Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Giza, Egypt.
Department of Therapeutic Chemistry, National Research Centre, Giza, Egypt.
Arch Pharm (Weinheim). 2024 Jan;357(1):e2300201. doi: 10.1002/ardp.202300201. Epub 2023 Nov 8.
Dementia is a cognitive disturbance that is generally correlated with central nervous system diseases, especially Alzheimer's disease. The limited number of medications available is insufficient to improve the lifestyle of the patients suffering from this disease. Thus, new benzimidazole-thiazole hybrids (3-10) were designed and synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory agents. The in vitro evaluation displayed that the derivatives 4b, 4d, 5b, 6a, 7a, and 8b demonstrated dual inhibitory efficiency against both AChE with IC ranging from 4.55 to 8.62 µM and BChE with IC ranging from 3.50 to 8.32 µM. By analyzing the Lineweaver-Burk plot, an uncompetitive form of inhibition was determined for the highly active compound 4d, revealing its inhibition type. The human telomerase reverse transcriptase-immortalized retinal pigment epithelial cell line was used to ensure the safety of the most potent cholinesterase inhibitors. Furthermore, compounds 4b, 4d, 5b, 6a, 7a, and 8b were evaluated for their neuroprotective and antioxidant properties, as well as their ability to suppress COX-2. The results demonstrated that compounds 4d, 5b, and 8b presented significant neuroprotection efficiency against H O -induced damage in SH-SY5Y cells with % cell viability of 67.42 ± 7.90%, 62.51 ± 6.71%, and 72.61 ± 8.10%, respectively, while the tested candidates did not reveal significant antioxidant activity. Otherwise, compounds 4b, 6a, 7a, and 8b displayed outstanding COX-2 inhibition effects with IC ranging from 0.050 to 0.080 μM relative to celecoxib (IC = 0.050 µM). In addition, molecular docking was carried out for the potent benzimidazole-thiazole hybrids with the active sites of both AChE (PDB ID: 4EY7) and BChE (PDB code: 1P0P). The tested candidates fit well in the active sites of both portions, with docking scores ranging from -8.65 to -6.64 kcal/mol (for AChE) and -8.71 to -7.73 kcal/mol (for BChE). In silico results show that the synthesized benzimidazole-thiazole hybrids have good physicochemical and pharmacokinetic properties with no Lipinski rule violations. The preceding results exhibited that compound 4d could be used as a new template for developing more significant cholinesterase inhibitors in the future.
痴呆症是一种与中枢神经系统疾病相关的认知障碍，特别是阿尔茨海默病。现有的治疗药物数量有限，无法有效改善此类患者的生活质量。因此，我们设计并合成了新的苯并咪唑噻唑类化合物（3-10）作为乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）抑制剂。体外评估显示，衍生物 4b、4d、5b、6a、7a 和 8b 对 AChE 具有双重抑制作用，IC50 范围为 4.55-8.62 μM，对 BChE 具有抑制作用，IC50 范围为 3.50-8.32 μM。通过分析 Lineweaver-Burk 图，确定了高活性化合物 4d 对 AChE 的抑制类型为非竞争性抑制，揭示了其抑制类型。我们使用人端粒酶逆转录酶永生化视网膜色素上皮细胞系来确保最有效的胆碱酯酶抑制剂的安全性。此外，我们还评估了化合物 4b、4d、5b、6a、7a 和 8b 的神经保护和抗氧化特性，以及抑制 COX-2 的能力。结果表明，化合物 4d、5b 和 8b 对 H2O2 诱导的 SH-SY5Y 细胞损伤具有显著的神经保护作用，细胞活力分别为 67.42%±7.90%、62.51%±6.71%和 72.61%±8.10%，而测试候选物没有显示出显著的抗氧化活性。此外，化合物 4b、6a、7a 和 8b 对 COX-2 的抑制作用较强，IC50 范围为 0.050-0.080 μM，与塞来昔布（IC50=0.050 μM）相当。此外，我们对具有活性的苯并咪唑噻唑类化合物与 AChE（PDB ID：4EY7）和 BChE（PDB 代码：1P0P）的活性部位进行了分子对接。测试的候选化合物与两个部分的活性部位都很好地结合，对接评分范围为-8.65 到-6.64 kcal/mol（用于 AChE）和-8.71 到-7.73 kcal/mol（用于 BChE）。基于计算机的结果表明，合成的苯并咪唑噻唑类化合物具有良好的理化和药代动力学性质，不违反 Lipinski 规则。上述结果表明，化合物 4d 可作为未来开发更有效的胆碱酯酶抑制剂的新模板。
