Received: 10 September 2019 Revised: 29 March 2020 Accepted: 20 April 2020

DOI: 10.1002/ptr.6715

REVIEW

Bio-actives of betel leaf (Piper betle L.): A comprehensive

review on extraction, isolation, characterization,
and biological activity

Mitali Madhumita1 | Proshanta Guha1 | Ahnidra Nag2

1
Agricultural and Food Engineering
Department, Indian Institute of Technology,
Kharagpur, India
2
Department of Chemistry, Indian Institute of
Technology, Kharagpur, India
Correspondence
Mitali Madhumita, Department of Agricultural
and Food Engineering, Indian Institute of
Technology, Kharagpur, West Bengal, 721302,
India.
Email: mitalimadhumitaiitkgp@gmail.com
Funding information
Indian Institute of Technology, Kharagpur
Abstract
Piper betle L., belonging to Piperaceae family, known as a traditional herbal medicinal
plant and used for several health benefits in Asian countries. Currently, demand for
its products such as herbal drugs, medicines, and natural herbal formulations has
increased. The beneficial effects of betel leaves and its products have traditionally
exploited for the treatment of several diseases like bad breath, cuts, injuries, inflam-
mations, cold cough, indigestion, etc. Till now, a broad range of bioactive compounds
including polyphenols, terpenes, etc., has been identified from the extracts and
essential oil (EO) of betel leaves. The structural and functional characterization of the
extract and EO bio-actives has been derived by various advanced standard methods.
Most of the health-related benefits of betel leaves have been associated with their
bioactive phenolic compounds. The extract of this highly perishable product can be
used in organic synthesis, food, and beverage industry, pharmaceuticals, etc., to the
environmental issues. The present review provides information on extraction tech-
niques, identification of bioactive compounds, and their biological activities. That
apart, information on processing, preservation, and health benefits along with their
mechanisms has also been added.

KEYWORDS

bioactive compounds, extraction, microbial activity, Piper betle

1 | I N T RO DU CT I O N Dube, 2010). Malaysia is the origin place of Paan (Chattapdayay &

Betel leaf (Piper betle L.) is a heart-shaped deep green leaf that grows on
a root climbing vine. It is a medicinal, recreational, and horticultural cash
crop. It is used as a traditional herbal medicine in Asian countries from
time immemorial (Khan, Bashir, Hussain, Kumar, & Ahmad, 2012). A
hundred varieties of betel leaf (local name paan in India) are found
across the world of which 40 found in India along with 30 found in
West Bengal and Bangladesh (Guha & Jain, 1997). It is widely cultivated
in different states (Orissa, Maharashtra, Uttar Pradesh, Tamil Nadu, and
Madhya Pradesh) in India along with other countries like Bangladesh,
Philippine Islands, Burma, Malay Peninsula, Malaysia, and Sri Lanka
(Guha, 2006; Jayaweera, 1982; Kumar, 1999; Kumar, Misra, &
Maity, 1967). Based on its color, size, taste, and aroma, Piper betle is
known by various types across the country and abroad such as Mag-
adhi, Kauri, Venmony, Mysore, Salem, Bangla, Kapoori, Meetha, Sanchi,
Ghanagete, Kasi, Banarasi, Desavari, and Bagerhati (Warrier, Nambair, &
Ramankutty, 1995). It is a perennial climbing vine with semi-woody
stem and short adventitious climbing roots. The leaves are glabrous
with aromatic odor and pungent taste and extensively found in damp
forests. In Hindu culture, betel leaf and areca nut play an important role
in various cultural, social, and religious occasions. The leaves, edible
parts of the plant, are the most valued medicinal, religious, and ceremo-
nial plant part and consumed as a mouth freshener having a strong pun-
gent and sweet taste with a strong aromatic flavor. The leaves vary in

