A Brief Review of Phenolic Compounds Identified from Plants: Their Extraction,Analysis,and Biological Activity

Abstract

Phenolic compounds are the most abundant secondary metabolites in plants, showing a wide range of distinct biological activities, have received more and more attention in recent years. This review aims to gather and systematize available information on the phenolic compounds from plants by discussing different types of phenolic compounds, extraction, and analysis methods, with an emphasis on their potential biological activities. The research direction and problems that should be paid attention to in the future are also put forward to provide some references for the further study of phenolic compounds.

Keywords

phenolic compounds chemistry extraction analysis biological activity

Introduction

Phenolic compounds are a large class of plant secondary metabolites, widely distributed in various higher plant organs such as vegetables,¹ fruits,^2,3 spices,⁴ grains,⁵ legumes, and nuts,⁶ playing important roles in diverse physiological processes such as plant quality, coloring, flavor, and stress resistance. The natural antioxidant, antimicrobial, anticarcinogenic, and antiinflammatory activities of phenolic compounds become a hot spot in terms of research and utilization at present. Phenolic compounds possess a common chemical structure comprising an aromatic ring with one or more hydroxyl substituents that can be divided into several classes, and the main groups of phenolic compounds include flavonoids, phenolic acids, tannins, stilbenes, and lignans.⁷

In recent years, with the increasing recognition for their bioactivity values, phenolic compounds have been found to exert various effects such as antioxidant,⁸ antimicrobial,⁹ anticarcinogenic,¹⁰ antiinflammatory,¹¹ and prevention of cardiovascular diseases, cancers, diabetes, and diseases associated with oxidative stress.¹² For example, four marker compounds from Dendrobii herba exhibit antiinflammatory activity by targeting different inflammation-related cytokines.¹³ The isolated phenolic compounds (anillic acid, isoferulic acid, and syringaresinol) from the roots of Taraxacum coreanum show radical scavenging activity with IC₅₀ values ranging from 30.4 to 75.2 μM.¹⁴ The synergistic of catechin, vanillic, and protocatechuic acids can inhibit the adhesion of uropathogenic Escherichia coli on silicone surfaces.¹⁵

The chemical composition of a plant product is determined by qualitative chemical analysis using various solvents for extraction. Primarily, extraction methods should be selected and optimized along with the corresponding analytical techniques, including the used solvents, the sources, and the properties of the compound itself.¹⁶ In the research or development of phenolic compounds, exploring qualitative or quantitative approaches to analyzing these bioactive compounds should be prioritized in abundant different natural sources, which contribute to developing rapid, sensitive, and reliable methods. Many different methods have been explored or improved in the past few years. General approaches allow the quantitation of a global estimation of phenolic compounds’ content, which is mainly achieved by spectrophotometry methods. However, more specific analyses are based on the identification of individual phenolic classes, typically by high-performance liquid chromatography (HPLC) or gas chromatography (GC), and their detection by sensitive detectors, such as mass spectrometry (MS).^17,18 Overall, developing an optimized and proper method for extraction and quantification of phenolic compounds is essential for achieving higher accuracy in results.

In the last few years, multiple biological activities of phenolic compounds toward various diseases and disorders have gained special attention. The health benefits of phenolic compounds include acting as anticarcinogenic, antithrombotic, antiulcer, antiartherogenic, antiallergenic, antiinflammatory, antioxidant, immune-modulating, antimicrobial, cardioprotective, and analgesic agents.¹⁹ Numerous studies have been discovering potential active compounds as well as investigating the underlying mechanisms to preventing and even reversing the occurrence of disease damages.^20-22 However, the mechanisms of action of these active phenolic compounds, in vivo effects, bioavailability and bio-efficacy still need research.

To the best of our knowledge, although some articles have been published in relevant fields, the studies are relatively less up-to-date. This review summarizes some aspects of different types of phenolic compounds, their extraction procedures, and related analytical methods for quantification in the last 5 years. The main biological activities of some important phenolic compounds are also demonstrated to profile useful information for the determination of phenolic compounds in plant materials.

Phenolic Compounds Identified from Plants

Over 8000 molecules have been reported in the phenolic compounds family and the list continues expanding. Phenolic compounds are mainly classified according to their chemical structures into phenolic acids, flavonoids, tannins, phenolic lignans, and phenolic stilbenes (Figure 1).⁷ It is found that phenolic compounds have 2 basic structures, one is the C6–C3–C6 ring structure, including flavonoids, partial phenolic acids, and condensed tannins, and the other is the C6–C1 structure, mainly including partial phenolic acids and hydrolyzed tannins.²³

Flavonoids

Flavonoids are a series of compounds with diphenylpropanes (C6–C3–C6) as the basic skeleton and 2 aromatic rings connected to each other through the central 3-carbon bridge. Flavonoids are currently the most diverse phenolic compounds which are closely related to flower color formation of plants and play an important role in plant–environment interaction (such as preventing ultraviolet [UV] damage, resisting disease, affecting root nodules formation of legumes, etc). The most common flavonoids found in nature are anthocyanins, flavones, flavonols, flavanones, isoflavones, flavanonols, and other subclasses.

