Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia.
Department of Chemistry, Faculty of Science and Education, University of Mostar, Matice hrvatske bb, 88000 Mostar, Bosnia and Herzegovina.
Int J Mol Sci. 2024 Jul 5;25(13):7401. doi: 10.3390/ijms25137401.
The targeted compounds in this research, resveratrol analogs -, were synthesized as mixtures of isomers by the Wittig reaction using heterocyclic triphenylphosphonium salts and various benzaldehydes. The planned compounds were those possessing the -configuration as the biologically active -resveratrol. The pure isomers were obtained by repeated column chromatography in various isolated yields depending on the heteroaromatic ring. It was found that butyrylcholinesterase (BChE) was more sensitive to the heteroaromatic resveratrol analogs than acetylcholinesterase (AChE), except for , the methylated thiophene derivative with chlorine, which showed equal inhibition toward both enzymes. Compounds and achieved the highest BChE inhibition with IC values of 22.9 and 24.8 μM, respectively. The same as with AChE and BChE, methylated thiophene subunits of resveratrol analogs showed better enzyme inhibition than unmethylated ones. Two antioxidant spectrophotometric methods, DPPH and CUPRAC, were applied to determine the antioxidant potential of new heteroaromatic resveratrol analogs. The molecular docking of these compounds was conducted to visualize the ligand-active site complexes' structure and identify the non-covalent interactions responsible for the complex's stability, which influence the inhibitory potential. As ADME properties are crucial in developing drug product formulations, they have also been addressed in this work. The potential genotoxicity is evaluated by in silico studies for all compounds synthesized.
本研究中的靶向化合物——白藜芦醇类似物，是通过使用杂环三苯基膦盐和各种苯甲醛的 Wittig 反应作为异构体混合物合成的。计划合成的化合物为具有生物活性的 - 白藜芦醇的 - 构型。根据杂芳环的不同，通过反复柱层析可以得到纯异构体，收率也各不相同。结果发现，除了带有氯的甲基噻吩衍生物外，丁酰胆碱酯酶 (BChE) 对杂芳环白藜芦醇类似物比乙酰胆碱酯酶 (AChE) 更为敏感。这两种酶对化合物 和 表现出最高的抑制活性，IC 值分别为 22.9 和 24.8 μM。与 AChE 和 BChE 相同，白藜芦醇类似物的甲基噻吩取代基比未甲基化的噻吩取代基具有更好的酶抑制活性。两种抗氧化分光光度法，DPPH 和 CUPRAC，被应用于测定新的杂芳环白藜芦醇类似物的抗氧化潜力。对这些化合物进行了分子对接，以可视化配体-活性部位复合物的结构，并确定了影响复合物稳定性和抑制潜力的非共价相互作用。由于 ADME 性质在开发药物产品配方中至关重要，因此在这项工作中也进行了研究。所有合成的化合物都通过计算机模拟研究进行了潜在的遗传毒性评估。
