Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Eur J Med Chem. 2017 Oct 20;139:280-289. doi: 10.1016/j.ejmech.2017.07.072. Epub 2017 Jul 31.
A novel series of tacrine-like compounds 7a-u possessing a fused pyrazolo[1,2-b]phthalazine structure were designed and synthesized as potent and selective inhibitors of AChE. The in-vitro biological assessments demonstrated that several compounds had high anti-AChE activity at nano-molar level. The more promising compound 7l with IC of 49 nM was 7-fold more potent than tacrine and unlike tacrine, it was highly selective against AChE over BuChE. The cell-based assays against hepatocytes (HepG2) and neuronal cell line (PC12) revealed that 7l had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against HO-induced damage in PC12 cells. This compound could also inhibit AChE-induced and self-induced Aβ peptide aggregation. The advantages including synthetic accessibility, high potency and selectivity, low toxicity, adjunctive neuroprotective and Aβ aggregation inhibitory activity, make this compound as a new multifunctional lead for Alzheimer's disease drug discovery.
设计并合成了一系列新型的他克林类似物 7a-u，这些化合物具有并合的吡唑并[1,2-b]酞嗪结构，作为强效和选择性的乙酰胆碱酯酶抑制剂。体外生物评估表明，几种化合物在纳摩尔水平具有高的抗乙酰胆碱酯酶活性。具有 IC₅₀为 49 nM 的更有前途的化合物 7l 比他克林的效力高 7 倍，与他克林不同，它对乙酰胆碱酯酶具有高度选择性，而对丁酰胆碱酯酶的选择性较低。对肝细胞（HepG2）和神经元细胞系（PC12）的基于细胞的测定表明，与他克林相比，7l 的肝毒性显著降低，并且对 PC12 细胞中 HO 诱导的损伤具有额外的神经保护活性。该化合物还可以抑制乙酰胆碱酯酶诱导和自身诱导的 Aβ 肽聚集。该化合物具有合成可及性、高活性和选择性、低毒性、辅助神经保护和 Aβ 聚集抑制活性等优点，使其成为阿尔茨海默病药物发现的一种新的多功能先导化合物。
