萘酰亚胺三唑新骨架结构化合物的合成及其抗烟曲霉菌作用

Synthesis of naphthalimide triazoles with a novel structural framework and their anti-Aspergillus fumigatus effects

本文从萘二酸酐出发设计开发了一类结构独特的萘酰亚胺三唑新抗真菌分子.目标化合物结构经波谱证实.抗真菌活性研究表明该系列萘酰亚胺三唑化合物对烟曲霉菌的抑制活性远优于氟康唑,尤其是强活性化合物5j具有快速的抗真菌能力,且对正常细胞的毒性较低和无明显耐药性.进一步的研究表明,5j不仅可以通过嵌入DNA形成生物超分子络合物的方式来阻碍微生物DNA的复制,也能够损伤烟曲霉菌细胞膜和诱导活性氧的生成而影响菌株的存活.此外,其还可以通过四个氢键与烟曲霉菌中甾醇14-α去甲基酶(CYP51B)结合形成生物超分子而影响其酶的功能从而达到抗真菌目的.以上结果显示出该类化合物具备多靶向抗真菌潜力.该系列化合物的药物化学生物学研究揭示出此类萘酰亚胺三唑新骨架结构分子可望作为专门抗烟曲霉菌的特效药而被深入开发.

This work designed and exploited a series of unique naphthalimide triazoles as antifungal molecules starting from naphthalic anhydride. The structures of the target compounds were confirmed by spectra. The antifungal activities showed that these naphthalimide triazoles against A. fumigatus exhibited superior bioactivities to fluconazole, especially the highly active compound 5j showed low toxicity to normal cells, no obvious drug resistance and rapid fungicidal potentiality. Further studies revealed that 5j could not only block the replication of microbial DNA by embedding in DNA to form supramolecular complexes, but also damage the cell membrane and induce ROS generation to affect the survival of fungi. Moreover, 5j could form a biosupramolecule with sterol 14-α demethylase(CYP51B) of A. fumigatus by four hydrogen bonds, and thus affect enzyme function to achieve anti-A. fumigatus purpose. These results revealed that these compounds exhibited multifarious antifungal effect. Therefore, this work implied that naphthalimide triazoles with this novel structural framework could be the potential anti-A. fumigatus drugs.