Tabular and image data of article "Morphing cholinesterase inhibitor amiridine into multipotent drugs for the treatment of Alzheimer's disease"

The search for novel drugs to address the medical needs of Alzheimer’s disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology morecomprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties to generate novel MTDLs endowed with additional properties like N-methyl-D-aspartate (NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridinebased drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy. Table 1. hBChE inhibitory activities of 5c-d, 7c and 7 g and reference compounds (amiridine hydrochloride and THA); their cytotoxicity profile on SH-SY5Y cell line, and predictions of BBB penetration. Table 2. Relative inhibitions (RIs) of 5c-d and 7 m and reference compound memantine at recombinant human GluN1/GluN2B NMDA receptor expressed in HEK293 cells. Fig_1. Chemical structures of rivastigmine, galantamine, and tacrine as representatives of cholinesterase inhibitors. Approaches to novel drugs for AD treatment on the selected candidates are displayed. Fig_2. Examples of previously published amiridine-based derivatives and design strategy applied in the current study below, using various pharmacophores. Fig_3. Top scored docking pose of 5b (A) and 5d (B) highlighting the key findings responsible for compound activity/inactivity. For the sake of clarity, superimposed ligands are aligned in the Fig. C with respect to key amino acid residue W82 to demonstrate the binding difference. Compounds 5b and 5d are colored in salmon and yellow, respectively. Essential amino acid residues responsible for ligand anchoring are rendered in green. Important interactions of different origin are displayed with dashed black lines. The figure was created with The PyMOL Molecular Graphics System, v. 2.5.2. Scheme 1. Preparation of the amiridine-based compounds 5a-d. Reagents and conditions: a) 2-chloroacetyl chloride (4 eq.), CHCl3, 90 ◦C, overnight, 8, 54%, 11, 90%, 12, 52%; b) CH3CN, K2CO3, KI, reflux, 3 h, 5a, 54%, 5b, 54%; c) amiridine (1.1 eq), CH3CN, K2CO3, KI, reflux, overnight, 5c, 48%, 5d, 41%. Scheme 2. Preparation of intermediate 13 and final compound 6. Reagents and conditions: a) potassium phthalimide, CH3CN, reflux, 3 h, then an excess of NH2NH2⋅H2O, reflux, overnight, 57%; b) DMF, TEA, BOP, room temperature, 2 days, 86%. Scheme 3. Preparation of amiridine-benzothiazole derivatives 7a-m. Reagents and conditions: a) for 7a: 2-chlorobenzothiazole, 110 ◦C, overnight, 32%; for 7b-m: corresponding 2-chlorobenzothiazole, DIPEA, 100 ◦C, overnight, 21–77%.针对阿尔茨海默病（Alzheimer’s Disease, AD）的新型药物研发始终是一项持续推进的研究工作，其核心依赖于疾病修饰剂的发现。鉴于该疾病的复杂性，可通过开发所谓的多靶点定向配体（Multi-Target Directed Ligands, MTDLs）来实现这一研发目标，这类配体能够更全面地干预疾病的病理生理过程。据此，我们将作为胆碱酯酶抑制剂的阿米瑞汀（amiridine）药物转化为新型MTDLs类别，以此探究其治疗功效。通过连接策略，我们将阿米瑞汀作为核心构建模块，分别与美金刚/金刚烷胺、托洛克斯（trolox）以及取代苯并噻唑（benzothiazole）基团结合，从而生成兼具N-甲基-D-天冬氨酸（N-methyl-D-aspartate, NMDA）受体亲和力、抗氧化能力以及抗淀粉样蛋白特性的新型MTDLs。我们还通过计算机模拟实验对排名靠前的基于阿米瑞汀的化合物5d进行了分析，以揭示其与结构近似的类似物5b在丁酰胆碱酯酶结合模式上的差异。本研究为新型阿米瑞汀类药物的研发提供了新思路，将其靶点参与谱从胆碱酯酶抑制剂拓展至多靶点定向配体，为阿尔茨海默病治疗带来潜在应用价值。 表1. 化合物5c-d、7c、7g及参比化合物（盐酸阿米瑞汀与他克林（THA））的人源丁酰胆碱酯酶（hBChE）抑制活性；它们在SH-SY5Y细胞系上的细胞毒性谱，以及血脑屏障（BBB）穿透性预测结果。 表2. 化合物5c-d、7m及参比化合物美金刚在HEK293细胞中表达的重组人源GluN1/GluN2B N-甲基-D-天冬氨酸受体上的相对抑制率（RIs）。 图1. 作为胆碱酯酶抑制剂代表的利伐斯的明、加兰他敏与他克林的化学结构。同时呈现了针对本研究所选候选化合物的阿尔茨海默病治疗新药研发策略。 图2. 已发表的基于阿米瑞汀的衍生物示例，以及本研究中采用的、基于多种药效团的设计策略。 图3. 化合物5b（A）与5d（B）的最高得分对接构象，突出了决定化合物活性/非活性的关键特征。为清晰起见，在图C中，配体以关键氨基酸残基W82为基准进行叠加，以展示二者的结合差异。化合物5b与5d分别以鲑鱼色与黄色标注。负责配体锚定的关键氨基酸残基以绿色渲染。不同类型的重要相互作用以黑色虚线表示。本图使用PyMOL分子图形系统v.2.5.2制作。 方案1. 基于阿米瑞汀的化合物5a-d的制备方法。试剂与条件：a) 2-氯乙酰氯（4 eq.），三氯甲烷（CHCl3），90 ℃，过夜反应，得到中间体8（产率54%）、11（产率90%）、12（产率52%）；b) 乙腈（CH3CN），碳酸钾（K2CO3），碘化钾（KI），回流反应3 h，得到5a（产率54%）、5b（产率54%）；c) 阿米瑞汀（1.1 eq.），乙腈（CH3CN），碳酸钾（K2CO3），碘化钾（KI），回流过夜反应，得到5c（产率48%）、5d（产率41%）。 方案2. 中间体13与终产物6的制备方法。试剂与条件：a) 邻苯二甲酰亚胺钾，乙腈（CH3CN），回流反应3 h，随后加入过量水合肼（NH2NH2·H2O），回流过夜反应，总产率57%；b) N,N-二甲基甲酰胺（DMF），三乙胺（TEA），苯并三氮唑-1-基氧基三（二甲氨基）磷鎓六氟磷酸盐（BOP），室温反应2 d，产率86%。 方案3. 阿米瑞汀-苯并噻唑衍生物7a-m的制备方法。试剂与条件：a) 针对7a：2-氯苯并噻唑，110 ℃，过夜反应，产率32%；针对7b-m：相应的2-氯苯并噻唑，N,N-二异丙基乙胺（DIPEA），100 ℃，过夜反应，产率21%~77%。