Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

Cholinesterase enzymes are important targets for the therapy of Alzheimer’s disease. Tacrine-based dual binding site cholinesterases inhibitors are potential disease-modifying anti-Alzheimer drug candidates. In the present work, we described the synthesis of a series of chiral homo- and heterodimers of bis(7)-tacrine connected by a heptylene chain as a spacer with the methyl substituent at the C-3 position of the alicyclic region of tacrine nucleus and/or a chlorine atom attached to the C-6. Friedländer cyclocondensation between (R) or (S) 3-methylcyclohexanone prepared from monoterpene pulegone and o-aminobenzoic acids in the presence of POCl3 afford 9-chloroacridines as intermediates, which were used to the synthesis of homo- and heterodimers. All compounds demonstrated to be potent inhibitors of acetylcholinesterase (AChE) at low nanomolar concentration and showed selectivity for AChE over butyrylcholinesterase (BuChE). Furthermore, the affinity difference between enantiomeric bis(7)-tacrine analogues series indicated some degree of stereoselectivity in the active site of AChE for chiral bis-cognitin compounds.胆碱酯酶（cholinesterase）是阿尔茨海默病治疗的关键靶点。基于他克林（tacrine）的双结合位点胆碱酯酶抑制剂是一类具有潜力的疾病修饰型抗阿尔茨海默病候选药物。本研究报道了一系列双(7)-他克林（bis(7)-tacrine）的手性同二聚体与异二聚体的合成路线：该类化合物以庚烯链作为连接臂，在他克林母核的脂环区域C-3位引入甲基取代基，或在C-6位连接氯原子，或同时具备上述两种修饰。以单萜胡薄荷酮（pulegone）制备得到的(R)或(S)-3-甲基环己酮，与邻氨基苯甲酸类化合物在三氯氧磷（POCl₃）存在下发生弗里德兰德（Friedländer）缩合反应，生成作为关键中间体的9-氯吖啶类化合物，后续利用该中间体完成同二聚体与异二聚体的合成。所有测试化合物均在低纳摩尔浓度下展现出强效的乙酰胆碱酯酶（AChE）抑制活性，且相较于丁酰胆碱酯酶（BuChE），对AChE表现出优异的选择性。此外，对映体双(7)-他克林类似物系列间的亲和力差异表明，乙酰胆碱酯酶活性位点对手性双靶点化合物存在一定程度的立体选择性。