Bisacridine derivatives as effective eukaryotic topoisomerase II inhibitors

Fungal infections, particularly those caused by Candida species, pose a growing clinical challenge due to the increasing resistance to conventional antifungal agents and, in general, the limited arsenal of such drugs. In this study, we synthesized and tested a series of novel derivatives of bisacridines as potential antifungal compounds targeting fungal topoisomerase II. These compounds were evaluated for their ability to inhibit yeast topoisomerase II, their antifungal activity, and their selectivity over the human enzyme. Enzymatic assays confirmed that among them, compound IKE16 exhibited a high level of yeast topoisomerase II inhibition with greater selectivity over its human counterpart, as well as a moderate antifungal activity in vitro. Based on in silico approaches, we propose mechanism for this behavior. In particular, molecular docking studies revealed that our compounds exhibit specific "non etoposide-like" type of yeast topoisomerase II inhibition. Moreover, in case of the human enzyme, the compounds are less accommodated to the potential binding sites than in the yeast counterpart. In consequence it may lead to their lower activity against human topoisomerase II. These findings highlight bisacridines as a potential new class of antifungal agents with a novel mechanism of action.