For example, rutin and quercetin exist in herbs, such as Flos sophorae Immaturus, Crateagus pinnatifida Bunge, Hypericum japonicum Thunb, and Folium Mori.²⁴ Epicatechin, a flavonoid isolated from the Mexican medicinal plant Geranium mexicanum HBK could affect the virulence properties of a human pathogen.²⁵ Another major flavonoid, kaempferol, which is obtained from Kalanchoe blossfeldiana Poelln, has antiherpes potential.²⁶ Flavanones are the major flavonoids of citrus; they are found as hesperitin in oranges, eriodictyol in lemons, and aglycones naringenin in grapefruit. In a glass of orange juice, between 40 and 140 mg flavanone glycosides can be found.²⁷ Isoflavones are a subclass of flavonoids, hold structural similarities to estrogens. Isoflavones are sometimes referred to as “phytoestrogens,” which are especially abundant in soybeans. Studies have shown that they can be used to prevent some important diseases, such as hypertension²⁸ and cancer,²⁹ and ameliorate intestinal health.³⁰ Anthocyanins are the largest type of water-soluble vacuolar pigments, appearing as red, blue, or purple, and occur in all plant tissues, including flowers, stems, leaves, roots, and fruits. Anthocyanins are abundant in cereals, red wine, and some root vegetables such as onions, cabbage, beans, and others. However, they are generally seen in certain fruits such as cherries, red berries, and pomegranates. Anthocyanins exert protective effects in preserving cardiovascular health by reducing the risk of myocardial infarction and cardiovascular disease-related mortality.³¹ Furthermore, anthocyanins have shown antiobesity³² and anti diabetes³³ effects through multiple mechanisms.

Phenolic Acids

Phenolic acids belong to a major class of phenolic compounds in plants and are present in free and bound forms. Phenolic acids can be divided into 2 subgroups: hydroxybenzoic acid (HBA) and hydroxycinnamic acid (HCA). HBAs are based on a C₆–C₁ structure and include p-HBA, protocatechuic, vanillic, gallic, and syringic acids. However, HCAs are aromatic compounds with a 3-carbon side-chain (C₆–C₃), including coumaric, caffeic, ferulic, and sinapic acids.³⁴ HBAs are found abundantly in oilseeds, cereals, coffee, cowpea, black currant, raspberry, squash shells and seeds, and blackberry. HCAs are majorly sourced from coffee, cherries, cereals, peaches, spinach, citrus juices and fruits, plums, tomatoes, potatoes, and almonds.

Studies have shown that phenolic acids have various biological functions. For instance, caffeic acid (CAA) and chlorogenic acid (CHA) are important members of HCA with natural antioxidant and cardio-protective properties. CAA and CHA exhibit blood pressure-lowering properties and reduce activities of key enzymes linked to the pathogenesis of hypertension in cyclosporine-induced rats.³⁵ Gallic acid has been shown to specifically target the adipose tissue to suppress lipogenesis, improve insulin signaling, and concomitantly combat raised proinflammatory response and oxidative stress, as well as reduce excessive lipid storage in obese subjects.³⁶ Vanillic acid is an effective inhibitor of Hypoxia-inducible factor 1 (HIF-1) and can cause significant inhibition of tumor growth in a xenografted tumor model, providing new perspectives into the mechanism of its antitumor activity.³⁷

Tannins

Tannins are a group of phenolic compounds that are widely present in cereals, leguminous seeds, and, predominantly, in many fruits and vegetables, where they possess various biological activities including antimicrobial, antiparasitic, antiviral, antioxidant, antiinflammatory, immunomodulation, etc.³⁸ Tannins are classified according to their chemical structures into hydrolyzable tannins (tannic acid) and condensed tannins (proanthocyanidins). Hydrolyzable tannins consist of gallic acid and its dimeric condensation product, hexahydroxydiphenolic acid esterified to a polyol, which is mainly glucose. Condensed tannins have been identified in longan bark, the content of extractable condensed tannins in longan bark is 198.3 ± 8.7 mg/g.³⁹ In brown seaweeds, HBAs, rosmarinic acid, and quinic acid derivatives have been characterized in Ascophyllum nodosum, Bifurcaria bifurcata, and Fucus vesiculosus.⁴⁰ Phlorotannins are oligomers of phloroglucinol, which is restricted to brown seaweeds, where they exert functions as primary and secondary metabolites. Phlorotannins have a wide range of biological activities, such as antioxidant, antibacterial, antiviral activity, antitumor, anticardiovascular disease, antidiabetic syndrome, liver protection, and hyaluronidase lysinase inhibition, which is of great significance for the development of marine drugs.⁴¹

