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.
Highlights
Invasive fungal diseases are associated with high mortality and morbidity, especially in immunocompromised patients (Edmond et al, 1999; Minari et al, 2002)
We found that neither F1 nor (E)- 2-[(3Amino-pyridin-4-ylimino)-methyl]-6-fluoro-phenol (F2) exerted an antifungal effect against a clinical, fluconazoleresistant strain of C. albicans (Table 5), suggesting that the mechanisms involved in fluconazole resistance could be participating in the F1 resistance
The results obtained with F1 included into βCD (βF1) and F2 included into βCD (βF2) show that the inclusion in β-cyclodextrin polymer (βCD) can reveal antimicrobial effects normally hidden by the presence of solvents with some inhibitory activity, such as dimethyl sulfoxide (DMSO)
Summary
Invasive fungal diseases are associated with high mortality and morbidity, especially in immunocompromised patients (Edmond et al, 1999; Minari et al, 2002). Complicated fungal infections are often produced by Candida albicans and Cryptococcus spp., two unicellular fungi (i.e., yeasts; Boral et al, 2017). Triazoles works by inhibiting the lanosterol 14α-demethylase, a member of the CYP51 class of cytochrome P450 enzymes involved in ergosterol biosynthesis in fungi (Lepesheva and Waterman, 2011; Sagatova et al, 2015). Inhibition of 14α-demethylase leads to the depletion of ergosterol (affecting membrane fluidity) and accumulation of toxic metabolites (e.g., 14α-methyl-3,6-diol; Watson et al, 1989). Some other nitrogen-containing heteroaromatic compounds (e.g., pyridine), have been reported to inhibit CYP51 enzymes by direct coordination of nitrogen with the heme iron (type II ligands) (Hitchcock et al, 1990; Lepesheva et al, 2008; Carreño et al, 2018). The combined effects of ergosterol depletion and toxic metabolite accumulation are fungistatic for many pathogenic fungi, including C. albicans and Cryptococcus spp. The excessive use of azoles has led to development of severe resistance, which significantly reduced their efficacy (Hoffman et al, 2000; Casalinuovo et al, 2004), remarking the need of new, efficient antifungal agents
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
