Novel tetralin compounds were designed and synthesized on the three-dimensional model of lanosterol 14α-demethylase of Candida albicans. All of the lead compounds exhibited potent antifungal activities, especially compounds 16, 20. The mode of the action of the lead compounds was different from that of azoles. The present study affords the possibility to develop novel antifungal agents that specifically interact with the amino acid residues in the active site and avoid the serious toxicity arising from coordination binding with the heme of mammalian P450s. Novel tetralin compounds were designed and synthesized on the three-dimensional model of lanosterol 14α-demethylase of Candida albicans. All of the lead compounds show potent antifungal activities, especially compounds 16, 20. The mode of the action of the lead compounds was different from that of azoles. The present study affords the possibility to develop novel antifungal agents that specifically interact with the amino acid residues in the active site and avoid the serious toxicity arising from coordination binding with the heme of mammalian P450s.