Farghaly Thoraya A, Rehman Wajid, Khan Yousaf, Sarfraz Hina
Chemistry Department, Faculty of Science, Umm Al-Qura University, Makkah, Saudi Arabia.
Department of Chemistry, Hazara University Mansehra, Pakistan.
Bioorg Chem. 2025 Sep;164:108812. doi: 10.1016/j.bioorg.2025.108812. Epub 2025 Jul 29.
This study unveils the rational design and stepwise synthesis of new thiazole-based thiazolidinone Schiff base derivatives (1-15), harnessing 2-amino-5-nitrothiazole as a crucial precursor. These newly synthesized derivatives were structurally characterized through spectroscopic techniques HNMR, CNMR and HREI-MS. Moreover, consider the crucial role of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition in Alzheimer's disease (AD) therapy, the synthesized compounds were evaluated for their cholinergic enzyme inhibitory potential against AChE and BuChE, with Donepezil (IC = 5.10 ± 0.10 μM) as the reference drug. Among all the derivatives, the compounds 2, 3, 5, and 7 has shown the best biological inhibition potency with the values of (IC = 2.98 ± 0.19 and 3.22 ± 0.51 μM), (IC = 2.80 ± 1.23 and 3.11 ± 0.78 μM), (IC = 4.34 ± 0.86 and 5.55 ± 0.91 μM) and (IC = 3.90 ± 1.42 and 3.75 ± 0.98 μM) respectively as compared to the standard drug. Additionally, molecular docking studies were conducted against AChE and BuChE enzymes, with docking validation confirming accuracy via RMSD values of 1.15 Å and 0.19 Å, respectively, indicating reliable binding predictions. Among the screened compounds, compound-5 showed the strongest binding affinity and was further investigated through in-silico techniques. Similarly, density Functional Theory (DFT) analysis revealed that compound-5 had the lowest HOMO-LUMO gap (2.36 eV), indicating high reactivity, while compound-2 exhibited the highest energy gap (3.39 eV), suggesting greater stability. Furthermore, molecular electrostatic potential (MESP) maps supported these findings by highlighting distinct charge distribution patterns. Similarly, ADMET predictions showed that compound-5 possessed favorable drug-like properties, including membrane permeability and optimal lipophilicity. Moreover, toxicity analysis confirmed that all selected compounds were non-carcinogenic, moderately toxic (LD ≥ 1000 mg/kg) and non-cytotoxic, with compound-3 having the highest LD (2604 mg/kg) and lowest toxicity class. None of the compounds were predicted to cross the blood-brain barrier or inhibit major cytochrome P450 enzymes. Hence, these findings highlight the potential of these newly synthesized thiazole-thiazolidinone Schiff base derivatives as promising therapeutic targets for Alzheimer's disease that were contributing to the development of next-generation cholinesterase inhibitors with promising efficacy and selectivity.
本研究揭示了以2-氨基-5-硝基噻唑为关键前体的新型噻唑基噻唑烷酮席夫碱衍生物（1-15）的合理设计与逐步合成。通过HNMR、CNMR和HREI-MS光谱技术对这些新合成的衍生物进行了结构表征。此外，鉴于乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）抑制在阿尔茨海默病（AD）治疗中的关键作用，以多奈哌齐（IC = 5.10±0.10 μM）作为参比药物，对合成的化合物进行了针对AChE和BuChE的胆碱能酶抑制潜力评估。在所有衍生物中，化合物2、3、5和7表现出最佳的生物抑制效力，其值分别为（IC = 2.98±0.19和3.22±0.51 μM）、（IC = 2.80±1.23和3.11±0.78 μM）、（IC = 4.34±0.86和5.55±0.91 μM）以及（IC = 3.90±1.42和3.75±0.98 μM），与标准药物相比。此外，针对AChE和BuChE酶进行了分子对接研究，对接验证通过分别为1.15 Å和0.19 Å的RMSD值证实了准确性，表明结合预测可靠。在筛选出的化合物中，化合物5表现出最强的结合亲和力，并通过计算机模拟技术进行了进一步研究。同样，密度泛函理论（DFT）分析表明，化合物5具有最低的HOMO-LUMO能隙（2.36 eV），表明其具有高反应活性，而化合物2表现出最高的能隙（3.39 eV），表明其具有更高的稳定性。此外，分子静电势（MESP）图通过突出不同的电荷分布模式支持了这些发现。同样，ADMET预测表明化合物5具有良好的类药物性质，包括膜通透性和最佳的亲脂性。此外，毒性分析证实所有选定的化合物均无致癌性、中度毒性（LD≥1000 mg/kg）且无细胞毒性，化合物3的LD最高（2604 mg/kg）且毒性类别最低。没有化合物被预测会穿过血脑屏障或抑制主要的细胞色素P450酶。因此，这些发现突出了这些新合成的噻唑-噻唑烷酮席夫碱衍生物作为阿尔茨海默病有前景的治疗靶点的潜力，有助于开发具有有前景的疗效和选择性的下一代胆碱酯酶抑制剂。
