A series of fluconazole (1) analogues, compounds 3a-k, were prepared as potential antifungal agents. They were designed by computational docking experiments to the active site of the cytochrome P450 14alpha-sterol demethylase (CYP51), whose crystal structure is known. Preliminary biological tests showed that most of the target compounds exhibit significant activities against the eight most-common pathogenic fungi. Thereby, the most potent congener, 1-[(4-tert-butylbenzyl)(cyclopropyl)amino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (3j), was found to exhibit a broad antifungal spectrum, being more active against Candida albicans, Candida tropicalis, Cryptococcus neoformans, Microsporum canis, and Trichophyton rubrum (MIC80 < 0.125 microg/ml) than the standard clinical drug itraconazole (2). The observed affinities of the lead molecules towards CYP51 indicate that a cyclopropyl residue enhances binding to the target enzyme. Our results may provide some guidance for the development of novel triazole-based antifungal lead structures.