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

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.

Ultrasound for Drug Synthesis: A Green Approach

“…The combination involving ultrasound as an activation method and IL as a solvent/catalyst was also reported for the synthesis of compounds presenting antibacterial and antifungal activities. New pyridinium ILs with hydrozones tethering fluorinated counter anions were also prepared under ultrasound, showing novel inhibitors of fungal ergosterol biosynthesis [84]. The origin of this antifungal activity could be explained by the binding of the ILs to membrane ergosterol, leading to pore creation in fungal cell membranes, and then to the loss of intracellular content.…”

“…Here, even if the exact role of IL and US was not demonstrated, the effect on yield and reaction time was shown, and the existence of a stabilization effect should be explored (Scheme 15).Pharmaceuticals 2020, 13,23 15 of Four-component condensation for the synthesis of spiro-oxindole derivatives. Adapted from Sing et al[84].…”

Novel Dipyridinium Lipophile-Based Ionic Liquids Tethering Hydrazone Linkage: Design, Synthesis and Antitumorigenic Study

“…As part of our ongoing progress in the field of potent ionic liquid frameworks bearing pyridine-hydrazone [ 16 , 17 , 18 , 19 ], these features have significantly improved our structural and functional expertise. Thus, we attempt in the present work to provide the design, synthesis and characterization of an array of dicationic pyridinium hydrazone incorporating long alkyl side chains.…”

Synthesis, Characterization, DNA Binding, Anticancer, and Molecular Docking Studies of Novel Imidazolium-Based Ionic Liquids with Fluorinated Phenylacetamide Tethers

“…In addition, several studies have been devoted to the use of ILs as antitumor agents against several human cancer cells such as breast, brain, colon, lung, liver, osteosarcomas, leukemia, and prostate . In view of encouraging observations and as a continuation of our interest in the development of novel functionalized bioactive ionic liquids, − we have anticipated the synthesis of novel imidazolium-ionic liquids carrying fluorinated phenylacetamide. The synthesized ILs were tested with DNA binding and screened for their anticancer activities.…”