Docking Studies and α-Substitution Effects on the Anti-Inflammatory Activity of β-Hydroxy-β-arylpropanoic Acids

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.

Determinación Computacional de la Afinidad y Eficiencia de Enlace de Antinflamatorios No Esteroideos Inhibidores de la Ciclooxigenasa-2

“…Por este motivo, el modelamiento molecular se enfocó únicamente en la zona del sitio activo ciclooxigenasa. Al comparar el resultado obtenido con el ibuprofeno (-7.7 kcal/mol) con el resultado obtenido en otro estudio con la utilización del programa "Autodock 4" (-6.21 kcal/mo) (Savic et al, 2011), se puede observar que la diferencia de energía entre ambas estructuras es de tan solo 1.49 kcal/mol. Tal como se explicó, estructuras se consideran homólogas cuando sus energías difieren en menos de 3 kcal/mol.…”

A modified RP-HPLC method for the determination of the pKa values of synthesized β-hydroxy-β-arylalkanoic acids

“…β-Hydroxy-β-arylalkanoic acids were previously synthesized and their anti--inflammatory activity was evaluated. [19][20][21] The general aim of the previous studies was to examine the impact of some structural modifications on selectivity towards COX-2 inhibition. The aim of this study was to determine pK a values of previously synthesized β-hydroxy-β-arylalkanoic acids.…”

Lipophilicity determination of β-hydroxy-β-arilalkanoic acids by reversed phase liquid chromatography under high pressure

“…Prvenstveno se primenjuju reverzno fazne hromatografske metode: RP-HPLC i RP-TLC. β-hidroksi-β-arilalkanske kiseline su prethodno sintetisane i procenjena je njihova antiinflmatorna aktivnost (12)(13)(14). Ispitan je uticaj nekih strukturnih modifikacija na aktivnost i selektivnost prema inhibiciji COX-2 izoforme.…”