Phytotherapy Research. 2020;1–19. wileyonlinelibrary.com/journal/ptr © 2020 John Wiley & Sons, Ltd. 1
2 MADHUMITA ET AL.
taste, like very pungent to mild in Bangla, and Sanchi variety whereas
sweet in Meetha variety depending on nutritional composition, chemi-
cal compounds, and also varieties of leaves (Pradhan, Suri, Pradhan, &
Biswasroy, 2013; Warrier et al., 1995). The aroma of the betel leaf is
due to the presence of phenols and terpenes in essential oil (EO). Sev-
eral studies have been conducted to identify the antioxidant from natu-
ral sources which can be used to develop new nutraceutical products.
These products can prevent oxidative damage in the body (Nouri,
Nafchi, & Karim, 2014). The phytochemicals or poly-phenolic com-
pounds present in plants can be used to regulate oxidation and stress-
related diabetes and cardiovascular diseases (Kwon, Apostolidis, &
Shetty, 2008). Betel leaf, rich in bioactive compounds possess several
activities like antibacterial, anti-cariogenic, anti-fungal, anti-larval, anti-
protozoal, anti-filarial, anti-allergic, anti-diabetic, antihelminthic, anti-
tumor, antibacterial hypotensive, respiratory, and depressant effects,
etc. (Chakraborthy & Shah, 2011; Choudhary & Kale, 2002; Majumdar,
Chaudhuri, Ray, & Bandyopadhyay, 2003; Ratnasooriya
Premakumara, 1997; Santhakumari, Prakasam, & Pugalendi, 2003;
Santhanam & Nagarajan, 1990; Saravanan, Prakasam, Ramesh, &
Pugalendi, 2002). The chemical compounds present in betel leaves are
extracted by a suitable extraction technique. The selection of a proper
extraction technique is important to perform an efficient extraction of
phytochemical compounds. Several extraction techniques are adopted
to extract the bioactive compounds from the plant sources. Conven-
tional extraction methods (distillation and solvent extraction) and non-
conventional extraction methods (supercritical extraction
accelerated solvent extraction) are implemented in the recovery of nat-
ural antioxidants (Ali et al., 2018; Ali, Lim, Chong, Mah, & Chua, 2018;
Ali, Lim, & Wahida, 2018). The common solvents (methanol, ethanol,
acetone, ethyl acetate, etc.) are used in extraction because of the
advantages of biodegradability and ease of handling with very low tox-
icity . Researchers have proposed the possible utilization of Piper betle
as a source of natural antioxidants in various applications like medicinal
industries, food, and pharmaceutical industries, etc., due to its efficacy
(Dwivedi & Tripathi, 2014; Venkadeswara et al., 2014). The leaves
extract can be used as food preservatives to deliver important nutrients
to consumers' diets (Putnik et al.,2017).
Betel leaf has several characteristics such as nutritional, organo-
leptic, therapeutic, prophylactic, functional, antimicrobial, antioxidant,
and other desirable qualities which can provide a challenging opportu-
nity to the food scientists and technologists to develop novel food
products with enhanced food safety, extended shelf life. The leaf
extract and EO having the above-discussed properties can also be
explored for manufacturing a large number of cosmetics, medicines,
pharmaceuticals, food product development in the food sector.
Several workers have attempted to explore the use of betel leaf
extract and EO as food preservatives in food products like apple
juice (Basak, 2018a), tomato paste (Basak, 2018b; Basak & Guha,
2017a, 2017b), food flavoring agents in novel ice cream (Bhoite,
Kamble, & Patil, 2019), noodles (Nouri, Nafchi, & Karim), food cupcake
(Roy & Guha, 2015), and other products, such as paan masala (spiced
and processed betel leaf), cold drinks, gutkha (non-tobacco-based
chewable mouth freshener), suji halwa (Bhagath & Guha, 2014), chili
Highlights
• Piper betle L., rich in nutritional composition, antioxidant
bioactive compounds.
• Recovery of bioactive compounds by several extraction
techniques was discussed.
• Useful in pharmaceutical, food and beverage, and cos-
metic industries etc.
• Bio-chemical characterization and antimicrobial activity
was thoroughly explained.
• Increase the economic value, productivity, and decrease
the waste and by-product utilization.
&
bo (Wendy, Ghali, & Rukayadi, 2014), and many other novel products.
Moreover, a sago starch-based edible film (Nouri & Nafchi, 2014) and
two products from Aloe vera gel and potato chips (Arambewela,
Arawwawala, & Rajapaksa, 2006) were developed by incorporating
betel leaf extract and betel leaf EO, respectively. Apart this, in the
pharmaceutical industry, some novel products can be taken up like
food supplements for the treatment of cancer (Kudva, Rao, &
Rao, 2018; Shukla, Johri, & Srivastava, 2018). Because of the entire
and discussions, it may be concluded that the EO of betel leaf has a poten-
tial future in the world food sector.
Taking into account the above discussed potential benefits prop-
erties of betel leaves from both technological and nutritional point of
view, the aim of the present review is focused on the extraction
methods to obtain the chemical compounds as well as their biological
activities. The current review aims to compile an updated comprehen-
sive literature analysis of nutritional composition, extraction of bioac-
tive compounds of extracts and EO by several adopted extraction
methods, phytochemistry, and antimicrobial activity of betel leaves
that covers all the valuable information.
2 | PI PE R BE TLE L.: A H OR TIC UL TU RAL
CASH C RO P
2.1 | Botanical description
Piper betle is glorified as an important perennial dicotyledonous
creeper, belongs to Piperaceae family. Based on shape, size, brittle-
ness, and taste of leaf blade, betel vine is divided into pungent and
non-pungent varieties. The leaves of the plant are simple and alter-
nate with acuminated apex. Mostly, the structure of the betel leaves
is heart-shaped, smooth, and shining (Figure 1). Moreover, the color
of the leaves varies from yellowish-green to bright green. The leaves
are long-stalked with two or three pairs of secondary veins with small
white flower spikes (Swapna, Ammani, & Saripalli, 2012). Generally,
the branches of the betel plant are strongly swollen at the nodes and
MADHUMITA ET AL.
F I G U R E 1 Images of (a) betel leaf
and (b) betel plant (Source: Guha, 2006)
[Colour figure can be viewed at
wileyonlinelibrary.com]
entirely glabrous (Arambewela, Arawwawala, & Ratnasooriya, 2005;
Arambewela, Kumaratunga, & Dias, 2005). Male and female spikes are
cylindrical dense and pendulous, respectively (Sengupta
Banik, 2013). The female spikes are 2.5–5.0 cm long, and the female
plants are found to rarely produce any flower or fruit in the Indian cli-
mate (Dassanayake & Fosberg, 1987; Jayaweera, 1982).
2.2 | Nutritional composition and health benefits
Betel leaves are very nutritive and contain some vitamins, minerals,
protein, enzymes, EO, and beneficial bioactive compounds for the treat-
ment of liver, brain, and heart diseases (Pradhan et al., 2013). Fresh green
betel leaves contains water (85–90%), protein (3–3.5%), fat (0.4–1.0%),
minerals (2.3–3.3%), fibre (2–2.3%), chlorophyll (0.01–0.25%), carbohy-
drate (0.5–6.10%), nicotinic acid (0.63–0.89 mg/100 g), vitamin C
(0.005–0.01%), vitamin A (1.9–2.9 mg/100 g), thiamine (10–70 μg/100 g),
riboflavin (1.9–30 μg/100 g), tannin (0.1–1.3%), nitrogen (2.0–7.0%),
phosphorus (0.05–0.6%), potassium (1.1–4.6%), calcium (0.2–0.5%), iron
(0.005–0.007%), iodine (3.2–3.4 μg/100 g), EO (0.08–0.2%), respectively
(Guha, 2006). Polyphenols, alkaloids, steroids, saponins, and tannins were
also found in the Piper betle leaves (Anonymous, 2004). Moreover, the
leaves also contain diastase and catalase enzymes (CSIR, 1969; Gopalan,
Ramasastri, & Balasubramanian, 1984; Guha, 2006; Guha & Jain, 1997).
Several value-added products (powder, leaves pieces, extract, and
EO) derived from the betel leaves have great benefit to human health.