Stilbenes

Stilbenes are a class of phenolic compounds, naturally found in a wide variety of dietary sources such as grapes, berries, peanuts, red wine, and some medicinal plants. But the main dietary origins are wines, peanuts, grapes, and peanut products. There are several well-known stilbenes including resveratrol, pterostilbene, and 3′-hydroxypterostilbene.⁴² The core chemical structure of stilbene compounds is 1,2-diphenylethylene. Recently, stilbenes have attracted extensive attention and interest due to their wide range of health-beneficial effects such as antiinflammation, anticarcinogenic, antidiabetes, and antidyslipidemia activities.⁴³ The main representative compound is resveratrol, which shows antioxidant effects in the cardiovascular system⁴⁴ and can reverse multidrug resistance in a variety of tumor cells by sensitizing them to chemotherapeutic agents.^45,46

Lignans

Lignans are a large group of natural products derived from the oxidative dimerization of 2 phenyl-propane units. Their food sources include linseed (probably the richest source), vegetables, fruits, nuts, oilseeds, garlic, olive oil, wine, tea, beer, and coffee. In recent years, the focus of research has been on their biological activities ranging from antioxidant, antitumor, antiinflammatory to antiviral properties,⁴⁷ thus they have been used for a long time both in ethnic as well as in conventional medicine. Recently, Yang et al⁴⁸ have isolated 16 lignans from the roots of Solanum melongena L. and they find that S melongena L. is an important source for the diverse structure of lignans, with a potential biological activity value for other biological activities for further investigation.

Extraction Methods of Phenolic Compounds

The chemical composition of a plant product is determined by qualitative chemical analysis using various solvents for extraction (Table 1). To extract bioactive phenolic compounds from a wide variety of plant materials, including herbs, fruits, and vegetables, researchers use multiple techniques and methods. The choice of method and solvent used for extraction is a particularly important step to obtain an optimal concentration of natural compounds in the extract. It is important to select an efficient extraction method and proper work phases to assure high performance and increased stability of the extracted compounds. Many conventional and original means can be used to extract phenolic compounds from plant samples, such as solid–liquid extraction (SLE), ultrasound-assisted extraction (UAE), microwave-assisted extraction (MAE), supercritical fluid extraction (SFE), pressurized liquid extraction (PLE), or enzyme-assisted extraction (EAE), are also applied in the extraction of phenolic compounds from plant materials.

Figure 1.

Typical phenolic compounds identified from plants.

Solid–Liquid Extraction

SLE is the simplest and most common method used for extracting phenolic compounds from various plants.⁴⁹ In general, SLE consists of direct extraction of fresh or freeze-dried plant materials with different solvents, such as methanol, ethanol, acetone, or the aqueous phase of solvent mixtures, and then requires an additional operation, such as subsequent column chromatography or solid-phase extraction, to remove these unwanted substances.⁵⁵

Table 1.

Comparison of Different Extraction Methods of Phenolic Compounds.

Extraction method	Advantages	Disadvantages	Affecting factors	Application	Reference
SLE	Simple; well established and widely used; can be easily applied on an industrial scale.	High solvent consumption; long extraction time.	Solvents, L/S, extraction time, temperature, stirring mode, plant materials used, and plant powder size.	Catechin syringic acid p-coumaric acid.	⁴⁹
UAE	Easy to execute; uses inexpensive equipment; consumes less solvents; fast extraction; good extraction yield; has low impacts to the environment.	Generation of excess hydroxyl radicals that may cause degradation of active compounds.	Solvents, L/S, plant materials, ultrasound properties, extraction time, and temperature.	Gallic acid and rutin pmanthocyanidin	⁵⁰
SFE	High selectivity; safer and cheaper solvent; easily controlled extraction conditions; low operating temperature; environmental friendliness; easy separation of solvent from solutes.	Low total yield; not suitable for extraction of polar active compounds.	Pressure, temperature, co-solvents, solvent flow rate, time, and plant materials.	Anthocyanin gallic acid and protocatechuic acid.	⁵¹
MAE	Short extraction time; low solvent consumption.	Degradation of thermally sensitive compounds.	Solvents, L/S, microwave power, temperature, extraction time, and plant materials.	3-caffeoylquinic acid, 5-caffeoylquinic acid, ellagic acid, and ferulic acid	⁵²
PLE	Consumes less organic solvents; fast and efficient; possibility to avoid organic solvents by using water only.	The need for optimal extraction temperature.	Solvents, L/S, temperature, extraction time, pressure, and plant materials.	Rutin quercetin	⁵³
EAE	Safe and green; do not require complex paraphernalia.	Long extraction time; low-efficiency	Type and concentration of enzyme, temperature, pH, solvents, extraction time, and substrate concentration.	Proanthocyanidin naringin hesperidin	⁵⁴

