Two New Fluorinated Phenol Derivatives Pyridine Schiff Bases: Synthesis, Spectral, Theoretical Characterization, Inclusion in Epichlorohydrin-β-Cyclodextrin Polymer, and Antifungal Effect

Abstract

It has been reported that the structure of the Schiff bases is fundamental for their function in biomedical applications. Pyridine Schiff bases are characterized by the presence of a pyridine and a phenolic ring, connected by an azomethine group. In this case, the nitrogen present in the pyridine is responsible for antifungal effects, where the phenolic ring may be also participating in this bioactivity. In this study, we synthesized two new pyridine Schiff Bases: (E)-2-[(3-Amino-pyridin-4-ylimino)-methyl]-4,6-difluoro-phenol (F1) and (E)- 2-[(3-Amino-pyridin-4-ylimino)-methyl]-6-fluoro-phenol (F2), which only differ in the fluorine substitutions in the phenolic ring. We fully characterized both F1 and F2 by FTIR, UV-vis, 1H; 13C; 19F-NMR, DEPT, HHCOSY, TOCSY, and cyclic voltammetry, as well as by computational studies (DFT), and NBO analysis. In addition, we assessed the antifungal activity of both F1 (two fluorine substitution at positions 4 and 6 in the phenolic ring) and F2 (one fluorine substitution at position 6 in the phenolic ring) against yeasts. We found that only F1 exerted a clear antifungal activity, showing that, for these kind of Schiff bases, the phenolic ring substitutions can modulate biological properties. In addition, we included F1 and F2 into in epichlorohydrin-β-cyclodextrin polymer (βCD), where the Schiff bases remained inside the βCD as determined by the ki, TGA, DSC, and SBET. We found that the inclusion in βCD improved the solubility in aqueous media and the antifungal activity of both F1 and F2, revealing antimicrobial effects normally hidden by the presence of common solvents (e.g., DMSO) with some cellular inhibitory activity. The study of structural prerequisites for antimicrobial activity, and the inclusion in polymers to improve solubility, is important for the design of new drugs.

Structural Characterization, DFT Calculation, NCI, Scan-Rate Analysis and Antifungal Activity against Botrytis cinerea of (E)-2-{[(2-Aminopyridin-2-yl)imino]-methyl}-4,6-di-tert-butylphenol (Pyridine Schiff Base)

“…By contrast, in a more stable IHB, we expect no changes, regardless of the solvent used. This strategy has been previously used to assess the stability of the IHB in other pyridine Schiff bases [ 8 ]. As stated, 1 H-NMR showed the proton from the hydroxyl group involved in the IHB was assigned around 13 ppm in all the deuterated solvents tested ( Figure S2 for acetone- D6 , and Figure S7 for CD 2 Cl 2 in the Supplementary Materials ).…”

“…When L1 and L2 structures are compared, we can observe that the nitrogen in the pyridine ring is more available in L2 than in L1 , providing a possible explanation for the better antifungal effect obtained with L2 against yeasts in comparison with L1 [ 42 ]. In general, it has been proposed that the nitrogen in the pyridine ring might be necessary for the antifungal activity of Schiff bases, remarking the structure-bioactivity relationship [ 7 , 8 , 63 ]. Nevertheless, in this work, we found that L1 exhibits a potent antifungal effect against Botrytis cinerea at 26 °C, even better than the commercial antifungal agent fenhexamid.…”

“…To evaluate antimicrobial activity in bacteria ( Klebsiella pneumoniae ) and yeasts ( Rhodotorula spp. ), we determined the minimal inhibitory concentration, as previously described [ 8 , 9 ].…”

“…CYP51 inhibition, in turn, leads to inhibition of ergosterol biosynthesis in fungi with the concomitant accumulation of toxic metabolites and cell death [ 14 , 15 , 16 ]. In this sense, pyridine Schiff bases have great potential as antifungal agents, as previously described [ 7 , 8 , 9 ].…”

“…Recently, pyridine Schiff bases constituted by a pyridine ring and a phenolic ring connected by an azomethine group were reported. The presence of a pyridine contributes to the antifungal activity in this kind of Schiff bases [ 7 , 8 , 9 ]. At present, the most used antifungal agents include triazoles, which exhibit good antifungal activity and a broad spectrum of action [ 10 , 11 ].…”