Betel leaf pieces and powder having analgesic and cooling properties
are used for headaches, arthritis, joint pain, treatment of sore throat
and nervous pains, nervous exhaustion, and debility (Guha, 2006). The
leaves are also supposed to prevent bad breath (halitosis), indigestion,
bronchitis, cough, asthma, etc., and improve the vocalization, harden
3
the gum, conserve the teeth, sweeten breath. The leaf juice also works
as a medicine that is generally used for the treatment of endo-parasites,
& fever, cough, fatigue, asthma, indigestion, and skin and eye diseases
along with to disinfect wounds externally in children (Arambewela,
Arawwawala, & Ratnasooriya, 2005; Arambewela, Kumaratunga, &
Dias, 2005; Jayaweera, 1982). Mouthwashes and tablets made from
betel leaves were also used for curing diseases like dental and peri-
odontal diseases. Not only the leaf but also the natural medicinal ingre-
dients contained in the betel oil are found to be very useful to health.
The EO derived from the betel leaf contains betel phenol, diastase,
sugar and Kavikol, anti-oxidation, and anti-fungal properties. The oil
also inhibits the growth of the deadly bacteria that cause typhoid, chol-
era, tuberculosis, etc., and used to treat several traditional remedies like
stomach ailments, respiratory catarrhs, infections, etc., (Chopra, Chopra,
Handa, & Kapur, 1982; Kumaratunga, 2003; Taukoorah, Lall, &
Mahomoodally, 2016).
2.3 | Cultivation, yield, processing, and
preservation
Piper betle L. grows in the tropical as well as subtropical climatic regions
(Rai et al., 2011) and requires high rainfall and a shady place for its vigor-
ous growth. This plant grows at altitudes of 150–1,400 m in the high
land, moist (soil rich in moisture), with a rainfall of about
2,250–4,750 mm along with 40–80% of relative humidity and 15–40 C
of temperature (Guha & Jain, 1997). It is cultivated in two different ways
like under forest ecosystem and artificially created with shade condition.
Betel vine requires loamy or sandy, soil with good organic matter which
is rich in humus and having best elements of soil with sufficient
moisture-holding capacity, sufficient drainage arrangements and laying
4 MADHUMITA ET AL.
on elevated sloppy lands formed an ideal soil for betel vine plantation
(Dasgupta, Sengupta, & Jha, 1993; Patil, 2016). Red loamy soil, both light
and heavy with good soil depth (fertile soil and excellent drained) and pH
(5.6–8.2) is most suitable for the growth of betel plants whereas saline,
alkali soils and waterlogged areas are unsuitable (Pradhan et al., 2013).
Open and closed systems of cultivation of betel vine are practiced in
India. The closed system of cultivation is called borojs made by an artifi-
cial rectangular structure with bamboo or jute sticks. These structures
are made up to a height of 2–2.5 m and covered with thatched coconut
leaves or straw (Guha, 2006). Borojs are normally made on slightly slopy
nearer to a source of irrigation at a higher level than the adjoining
area for quick drainage of excess water. Its cultivation is highly labor-
intensive and offers employments to millions of people (Kaleeswari &
Sridhar, 2013).
Depending on the cultivation of betel vine, planting season varies
from state to state in India, but the onset of monsoon and October
are the correct time of planting season for cultivation. The peak
harvesting season extends from May to January. The usual productive
life span of a betel vine is 12–15 years. Betel leaf can be plucked five
times a year from a vine. To make the betel leaf plants available to the
society in a large number, its widespread cultivation must be
engineered. The production yield of this crop is about 60–70 leaves/
plant and 6–7 million leaves/ha in a year (Guha, 2006).
Generally, highly perishable products are naturally wasted due to
several environmental factors. Therefore, the application of these
products in research work and industries like organic synthesis, food,
and beverage industry, pharmaceuticals should be improved to avoid
those environmental issues. Moreover, the extract of the natural feed-
stock which is environmentally friendly can be used in the chemical
industry without purification as well as characterization. However,
these methods are very challenging and appealing. Plants and deriva-
tives have been explored for their unlimited applications like providing
food and animal feed, cosmetics, therapeutics, and energy, etc. Betel
leaves and their applications were explored through a literature
review. Betel leaves are highly perishable in nature. Therefore, during
storage and transportation period, these can easily spoiled due to
microbial infections, pest attacks, and discoloration. Betel leaf involves
a good deal of post-harvest processing, that is, storing the harvested
leaves over some time (Caburian & Osi, 2010; Sugumaran
et al., 2011). Traditionally, harvested betel leaves carried by farmers
are kept on banana leaves or cotton material, and water is sprayed on
the leaves to make them look fresh (Haider, Khair, Rahman, &
Alam, 2013). It cannot be stored for a long period; as a result, a large
portion of the leaves remain unsold or sold in the rainy season. These
post-harvest losses of betel leaves (35–70%) can be reduced if proper
preservation methods are adopted like drying the leaves, extracting
EO from the leaves, controlling senescence by different chemical
treatments, bleaching, and curing of the leaves, and adopting better
packaging materials, etc. (Guha, 2006; Madan, Balan, & Barma, 2014).
All drying process such as solar drying, shade-drying, hot air drying,
thin-layer drying experiments has been practiced for removing mois-
ture from betel leaves. This removal of moisture helps to reduce
microbial spoilage, deterioration, etc. Depetiolation is the process in
which petioles are removed by which weight of leaves is reduced to
10–25% (Madan et al., 2014) to delay the senescence and minimize
the post-harvest losses. These losses can also be minimized by a mod-
ified packaging called Modified atmospheric packaging (MAP) in which
the atmospheric gas composition surrounding the leaves is modified
to delay the senescence process and to hold the quality attributes of
the leaves (Madan et al., 2014; Pradhan et al., 2013).
Moreover, recent studies also emphasize the potential use of
plant extract and EO as ingredients in the food and non-food sectors.
Besides, these leaves having high nutritive value can be an important
source, not only for food, but also for animal feed industries which
can be very applicable for the development of rural areas (Chiesa &
Gnansounou, 2011; Contreras et al., 2019; Raman, Alves, &
Gnansounou, 2018). This scientific-based concept which enhances
the benefits of agri-food biomass having nutritional, bioactive and
techno-functional properties, and also for the reduction of the envi-
ronmental impact. Several authors have used the extract of highly
abundant different natural feedstock like rice straw, banana peel, etc.,
as a biodegradable medium for developing greener cross-coupling
reactions instead of using synthetic media. Boruah, Ali, Saikia, and
Sarma (2015) and Saikia, Borah, and Barua (2015) prepared the water
extract of rice straw ash and banana peel ash, respectively, which was
used as an alternative green medium in cross-coupling reactions at
room temperature. This result enhanced the utility of the newly devel-
oped compounds which suggest a new dimension to the chemistry
and increase the economic benefit as well as reduce the environmen-
tal impact. Keeping all these described techniques in mind, the unsold
betel leaves which are being wasted by several external factors can
become an alternative green medium in the research industry. There-
fore, the present review discusses extraction techniques that have
been adopted to recover the bioactive compounds and also focuses