Abbreviations: SLE, solid–liquid extraction; UAE, ultrasound-assisted extraction; SFE, supercritical fluid extraction; MAE, microwave-assisted extraction; PLE, pressurized liquid extraction; EAE, enzyme-assisted extraction; L/S, solvent-to-solid ratio.

However, there are still doubts regarding the most suitable solvent for polyphenols extraction. For instance, acetone has been proven efficient in polyphenols extraction from lychee flowers compared to methanol, water, and ethanol.⁵⁶ However, another study reported water as the better solvent for polyphenols extraction from walnut green husks.⁵⁷ A recent study found aqueous and organic solvents to achieve better extraction efficiencies compared to absolute organic solvents.⁵⁸ The literature evidenced that there is no solvent generally acceptable as the best for extraction of polyphenols; nevertheless, it is generally believed that solvents of higher polarity often perform best in terms of polyphenols extraction because of the high solubility of polyphenols in such solvents.

Medina-Medrano et al⁵⁹ have found that SLE solvent combination ethanol–water can greatly influence the concentration of phenolic content extracted from leaves of Stevia origanoides, Stevia ovata, and Stevia viscida. It is found that hydrochloric acid hydrolysis is of similar effectiveness to, but much cheaper than, the enzymatic method. In addition, to obtain the best yield of phenolic compounds, researchers have also added formic acid and sulfuric acid.^60,61 Furthermore, researchers can obtain the best results with the addition of an alkaline catalyst (sodium hydroxide). SLE is a simple and easy-operating extraction method, but there may be various shortcomings such as long extraction time, low efficiency, and increased amounts of hazardous organic solvent use.

Ultrasound-Assisted Extractions

UAE is one of the useful extraction techniques which is more efficient in comparison to conventional extraction. In addition to increasing extraction yields through the cavitation phenomena and improved mass transfer, the advantages of UAE include low instrumental requirements, simplicity of operation, shorter operation time, and reduced solvent consumption and temperature.⁵⁰ The UAE process is influenced not only by sonication time, temperature, and ultrasonic wave frequency, but also by the property of solvent and sample.

For instance, UAE had been reported to be more effective in extracting rosmarinic and carnosic acids than conventional extraction techniques.⁶² A recent report presented a maximum polyphenols extraction yield of 13.20 mg/g dry weight (DW) from spruce wood bark using the UAE method.⁶³ Furthermore, the yield of anthocyanin from purple sweet potato was reported to be higher when the UAE was employed.⁶⁴ Nipornram et al⁶⁵ have developed a UAE method for extracting the phenolic compounds (flavonoid, hesperidin) from mandarin (Citrus reticulata Blanco cv. Sainampueng) peel, which applies a 48 °C and 56.71 W for 40 min treatment as the optimal extracting conditions, with the maximum yield as 26.52%, total phenolic (15, 263.32 mg eq. gallic/100 g dry weight [DW]) and hesperidin (6435.53 mg/100 g DW).⁶⁵ Furthermore, UAE has been also developed for the extraction of phenolic compounds from olive trees with the optimization of ethanol/water ratio, amplitude percentage, and ultrasonication time.⁶⁶ In addition, Espada-Bellido et al⁶⁷ have developed new UAE methods for the determination of anthocyanins and total phenolic compounds present in mulberries. In summary, UAE is a simple, efficient, and economical method in the extraction of phenolic compounds.

Supercritical Fluid Extraction

SFE is considered an environmentally friendly extraction technique for phenolic compounds that provides a selective extraction using a supercritical solvent. Supercritical CO_2, ethane, butane, pentane, nitrous oxide, ammonia, trifluoromethane, and water are commonly used as essential supercritical fluids. Pimentel et al⁵¹ have developed supercritical CO₂ extraction to extract the phenolic compounds from Hibiscus sabdariffa. Compared to other conventional and green extraction technologies, SFE can improve the collection of hibiscus acid and derivatives.⁵¹ Yang et al⁶⁸ have optimized SFE of phenolic compounds from peach blossom (Amygdalus persica) by response surface methodology (RSM), confirming that 64 °C, 30 MPa, 143 min, and 35 ml ethanol (100%) as modifier exhibits maximum total phenolic contents (54.10 mg gallic acid equivalent [GAE]/g DW) higher than the yield achieved by ultrasonic-assisted extraction (44.04 mg GAE/g DW). In addition, an effective Medicago sativa extraction method using enzyme-assisted SFE has been developed, with the application of RSM based on Box-Behnken design.⁶⁹ Compared with other conventional and original methods, SFE may consume less toxic organic reagents and extraction times, increase safety and selectivity, and avoid sample oxidization in the presence of air.

