新型BuChE-IDO1双靶标抑制剂的设计、合成及其抗阿尔茨海默症活性研究

Alzheimer 's disease (AD) is a complicated disease that threaten the social medical care system. So far there is no therapy that meet the requirement of clinical use to cure AD. Therefore, it is imperative to develop new therapeutic strategy and effective drugs. Based on the “old drug new use” strategy and “multi-target-directed ligands” strategy, the applicant and collaborators found that, miconazole, an old drug as anti-fungi agent, and its analogs (5i, 5j), have potent inhibitory activity on both butyrylcholinesterase (BuChE) and indoleamine-2,3 dioxygenase 1 (IDO1). Besides, the in vivo study showed that 5i and 5j can obviously ameliorate the cognitive impairment without displaying any hepatotoxicity. In this project, several series of 5i and 5j derivatives will be designed via rational drug design strategy, followed by in vitro and in vivo biological evaluation. Based on this strategy, we anticipate to discover new BuChE-IDO1 dual-target inhibitors with high in vitro and in vivo potency, as well as good safety. Additionally, we will select the preferred compound as a template molecule, and use computational-based methods including establishment of characterized model and virtual screening and biological evaluations to discover BuChE-IDO1 dual-target inhibitor hits with new chemical scaffolds.

阿尔茨海默症（AD）是当今社会医疗事业上的一项难题，其病因复杂，至今尚未有令人满意的药物疗法，发现全新的治疗策略并据此发展针对性药物具有重要的研究价值。申请人与合作者前期基于“老药新用”策略以及“多靶向配体”策略，首次发现抗真菌药物咪康唑及其衍生物5i，5j作为有效的丁酰胆碱酯酶（BuChE）-吲哚-2，3双加氧酶1（IDO1）双靶标抑制剂，在动物水平能够明显改善认知障碍且没有显示肝毒性。本项目拟在先导化合物5i，5j的结构基础上，开展合理药物设计及活性评价，以期获得结构新颖，体内外活性优良，具有良好成药性及安全性的BuChE-IDO1双靶标抑制剂。同时，以优选化合物为模板，构建表征模型并开展虚拟筛选，骨架融合，活性评价等工作，以期发现具有全新结构的BuChE-IDO1双靶标抑制剂苗头化合物，为进一步拓展本项目的研究打下基础。

阿尔茨海默症（Alzheimer's disease, AD）是当今社会医疗事业上的一项难题，发现全新的治疗策略并据此发展针对性药物具有重要的研究价值。在前期研究基础上，本项目围绕先导化合物5j的结构，基于结合模式预测结果，有针对性的开展了咪唑类丁酰胆碱酯酶（BuChE）-吲哚-2,3-双加氧酶1（IDO1）双靶标抑制剂的构效关系研究工作，设计合成了45个化合物，获得了初步的构效关系信息。对体外活性与靶标选择性表现较好的化合物，进一步在细胞水平与动物水平对其开展了活性以及安全性方面的研究，获得了体内外活性优良，具有良好成药性及安全性的BuChE-IDO1双靶标抑制剂1个。本项目还采用分子动力学方法，对优选化合物与靶标的分子结合机制进行了研究。最后，通过虚拟筛选发现潜在新型BuChE-IDO1双靶标抑制剂8个。