Synthesis and antioxidant activity of selected 4-methylcoumarins Sanja C ´ avar a,b , Franci Kovac ˇ a, * , Milka Maksimovic ´ b a University of Ljubljana, Faculty of Chemistry and Chemical Technology, Aškerc ˇeva 5, 1000 Ljubljana, Slovenia b University of Sarajevo, Faculty of Science, Department of Chemistry, Zmaja od Bosne 33-35, 71000 Sarajevo, Bosnia and Herzegovina article info Article history: Received 21 January 2009 Received in revised form 18 February 2009 Accepted 24 March 2009 Keywords: 4-Methylcoumarins Radical-scavenging activity DPPH Å Reducing power Trolox abstract A series of selected 4-methylcoumarins (4-methyl-2H-1-benzopyran-2-ones) were synthesised and tested for radical-scavenging ability using the stable 1,1-diphenyl-2-picrylhydrazyl radical, and for reducing power ability with a test based on the reduction of ferric to ferrous cation. All studied com- pounds showed activity comparable to Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), an already known antioxidant, which is used as standard in most of the testing methods. Observa- tions from the study were made with regard to structural features that regulated the behaviour of the compounds. The antioxidant activity of some 4-methylcoumarin representatives is presented here for the first time and extends our knowledge of the range of valuable biological activities and possible roles in therapy and for food preservation associated with this group of compounds. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction Coumarins (2H-1-benzopyran-2-ones) occupy an important place in the realm of natural products and synthetic organic chem- istry. They have been used as anticoagulants (Cravotto, Nano, Palmisano, & Tagliapietra, 2001), additives in food and cosmetics, and in the preparations of insecticides (O‘Kennedy & Zhorenes, 1997). As substitutions can occur at any of the six available sites of their basic molecular moiety, these compounds are extremely var- iable in structure and activity. This structural diversity leads to coumarins displaying multiple biological properties that promote human health and help reducing the risk of diseases. Coumarins comprise a vast array of biologically active compounds ubiquitous in plants, many of which have been used in traditional medicine for thousands of years. The medicinal properties of coumarins include inhibition of platelet aggregation, cytochrome P450, and steroid 5a-reductase, spasmolytic, anticoagulant, antibacterial, anticancer, and antiHIV activities (Hoult & Paya, 1996; Kostova, 2005, 2007). A number of coumarins were found to affect the formation and scav- enging of reactive oxygen species (ROS), and reactive nitrogen spe- cies (RNS), exhibiting tissue-protective antioxidant properties (Bermejo, Pinero, & Villar, 2008; Surveswaran, Cai, Corke, & Sun, 2007; Wu, Huang, Lin, Ju, & Ching, 2007), which may include numerous different molecular mechanisms and are probably re- lated to their structural analogy with flavonoids and benzophenon- es. Such studies are of importance in view of the presence in the human diet of many coumarins and other plant polyphenolics, some of which are attracting interest on account of their antioxi- dant properties and possible roles in therapy and for food preser- vation (Grace, 2005). Many coumarin structures can be found in dietary products, as flavouring additives or as natural components, such as wine and other alcoholic beverages, tobacco products, cit- rus fruits, vegetables, bakery products and cereals (Lake, 1999; Sproll, Ruge, Andlauer, Godelmann, & Lachenmeier, 2008). Coumarins have been essentially found in green plants belong- ing to the family of Rutaceae and Umbelifferae. These compounds can be obtained from plants by different extraction methods. How- ever, the extraction from plants is a time consuming job and needs sophisticated instruments to get the pure product. Therefore, the chemical synthesis of coumarin derivatives is done to fulfil their requirements in vast applications. Chemically, coumarins can be synthesised by several synthetic routes such as Pechmann, Perkin, Knoevenagel, Reformatsky and Wittig reactions (Sethna & Shah, 1945). However, due to simple and relatively inexpensive starting materials, the Pechmann reaction was widely used for the synthe- ses of coumarins. The importance of free radicals, especially ROS in the pathoge- nicity of various diseases, including hepatic and vascular diseases 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 ef- fects of the oxygen radicals. In addition, some natural coumarins also affect the formation and scavenging of ROS and influence free radical-mediated oxidative damage (Grace, 2005). Very few sys- tematic studies have been reported on structure-antioxidant activ- ity correlations in coumarins. In a study of superoxide scavenging 0308-8146/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.foodchem.2009.03.087 * Corresponding author. Tel.: +386 01 2419 252; fax: +386 01 2419 220. E-mail addresses: franci.kovac@fkkt.uni-lj.si, franci.kovac@gmail.com (F. Kovac ˇ). Food Chemistry 117 (2009) 135–142 Contents lists available at ScienceDirect Food Chemistry journal homepage: www.elsevier.com/locate/foodchem