槟榔生物碱衍生物的设计合成与体外抗菌活性研究

Design,Synthesis and in vitro Anti-Bacterial Activity of Areca Alkaloids Derivatives

目的:合成新型槟榔生物碱衍生物,并研究体外抗菌活性。方法:以β-酮酰胺和一系列α,β-不饱和醛为原料,基于LUMO活化模式,经过仲胺催化的Michael加成/环化和三甲基硅烷化反应,合成出一系列结构新颖的槟榔生物碱衍生物—哌啶环戊烷螺环化合物;用琼脂平皿二倍稀释法测定新型哌啶螺环化合物的体外抗菌活性。结果:目标化合物结构经HRMS,1H-NMR和13C-NMR确证,立体选择性经HPLC和X-ray确证。体外抗菌活性研究表明,目标化合物均有一定的抑菌作用,其抑菌活性好于哌啶类抗菌天然产物槟榔碱;化合物9b对金黄色葡萄球菌具有最佳抑菌效果,其MIC值达到33.4μg/m L。结论:该新型哌啶环戊烷螺环化合物具有良好的体外抗菌活性,可作为新的抗菌药物先导化合物进行进一步的研究与开发。

Objective： To synthesize a series of new areca alkaloids derivatives and evaluate their anti-bacterial activity. Methods： Fourteen novel areca alkaloids derivatives with cyclopentane and spiro-piperidine units were synthesized by utilizing β-ketoamide and α, β-unsaturated aldehydes as starting materials, subsequently undergoing secondary-amine catalyzed Michael addition based on LUMO catalytic activation mode and trimethylsilane （TMS） reaction. In vitro anti-bacterial activities were assessed with agar double dilution method. Results： The structures of target compounds were characterized by HRMS,1H-NMR and 13 C-NMR, stereoselectivities were characterized by HPLC and X-ray. The results of in vitro anti-bacterial activities showed that all target products have certain anti-bacterial activities which are better than arecoline. Compound 9b exhibited excellent inhibition on staphylococcus aureus with MIC 33.4 μg/mL. Conclusion： The novel areca alkaloids derivatives with cyclopentane and spiro-piperidine units provided a possibility for further research as lead compouds of new antibacterial agents.