喹唑酮咪唑类化合物的设计、合成及其抗菌活性与靶向DNA研究

Design and synthesis of quinazolinone imidazoles and their antibacterial and DNA-targeting investigation

多药耐药菌的频繁出现已日益严重威胁人类健康,开发结构新型的抗菌药物已成为全世界战胜耐药菌的重要课题.本文设计合成了一系列具有抗微生物潜力的酰腙桥链的喹唑酮咪唑类新化合物,其结构经核磁共振氢谱(~1H NMR)、核磁共振碳谱(^(13)C NMR)和高分辨质谱(HRMS)进行表征.生物活性研究发现,一些目标化合物具有较好的抗微生物活性,特别是十八烷基衍生物6h和4-氟苄基取代的化合物7i,抗痢疾杆菌和大肠杆菌DH52的活性是氯霉素的2.5~3.3倍,抗黄曲霉菌活性是临床药物氟康唑的28和8.4倍.用紫外-可见光谱法进行了高活性化合物7i靶向DNA的初步研究,发现咪唑衍生物7i可嵌入小牛胸腺DNA形成7i-DNA超分子络合物,从而阻断DNA复制,展现出较好的抗细菌活性.分子模拟研究表明,活性分子7i与DNA碱基通过氢键结合.该类化合物作为新型抗真菌黄曲霉菌专一特效药及新型抗细菌药值得深入研究.

The rising emergence of multidrug-resistant bacteria is becoming an increasingly serious threat to human health, therefore the development of structurally novel drugs has been an important topic worldwide to overcome drug-resistant strains. In this work, a series of novel acylhydrazone-bridged quinazolinone imidazoles were designed, synthesized and characterized by ~H NMR, ~3C NMR and HRMS spectra. Bioactive assays showed that some target compounds exhibited significant antimicrobial potency. Especially, octadecyl derivative 6h and 4-fluorobenzyl derivative 7i showed 2.5~3.3 folds stronger activities against bacteria S. dysenteriae and E. coli DH52 than chloramphenicol, and 28 as well as 8.4 times higher efficacies toward fungus A. flavus than clinical drug fluconazole. The DNA-targeting preliminary exploration of highly active compound 7i by UV-Vis spectroscopy revealed that imidazole derivative 7i could intercalate into calf thymus DNA to form 7i-DNA supramolecular complex and thus block DNA replication to exert powerful antibacterial activities. Molecular docking study displayed that the active molecule 7i could form hydrogen bond with DNA base. This class of compounds as new type of specific anti-A, flavus and antibacterial drugs were worthy of being deeply investigated.