4-Ethylphenol: Synthesis and Applications

4-Ethylphenol is found in arabica coffee which is a phenolic compound produced in wine and beer by the spoilage yeast Brettanomyces. 4-Ethylphenol belongs to the family of Phenols and Derivatives. These are compounds containing a phenol moiety, which is a benzene bearing an hydroxyl group.

Synthesis of 4-Ethylphenol

General procedure: Sodium borohydride (1.0 molar equiv.) was added to a solution of aryl alcohol (4a-c, 7, or 9a-b; 1.0 equiv.) in MeCN (2.0 mL) under an argon atmosphere at 0 °C. The mixture was stirred at 0 °C for 15 min. Trimethylsilyl chloride (2.0 equiv.) and potassium iodide (1.5 equiv.) were added to the mixture at 0 °C. The reaction mixture was stirred at rt under an argon atmosphere until no further TLC changes were observed. After the mixture was diluted with EtOAc (5 mL), the reaction was quenched by the addition of a saturated aqueous NaHCO3 solution (2 mL) and Na2S2O3 solution (2 mL). The layers were separated. The aqueous layer was extracted with EtOAc (5 mL). The combined organic layer was washed with water, brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography to give the corresponding product 4-Ethylphenol.[1]

Applications

Potential Botanical Agrochemical Against Oomycetes

Oomycetes, represented by Phytophthora, are seriously harmful to agricultural production, resulting in a decline in grain quality and agricultural products and causing great economic losses. Integrated management of oomycete diseases is becoming more challenging, and plant derivatives represent effective alternatives to synthetic chemicals as novel crop protection solutions. Biologically active secondary metabolites are rapidly synthesized and released by plants in response to biotic stress caused by herbivores or insects, as well as pathogens. In this study, we identified groups of volatile organic compounds (VOCs) from soybean plants inoculated with Phytophthora sojae, the causal agent of soybean root rot. 4-Ethylphenol was present among the identified VOCs and was induced in the incompatible interaction between the plants and the pathogen. 4-Ethylphenol inhibited the growth of P. sojae and Phytophthora nicotianae and had toxicity to sporangia formation and zoospore germination by destroying the pathogen cell membrane; it had a good control effect on soybean root rot and tobacco black shank in the safe concentration range. Furthermore, 4-Ethylphenol had a potent antifungal activity against three soil-borne phytopathogenic fungi, Rhizoctonia solani, Fusarium graminearum, and Gaeumannomyces graminis var tritici, and four forma specialis of Fusarium oxysporum, which suggest a potential to be an eco-friendly biological control agent.[2]

Hyphal plugs of P. sojae and P. nicotianae were cultured in 10% V8 agra medium containing different concentrations of 4-Ethylphenol, or the same volume of sterile water as a control. The medium was incubated in the darkness at 25°C for 5 days; then, the colony diameter was measured, and the mycelium status was observed under the microscope. Each treatment was repeated three times. Washed mycelia were placed in different concentrations of 4-Ethylphenol. After incubation at 25°C for 6 h, the number of zoosporangia was observed and recorded under the microscope using Mallassez cell counting. 4-Ethylphenol was added to the sporangium-forming dishes, and after 2 h, the number of zoospores was measured under the microscope using Mallassez cell counting. Each treatment was repeated three times.

Among the 150 components identified, a potent antifungal compound, 4-Ethylphenol, requires further exploration as a source or template for novel crop protection chemistry. There have been a few reports demonstrating the antimicrobial potential of 4-Ethylphenol. In this study, 4-Ethylphenol had a good inhibitory effect on P. sojae and P. nicotianae. Zoospore germination and mycelium growth are important for disease epidemics. Our results showed that 1 mM (144.15 mg/L) 4-Ethylphenol completely inhibited Phytophthora spp. sporangium formation and mycelium growth. This inhibition is comparable to that of the plant-derived antifungal agent poacic acid when applied with an IC50 of 1,000 mg/L against P. sojae. 4-Ethylphenol has a potent antifungal activity against three soil-borne phytopathogenic fungi, Rhizoctonia solani, Fusarium graminearum, and Gaeumannomyces graminis var tritici, and four Fusarium oxysporum forma specialis. Usually, these fungi are associated with Phytophthora spp. in the soil and cause compound infection complications, which aggravate the occurrence of plant root rot. The potent antifungal activity of 4-Ethylphenol could block the spread of these pathogens, and may play a key role in inhibiting soil-borne disease epidemics. This study provides the first report of the activity of 4-Ethylphenol against a series of Phytophthora spp. and fungi pathogens, demonstrates its potential as a universal broad-spectrum fungicide for soils, and justifies efforts to investigate its mechanism of action in detail.

