Pharmacological evaluation of novel dimers of an arylpropionic acid class of non-selective cyclooxygenase inhibitors

Purpose: To explore and identify cyclooxygenase (COX) inhibitors with optimal potency and efficacy using an arylpropionic acid class of drugs as lead molecules. Methods: The selected lead molecules were dimerised through chemical processes (reflux condensation) and characterised in terms of structural properties using infrared, proton nuclear magnetic resonance, electron impact mass spectrometry, and elemental analysis techniques. The molecules were evaluated pharmacologically for acute toxicity and anti-inflammatory (carrageenan-induced paw oedema test), analgesic (acetic acid-induced writhing test in mice), and antipyretic (Brewer's yeast-induced pyrexia test in mice) activities against control (normal saline) and relevant reference standard drugs. Docking analyses were also performed to assess possible protein-ligand interactions. Results: The test compounds were non-toxic at doses of 50, 100 and 150 mg/kg body weight, ip. Pharmacological evaluation revealed that the test compounds, TC-I through TC-IV, had significant anti-inflammatory and peripheral analgesic activities (p < 0.001). An antipyretic test showed that TC-I, -II, and -III showed highly significant antipyretic activities at all doses tested. TC-IV at 20 and 30 mg/kg body weight exhibited significant antipyretic activities (p < 0.05), while at 50 mg/kg body weight, the activity was highly significant (p < 0.001). Molecular modelling revealed strong inhibitory interactions with docking scores of 116.2, 128.8, 144.2, and 136.0 kcal/mol, respectively, in comparison with the reference ligand, flurbiprofen (94.9 kcal/mol). Conclusion: The dimerised lead drug molecules showed significant anti-inflammatory, analgesic, and antipyretic activities in animals and may further be explored as potential new drug candidates for inflammatory conditions.