationship. Our studies demonstrated that amino group is an effective substitute for the hydroxyl group for antioxidant property and produced a dramatic inhibition of lipid peroxidation. Ortho dihydroxy and ortho hydroxy-amino coumarins were found to possess highest antioxidant and radical scavenging activities.

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.

Section snippets

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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