A new 1-nitro-9-aminoacridine derivative targeting yeast topoisomerase II able to overcome fluconazole-resistance

Fungal resistance remains a significant threat and a leading cause of death worldwide. Thus, overcoming microbial infections have again become a serious clinical problem. Although acridine derivatives are widely analyzed as anticancer agents, only a few reports have demonstrated their antifungal activity. In an effort to develop biologically active antifungals, twelve novel C-857 (9-(2'-hydroxyethylamino)-1-nitroacridine) and C-1748 (9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine) derivatives were synthesized. The evaluation of biological properties suggests that starting compounds: C-1748, C-857 and IE3 (2-[(4-methyl-1-nitroacridin-9-yl)amino]ethyl lysinate), IE4 (2-[(1-nitroacridin-9-yl)amino]ethyl lysinate) antifungal mode of action differ from that determined for IE5 (N'-{3-[(4-methyl-1-nitmacridin-9-yl)amino]propyl}lysinamide), IE6 (N'-{3-[(1-nitro-acridin-9-yl)amino]propyl}lysinamide) and IE10 (3,3'-Bis-(1-nitroacridin-9-yl)amino)-amino-ethylaminoethylaminoethylamine). Although MIC values determined for the latter were higher, in contrast to C-857 and C-1748, newly synthesized IE5, IE6 and IE10 reduced C. albicans hyphal growth in different inducing media. Those compounds also exhibited antibiofilm activity, whereas IE10 was the most effective. Moreover, only IE6 exhibited antifungal activity against fluconazole resistant C. albicans strains with MICs values in the range of 16-64 mu g mL(-1). Our results also indicate that, in contrast to other analyzed derivatives, novel synthetized compounds IE6 and IE10 with antifungal activity target yeast topoisomerase II activity.

Automated summary

The study synthesized 12 novel antifungal compounds and found that some of them were effective in inhibiting Candida albicans with different mechanisms compared to other drugs. These newly synthesized compounds also exhibited anti-biofilm activity, with IE10 showing the best performance, and only IE6 showed antifungal activity against fluconazole-resistant C. albicans strains.