Najri Bassam A, Saidi Katia Mohand, Guendouzi Abdelmadjid, Khelili Smail, Kivrak Arif
Department of Chemistry, Faculty of Sciences, Eskisehir Osmangazi University, Eskisehir, Turkey.
Laboratory of Phytochemistry and Pharmacology, Team of Pharmaceutical Chemistry and Drug Ruality Control, Faculty of Exact Sciences and Informatics, University of Jijel, Jijel, Algeria.
Chem Biodivers. 2025 Jul 21:e00895. doi: 10.1002/cbdv.202500895.
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.
本研究采用体内和计算机模拟方法探索碘苯并呋喃衍生物的抗炎潜力。所测试的五种衍生物（2a - e）显示出高活性，尤其是化合物2b和2c，它们具有强烈的抗炎活性，超过了参考药物双氯芬酸（DCF）。计算机模拟分析为该研究提供了支持，包括ADMET（吸收、分布、代谢、排泄和毒性）分析、分子对接、分子动力学模拟和密度泛函理论（DFT）。这些计算结果与实验结果一致，为碘苯并呋喃与环氧化酶 - 1（COX - 1）和COX - 2的相互作用提供了见解。ADMET分析证实了所有化合物具有良好的药代动力学性质。分子对接显示，COX - 1的结合能在 - 8.37至 - 10.94 kJ/mol之间，COX - 2的结合能在 - 8.08至 - 9.67 kJ/mol之间，而DCF的结合能分别为 - 7.69和 - 5.84 kJ/mol。分子动力学模拟支持了化合物 - 蛋白质复合物的稳定性。DFT结果进一步证实了这些衍生物的潜力，表明其具有良好的电子性质，如最佳的最高占据分子轨道（HOMO） - 最低未占据分子轨道（LUMO）能隙，这反映了化合物的稳定性和反应性，并表明与靶蛋白有强烈相互作用。使用角叉菜胶诱导的水肿模型在4小时内评估体内抗炎活性。试验结果表明，化合物2b和2c表现出比DCF更高的抑制率，特别是在早期阶段（30 - 90分钟）。这种优势一直持续到240分钟。此外，这些目标化合物没有酸性基团是一个额外的优势，表明它们将不会有大多数非甾体抗炎药通常伴随的胃肠道刺激性副作用。通过整合实验和计算方法，这项工作全面评估了碘苯并呋喃，突出了它们作为慢性炎症疾病有效且更安全治疗剂的潜力。进一步的研究应涉及更多系列的衍生物，并以实验药代动力学研究为支撑。