their biochemical characterization worldwide.
2.4 | Economic status
The economic status of betel leaves in the worldwide market depends
on the physical nature of the end products. Betel leaf and its products
in different forms such as powder, liquid, capsules, etc., are highly
remarkable due to its various medicinal applications. Several types of
value-added products are available in a wide range in the market as die-
tary supplements, food and beverage products, pharmaceuticals, oral
care, and cosmetic products. The value-added products have been
manufactured in industrial level namely betel leaf oil, betel toothpaste,
and powders, paan masala, perfumes, mouthwash, betel ointment,
shampoo, face cream, instant betel quid and pellets, antiseptic lotions,
different medicinal and cosmetics products (Guha, 2000; Guha, 2007).
The above-mentioned products have gained a good export potential
and earned some foreign exchange through exports. India exports betel
leaves to many countries like Bangladesh, Pakistan, Indonesia, Malaysia,
Burma, and Thailand. The marketing cost of betel leaves mostly
depends on packing and transportation costs. The annual turnover of
betel vine is estimated at Rs. 10,000 million (Kumar, 1999). The cost of
MADHUMITA ET AL.
cultivation of betel vine from boroj varies, that is, about Rs 1–2 lakh/ha
in the first year (Chattopadhyay, 1981; Guha, 2006; Jana, 1995).
According to the Food and Agricultural Organization (FAO), the betel
leaf farming yield variation depends on the region, vine, season, etc.,
and net income may be Rs. 735 per 150 square feet (14 m2) of betel
farm every 6 months. However, the economic stability of the farmers
decreased due to the fluctuation in the price of betel leaves. To over-
come these problems, a well-regulated marketing system should be
developed (Guha, 2006).
3 | ISOLATION AND CHARACTERIZATION
OF COMPOU NDS
Extraction of bioactive compounds from medicinal herbs is a compli-
cated process used to find out the bioactive compounds that may be
applicable in pharmaceuticals, food, beverage industries, etc., this pro-
cess involves various steps such as, selection of plant species, collec-
tion, and identification of material, unit operations, extraction, and
characterization (Chikezie, Ibegbulem, & Mbagwu, 2015; Patra, Das,
Lee, Kang, & Shin, 2018). The selection of plant species are based on
the available literature, chemo-taxonomical studies, age and maturity
of the plant, traditional and medicinal properties, and uses. Before the
extraction process, a unit operation like drying (sun drying, cabinet
tray drying, foam mat drying, freeze-drying, refractive window drying,
superheated steam drying, radiation drying, etc.) was followed
depending on the research work. After drying, the dried materials are
subjected to the different extraction processes, which involve separa-
tion and identification of the bio-active compounds present in plant
materials (Zhang, Lin, & Ye, 2018). For an efficient extraction, it is nec-
essary to optimize the processing conditions, such as extraction time,
temperature, solid–liquid ratio, type of solvent, etc. Different types of
extraction processes, such as the common extraction technique and
advanced extraction techniques are followed (Brusotti, Cesari,
Dentamaro, Caccialanza, & Massolini, 2014). Common extraction
techniques including percolation, digestion, boiling under reflux, infu-
sion along with maceration are the simplest extraction processes
which take a long time for extraction. Advanced extraction techniques
including soxhlet extraction, sonication (ultrasound-assisted extrac-
tion), accelerated solvent extraction, hydro-distillation, steam distilla-
tion, microwave distillation, and supercritical fluid extraction are
adopted to avoid the drawbacks of common extraction technique.
Conventional extraction methods such as distillation and solvent
extraction (maceration, soxhlet, percolation, infusion extraction) and
non-conventional methods including supercritical fluid extraction,
accelerated solvent are typically been implemented in the recovery of
natural antioxidants (Azwanida, 2015) from plant sources. As effective
as they may be, high solvent and energy consumption and prolonged
extraction period make them undesirable from economical perspec-
tive (González-Centeno, Comas-Serra, Femenia, Rosselló, & derived from the extract and EO by different extraction method is
Simal, 2015). Among the distillation techniques (hydro-distillation,
steam distillation, microwave-assisted hydro-distillation, ultrasound-
assisted hydro-distillation, vacuum distillation, etc.), hydro-distillation
5
has become the most popular method because of several advantages
like simplicity, easy repair and maintenance, cheapness, and purity of
the extracted oil. Clevenger's apparatus is commonly used for the
extraction of betel leaf EO, but it has several drawbacks such as slow
extraction process, long extraction time (3–8 h) duration, poor cooling
efficiency, etc. (Arambewela et al., 2006; Arambewela, Arawwawala, &
Ratnasooriya, 2005; Arambewela, Kumaratunga, & Dias, 2005; Das
et al., 2016;
Guha 2010; Jantan et al., 1994; Periyanayagam et al. 2011; Preethy,
Elsy, & Beena, 2017; Saxena, Khare, & Saxena, 2014). To avoid these
drawbacks and to improve the efficiency of the extraction process and
the yield of EO, other modified techniques were adopted like betel leaf
oil extractor (modified Clevenger's apparatus, Guha, 2007, 2007b
and 2010), microwave-assisted hydro-distillation (Amaresh, Guha, &
Khan, 2017), ultrasound-assisted hydro-distillation, (González-Centeno
et al., 2015; Tomsik et al., 2016), etc. Recently, the use of ultrasound in
the recovery of desired compounds has been proven as an effective and
efficient extraction technique in terms of garnering more yield with
reduced solvent usage and extraction time. Ultrasound-assisted extrac-
tion (UAE) relies on the phenomenon of acoustic cavitation and mechani-
cal effects for the extraction of compounds from plant sources. The
collapse of the cavitational bubbles on the plant matrix's surface causes
the cell walls to rupture, resulting in higher and faster penetration of the
solvent into the plant material. Thus, due to enhanced overall mass trans-
fer, the extraction of the desired compounds is accelerated (Tomsik
et al., 2016). The bioactive compounds identified by the extraction
methods are characterized through several chromatographic techniques
such as thin-layer chromatography, column chromatography, high-
performance liquid chromatography, gas chromatography–mass spec-
trometry, liquid chromatography–mass spectrometry, Fourier transform
infrared spectrometry, etc. (Chikezie et al., 2015; Patra et al., 2018).
3.1 | Extraction of bioactive compounds from
betel leaves
The demand for bioactive compounds identified from natural plant
materials and its products is increasing day by day and used in various
sectors such as food, beverage, cosmetics, and pharmaceutical indus-
tries, etc. Piper betle L. is selected based on the review of their medici-
nal benefits, presence of major bioactive compounds and their
isolation, extraction, and characterization. Nowadays, the market
demands healthy and functional products that can be helpful for con-
sumers. Bioactive compounds, isolated from both the extract and EO
of betel leaves are discussed along with structural formation
(Figure 2). Compared to the extracts resulting from betel leaves using
the different extraction method, EOs has received much less atten-
tion. The extraction of EO and their compositional analysis is far more
extensive due to the volatile nature. All the bioactive compounds
presented in Tables 1 and 2, respectively.
The bio-active compounds of Piper betle L. isolated by several
authors were briefly discussed in Table 1. The extracts of betel leaves
6 MADHUMITA ET AL.

