奥莫康唑类似物的设计合成及其抗真菌活性研究

Design,synthesis and antifungal activity of omoconazole analogues

目的合成系列硝酸奥莫康唑的类似物并测试其体外抗真菌活性。方法以2-溴丙酰溴和取代苯为起始原料,经Friedel-Crafts酰化、N-烷基化、烯醇化、醚化等反应制得目标化合物。以氟康唑和奥莫康唑为阳性对照药,采用二倍浓度稀释法测试目标化合物对热带假丝酵母菌、白色念株菌、新生隐球菌格特变种、烟曲霉菌、耐氟康唑白色念珠菌100、103、SC5314的体外抗真菌活性。结果与结论合成18个目标化合物,其中17个是未见文献报道的新化合物,其结构经HRMS、~1H-NMR谱确证;活性测试结果表明,多个目标化合物对测试真菌表现出一定的体外抑菌活性。

The incidence of fungal infections has increased dramatically in recent years. Oxiconazole nitrate is azole antifungal agent by inhibiting 14ot-demethylase（ CYP51 ）. It has antifungal activity on Candida albi- cans, Trichophyton mentagrophytes and Gram-positive bacteria, used for the treatment of superficial fungal infections. In order to explore the SAR of oxiconazole, a series of omoconazole analogues were designed and synthesized form 1,3-substituted benzene and 2-bromo-propionyl bromide via Friedel-Crafts acylation, N- alkylation and etherification. Totally 18 omoconazole analogues were obtained and their structures were confirmed by HRMS and 1H-NMR. The antifungal activities of target compounds were tested in vitro against 7 kinds of clinical fungis, Candida tropicalis, Canidia albicans, Cryptococcus neoformans, Aspergillus fumigates, Fluconazole-resistant Canidia albican stainl00, stainl03, stain SC5314 with fluconazole and omoconazole as control drugs by using two-fold dilution method. The preliminary results showed that most compounds had antifungal activities in different levels.