Abstract

A small family of novel modular monofunctional epicinchonidine-1,2,3-triazole compounds was prepared in very good overall yield (3 steps from cinchonidine, 49–87% yield) using simple Cu(I) catalyzed click-chemistry. The objective of this study was to access their hitherto unknown catalytic role in some key organic reactions like: ketimine hydrosilylation, Michael-addition and the Biginelli reaction. This is the first report on the application of cinchonidine derived 1,2,3-triazoles in organocatalysis, and includes catalytic screening and preliminary Density Functional Theory (DFT) mechanistic studies. The new compounds were screened for antimalarial activity against Plasmodium falciparum (W2 strain), exhibiting IC₅₀ values in the range 2.0–6.8 µM; and cholinesterase inhibition, showing activity against eqBuChE, but their main potential is for tumor anti-proliferation (showing a lowest GI₅₀ of 8.1 µM). Gratifyingly, all our compounds were non-cytotoxic against the non-tumor healthy cell line, BJ-hTERT and they presented excellent simulated pharmacological properties.

摘要

使用简单的 Cu(I) 催化点击化学以非常好的总收率（从辛可尼丁开始 3 个步骤，收率 49-87%）制备了一小群新型模块化单功能表辛可尼丁-1,2,3-三唑化合物。这项研究的目的是了解它们在一些关键有机反应中迄今为止未知的催化作用，例如：酮亚胺氢化硅烷化、迈克尔加成和 Biginelli 反应。这是关于辛可尼丁衍生的 1,2,3-三唑在有机催化中的应用的第一份报告，包括催化筛选和初步密度泛函理论 (DFT) 机理研究。筛选了新化合物对恶性疟原虫（W2 株）的抗疟活性，IC ₅₀值在 2.0–6.8 µM 范围内；和胆碱酯酶抑制，显示出针对eq BuChE 的活性，但它们的主要潜力是抗肿瘤增殖（显示最低 GI ₅₀为 8.1 µM）。令人欣慰的是，我们所有的化合物对非肿瘤健康细胞系 BJ-hTERT 均无细胞毒性，并且它们具有出色的模拟药理特性。