Microwave-Assisted Extraction

MAE is a mature technique used for phenolic compound extraction from various plant materials. MAE procedure utilizes the direct effect of microwave irradiation to facilitate molecules vibration and separation from the immerged sample into the solvent. The major physical parameters important for MAE include microwave power, extraction time, solubility, dielectric constant, and solvent property. Dahmoune et al⁵² have developed MAE to extract phenolic compounds from Myrtus communis L. instead of conventional extraction methods and observed that the antioxidant activities of tannins and total flavonoids in MAE extracts are higher than that of the products extracted by other extraction methods.⁵² The optimal MAE conditions of pistachio green hull pectin (extraction yield of 18.13%) are in microwave power of 700 W, irradiation time of 165 s, and pH of 1.5.⁷⁰ MAE coupled with UAE and deep eutectic solvents have been considered as a high-efficiency and environmentally-friendly extraction method for grape skin phenolic compounds extraction.⁷¹ This method has many advantages such as low operation time, consumed solvent and production cost, and also high extraction yield.⁷²

Other Extraction Methods

Enhanced solvent extraction (ESE) and PLE give higher global extraction yields (up to 37%) than SFE using CO₂ + 20% ethanol (around 8%) in the pilot-plant scale extraction of phenolic compounds from mango leaves.⁵³ Enhance-fluidity liquid extraction can be used for extracting total phenolic compounds from spent blackberry pulp using a modified solvent (CO₂–ethanol mixture).⁷³ EAE can also be used to enhance active compounds extraction from plant materials.⁵⁴ Microwave-assisted solvent extraction (MASE) has been used in extracting phenolic compounds from pistachio (Pistacia vera L.) hull. Compared with conventional solvent extraction, MASE gives higher total phenolic content (TPC), yield, and antioxidant activity.⁷⁴

Phenolic Compounds Analysis Methods

Phenolic compound quantification depends on different parameters, such as the chemical nature of compounds, extraction method used, particle size, standard selection, and interfering substances and impurities. With the advancement of analytical science, numerous methods have been used for quantifying phenolic compounds from plant materials, such as spectrophotometry, HPLC, GC, and their combinations.

Spectrophotometry

Spectrophotometry is a simple and fast technique for quantifying phenolic compounds from plant materials, which is mainly based on different principles for measuring the various structures present in the phenolic compounds. The Folin–Ciocalteu assay has been widely used to detect phenolic compounds in plants for many years. This assay is based on a chemical reduction involving reagents containing tungsten and molybdenum.⁷⁵ The Folin–Ciocalteu method is a modified method of the Folin–Denis assay, which slightly changes the composition of the reagent used. The general principle of this analysis is to prepare an extract of phenolic compounds from the material and to add the Folin-Ciocalteu reagent, sodium carbonate (7-35% or 0.1 N), and distilled water. The solution prepared in this way is allowed to react for 15 to 120 min. In general, the flavonoid content is often measured with spectrophotometry.⁷⁶ In addition, total phenolic quantification and the condensed tannin content can also be estimated by spectrophotometry.⁷⁷ Spectroscopy is the common technique used for quantifying different classes of phenolic compounds because of its simplicity and low cost.

Gas Chromatography

GC is a useful technique utilized for the separation, identification, and quantification of some phenolic compounds in plants, such as tannins, flavonoids, and anthocyanins. It employs the evaporation temperature specific for each compound to separate it from the solution by passing the sample through a heated column where it is divided between an inert gas under pressure and a thin layer of nonvolatile liquid covered with an inert substrate inside the column.⁷⁸ The derivatization and volatility of phenolic compounds are the main components detected by GC. Vaiciulyte et al⁷⁹ have applied GC–FID (flame ionization detector) to detect carvacrol obtained from Thymus pulegioides L. In recent years, GC coupled with MS detector has become widespread in measuring complex compounds because of its high selectivity and sensitivity in quantitation. For example, the low-molar-mass fraction of hydrophilic extracts in Norway spruce knotwood, which are mainly lignans, has been characterized by GC–MS.⁸⁰ The columns most commonly used in the GC technique to analyze phenolic compounds include 30 m long capillary columns, with an outer diameter of 0.25 to 0.30 mm, and an inner diameter of 0.25 μm. Helium is usually used as the carrier gas.

