Synthesis and Physicochemical Characterization of Novel Dicyclopropyl-Thiazole Compounds as Nontoxic and Promising Antifungals.

Anna Biernasiuk,Angelika Baranowska-Łączkowska,Maciej Masłyk,Anna Banasiewicz,Anna Malm,Monika Janeczko,Krzysztof Z Łączkowski,Aleksandra Martyna

doi:10.3390/ma14133500

Abstract

There is a need to search for new antifungals, especially for the treatment of the invasive Candida infections, caused mainly by C. albicans. These infections are steadily increasing at an alarming rate, mostly among immunocompromised patients. The newly synthesized compounds (3a–3k) were characterized by physicochemical parameters and investigated for antimicrobial activity using the microdilution broth method to estimate minimal inhibitory concentration (MIC). Additionally, their antibiofilm activity and mode of action together with the effect on the membrane permeability in C. albicans were investigated. Biofilm biomass and its metabolic activity were quantitatively measured using crystal violet (CV) staining and tetrazolium salt (XTT) reduction assay. The cytotoxic effect on normal human lung fibroblasts and haemolytic effect were also evaluated. The results showed differential activity of the compounds against yeasts (MIC = 0.24–500 µg/mL) and bacteria (MIC = 125–1000 µg/mL). Most compounds possessed strong antifungal activity (MIC = 0.24–7.81 µg/mL). The compounds 3b, 3c and 3e, showed no inhibitory (at 1/2 × MIC) and eradication (at 8 × MIC) effect on C. albicans biofilm. Only slight decrease in the biofilm metabolic activity was observed for compound 3b. Moreover, the studied compounds increased the permeability of the membrane/cell wall of C. albicans and their mode of action may be related to action within the fungal cell wall structure and/or within the cell membrane. It is worth noting that the compounds had no cytotoxicity effect on pulmonary fibroblasts and erythrocytes at concentrations showing anticandidal activity. The present studies in vitro confirm that these derivatives appear to be a very promising group of antifungals for further preclinical studies.

Highlights

In the last years, the prevalence of Candida infections, which range from superficial to deep-seated invasive candidiasis, has increased at an alarming rate, especially among immunocompromised individuals [1,2]
The first step was the reaction of the appropriate dicyclopropyl ketone and thiosemicarbazide in anhydrous ethyl alcohol in the presence of acetic acid as catalyst
Hydrazinecarbothioamide 1 was reacted with the appropriate bromoketones in ethyl alcohol and under reflux to produce target products 3a–3k with good to excellent yields (32–99%)

Summary

Introduction

The prevalence of Candida infections, which range from superficial to deep-seated invasive candidiasis, has increased at an alarming rate, especially among immunocompromised individuals [1,2]. Infections caused by Candida spp. are primarily dependent on the immunological status of the host Both local and systemic risk factors may result in weakened immune functions that mediate Candida colonization on host surfaces. These fungi mostly affect neutropenic patients, individuals with haematological malignancies, older patients, diabetics or individuals pre-exposed to azoles or echinocandins [1,2,3,4,5]. The most common isolated Candida species of clinical significance in fungal invasive infection is Candida albicans It is associated with the occurrence of mortality rates as high as 35–50% [6,7]. The biofilm structure can be observed both on the surfaces of different host tissues and various medical devices (such as central venous catheters, prosthetic heart valves, contact lenses, urinary catheters or dentures)

Methods

Results

Discussion

Conclusion