新型1,2,4-三唑联喹唑啉类衍生物的设计、合成及抗菌活性研究

Quinazoline compounds possess excellent bioactivities, such as antimicrobial,insecticidal,antiviral and antitumor activities et al. Moreover, 1,2,4-triazole heterocyclic compounds are found to be important systemic fungicides with unique mechanism of action, which can effectivly protect the human and crops from harm caused by lots of fungi. In this program, we plan to introduce the 1,2,4-triazole ring functionalized with various pharmacophores into different positions of quinazoline backbone to synthesize five kinds of novel 1,2,4-triazole-quinazoline compounds, measure their antimicrobial activities and examine their structure-activity relationships (SAR). Additionally, antimicrobial mechanism of high-activity compounds will be investigated in detail. Based on these good lead compounds and research results of SAR, further structural modification will be made in order to screen out new candidate antimicrobial agents possessing higher activity, broader antimicrobial spectrum and better safety.

喹唑啉类化合物具有优良的生物活性，在农药和医药等领域有着广泛的应用，如杀菌、杀虫、抗病毒和抗肿瘤等。1,2,4-三唑类杂环化合物是重要的内吸性杀菌剂且具有独特的杀菌机制，对临床和农业上的许多致病菌均有良好的防治效果。本课题拟把不同药效团修饰的1,2,4-三唑环引入到喹唑啉骨架的不同位置上，合成五类结构新颖的1,2,4-三唑联喹唑啉类化合物，测试这些化合物对常见致病菌的抑制活性并考察其构效关系，研究高活性化合物的抗菌机理；以高活性化合物作为先导化合物，结合构效关系的研究结果对其作进一步的结构优化，期望能找到活性更高、杀菌谱更广和安全性更好的新型候选杀菌剂。

本研究项目以具有良好生物活性的喹唑啉(或喹唑啉酮)为核心骨架，通过组合优化法将硫代乙酰胺修饰的1,2,4-三唑基哌啶基、1,2,4-三唑并[3,4-b]1,3,4-噻二唑、1,2,4-三唑基苯乙烯基、7-氧-1,2,4-三唑[1,5-a]嘧啶、1,2,4-三唑基硫醚、1,2,4-三唑曼尼希碱、1,2,4-三唑席夫碱或1,2,4-三唑酰腙等活性片段巧妙地引入到上述骨架中，设计合成了140个结构新颖的喹唑啉(酮)类化合物。这些化合物结构经核磁共振氢谱、核磁共振碳谱、红外光谱和高分辨质谱等进行表征，部分化合物的结构进一步由单晶X射线衍射加以确认。体外抗菌活性测试表明，部分化合物对受试菌害(植物致病细菌和致病真菌)表现出较商品化药剂更好的抑制能力。根据获得的抗菌初筛实验结果或EC50值大小，我们探讨了每类化合物的分子结构与其抗菌活性之间的相互关系。总之，本课题的研究表明1,2,4-三唑-喹唑啉类杂合物具有可开发为高效农用杀细菌剂的潜力，值得进一步的研究。