High-Pressure Liquid Chromatography

HPLC is the most used technique for the separation and detection of phenolic compounds. It is a versatile and adaptable instrument with various advantages, such as high selectivity, sensitivity, resolution, precision, and sample behavior.⁸¹ The method's principle lies in the separation of compounds from complex mixtures on the basis of their solubility and/or interaction between a less polar stationary phase and a more polar mobile phase.⁸² Thus, some factors affect HPLC analysis of phenolic compounds, such as column types, applied detectors, mobile phase, and the properties of the tested compounds. To obtain information about a specific phenolic compound, it is necessary to compare its retention time with the standard. But some classes of polyphenols, mainly flavonoid glycosides and proanthocyanidins lack standards, so this is a major disadvantage when using the HPLC technique.⁸³

HPLC–Mass Spectrometry

Phenolic compounds can be analyzed by HPLC combined with tandem MS. HPLC assisted by MS detection is an advanced analytical technique that exhibits high sensitivity and selectivity. This approach can measure structural information about unknown compounds from crude or partially purified samples of natural sources.⁸⁴ Recently, numerous studies on phenolic compounds analyses have been focused on the assessment of methods that involve different couplings between HPLC and MS. Chen et al⁸⁵ have analyzed the phenolic compounds in Jerusalem artichoke (Helianthus tuberosus L.) responding to salt stress by HPLC/tandem MS. In recent years, MS is usually used for the analysis of phenolic compounds because of its high sensitivity and selectivity; in addition, it could provide structural information about unknown compounds. Overall, this technique is currently the best analytical approach to studying phenolic compounds of various biological resources and the most effective tool in analyzing their structure. However, its main disadvantage is the high cost of the device.

HPLC–Diode Array Detector

HPLC coupled with diode array detector (HPLC–DAD) is another common method for analyzing the phenolic compounds in plants.^86,87 Of all detectors coupled with HPLC to enable the determination of phenolic compounds, MS is the most expensive and unusual, while DAD is the most useful and common.⁸⁸ The DAD detector can simultaneously scan the whole UV/visible spectrum of the analytes and provide information about special spectral properties for compound identification. da Silva Siqueira et al⁸⁶ have developed HPLC–DAD to determine the phenolic compounds (CHA, CAA, rutin, and isoquercitrin) from Spondias tuberosa. Some phenol substituting compounds are considered highly toxic compounds usually found in environmental water samples, especially in urban wastewaters. HPLC–DAD is applicative to the tested compounds with a suitable chromophore. Overall, HPLC–DAD is deemed a simple, cost-effective, reliable, and sufficiently sensitive analytical platform for analyzing food constituents.⁸⁹

Other Analytical Methods

HPLC combined with fluorescence detection (HPLC–FLD) is also used to analyze phenolic compounds.⁹⁰ HPLC–FLD can be used to detect the substance which emits fluorescent or emit fluorescent after proper derivations. Thin-layer chromatography (TLC) is a chromatographic technique with relatively low cost.⁹¹ Through this process, phenolic compounds in crude plant extracts can be separated and detected for multiple substances on the same TLC plate within a short analysis time. In addition, capillary electrophoresis is an advanced analysis technique for measuring phenolic compounds in plants, which is especially suitable for separating and quantifying those polar and charged compounds with low to medium molecular weight.⁹² Recently, a new, sensitive, and selective ultra-HPLC–electrospray ionization–tandem MS method was developed and validated for the determination of phenolic acids and flavonoids in 14 mangrove species.⁹³ This method can also be used for the analysis of other biological extracts.

Biological Activities of Phenolic Compounds

Natural plants represent an important source of phenolic compounds that are useful in a wide range of applications, especially those with biological activities. Phenolic compounds play an essential role in natural antioxidant, antimicrobial, and antiinflammatory effects as well as the treatment of diseases such as obesity, cancer, and diabetes. Some important biological activities of phenolic compounds are illustrated below.

