In search of more effective antifungal agents, twenty-two new fluconazole derivatives containing 4-methyl phenol and thymine have been designed and synthesized based on the previous results of computer-aided drug design. All the derivatives retain the essential pharmacophore of fluconazole. Their structures are elucidated by ¹H NMR, elemental analysis and ESI-MS. Preliminary in vitro antifungal activities bioassay showed that compound 5l exhibits better in vitro antifungal activities against eight fungi except Aspergillus fumigatus (7544) than fluconazole, compounds 5a～5e, 5g, 5h, 7a and 7b show only moderate in vitro antifungal activities against different fungus. The introduction of propargyl group to nitrogen atom can enhance in vitro antifungal activities of this type derivative and it is worth of further research.

Key words: fluconazole, derivative, synthesis, design, in vitro antifungal activity