Synthesis And Antifungal Activity Of Novel Triazole Compounds

The incidence of systemic fungal infections has increased substantially over the past few decades, especially in those individuals with immunocompromised hosts, such as patients undergo anticancer chemotherapy or organ transplation and patients with AIDS. Currently, systemic fungal infections are a common cause of morbidity and mortality in patients with haematological malignancies or those undergoing bone marrowt ransplantation. Therefore, there is an emergent need to develop novel antifungal agents with higher eficiency, broader spectrum and lower toxicity.In an effort to search for new potent, less toxic and broad spectrum antimycotics, sixty-seven compounds were designed and synthesized according to the antifungal mechanisms and structure-activity relationships of the triazole antifungals. All the title compounds were first reported. All title compounds were confirmed by element analysis, 1H-NMR, ESI-MS and IR.MICs of all the title compounds were determined by the method recommended by the National Committee for Clinical Laboratory Standards(NCCLS) using RPMI1640 test medium. Eight fungi were used: Candida albicans, Candida parapsilosis, Cryptococcus neoformans, Candida tropicalis, Trichophyton rubrum, Aspergillus fumigatus, Microsporum gypseum and Fonsecaea compacta.The results of preliminary antifungal test showed that all title compounds exhibited potent antifungal activities against eight pathogenic fungi to a certain extent, most of them showed stronger activities against Microsporum gypseum and Candida albicans than those of fluconazole and itraconazole. Compounds A1,A2,A16,A17,B1,B2,B3,B15,B16,B17,C2,C8,C9 exhibited strong antifungal activities against eight test fungi comparable to the control itraconazole except Aspergillus fumigatus. Our research indicated that an cyclopropyl or isopropyl can help to enhance the binding strength towards CYP51, and also showed that a benzyl moiety with a group of shorter length substituted on 4-position is required for high activity. These results may provide some guidance for the development of novel triazole-based antifungal lead structures. Currently, further studies along this line are in progress.