Fenamates and ibuprofen as foundational components in the synthesis of innovative, targeted COX-2 anti-inflammatory drugs, undergoing thorough biopharmacological assessments and in-silico computational studies

[Display omitted] •Fenamates and ibuprofen were used for synthesis of novel anti- inflammatory drugs.•7b, c and 12a, b showed potent selective COX-2 inhibition in contrast to reference drugs.•7c exhibited potent in vivo activity by reducing the thickness of paw swelling.•7c demonstrated promising analgesic properties in the hot plate latency test.•7c revealed no significant adverse effects on liver and kidney functions.•potent compound 7c was further introduced for in silico studies. Cyclooxygenase-2 plays a vital role in inflammation by catalyzing arachidonic acid conversion toward prostaglandins, making it a prime therapeutic objective. Selective COX-2 inhibitors represent significant progress in anti-inflammatory therapy, offering improved efficacy and fewer side effects. This study describes the synthesis of novel anti-inflammatory compounds from established pharmaceutically marketed agents like fenamates III-V and ibuprofen VI. Through rigorous in vitro testing, compounds 7b-c, and 12a-b demonstrated substantial in vitro selective inhibition, with IC50 values of 0.07 to 0.09 μM, indicating potent pharmacological activity. In vivo assessment, particularly focusing on compound 7c, revealed significant anti-inflammatory effects. Markedly, it demonstrated the highest inhibition of paw thickness (58.62 %) at the 5-hr mark compared to the carrageenan group, indicating its potency in mitigating inflammation. Furthermore, it exhibited a rapid onset of action, with a 54.88 % inhibition observed at the 1-hr mark. Subsequent comprehensive evaluations encompassing analgesic efficacy, histological characteristics, and toxicological properties indicated that compound 7c did not induce gastric ulcers, in contrast to the ulcerogenic tendency associated with mefenamic acid. Moreover, compound 7c underwent additional investigations through in silico methodologies such as molecular modelling, field alignment, and density functional theory. These analyses underscored the therapeutic potential and safety profile of this novel compound, warranting further exploration and development in the realm of pharmaceutical research.