Non-azole lead molecules were designed by coupling structure-based de novo design based on the structure of lanosterol 14α-demethylase (CYP51). The chemical synthesis and the evaluation of in vitro antifungal activities of them were reported. The results exhibited that all of the lead compounds showed potent antifungal activities., especially compounds 5f and 5g, which had stronger or equal antifungal activities against 5 test fungi than that of fluconazole. The studies presented here provided the antifungal lead compounds. Because the affinity of the lead molecules for CYP51 was mainly attributed to their nonbonding interaction with the apoprotein, which was different from the azole antifungal agents. The studies presented here afford the opportunity to develop novel antifungal agents that specifically interact with the residues in the active site and avoid the serious toxicity arising from coordination binding with the heme of mammalian P450s.

Key words: lanosterol 14α-demethylase of fungi, inhibitor, design, synthesis, antifungal activity