and stalks possess strong nitrogen oxide scavenging effect and free
radical scavenging effect using different assays like di(phenyl)-(2,-
4,6-trinitrophenol) iminoazanium (DPPH), hydrogen peroxide (H2O2),
superoxide radical and hydroxyl radicals (Jagetia & Baliga, 2004;
Rathee, Patro, Mula, Gamre, & Chattopadhyay, 2006). The phyto-
chemical analysis of P. betle leaves revealed the presence of terpenes
and phenols (Bajpai, Sharma, Kumar, & Madhusudanan, 2010).
Besides, the phytochemical analysis performed by Chakraborthy and
Shah (2011) and Sugumaran et al. (2011) showed that the betel leaves
extract contain saponin, phenol, alkaloids, amino acids, tannins, flavo-
noid, steroid, and other compounds. Two of the eight components
(3-ρ-coumaroylquinic acid and 4-ρ-coumaroylquinic acid) were identi-
fied by HPLC/electrospray ionization mass spectrometric (ESI-MS)
using solvent extracted betel leaves (Ma et al., 2013). In another
study, compounds like 27.81% of 4-chromanol (Piper betel aqueous
extract), 61.15% of phenol 2 methoxy 4–(−2 propenyl) acetate (etha-
nol extract), 20.37% of eugenol and 27.81% of 4 chromanol (aqueous
and ethanol extract) were identified by gas chromatography–mass

