Letters in Drug Design & Discovery, 2012, 9, 479-488 479 1875-628X/12 $58.00+.00 © 2012 Bentham Science Publishers Design, Synthesis and Evaluation of Chalcone Derivatives as Anti- Inflammatory, Antioxidant and Antiulcer Agents Alka N. Choudhary*, Arun Kumar and Vijay Juyal Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Bhimtal campus, Kumaun University, Bhimtal-263136, Nainital, Uttarakhand, India Received January 24, 2012: Revised February 14, 2012: Accepted February 22, 2012 Abstract: In the present study, a series of chalcone derivatives were designed based on QSAR analysis. The designed compounds were synthesized by Claisen Schmidt condensation and evaluated for anti-inflammatory, antioxidant and antiulcer activities. The results of the best 2D & 3D QSAR models suggested that by introducing electron releasing groups at R 2 and introducing heteroatom with increasing bulkiness at R 4 in the benzylideneacetophenone nucleus will increase the activity. The structures of the compounds were established by IR, 1 H NMR and mass spectral analysis. All the compounds were evaluated for their anti-inflammatory (carrageenan-induced rat paw edema assay), antioxidant (inhibition of lipid peroxidation) and antiulcer activity (indomethacin-induced gastric damage). Of 10 compounds screened, compounds 1e and 1d exhibited promising anti-inflammatory activity with 68-70% inhibition at 100mg/kg , inhibition of lipid peroxidation with IC 50 2.47 & 3.1 μg/ml respectively. The Compounds 1e, 1j and 1d exhibited good gastro protective action as indicated by their low ulcer score. Overall, 1e was obtained as lead compound with promising anti-inflammatory, antioxidant and antiulcer activities. Keywords: Antioxidants, Antiulcer, Chalcones, Inflammation, Rheumatoid Arthritis, NSAIDs. 1. INTRODUCTION Non-steroidal anti-inflammatory drugs (NSAIDs) still remain among the most extensively used drugs world wide and have been used in the treatment of inflammatory conditions like rheumatoid arthritis, osteoarthritis, orthopedic injuries, postoperative pain, etc [1-2]. However, the use of conventional NSAIDs has been restricted due to their side effects especially gastric erosion and ulcers [3-5]. Thus, there is an urgent need for new targets that are required for the design and development of novel anti- inflammatory agents as an alternative to NSAIDs. Reactive oxygen species (ROS) in the form of super oxide anion (O 2 - . ), hydroxyl radical (OH . ) and hydrogen peroxide attack various biological macromolecules (proteins, enzyme, DNA, etc) under ‘oxidative stress’ conditions, giving rise to a number of inflammatory, metabolic disorders, cellular aging, reperfusion damage and cancer [6-7]. Interestingly a number of therapeutically useful NSAIDS have been shown to act by virtue of their free radical scavenging activity [8-10]. Antioxidants are the compounds that prevent oxidative damage induced by free radicals and reactive oxygen species. Thus, antioxidant therapy has also gained immense importance in the treatment of above-mentioned diseases [11]. Chalcones, or 1,3 –diaryl-2-propen-1-ones, belong to the flavanoid family [12]. Chemically they consist of open-chain flavanoids in which the two aromatic rings are joined by a three-carbon α, β unsaturated carbonyl system [13]. A vast number of naturally occurring chalcones are *Address correspondence to this author at the Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Bhimtal campus, Kumaun University, Bhimtal-263136, Nainital, Uttarakhand, India; Tel: +919411313837; Fax: 05942-248307; E-mail: alka_pharma@rediffmail.com polyhydroxylated in the aryl rings. The radical quenching properties of the phenolic groups present in many chalcones have raised interest in using the compounds [14-15]. The aim of the present study is to design, synthesize & evaluate chalcone derivatives based on best QSAR model. A Quantitative structure–activity relationship (QSAR) enables the investigators to establish a reliable quantitative structure– activity and structure–property relationships to derive QSAR model [16] to predict the activity of novel molecules prior to their synthesis. 2. EXPERIMENTAL 2.1. QSAR Analysis Nineteen compounds belonging to chalcone derivatives were taken from literature [17] (Table 1). All the biological activity data had been converted to negative logarithmic mole dose (pIC50) for QSAR analysis. The correlations were sought between inhibitory activity and various substituents constants at position R 1, R 2, R 3 & R 4 of molecule and indicator variable for the presence of methoxy at R 5 (I V 1) and presence of hydroxy group in the ring system at R 6 position (I V 2). The value of substituent constants like hydrophobic (π), steric (molar refractivity MR), hydrogen acceptor (HA), and hydrogen donor (HD) and electronic (field effect F, resonance effect or R) and Hammett’s constant (σ) were taken from literature for position R 1, R 2, R 3 & R 4. The series was also subjected to Molecular Modeling studies and Quantum mechanical calculations were performed using CS Chem. Office version 10.0 (Cambridge soften ware) running on a P-IV processor [18]. All molecules were built using Chemdraw Ultra ver 10.0 and subjected to energy minimization using Allinger’s MM2 force field. The minimization is continued until the root mean square (RMS) gradient value reaches a value smaller than 0.1 kcal/molA º .