Abstract
Our study aimed to characterise the action mode of N-phenacyldibromobenzimidazoles against C. albicans and C. neoformans. 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 C. albicans vs. 4,6-dibromobenzimidazole analogues (5e–f and 5h). The substitution of chlorine atoms to the benzene ring of the N-phenacyl substituent extended the anti-C. albicans action (5e with 2,4-Cl2 or 5f with 3,4-Cl2). The excellent results for N-phenacyldibromobenzimidazole 5h against the C. albicans reference and clinical isolate showed IC50 = 8 µg/mL and %I = 100 ± 3, respectively. Compound 5h was fungicidal against the C. neoformans isolate. Compound 5h at 160–4 µg/mL caused irreversible damage of the fungal cell membrane and accidental cell death (ACD). We reported on chitinolytic activity of 5h, in accordance with the patterns observed for the following substrates: 4-nitrophenyl-N-acetyl-β-d-glucosaminide and 4-nitrophenyl-β-d-N,N′,N″-triacetylchitothiose. Derivative 5h at 16 µg/mL: (1) it affected cell wall by inducing β-d-glucanase, (2) it caused morphological distortions and (3) osmotic instability in the C. albicans biofilm-treated. Compound 5h exerted Candida-dependent inhibition of virulence factors.
Highlights
Published: 8 September 2021Studies conducted during the past two decades have documented changes in the causative agents of nosocomial blood stream infections, and emphasized an increase of very critical fungal infections, due to Candida spp. and Cryptococcus spp. [1].The emergence of antifungal resistance required more concern to find out effective antimycotics with novel modes of action
We evaluated the toxicity of various N-phenacyldibromobenzimidazoles towards a mammalian cell line as well as the fungistatic and fungicidal effect against the C. albicans and Cryptococcus neoformans reference and clinical isolates resistant to azoles and echinocandins
Antifungal structure–activity relationships showed that the group of 5,6-dibromobenzimidazole derivatives are less active against C. albicans vs. 4,6-dibromobenzimidazole analogues (Table 2 and Figures S1–S12)
Summary
Studies conducted during the past two decades have documented changes in the causative agents of nosocomial blood stream infections, and emphasized an increase of very critical fungal infections, due to Candida spp. and Cryptococcus spp. The emergence of antifungal resistance required more concern to find out effective antimycotics with novel modes of action. Introduction of N-phenacyldibromobenzimidazoles as another antimycotics destroying the fungal cell wall and membrane may be a milestone in the development of antifungal therapies. Treatment with anti-filamentation compound benefits the host by modulating immune responses [1]. An inhibition of morphological switch may provide an alternative approach to finding compounds with a potential to control the Candida albicans infections [2]. Morphogenesis is critical for biofilm formation, compounds able to inhibit sessile growth are needed [3]
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