New antifungal and less toxic zwitterionic derivatives of 26-membered polyene antibiotic – pimaricin containing N-benzyl and N-alkyl moieties and their molecular mechanism

Abstract

Abstract N-derivatives of pimaricin (PIM) were synthesised as zwitterions or in a non-ionic form, influencing water solubility and toxicity in normal cells (HDF). The introduction of benzyl-O-aliphatic (15) and methylene-nitrophenol (7) moieties into the polyene resulted in high and broad-spectrum antifungal activities, even better than known antifungal agents. The promising antifungal potency of 7 is attributed to formation of a 6:1 complexes with ergosterol (ERG) as indicated by ITC, FT-IR and NMR studies. The self-assembly of 6:1 complexes into greater structures of polar channels explains antifungal activity of 7, as suggested by MOG-PM6 calculations. In contrast, fluorobenzyl derivative 3 despite weak antifungal potency, revealed unexpected high anticancer activity in PC-3 and SKOV-3 cells, at improved selectivity (IC50 = 0.6 µM; SI ∼ 3–4) and lower toxicity, compared to PIM. The activity of N-derivatives of PIM towards fungi strains or cancer cells, depending on polar head structure, is discussed.