Antioxidant Activity

Phenolic compounds have shown promising antioxidant properties, with their potential being directly related to the type of solvent used in the extraction, but also with plant origin, growing conditions, harvesting time, and storage conditions. The study of the antioxidant potential of phenolic extracts derived from plant species is one of the hot topics among the scientific community.⁹⁴ The biological activity tests indicated that the phenolic extracts of tartary buckwheat bran may serve as functional compounds that exert antioxidant activities in vitro (oxygen radical antioxidant capacity) and ex-vivo (cellular antioxidant activities, CAA), as well as antiproliferative activity against human liver cancer cells (HepG2) in vitro.⁹⁵ The phenolic compounds extracted from the species of the medicinal plant (Buchenavia tetraphylla, Buchenavia tomentosa, and Lippia sidoides) provide the main contributions to the antioxidant potential.⁹⁶ The stem of Dendrophthoe falcata (Loranthaceae) plant shows a high content of phenolic and flavonoid compounds and very high antioxidant activities.⁹⁷

In addition to the concentration of phenols,⁹⁸ the antioxidant activity of phenolic compounds is in direct relation with their chemical structures such as number as well as the position of the hydroxyl groups.⁹⁹ Because of seasonal variations, the trends of different phenolic compounds are also different. Contents of both total phenolics and total flavonoids were strongly correlated with antioxidant activity.¹⁰⁰ The total phenolics, total flavonoid, and antioxidant capacity of all blueberries cultivars increased nonlinearly with ripening.¹⁰¹

Antiinflammatory Activity

It has been demonstrated that besides the essential antioxidant effect, phenolic compounds reduce lipid peroxidation and DNA damage.¹⁰² The extracted phenolic compounds from Ficus hirta Vahl. exhibit pronounced inhibitory effects on the lipopolysaccharides (LPS) induced nitric oxide (NO) production in murine macrophage RAW 264.7 compared to indomethacin, which suggested that hairy fig could be served as an antiinflammatory agent for health products.¹⁰³ Most of the phenolic compounds isolated from durian shells exhibit pronounced inhibitory activities on LPS-induced NO production in RAW 264.7 cells, indicating the potential to serve as antiinflammatory agents.¹⁰⁴ A variety of phenolic compounds and stilbene derivatives in different parts of germinated peanut suggests that the peanut sprout exerts high antiinflammatory effects and may be related to the polyphenolic content and antioxidant properties.¹⁰⁵

Antibacterial Activity

Besides the antioxidant and antiinflammatory activity of plant phenolic compounds, antimicrobial activities have also been focused on. Many studies have been conducted on antibacterial activity.¹⁰⁶ The ethyl acetate fraction of Scirpus holoschoenus shows the highest antioxidant activity and antibacterial effect, with minimal inhibitory concentration values of 0.4 and 0.6 mg/mL for Staphylococcus aureus and Bacillus subtilis, respectively.¹⁰⁷ The green tea kombucha presents antibacterial activity against all the bacteria tested and an increased antiproliferative activity against the cancer cell lines, which is attributed to the presence of catechins among the most abundant phenolic compounds and verbascoside as an exclusive compound.¹⁰⁸

Boussoussa et al¹⁰⁹ first reported the seasonal changes of phenolic compounds and antibacterial activity on Rhanterium adpressum. The highest phenolic content was detected in R adpressum methanolic extracts collected in April and the extracts activity was related to the concentration of phenolic compounds in active extracts.¹⁰⁹ Further analysis has shown a close correlation between antibacterial activity and phenolic content. The lignum of Rhus verniciflua contains high content of phenolic compounds with less urushiols, which suggests efficient antibacterial activity with less toxicity.¹¹⁰

Anticoronavirus Properties

The highly contagious novel disease COVID-19 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in a major international concern all over the globe. However, antiviral therapeutics options that specifically target this new coronavirus remain limited. Natural compounds with a great diversity of chemical structures may provide an alternative approach for the discovery of new antivirals. Studies have shown that natural phenolic compounds have anticoronavirus properties in supportive and prophylaxis treatments.¹¹¹

A recent review presented that resveratrol stably binds to the viral protein/angiotensin-converting enzyme 2 (ACE2) receptor complex of SARS-CoV-2, indicating it to be a promising agent in the therapeutics of COVID-19 by disrupting the virus S protein.¹¹² Curcumin has been suggested as a potential treatment option for patients with COVID-19 because it inhibits ACE2 and suppresses the entry of SARS-CoV-2 into the cells.¹¹³ In the prophylaxis and treatment of COVID-19, the antiviral activity of green tea and black tea PC has also been proven and emphasized. Theaflavin, the compound responsible for the orange/black color of black tea, is a potent inhibitor of the RNA polymerase of SARS-CoV-2.¹¹⁴ Catechin gallate and gallocatechin gallate also showed high inhibitory activity against SARS-CoV-2 N protein in a concentration-dependent manner and affected virus replication.¹¹⁵ A study has also demonstrated potent inhibition of recombinant SARS-CoV-2 3CLpro by myricetin, which suggests that myricetin could be further tested and developed as a potential SARS-CoV-2 antiviral.¹¹⁶

Neuroprotective Potential

Phenolic compounds are able to pass through the blood–brain barrier following dietary intake. Thus, they may have great potential for central nervous system diseases protection and treatment.¹¹⁷ Indeed, current evidence is in favor of the hypothesis.

