Evaluation of the Anti‐Inflammatory Activity of Iodo Benzofuran Derivatives: In Vivo and In Silico Studies

This study explores the anti-inflammatory potential of iodobenzofuran derivatives using both in vivo and in silico approaches. The five derivatives tested (2a-e) revealed high activity, particularly compounds 2b and 2c, which had vigorous anti-inflammatory activity, surpassing the reference drug, diclofenac (DCF). In silico analyses supported the study, including ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling, molecular docking, molecular dynamics simulations, and density functional theory (DFT). These computational results aligned with experimental outcomes, providing insights into the interactions of iodobenzofurans with cyclooxygenase-1 (COX-1) and COX-2. The ADMET analysis confirmed favorable pharmacokinetic properties for all compounds. Molecular docking revealed binding energies between -8.37 and -10.94 kJ/mol for COX-1 and between -8.08 and -9.67 kJ/mol for COX-2, compared to -7.69 and -5.84 kJ/mol, respectively, for DCF. Molecular dynamics simulations supported the stability of the compound-protein complexes. The DFT results further confirmed the potential of the derivatives, indicating favorable electronic properties such as optimal highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gaps, which reflect the stability and reactivity of the compounds, and suggest strong interactions with the target proteins. The in vivo anti-inflammatory activity was evaluated using the carrageenan-induced edema model over a period of 4 h. Results from the assay demonstrated that compounds 2b and 2c exhibited higher inhibition rates than DCF, particularly at the early phase (30-90 min). This superiority was kept until 240 min. Furthermore, the absence of an acidic group is an additional advantage for these target compounds, indicating they will lack gastrointestinal irritant side effects typically associated with most non-steroidal anti-inflammatory agents. By integrating experimental and computational methodologies, this work comprehensively assesses iodobenzofurans, highlighting their potential as effective and safer therapeutic agents for chronic inflammatory diseases. Further investigations should involve a larger series of derivatives and be backed by experimental pharmacokinetic studies.