Al-Karmalawy Ahmed A, Mohamed Ahmed F, Shalaby Heba Nasr, Elmaaty Ayman Abo, El-Shiekh Riham A, Zeidan Mohamed A, Alnajjar Radwan, Alzahrani Abdullah Yahya Abdullah, Al Mughram Mohammed H, Shaldam Moataz A, Tawfik Haytham O
Department of Pharmaceutical Chemistry, College of Pharmacy, The University of Mashreq Baghdad 10023 Iraq.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt New Damietta 34518 Egypt
RSC Med Chem. 2025 Feb 13. doi: 10.1039/d4md00778f.
Alzheimer's disease (AD) stands as one of the most outstanding progressive neurodegenerative disorders. Obviously, acetylcholine esterase (AChE) is the primary enzyme responsible for breaking down acetylcholine (ACh) with a much more prominent effect than butyrylcholine esterase (BuChE). Hence, novel quinazoline derivatives (3a-p) were designed and synthesized as AChE inhibitors for AD treatment. The newly synthesized quinazoline derivatives (3a-p) were pursued for their inhibitory potential towards both AChE and BuChE. Notably, compound 3e displayed the highest inhibitory potential towards AChE (IC = 9.26 nM) surpassing donepezil (IC = 16.43 nM). On the other side, compound 3e effectively negated the decline in memory acquisition and retention instigated by ICV administration of streptozotocin (STZ) in mice, an effect that was comparable to that produced by donepezil. Moreover, compound 3e, reduced BACE1 by 51.08% ( < 0.0001), Aβ42 by 52.47% ( < 0.0001), and p(Ser199)-tau by 69.16% ( < 0.0001) compared to STZ mice. Such effects were similar to those of donepezil which reduced all 3 parameters by 57.53%, 58.5%, and 66.78%, respectively, compared to STZ mice. Furthermore, molecular docking studies showed that the superimposition view clarified the similar binding mode of both 3e and the co-crystallized donepezil at the AChE binding pocket. Moreover, the docked complexes (3e-AChE and 3e-BuChE) were further subject to molecular dynamics simulations for 100 ns. In addition, eligible pharmacokinetic profiles as well as feasible BBB penetration were anticipated for compound 3e using ADME and BBB permeation prediction studies. Accordingly, the synthesized compounds, in particular compound 3e, can be treated as promising lead compounds for AD treatment with future further optimization.
阿尔茨海默病（AD）是最典型的进行性神经退行性疾病之一。显然，乙酰胆碱酯酶（AChE）是负责分解乙酰胆碱（ACh）的主要酶，其作用比丁酰胆碱酯酶（BuChE）更为显著。因此，设计并合成了新型喹唑啉衍生物（3a - p）作为治疗AD的AChE抑制剂。对新合成的喹唑啉衍生物（3a - p）进行了对AChE和BuChE的抑制潜力研究。值得注意的是，化合物3e对AChE显示出最高的抑制潜力（IC = 9.26 nM），超过多奈哌齐（IC = 16.43 nM）。另一方面，化合物3e有效抵消了小鼠脑室内注射链脲佐菌素（STZ）引起的记忆获取和保留能力下降，其效果与多奈哌齐相当。此外，与STZ处理的小鼠相比，化合物3e使β - 分泌酶1（BACE1）降低了51.08%（< 0.0001），β - 淀粉样蛋白42（Aβ42）降低了52.47%（< 0.0001），磷酸化（Ser199） - 微管相关蛋白tau（p(Ser199)-tau）降低了69.16%（< 0.0001）。这些效果与多奈哌齐相似，与STZ处理的小鼠相比，多奈哌齐分别使这三个参数降低了57.53%、58.5%和66.78%。此外，分子对接研究表明，叠加视图阐明了3e和共结晶的多奈哌齐在AChE结合口袋的相似结合模式。此外，对接复合物（3e - AChE和3e - BuChE）进一步进行了100 ns的分子动力学模拟。另外，使用药物代谢动力学（ADME）和血脑屏障（BBB）渗透预测研究预测了化合物3e符合要求的药代动力学特征以及可行的BBB穿透性。因此，合成的化合物，特别是化合物3e，可被视为治疗AD的有前景的先导化合物，有待未来进一步优化。