FIGURE 2 Structures of important compounds isolated from Pipre betle L

MADHUMITA ET AL. 7

FIGURE 2 (Continued)
8 MADHUMITA ET AL.

TABLE 1 List of bioactive compounds identified from leaves extract of Piper betle L.

Sl. No. Piper betle leaves extract Isolated bioactive compounds References

1 Dried leaves extract using ethanol by Hydroxychavicol (66.55%), eugenol (11.92%), Ali, Chong, Mah, et al. (2018), Ali, Lim,
ultrasound assisted extraction isoeugenol (2.90%) and 4-allyl- Chong, et al. (2018), and Ali, Lim, and
1,2-diacetoxybenzene (3.21%). Wahida (2018)

2 Leaf extract var. haldia using chloroform by 1-n-dodecanyloxy resorcinol (H1) and Atiya, Sinha, & Lal, 2018
nuclear magnetic resonance (NMR) desmethylenesqualenyl deoxy-
analysis cepharadione-A (H4)

3 Dried leaves extract using ethanol by Hydroxychavicol, eugenol, isoeugenol and Ali, Chong, Mah, et al. (2018), Ali, Lim,
ultrasound assisted extraction allylpyrocatechol 3,4-diacetate Chong, et al. (2018), Ali, Lim, and
Wahida (2018)

4 Dried leaf extract var. Meetha and Banarasi Proximate analysis highest phyosterols Sarma et al. (2018)
paan using distilled water, hexane,
acetone and ethanol solvent extraction

5 Soxhlet extraction Hydroxy chavicol (69.46%), 4-Chromanol (24%) Muruganandam, Krishna, Reddy, and
and Eugenol (4.86%), 1-phenylpropene- Nirmala (2017)
3,3-diol diacetate (0.923) and 4-allyl-
1,2-diacetoxybenzene

6 Ethanolic extract of red betel leaves by Neophytadiene, propionic acid, and elemicin Anugrahwati, Purwaningsih, Rustina,
soxhlet extraction Manggalarini, Alnavis, Wulandari, and
Pranowo (2016)

7 Dry leaf extract maceration extraction, TPC, TFC and tannin Taukoorah et al. (2016)
phytochemical screening

8 Leaf extract using hexane, ethyl acetate 4-Allyl-1,2-Diacetoxybenzene, chavicol and Choopayak et al., 2016, Murata et al. (2009),
and ethanol eugenol and Venkadeswaran, Thomas, and
Geraldine (2016)

9 Betel leaf extract powder using Soxhlet Alkaloids, fatty acids, phenolic compounds, Foo, Salleh, and Mamat (2015)
apparatus with 70% deionised water alcoholic compounds, flavonoids
and ethanol compounds, terpenes compounds, coumaran
compounds and organic acids

10 Solvent extraction (methanol) and TPC, TFC and CQAC Tan and Chan (2014)
microwave treatment

11 Solvent extraction method using four Higher polyphenolic contents Nouri et al. (2014)
different solvents (methanol, ethanol,
acetone, and ethyl acetate

12 Leaf extract Tannins, anthraquinones, flavonoids, alkaloids, Kumari and Rao (2014) and Rekha, Kollipara,
terpenoids, saponins, cardiac glycosides, Gupta, Bharath, and Pulicherla (2014)
glycosides, phlobatanins, hydroxychavicol
acetate, allylpyrocatechol piperbetol,
isoeugenol, anethole, stearic acid, methyl
eugenol, carvacrol, chavicol, and
allylpyrocatechol

13 Betel leaf extract phytochemicals Hydroxychavicol Gundala et al. (2014)

14 Solvent extraction and HPLC/ESI-MS–MS Eight components with major compounds 3-ρ- Ma et al. (2013)
coumaroylquinic acid and 4-ρ-
coumaroylquinic acid

15 Piper betel aqueous and ethanol extract 4-chromanol, phenol 2 methoxy 4–(−2 Deshpande and Kadam (2013)
propenyl) acetate, eugenol,

16 Chavibetol and eugenol Akhtar and Naveed (2012)

17 Spray dried powder of leaf Phenolic compounds, tannins, flavonoids Arawwawala et al. (2011)
steroids, and alkaloids

PBL extract Eugenol, a-tocopherol, b-carotene, Rai et al. (2011)

hydroxychavicol and ursolic acid
18 Crude aqueous extract Hydroxychavicol, Hexadecanoic acid, Lakshmi and Naidu (2010); Thurairajah and
Octadecanoic acid,2,3- bis(hydroxy)propyl rahim (2007)
ester, Benzeneacetic acid, Eugenol

19 Chloroform extraction of Hydroxychavicol Ali et al. (2010)

the aqueous leaf extract
MADHUMITA ET AL. 9

TABLE 2 List of bioactive compounds identified from Piper betle L. EO

Sl. No. Piper betle leaves EO Isolated bioactive compounds References

1 EO of leaf by microwave extraction
(modified microwave oven with clevenger
apparatus)
2 EO of leaf var. Bangla, Bagerhati,
Manikdanga, Meetha, Kalibangla,
Chhaanchi and Ghanagete
3 EO of leaf var. Tamluk Meetha
4 Essential oil of leaves var. magahi hydro-
distillation using Clevenger's
Apparatus
5 EO of leaves by Clevenger-type apparatus
6 EO of Piper betle L.
7 EO of Piper betle L.
8 EO of Piper betle L. (cultivar: Galdalu,
mahamaneru, Kudamaneru, Ratadalu,
Nagawali, and Malabulath)
9 EO of Piper betle L.
Phenylpropene compounds Agarwal and Gupta (2018)
43 compounds with major compounds Karak et al. (2018)
eugenol acetate and eugenol
46 compounds among with major Basak and Guha (2015)
compounds like chavibetol (22.0%),
estragole (15.8%), β-cubebene (13.6%),
chavicol (11.8%), and caryophyllene
(11.3%)
32 chemical compounds with Eugenol Prakash et al. (2010)
(63.39%) and acetyleugenol (14.05%)
Eugenol (36.2%), chavibetol acetate (16.9%), Row and Ho (2009)
4-allylphenyl acetate (9.4%) and
4-allylphenol
(7.2%)
Fourteen chemical constituents chavibetol Ghosh and Bhattacharya (2005) and
(53.1%), chavibetol acetate (15.5%), Rimando, Han, Park, and
allypyrocatechol diacetate (0.71%), Cantoria (1986)
camphene (0.48%), chavibetol methyl
ester (methyl eugenol 0.48%), eugenol
(0.32%), ß-pinene (0.21%), a-limonene
(0.14%), safrole (0.11%), 1,8-cineole
(0.04%) and allypyrocatechol
monoacetate
Eugenol, hydroxychavicol Bhide, Zariwala, Amonkar, and
Azuine, (1991), Garg and Jain (1996),
Ramalakshmi, Sulochanamm, Rao,
Borse, and Raghavan (2002), Rawat,
Tripathi, Khan, and
Balasubrahmanyam (1989), and Sankar,
Sridevi, and Babu, (1996),
Major compounds like safrole, Arambewela, Arawwawala, and
β-phellandrene, 4-terpineol, eugenol, Ratnasooriya (2005), Arambewela,
chavitol acetate, allylpyrocatechol Kumaratunga, and Dias (2005), and
diacetate Gundala et al. (2014)
4-allyl-2-methoxy-phenolacetate (31.47%), Apiwat et al. (2006)
3-allyl-6-methoxyphenol (25.96%), and
4-allylpheny acetate (5.21%) with other
minor compounds

