Synthesis, Characterization, Biological Evaluations, and Computational Analysis of Some 6‐Methoxy‐2,3‐Dihydro‐1H‐Inden‐1‐One Derivatives for Analgesic and Anti‐inflammatory Activity

ABSTRACT Traditional treatments for inflammation, like nonsteroidal anti‐inflammatory drugs (NSAIDs), come with serious side effects, motivating the need for new and safer alternatives. In this study, a series of novel 6‐methoxy‐2,3‐dihydro‐1H‐inden‐1‐one derivatives were synthesized, characterized, and evaluated for their anti‐inflammatory activity. The compounds were designed to enhance their pharmacological effects by modifying their chemical structure. Their synthesis was confirmed through several spectroscopic techniques, including NMR and mass spectrometry. To assess their biological activity, both in vivo and in silico methods were employed. The synthesized compounds were tested for their ability to reduce inflammation using the carrageenan‐induced rat paw edema model. Among the synthesized derivatives, compounds D8 and E8 demonstrated the highest anti‐inflammatory effects. Compound D8 exhibited a significant inhibition of paw edema at 3 h, with a reduction of 65%, while E8 showed 54% inhibition at the same time point. The standard drug indomethacin (20 mg/kg) resulted in a 72% inhibition of paw edema. In terms of analgesic activity, compound D8 displayed a pain response latency increase of 10.11 ± 0.27 s, showing 56.68% inhibition, which was comparable to morphine (5 mg/kg), with a pain response latency of 13.12 ± 0.79 s and 84.17% inhibition. Molecular docking studies revealed that these compounds interacted strongly with orphan nuclear receptor ROR (gamma), an important target for anti‐inflammatory activity, with binding energies ranging from −9.55 to −10.97 kcal/mol. These findings provide valuable insights into the structure–activity relationships of indene derivatives and suggest that further optimization of these compounds could lead to the development of effective anti‐inflammatory drugs with fewer side effects compared to current treatments.