Gut microbiome derived neuromodulator

Catabolism of the aromatic amino acids phenylalanine and tyrosine by certain gut microbiota yields 4-ethylphenol [4EP]. Dietary and systemic availability of aromatic amino acids and the presence of microbiota with the functional capacity to create 4EP regulate its production in the body. Rates of production are important to health as plasma concentrations of 4EP and its more polar, sulfated form, 4-ethylphenol sulfate [4EPS], correlate with neurological changes in humans and mice. For example, a reduction of plasma 4EPS concentrations from 29 μg/L to 9 μg/L correlated with significant reductions in core autism-behaviours, such as anxiety, in autistic children. Similarly, accumulation of 4EPS in the mouse brain increased degradation of neuronal axon myelin sheath; the insulator of the neurons.[3]

Gut-microbiome-derived metabolites, such as 4-Ethylphenol [4EP], have been shown to modulate neurological health and function. Although the source of such metabolites is becoming better understood, knowledge gaps remain as to the mechanisms by which they enter host circulation, how they are transported in the body, how they are metabolised and excreted, and the way they exert their effects. High blood concentrations of host-modified 4EP, 4-ethylphenol sulfate [4EPS], are associated with an anxiety phenotype in autistic individuals. We have reviewed the existing literature and discuss mechanisms that are proposed to contribute influx from the gut microbiome, metabolism, and excretion of 4EP. We note that increased intestinal permeability is common in autistic individuals, potentially explaining increased flux of 4EP and/or 4EPS across the gut epithelium and the Blood Brain Barrier [BBB]. Similarly, kidney dysfunction, another complication observed in autistic individuals, impacts clearance of 4EP and its derivatives from circulation. Evidence indicates that accumulation of 4-ethylphenol in the brain of mice affects connectivity between subregions, particularly those linked to anxiety. However, we found no data on the presence or quantity of 4EP and/or 4EPS in human brains, irrespective of neurological status, likely due to challenges sampling this organ. We argue that the penetrative ability of 4EP is dependent on its form at the BBB and its physicochemical similarity to endogenous metabolites with dedicated active transport mechanisms across the BBB. We conclude that future research should focus on physical (e.g., ingestion of sorbents) or metabolic mechanisms (e.g., conversion to 4-ethylphenol -glucuronide) that are capable of being used as interventions to reduce the flux of 4EP from the gut into the body, increase the efflux of 4EP and/or 4EPS from the brain, or increase excretion from the kidneys as a means of addressing the neurological impacts of 4-ethylphenol.

References

[1] Kato, Yuichi; Inoue, Tomoka; Furuyama, Yuuki; Ohgane, Kenji; Sadaie, Mahito; Kuramochi, Kouji[Tetrahedron Letters, 2021, vol. 86, art. no. 153519]

[2] Ge T, Gao W, Liang C, Han C, Wang Y, Xu Q, Wang Q. 4-Ethylphenol, A Volatile Organic Compound Produced by Disease-Resistant Soybean, Is a Potential Botanical Agrochemical Against Oomycetes. Front Plant Sci. 2021 Sep 22;12:717258.

[3] Day F, O'Sullivan J, Pook C. 4-Ethylphenol-fluxes, metabolism and excretion of a gut microbiome derived neuromodulator implicated in autism. Front Mol Biosci. 2023 Oct 12;10:1267754.

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