The Antifungal Action Mode of <i>N</i>-Phenacyldibromobenzimidazoles

• Main Authors: Monika Staniszewska, Łukasz Kuryk, Aleksander Gryciuk, Joanna Kawalec, Marta Rogalska, Joanna Baran, Anna Kowalkowska
• Format: Article
• Language: English
• Published: MDPI AG 2021-09-01
• Series: Molecules
• Subjects: <i>N</i>-phenacyldibromobenzimidazoles; <i>Candida</i> spp.; <i>Cryptococcus neoformans</i>; action mode
• Online Access: https://www.mdpi.com/1420-3049/26/18/5463

Our study aimed to characterise the action mode of <i>N</i>-phenacyldibromobenzimidazoles against <i>C. albicans</i> and <i>C. neoformans</i>. Firstly, we selected the non-cytotoxic most active benzimidazoles based on the structure–activity relationships showing that the group of 5,6-dibromobenzimidazole derivatives are less active against <i>C. albicans</i> vs. 4,6-dibromobenzimidazole analogues (<b>5e</b>–<b>f</b> and <b>5h</b>). The substitution of chlorine atoms to the benzene ring of the <i>N</i>-phenacyl substituent extended the anti-<i>C. albicans</i> action (<b>5e</b> with 2,4-Cl₂ or <b>5f</b> with 3,4-Cl₂). The excellent results for <i>N</i>-phenacyldibromobenzimidazole <b>5h</b> against the <i>C. albicans</i> reference and clinical isolate showed IC₅₀ = 8 µg/mL and %I = 100 ± 3, respectively. Compound <b>5h</b> was fungicidal against the <i>C. neoformans</i> isolate. Compound <b>5h</b> at 160–4 µg/mL caused irreversible damage of the fungal cell membrane and accidental cell death (ACD). We reported on chitinolytic activity of <b>5h</b>, in accordance with the patterns observed for the following substrates: 4-nitrophenyl-<i>N</i>-acetyl-β-<span style="font-variant: small-caps;">d</span>-glucosaminide and 4-nitrophenyl-β-<span style="font-variant: small-caps;">d</span>-<i>N</i>,<i>N</i>′,<i>N</i>″-triacetylchitothiose. Derivative <b>5h</b> at 16 µg/mL: (1) it affected cell wall by inducing β-<span style="font-variant: small-caps;">d</span>-glucanase, (2) it caused morphological distortions and (3) osmotic instability in the <i>C. albicans</i> biofilm-treated. Compound <b>5h</b> exerted <i>Candida</i>-dependent inhibition of virulence factors.