Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini St, Cairo, 11562, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini St, Cairo, 11562, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt.
Eur J Med Chem. 2019 Nov 15;182:111651. doi: 10.1016/j.ejmech.2019.111651. Epub 2019 Aug 28.
Twenty four 6-aminocoumarin based derivatives were synthesized according to two schemes. All the compounds were screened for their acetylcholinesterase inhibitory activity where compound 5b proved to be the most potent AChE inhibitor with (IC = 37 nM) compared to tacrine and donepezil (IC = 55.0 and 59.0 nM, respectively). Six compounds 2f, 2g, 4b, 5b, 8b and 9b revealed superior activity over donepezil and a conclusive structure activity relationship study was conducted explaining the obtained results. Furthermore, compounds 2f, 4b and 5b were investigated for their neurobehavioral effect in vivo. All the tested compounds showed improvement of neurobehavioral experiments using donepezil as reference drug. In addition, compounds 2f, 4b and 5b were able to reduce extracellular deposition of amyloid beta 42 in a comparable manner to donepezil. The binding modes of the synthesized compounds were evaluated in silico via molecular docking in the active site of AChE, as well as molecular dynamics simulation study. A pharmacophore model was generated for the newly synthesized compounds.
根据两个方案合成了 24 种 6-氨基香豆素类衍生物。所有化合物均进行了乙酰胆碱酯酶抑制活性筛选，其中化合物 5b 的抑制活性最强，IC50 值为 37 nM，与他克林和多奈哌齐（IC50 值分别为 55.0 和 59.0 nM）相比。6 种化合物 2f、2g、4b、5b、8b 和 9b 的活性优于多奈哌齐，进行了明确的构效关系研究，解释了所得结果。此外，还研究了化合物 2f、4b 和 5b 在体内的神经行为效应。所有测试的化合物均显示出与多奈哌齐作为参考药物相比，神经行为实验得到改善。此外，化合物 2f、4b 和 5b 能够以与多奈哌齐相当的方式减少细胞外淀粉样蛋白β42 的沉积。通过在 AChE 的活性部位进行分子对接以及分子动力学模拟研究，对合成化合物进行了计算机模拟评估。为新合成的化合物生成了药效团模型。
