Khalfaoui Massaab, Frites Wahiba, Mermer Arif, Kisa Dursun, Yildirim Buket, Chouiter Mohamed I, Silva Artur M S, Boulebd Houssem
Laboratory of Polymeric Materials (LPM), Faculty of Chemistry, U.S.T.H.B., BP 32 El-Alia, Algiers, 16111, Algeria.
Laboratory of Applied Organic Chemistry (LCOA), Faculty of Chemistry, USTHB, BP 32 EL-Alia, Bab-Ezzouar, Algiers, 16111, Algeria.
Eur J Med Chem. 2025 Nov 5;297:117927. doi: 10.1016/j.ejmech.2025.117927. Epub 2025 Jul 3.
A series of new hybrid styrylchromone (3a-3h) molecules incorporating imidazole and chromone nuclei were synthesized and characterized. A Diels-Alder cycloaddition reaction was performed on these compounds, leading to the formation of a new series of tricyclic molecules (4a-4h). The evaluation of their biological activity revealed that the cyclization of the styrylchromones significantly enhances their bioactive potential, in particular their inhibitory capacity towards acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase enzymes. Among the tested compounds, derivative 4c exhibited the most promising inhibitory activity against both AChE (3.93 μM) and α-glucosidase (9.61 μM), with an efficacy comparable to or even exceeding that of the standard inhibitors tacrine and acarbose. This compound also showed remarkable inhibition of BChE enzyme with an IC of 9.41 μM. Furthermore, derivative 4a was identified as the most potent inhibitor of this enzyme, displaying an activity approximately two times greater than that of tacrine (IC 10.01 vs 22.30 nM). In silico studies, including molecular docking and DFT calculations, were conducted to better understand the interaction modes between the synthesized molecules and their target enzymes, as well as the reaction mechanism underlying their synthesis. Overall, the results of this study highlight the therapeutic potential of the synthesized compounds, particularly the cyclized derivatives.
合成并表征了一系列包含咪唑和色酮核的新型杂化苯乙烯基色酮（3a - 3h）分子。对这些化合物进行了狄尔斯 - 阿尔德环加成反应，生成了一系列新的三环分子（4a - 4h）。对其生物活性的评估表明，苯乙烯基色酮的环化显著增强了它们的生物活性潜力，特别是对乙酰胆碱酯酶（AChE）、丁酰胆碱酯酶（BChE）和α - 葡萄糖苷酶的抑制能力。在测试的化合物中，衍生物4c对AChE（3.93 μM）和α - 葡萄糖苷酶（9.61 μM）均表现出最有前景的抑制活性，其效果与标准抑制剂他克林和阿卡波糖相当甚至超过它们。该化合物对BChE酶也表现出显著抑制作用，IC为9.41 μM。此外，衍生物4a被确定为该酶的最有效抑制剂，其活性比他克林高约两倍（IC分别为10.01和22.30 nM）。进行了包括分子对接和密度泛函理论计算在内的计算机模拟研究，以更好地理解合成分子与其靶酶之间的相互作用模式以及它们合成的反应机制。总体而言，本研究结果突出了合成化合物，特别是环化衍生物的治疗潜力。
