Green Ultrasound versus Conventional Synthesis and Characterization of Specific Task Pyridinium Ionic Liquid Hydrazones Tethering Fluorinated Counter Anions: Novel Inhibitors of Fungal Ergosterol Biosynthesis.

Nadjet Rezki,Rayees Shiekh,Mouslim Messali,Salsabeel Al-Sodies,Mohamed Aouad,Sheikh Shreaz,Vaseem Raja

doi:10.3390/molecules22111532

Abstract

A series of specific task ionic liquids (ILs) based on a pyridiniumhydrazone scaffold in combination with hexafluorophosphate (PF6−), tetrafluoroboron (BF4−) and/or trifluoroacetate (CF3COO−) counter anion, were designed and characterized by IR, NMR and mass spectrometry. The reactions were conducted under both conventional and green ultrasound procedures. The antifungal potential of the synthesized compounds 2–25 was investigated against 40 strains of Candida (four standard and 36 clinical isolates). Minimum inhibitory concentrations (MIC90) of the synthesized compounds were in the range of 62.5–2000 μg/mL for both standard and oral Candida isolates. MIC90 results showed that the synthesized 1-(2-(4-chlorophenyl)-2-oxoethyl)-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)-pyridin-1-ium hexafluorophosphate (11) was found to be most effective, followed by 4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)-1-(2-(4-nitrophenyl)-2-oxoethyl)-pyridin-1-ium hexafluorophosphate (14) and 1-(2-ethoxy-2-oxoethyl)-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)pyridin-1-ium hexafluorophosphate (8). All the Candida isolates showed marked sensitivity towards the synthesized compounds. Ergosterol content was drastically reduced by more active synthesized compounds, and agreed well with MIC90 values. Confocal scanning laser microscopy (CLSM) results showed that the red colored fluorescent dye enters the test agent treated cells, which confirms cell wall and cell membrane damage. The microscopy results obtained suggested membrane-located targets for the action of these synthesized compounds. It appears that the test compounds might be interacting with ergosterol in the fungal cell membranes, decreasing the membrane ergosterol content and ultimately leading to membrane disruption as visible in confocal results. The present study indicates that these synthesized compounds show significant antifungal activity against Candida which forms the basis to carry out further in vivo experiments before their clinical use.

Highlights

Candida species are pleomorphic diploid organisms existing within the normal microflora of skin, oral cavity and gastrointestinal tract [1]
In view of the promising bioactivity associated with the presence of fluorine substitution in organic molecules, we present here another significant synthetic contribution which aimed to preserve the basic structural skeleton of pyridinium hydrazone and fluorinated counter anions of lead compounds by changing the alkyl chain on the pyridine ring to a functionalized alkyl group
The preparationand andstructure structureof of fluorinated fluorinated pyridinium pyridinium hydrazones alkyl side chains encountered with three fluorinated anions are illustrated in

Summary

Introduction

Candida species are pleomorphic diploid organisms existing within the normal microflora of skin, oral cavity and gastrointestinal tract [1]. Infections due to Candida species are the leading cause of hematogenous infections worldwide [5]. It is well-known that most of the available antifungal drugs like azoles, allylamines and morpholines target ergosterol in the fungal cell membranes or inhibit the ergosterol biosynthetic pathway. Most of these antifungals, like amphotericin B and some commonly used azoles, are linked to severe toxicity issues [6,7], and in addition, most of the emerging fungal strains have developed resistance to the present antifungal agents [8,9]

Methods

Discussion

Conclusion