Department of Chemistry, Biochemistry and Physics, Université du Québec à Trois-Rivières, Trois-Rivières, QC G8Z 4M3, Canada.
Department of Chemistry, Université du Québec à Montréal, Montréal, QC H2L 2C4, Canada.
Molecules. 2024 Sep 19;29(18):4442. doi: 10.3390/molecules29184442.
Norbelladine derivatives have garnered attention in recent years due to their diverse biological activities and pivotal role in the biosynthetic pathway of Amaryllidaceae alkaloids. This study reports the synthesis and biological evaluation of four O,-methylated derivatives of norbelladine. These derivatives were synthesized through a three-step process: forming imine intermediates from benzaldehydes with tyramine, hydrogenating them to secondary amines, and -methylating these amines. The products were purified and characterized by H and C NMR spectroscopy. Their biological activities were assessed by evaluating their ability to inhibit Alzheimer's disease-related enzymes acetylcholinesterase and butyrylcholinesterase. Additionally, the cytotoxic activity of the novel derivatives was tested against cancer cell lines derived from hepatocarcinoma (Huh7), adenocarcinoma (HCT-8), and acute myeloid leukemia (THP-1) cells, and their antiviral properties against a human coronavirus (HCoV-OC43), a flavivirus (dengue virus), and a lentivirus (pseudotyped HIV-1). Docking analysis was performed to understand the impact of the -methylation on their pharmacological relevance. The results indicate that while -methylation does not significantly affect antiviral activity, it enhances butyrylcholinesterase inhibition for -methylnorbelladine and 4'-,-dimethylnorbelladine. Overall, this work enhances our understanding of norbelladine derivatives, provides new tools for Alzheimer's disease research, and lays the groundwork for future pharmaceutical developments.
近年来，贝拉啶衍生物因其多样的生物活性和在石蒜科生物碱生物合成途径中的关键作用而受到关注。本研究报道了四种 O，-甲基化贝拉啶衍生物的合成与生物评价。这些衍生物通过三步法合成：苯甲醛与酪胺形成亚胺中间体，将其氢化得到仲胺，然后对这些胺进行 -甲基化。通过 1 H 和 13 C NMR 光谱对产物进行了纯化和表征。通过评估它们抑制阿尔茨海默病相关酶乙酰胆碱酯酶和丁酰胆碱酯酶的能力来评估其生物活性。此外，还测试了新型衍生物对肝癌（Huh7）、腺癌（HCT-8）和急性髓系白血病（THP-1）细胞系的癌细胞、以及对人类冠状病毒（HCoV-OC43）、黄病毒（登革热病毒）和慢病毒（假型 HIV-1）的抗病毒活性。通过对接分析来理解 -甲基化对其药理相关性的影响。结果表明，-甲基化虽然不会显著影响抗病毒活性，但会增强 -甲基贝拉啶和 4'，-二甲基贝拉啶对丁酰胆碱酯酶的抑制作用。总的来说，这项工作增进了我们对贝拉啶衍生物的理解，为阿尔茨海默病研究提供了新工具，并为未来的药物开发奠定了基础。
