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Docking Studies and α-Substitution Effects on the Anti-Inflammatory Activity of β-Hydroxy-β-arylpropanoic Acids
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia
Department of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia
Department of Molecular Biology and Immunology, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia
Department of Organic Chemistry, Faculty of Chemistry, University of Belgrade, Box 158, 11001, Belgrade, Serbia
* Author to whom correspondence should be addressed.
Received: 2 June 2011; in revised form: 26 July 2011 / Accepted: 3 August 2011 / Published: 5 August 2011
Abstract: Six β-hydroxy-β-aryl propanoic acids were synthesised using a modification of Reformatsky reaction which has already been reported. These acids belong to the aryl propanoic acid class of compounds, structurally similar to the NSAIDs, such as ibuprofen, and an anti-inflammatory activity is thus expected. The aim of this work was to determine anti-inflammatory activity, examine gastric tolerability, and to carry out molecular docking experiments to identify potential COX-2 inhibitors among the β-hydroxy-β-aryl propanoic acids, and to elucidate the effect α-methyl substitution on the anti-inflammatory activity. Anti-inflammatory activity and gastric tolerability were determined on rats using carragenan induced paw oedema method, and docking studies were carried out using Autodock v4.0.1. The range of ED50 values is between 127 µmol/kg and 15 µmol/kg, while the result for ibuprofen is 51.7 µmol/kg. Only slight hyperaemia or few petechiae were spotted on rat’s stomach. The results indicate that all compounds possess significant anti-inflammatory activity after oral administration, and that 2-methyl-3-hydroxy-3,3-diphenyl-propanoic acid has greatest activity, surpassing that of ibuprofen, a standard NSAID. Another compound, 3-hydroxy-3,3-diphenylpropanoic acid, shows activity matching that of ibuprofen, and is non-chiral and is proven to be non-toxic. The most of investigated compounds have interactions with P3 anchor site like COX-2 selective inhibitors. No tested substances or ibuprofen produced any significant gastric lesions.
Keywords: β-hydroxy-β-arylpropanoic acids; Reformatsky reaction; anti-inflammatory activity; molecular docking simulations; COX-2 selective inhibitor
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Savić, J.S.; Dilber, S.P.; Marković, B.D.; Milenković, M.T.; Vladimirov, S.M.; Juranić, I.O. Docking Studies and α-Substitution Effects on the Anti-Inflammatory Activity of β-Hydroxy-β-arylpropanoic Acids. Molecules 2011, 16, 6645-6655.
Savić JS, Dilber SP, Marković BD, Milenković MT, Vladimirov SM, Juranić IO. Docking Studies and α-Substitution Effects on the Anti-Inflammatory Activity of β-Hydroxy-β-arylpropanoic Acids. Molecules. 2011; 16(8):6645-6655.
Savić, Jelena S.; Dilber, Sanda P.; Marković, Bojan D.; Milenković, Marina T.; Vladimirov, Sote M.; Juranić, Ivan O. 2011. "Docking Studies and α-Substitution Effects on the Anti-Inflammatory Activity of β-Hydroxy-β-arylpropanoic Acids." Molecules 16, no. 8: 6645-6655.