Design, Synthesis and Antifungal Evaluation of Novel Pyrylium Salt In Vitro and In Vivo

Abstract

Nowadays, discovering new skeleton antifungal drugs is the direct way to address clinical fungal infections. Pyrylium salt SM21 was screened from a library containing 50,240 small molecules. Several studies about the antifungal activity and mechanism of SM21 have been reported, but the structure–activity relationship of pyrylium salts was not clear. To explore the chemical space of antifungal pyrylium salt SM21, a series of pyrylium salt derivatives were designed and synthesized. Their antifungal activity and structure-activity relationships (SAR) were investigated. Compared with SM21, most of the synthesized compounds exhibited equivalent or improved antifungal activities against Candida albicans in vitro. The synthesized compounds, such as XY10, XY13, XY14, XY16 and XY17 exhibited comparable antifungal activities against C. albicans with MIC values ranging from 0.47 to 1.0 μM. Fortunately, a compound numbered XY12 showed stronger antifungal activities and lower cytotoxicity was obtained. The MIC of compound XY12 against C. albicans was 0.24 μM, and the cytotoxicity decreased 20-fold as compared to SM21. In addition, XY12 was effective against fluconazole-resistant C. albicans and other pathogenic Candida species. More importantly, XY12 could significantly increase the survival rate of mice with a systemic C. albicans infection, which suggested the good antifungal activities of XY12 in vitro and in vivo. Our results indicated that structural modification of pyrylium salts could lead to the discovery of new antifungal drugs.

Combined Transcriptome and Metabolome Analysis Reveals That the Potent Antifungal Pyrylium Salt Inhibits Mitochondrial Complex I in Candida albicans

“…The synthesis of new structural antifungal compounds and elucidation of their antifungal mechanisms are urgently needed. In this study, through structural modification of SM21, we synthesized a compound, xy12, with stronger activity and lower toxicity ( 17 ). The skeleton structure of SM21 is pyrylium.…”

“…However, its specific mechanism of action is still unclear. In our study, based on the structure of SM21, we obtained a new lipophilic pyrylium salt, xy12, which showed improved antifungal activity and reduced cytotoxicity both in vitro and in vivo ( 17 ). In the present study, integrated analysis of the transcriptome and metabolome revealed that oxidative phosphorylation could be suppressed by treatment with xy12.…”

Synthesis of Triarylpyrylium Salts Using a Mild, Eco-friendly Route

“…All solvents and reagents were obtained commercially and used without any further purification unless otherwise noted. 1 H and 13 C NMR spectra were collected at room temperature using a 400 MHz Bruker Avance III Spectrometer. Mass spectra were taken on 20 μg/mL methanol solutions using an Advion Expression Compact Mass Spectrometer.…”

“…3 Pyrylium salts (Figure 1) are used in a wide variety of applications, including organic synthesis, [4][5][6][7][8][9] photocatalysis, [10][11][12][13] and medicine. 14,15 In the field of photocatalysis, pyryliums have been used as effective replacements for precious metal catalysts in [2+2] and [4+2] cycloadditions as well as Diels-Alder reactions and ring-opening metathesis polymerization of norbornene. 16 Despite these promising applications, the current library of known pyrylium salts is largely limited to salts which absorb violet light and appear yellow 17 .…”

Use of Povidone Iodine Vaginal Swabbing in Treatment of Recurrent Vulvovaginal Candidiasis

“…Additionally, the local formulations may lead to itching, redness with low efficacy. Advanced agents improve tolerability and widen the toxic therapeutic ratio [10,11] .…”