A series of novel pyrazino [2,1-a] isoquinolin compounds were designed and synthesized, and their antifungal activities in vitro were evaluated. All these compounds had potent antifungal activity against five pathogenic fungi. Compounds 5h, 5j～5l, 6g～6k, and 6l showed comparable or stronger inhibitory activities against nearly all the test fungi except Candida albicans than that of fluconazole. In particular, the most compounds exhibited activities with broad antifungal spectrum, and showed potent activities against Aspergillus fumigatus, which is not inhibited effectively by fluconazole. Moreover, the mode of action of the pyrazino [2,1-a] isoquinolin molecules showed that the affinity of the lead molecules for CYP51 was mainly attributed to their nonbonding interaction with the residues of apoprotein but without binding with the heme. These pyrazino [2,1-a] isoquinolin provided lead compounds for the development of antifungal drugs. The studies presented here provide a new structural type for the development of novel antifungal agents.

Key words: antifungal, lanosterol 14α-demethylase inhibitor, pyrazino [2,1-a] isoquinolin