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.
Highlights
Cyclooxygenase (COX), known as prostaglandin endoperoxide synthase, is a bifunctional enzyme that catalyzes the conversion of arachidonic acid to prostaglandin (PG) H2, the immediate precursor to prostaglandins, thromboxane and prostacyclin
PGH2 proceeds through two separate reactions in which two molecules of O2 are incorporated into arachidonic acid bound in the COX site to form PGG2, which diffuses to the peroxidase site (POX) to undergo a two-electron reduction to form the final product PGH2
Results and Discussion β-Hydroxy-β-aryl propanoic acids were synthesized by the two-step reaction
Summary
Cyclooxygenase (COX), known as prostaglandin endoperoxide synthase, is a bifunctional enzyme that catalyzes the conversion of arachidonic acid to prostaglandin (PG) H2, the immediate precursor to prostaglandins, thromboxane and prostacyclin. COX-1 Is formed in many different cells to create prostaglandins that serve for basic "housekeeping" messages throughout the body. This is a constitutively expressed protein that is responsible for the physiological production of prostaglandins. Since selective COX-2 inhibitors fail to inhibit constitutive COX-1 isoform, they have no gastrointestinal adverse effects. We have synthesized six β-hydroxy-β-aryl propanoic acids having none, one, or two methyl groups at the α-position. These acids are structurally similar to COX inhibitors: p-isobutylphenyl acetic acid (ibufenac), 4-biphenylacetic acid (felbinac), α-(4-isobutylphenyl)propanoic acid (ibuprofen), α-(6-methoxy-2-naphtyl)propanoic acid (naproxen). 2. Results and Discussion β-Hydroxy-β-aryl propanoic acids were synthesized by the two-step reaction.
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