Synthesis and antioxidant activity of thymol and carvacrol based Schiff bases Beena, Deepak Kumar, Diwan S. Rawat ⇑ Department of Chemistry, University of Delhi, Delhi 110007, India article info Article history: Received 6 August 2012 Revised 27 November 2012 Accepted 1 December 2012 Available online 8 December 2012 Keywords: Antioxidant Thymol Carvacrol Schiff base DPPH ABTS abstract Thymol and carvacrol are well known antioxidants found in the extract of the plants of thyme species. The Schiff bases of 2-iso-propyl-5-methyl-phenol (thymol/1a), 2-tert-butyl-5-methyl-phenol (1b) and 5-iso-propyl-2-methyl-phenol (carvacrol/1c) exhibited much better antioxidant activity than thymol and carvacrol in DPPH assay. Ten compounds (4k, 4l, 4r, 5k, 5l, 5q, 5r, 6k, 6l and 6r) showed better or similar activity as compared to the reference compound ascorbic acid. Twenty-four most active com- pounds were also screened by ABTS method and showed 60–90% inhibition at 5 lg/mL concentration. Ó 2012 Elsevier Ltd. All rights reserved. Reactive oxygen species (ROS) such as hydroxyl radicals, super- oxide radicals, singlet oxygen, hydrogen peroxide radical are con- stantly formed as a result of normal organ functions or excessive oxidative stress. 1,2 Their presence in the biological system is very harmful as these species are responsible for the damage of biomol- ecules such as nucleic acid, proteins, lipids, DNA and carbohy- drates 3 and this may cause many diseases such as cancer, atherosclerosis, aging, hair loss, inflammation, immunosupress- sion, diabetes and neurodegenerated disorders (such as Alzhei- mer’s and Parkinson’s diseases). 4–7 The balance between the production and elimination of ROS is normally controlled by the body defence mechanism through the use of different enzymes such as superoxide dismutase (SOD), catalase and glutathione per- oxidase. However when it is disturbed oxidative stress is generated leading to oxidative damage to biomolecules. Antioxidants are compounds which slow down or prevent the oxidation of other molecules. 8,9 They interact with free radicals and prevent the dam- age by ROS. Thus the treatment with antioxidants is potentially a way to overcome the oxidative stress. Because of this, there is a great interest in the discovery of natural and synthetic antioxi- dants that can serve as protective agents against these diseases. Phenolic compounds are known for their antimicrobial and antiox- idant properties. They act as free radical scavengers and their anti- oxidant potential depends on the substituent present and the extent of structure conjugation. 10 Extracts of the plants of thyme species possess a wide range of biological and pharmacological properties. 11–13 The rich essential oils present in thyme species are used for the treatment of several diseases as well as for food preservatives. 14 The most frequently occurring constituents of these species are thymol (2-iso-propyl- 5-methylphenol, 1a) and its isomer carvacrol (5-iso-propyl-2- methyl-phenol, 1c). They exhibit antibacterial, antifungal, antiviral, antitumor and anti-inflammatory activities. 15–22 They also act as antioxidant, 23 free radical scavenger 24 and anti-lipidperoxidative agents. 25 Thymol and carvacrol act as biocidal agent by causing disruption of the bacterial membrane. Thymol and carvacrol are used as antiseptic, in medical practice, agriculture, cosmetics and food industry. Thymol has antimicrobial properties and has the ability to reduce bacterial resistance to drugs such as penicillins (synergistic) and it is an active ingredient of Listerine (mouthwash) and Vicks. Encouraged by these observations and as a part of our ongoing programme towards the synthesis of medicinal relevant molecules 26–35 we became interested to modify thymol and carva- crol, and study their antioxidant activity. The synthesis of the compounds was carried out according to the procedure outlined in Schemes 1 and 2. Firstly, 2-iso-propyl- 5-methyl-phenol (thymol/1a) or 2-tert-butyl-5-methyl-phenol (1b) or 5-iso-propyl-2-methyl-phenol (carvacrol/1c) were con- verted to compound with 4-nitroso substituent (2a/2b/2c) by treating ethanolic solution of these phenols (1a/1b/1c) with concd hydrochloric acid and sodium nitrite at 0 °C. 36,37 The nitroso com- pounds (2a–2c) were reduced in an ammonical solution by passing H 2 S gas (Scheme 1). The substituted 4-aminophenols (3a–3c) ob- tained are highly unstable and subject to oxidation over a period 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.12.001 ⇑ Corresponding author. Tel.: +91 11 27662683; fax: +91 11 27667501. E-mail address: dsrawat@chemistry.du.ac.in (D.S. Rawat). Bioorganic & Medicinal Chemistry Letters 23 (2013) 641–645 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl