Synthesis and biological evaluation of hydrazone derivatives as antifungal agents.

Bruna Casanova,Michel Machado,Thayse De Oliveira,Mauro Muniz,Alexandre Fuentefria,Simone Gnoatto,Luís De Oliveira,Grace Gosmann

doi:10.3390/molecules20059229

Bruna Casanova, Michel Machado + Show 6 more

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https://doi.org/10.3390/molecules20059229

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Abstract

Emerging yeasts are among the most prevalent causes of systemic infections with high mortality rates and there is an urgent need to develop specific, effective and non-toxic antifungal agents to respond to this issue. In this study 35 aldehydes, hydrazones and hydrazines were obtained and their antifungal activity was evaluated against Candida species (C. parapsilosis, C. tropicalis, C. krusei, C. albicans, C. glabrata and C. lusitaneae) and Trichosporon asahii, in an in vitro screening. The minimum inhibitory concentrations (MICs) of the active compounds in the screening was determined against 10 clinical isolates of C. parapsilosis and 10 of T. asahii. The compounds 4-pyridin-2-ylbenzaldehyde] (13a) and tert-butyl-(2Z)-2-(3,4,5-trihydroxybenzylidine)hydrazine carboxylate (7b) showed the most promising MIC values in the range of 16–32 μg/mL and 8–16 μg/mL, respectively. The compounds’ action on the stability of the cell membrane and cell wall was evaluated, which suggested the action of the compounds on the fungal cell membrane. Cell viability of leukocytes and an alkaline comet assay were performed to evaluate the cytotoxicity. Compound 13a was not cytotoxic at the active concentrations. These results support the discovery of promising candidates for the development of new antifungal agents.

Highlights

Since the 1980s yeasts have emerged as some of the main agents of nosocomial systemic infections, in immunocompromised people or those who are undergoing intensive chemotherapy [1,2].Approximately two decades ago Candida albicans represented 70%–80% of the clinical isolates from fungaemia cases [3,4], but in the last years this has been changing
Thereby, the emergent pathogenic species associated with the increase of antifungal resistance have become a global problem for the success of the therapy against these microorganisms
Considering the clinical relevance of fungal infections and the broad biological activity demonstrated for hydrazines and hydrazones, this study aimed to synthesize a series of compounds containing these chemical functions and evaluate their antifungal activity against emerging species of C. parapsilosis and

Summary

Introduction

Two decades ago Candida albicans represented 70%–80% of the clinical isolates from fungaemia cases [3,4], but in the last years this has been changing. The most frequent species of non-albicans Candida are C. glabrata, C. parapsilosis and C. tropicalis being the. C. parapsilosis the third most common species in clinical isolates [5,6,7]. Trichosporon is considered the second most common genus cause of fungaemia in patients with hematologic malignant diseases, being besides resistant to amphotericin and echinocandins. Thereby, the emergent pathogenic species associated with the increase of antifungal resistance have become a global problem for the success of the therapy against these microorganisms. Most of the antifungals used in fungaemia cases have several adverse effects and high costs [8]

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