Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2018-11-13 , DOI: 10.1016/j.bioorg.2018.11.010 Naeimeh Salehi , Bi Bi Fatemeh Mirjalili , Hamid Nadri , Zahra Abdolahi , Hamid Forootanfar , Alireza Samzadeh-Kermani , Tuba Tüylü Küçükkılınç , Beyza Ayazgok , Saeed Emami , Ismaeil Haririan , Mohammad Sharifzadeh , Alireza Foroumadi , Mehdi Khoobi
A novel series of benzylpyridinium-based benzoheterocycles (benzimidazole, benzoxazole or benzothiazole) were designed as potent acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. The title compounds 4a-q were conveniently synthesized via condensation reaction of 1,2-phenylenediamine, 2-aminophenol or 2-aminothiophenol with pyridin-4-carbalehyde, followed by N-benzylation using various benzyl halides. The results of in vitro biological assays revealed that most of them, especially 4c and 4g, had potent anticholinesterase activity comparable or more potent than reference drug, donepezil. The kinetic study demonstrated that the representative compound 4c inhibits AChE in competitive manner. According to the ligand-enzyme docking simulation, compound 4c occupied the active site at the vicinity of catalytic triad. The compounds 4c and 4g were found to be inhibitors of Aβ self-aggregation as well as AChE-induced Aβ aggregation. Meanwhile, these compounds could significantly protect PC12 cells against H2O2-induced injury and showed no toxicity against HepG2 cells. As multi-targeted structures, compounds 4c and 4g could be considered as promising candidate for further lead developments to treat Alzheimer’s disease.
中文翻译:
新的基于N-苄基吡啶鎓的苯并杂环化合物作为潜在的抗阿尔茨海默氏病药物的合成和生物学评估
设计了一系列新的基于苄基吡啶鎓的苯并杂环化合物(苯并咪唑,苯并恶唑或苯并噻唑)作为有效的乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BuChE)抑制剂。通过1,2-苯二胺,2-氨基苯酚或2-氨基硫代苯酚与吡啶-4-甲醛的缩合反应,然后使用各种苄基卤化物进行N-苄基化,可以方便地合成标题化合物4a-q。体外生物学分析的结果表明,它们中的大多数,特别是4c和4g,具有比参考药物多奈哌齐有效或更强的抗胆碱酯酶活性。动力学研究表明,代表性的化合物4c以竞争性方式抑制AChE。根据配体-酶对接模拟,化合物4c占据了催化三联体附近的活性位点。发现化合物4c和4g是Aβ自聚集以及AChE诱导的Aβ聚集的抑制剂。同时,这些化合物可以显着保护PC12细胞免受H 2 O 2诱导的损伤,并且对HepG2细胞没有毒性。作为多靶点结构,化合物4c和4g可以被视为治疗阿尔茨海默氏病的进一步先导药物的有前途的候选物。