Accumulating evidence indicates that hydroxytyrosol extracted from olive exhibits neuroprotective effects on multiple chronic neurodegenerative diseases including Alzheimer's disease,¹¹⁸ Parkinson's disease,^119,120 multiple sclerosis,¹²¹ etc. The protective effect of oil palm phenolics against neurodegenerative diseases has been recently reviewed.¹²² N-methyl-d-aspartate (NMDA) receptors are glutamate-coupled ion channels that are critically involved in the survival of neuronal cells and neurodegenerative diseases. Thus, it is considered a promising target for the therapy of neurodegenerative disease. In a new study, 2 new catechin derivatives showed neuroprotective effects for the prevention of excitable brain injury via NMDA receptors inhibition.¹²³

Nowadays, it is well known that the impact of coffee on health and its neuroprotective effect is not due to caffeine alone, but to other bioactive coffee components such as phenolic acids, which are independently able to improve motor and cognitive performances in aging and depression.¹²⁴ Among coffee components, quercetin could represent the major neuroprotective compound. In comparison with caffeine and CHA, quercetin demonstrated the most protective effect on neuronal cells, inhibiting glial and Glu-mediated toxicity.¹²⁵

Other Activities

Evidence suggests that people can benefit from plant phenolics obtained either by the diet or through skin application, because they can alleviate symptoms and inhibit the development of various skin disorders. Due to their natural origin and low toxicity, phenolic compounds are a promising tool in eliminating the causes and effects of skin aging, skin diseases, and skin damage, including wounds and burns. Polyphenols also act protectively and help prevent or attenuate the progression of certain skin disorders, both embarrassing minor problems (eg, wrinkles and acne) or serious, potentially life-threatening diseases such as cancer.¹²⁶

Phenolic plant secondary metabolites actively participate in a broad range of important reactions that affect livestock, plants, and soil. In soil, phenolic compounds can affect nutrient dynamics and mobility of metals, and thus may be part of future management strategies to improve nutrient use efficiency.¹²⁷

Furthermore, chrysin, carvacrol, hesperidin, zingerone, and naringin as natural phenolic compounds have shown excellent inhibitory effects against human (h) carbonic anhydrase (CA) isoforms I and II (hCA I and II), –glucosidase (–Gly), acetylcholinesterase, and butyrylcholinesterase exhibiting important antidiabetic, anticholinergic, and antiepileptic activities.¹²⁸

Experimental studies have shown that the extracts and phenolic compounds derived from many plants, such as cocoa, green tea, grape, pomegranate, and some marine algae, can decrease the levels of reactive oxygen species in cells and/or enhance cellular antioxidant capacity and, thereby, can attenuate particulate matter (PM)-induced oxidative damage to nucleic acids, proteins, and lipids. They also lower the levels of cytokines, chemokines, cell adhesion molecules, prostaglandins, and matrix metalloproteinases implicated in cellular inflammatory responses to PM.¹¹

Conclusions

This review presented some advanced information about phenolic compound types identified from plants, extraction and analysis techniques, as well as biological effects. Phenolic compounds are mainly classified into phenolic acids, flavonoids, tannins, phenolic lignans, and phenolic stilbenes. The advanced extraction methods include SLE, SFE, UAE, MAE, ESE, and PLE. Conventional extraction methods are very simple and widely used for isolating plant phenolic compounds, while nonconventional technologies can offer superior extraction efficiency in terms of cost, yield, extraction time, and/or selectivity. Among analytical methods, HPLC has major advantages, especially when coupled with highly sensitive sophisticated detectors (eg, MS). The diversification of the detectors enhances the sensitivity and specificity of the analysis of the tested compounds. Overall, the study of the biological potential of numerous natural plant phenolic compounds still remains a hot topic among the scientific community. Despite all of those advances, the available knowledge about the responsible phytochemicals for the biological potential, their mechanisms of action, the establishment of therapeutic and prophylactic doses, and even the occurrence of biochemical inter-relations, is considerably scarce. This review offers a valuable reference for the identification, quantification, and further biological activity research of phenolic compounds from natural plant products.

Footnotes

Acknowledgments

We thank Dr Qinglin Luo, Dr Bingchuan Zhang for their suggestions for this manuscript.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was financially supported by Chongqing Basic Research and Frontier Exploration Project (cstc2018jcyjAX0501), the Fundamental Research Fund for the Central Universities of China (No. XDJK2019B035), the Mission Statement of Key Special Projects of “Science and Technology Help Economy 2020 (SQ2020YFF0405970), and National Citrus Engineering Research Center opening project (NCERC2019006).

ORCID iD

Yongqiang Zhang

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