Synthesis and Pharmacological Evaluation of New Chemical Entities Based on Paracetamol and Their Ibuprofen Conjugates as Novel and Superior Analgesic and Anti-Inflammatory Candidates

Abstract

p-Aminophenol had been evaluated in the past as an analgesic–antipyretic drug, but its N-acetylated derivative acetaminophen (paracetamol) was found to be the most suitable therapeutically. Acetaminophen is still one of the most popular drugs, which is frequently used for the relief of acute and chronic pain. In this study, new analogs of paracetamol with dimethyl and ethyl substitutions in the phenyl moiety and sulfonamide, which was modified by inserting morpholine, were synthesized (compounds 4 and 5). Then, their conjugated compounds with ibuprofen (6) were synthesized (8 and 9) and the analgesic and anti-inflammatory activities of these new drugs (4, 5, 8, 9) were evaluated in formalin-induced edema test (as a model of acute and chronic chemical pain and also paw edema inflammation) on rats. The results were compared to paracetamol, ibuprofen (as standards), and control (saline) groups. Results showed that the new synthesized derivatives exhibit higher analgesic and anti-inflammatory effects compared to acetaminophen alone for compounds 4, 5, 8 and 9 or ibuprofen for compounds 4, 8 and 9. Moreover, it was concluded that chemical-structural binding of the potent synthesized drugs (4 and 5) with ibuprofen (6) produced new superior anti-nociceptive and anti-inflammatory drugs (8 and 9).