Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA.
Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia 4072, Queensland, Australia.
Bioorg Chem. 2018 Oct;80:245-252. doi: 10.1016/j.bioorg.2018.06.031. Epub 2018 Jun 25.
Multi-target-directed ligands (MTDLs) centered on β-secretase 1 (BACE-1) inhibition are emerging as innovative therapeutics in addressing the complexity of neurodegenerative diseases. A new series of donepezil analogues was designed, synthesized and evaluated as MTDLs against neurodegenerative diseases. Profiling of donepezil, a potent acetylcholinesterase (hAChE) inhibitor, into BACE-1 inhibition was achieved through introduction of backbone amide linkers to the designed compounds which are capable of hydrogen-bonding with BACE-1 catalytic site. In vitro assays and molecular modeling studies revealed the dual mode of action of compounds 4-6 against hAChE and BACE-1. Notably, compound 4 displayed potent hAChE inhibition (IC value of 4.11 nM) and BACE-1 inhibition (IC value of 18.3 nM) in comparison to donepezil (IC values of 6.21 and 194 nM against hAChE and BACE-1, respectively). Moreover, 4 revealed potential metal chelating property, low toxicity on SH-SY5Y neuroblastoma cells and ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay which renders 4 a potential lead for further optimization of novel small ligands for the treatment of Alzheimer's disease.
以β-分泌酶 1（BACE-1）抑制为中心的多靶点定向配体（MTDL）作为治疗神经退行性疾病复杂性的创新疗法正在出现。设计、合成并评价了一系列新的多奈哌齐类似物作为针对神经退行性疾病的 MTDL。通过在设计的化合物中引入与 BACE-1 催化位点形成氢键的骨架酰胺键，将具有强大乙酰胆碱酯酶（hAChE）抑制作用的多奈哌齐进行了 BACE-1 抑制作用的研究。体外测定和分子模拟研究揭示了化合物 4-6 对 hAChE 和 BACE-1 的双重作用模式。值得注意的是，与多奈哌齐（hAChE 和 BACE-1 的 IC 值分别为 6.21 和 194 nM）相比，化合物 4 对 hAChE 具有更强的抑制作用（IC 值为 4.11 nM）和 BACE-1 抑制作用（IC 值为 18.3 nM）。此外，4 还显示出潜在的金属螯合特性、对 SH-SY5Y 神经母细胞瘤细胞的低毒性以及在 PAMPA-BBB 测定中穿过血脑屏障（BBB）的能力，这使得 4 成为进一步优化用于治疗阿尔茨海默病的新型小分子配体的潜在先导化合物。
