The compound containing polar nitro group in para position has shown the best docking results, anti-inflammatory activity, low hepatotoxicity and good gastric tolerability.
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.
The pKa values of twelve ?-hydroxy-?-arylalkanoic acids and ibuprofen were determined using a modified RP-HPLC method. The stationary phase was octadecyl modified (C-18) silica gel, and the mobile phases were mixtures of methanol and one of ten different buffers (60:40 volume ratio). The mean retention time of each compound was plotted against the pH of each of the ten used mobile phases. The inflection point of the obtained sigmoidal curve represents the s w pKa of a compound. Using s w pKa in previously established equations for the specific methanol/buffer mixture, the w w pKa values (in pure water) were calculated. The obtained w w pKa values for the synthesized compounds were in a range from 3.40 to 3.74, and the w w pKa for ibuprofen was 4.27. The Predicted pKa values for this type of compounds in the MarvinSketch 5.11.5. Program were in poor correlation with the experimental results, while in ACD/ /I-Labs pKa values were calculated as a wide range. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 172041]
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