spectrometry (Deshpande & Kadam, 2013). Kumari and Rao (2014)
with Rekha et al. (2014) reported the presence of major chemical
compounds like chavicol, carvacrol, methyl eugenol, isoeugenol,
hydroxychavicol, etc., along with other constituents in P. betle.
Gundala et al., 2014 identified the most abundant phytochemicals,
that is, hydroxychavicol in betel leaf extract that contributes to the
antiproliferative efficacy of leaf. Tan and Chan (2014) studied the anti-
oxidant properties along with antityrosinase and antibacterial proper-
ties of Anacardiumoccidentale (cashew) and Piper betle (betel) fresh
and processed leaves through a solvent (methanol) and microwave
extraction treatment. They found that total phenolic content (TPC),
total flavonoid content (TFC), and caffeoylquinic acid content (CQAC)
were declined for both blanched leaves. Comparing both treatments,
microwave-treated extract has a significant increase in tyrosinase inhi-
bition (4,974.0%). Nouri et al. (2014) is also reported the solvent
extraction method using four types of solvent (ethanol, methanol, ace-
tone, and ethyl acetate) with five different concentrations of 30, 50,
70, 90, and 100% (vol/vol) in deionized water and 100% deionized
water. The results revealed that among all the solvents, higher antioxi-
dant activities and polyphenolic contents were found in 90% of etha-
nol and methanol extracts. Foo et al. (2015), identified some valuable
bioactive compounds by GC–MS analysis from betel leaf extract pow-
der using the Soxhlet apparatus with 70% deionized water and etha-
nol. The bioactive compounds like phenolic, flavonoids, alcoholic,
10
terpenes, alkaloids, fatty acids, and organic acids were identified. In
another study, the ethanolic extract of red betel leaves contained
neophytadiene, propionic acid, and elemicin compounds were
obtained by the soxhlet extraction method. Propionic acid and
elemicin significantly inhibited the microbial growth (Anugrahwati,
Purwaningsih, Rustina, Manggalarini, Alnavis, Wulandari, and
Pranowo, 2016). Taukoorah et al. (2016) reported the phytochemical
screening of dry betel leaf extract obtained by the maceration extrac-
tion method. The statistical results revealed that tannin content
(R2 = 0.9971), TPC (R2 = 0.9881) and TFC (R2 = 0.9981) was found to
be significant. Recently, Muruganandam et al. (2017) studied the opti-
mization of Soxhlet extraction conditions to obtain the maximum yield
(10.94%) of Piper betle extract using Box–Behnken design at the opti-
mized condition: material quantity of 2 g, the solvent quantity of

281.4 ml, the temperature of 72 C and extraction time 3 hr. They also
reported FT-IR and GC–MS analysis of optimized extract to find out
the presence of chemical groups and compounds. GC–MS revealed
valuable compounds such as 69.46% of hydroxy chavicol, 24% of
4-chromanol and 4.86% of eugenol, 0.923% of 1-phenylpropene-
3,3-diol diacetate and 0.765% of 4-allyl-1,2-diacetoxybenzene that
possess antioxidant, anti-inflammatory, antithrombotic, and antimicro-
bial activities. Moreover, FT-IR analysis of betel leaves extracts
obtained by ethanol solvent confirmed the presence of alcoholic
groups with respect to major peak areas like amines (3,311.78/cm),
monomeric alcohols, phenols (2,927.94/cm), carboxylic acids
(1,707.00/cm); alkanes (1,367.53/cm); ethers (1,045.42/cm), and
esters and alkenes (879.54/cm), respectively. In another study, com-
pounds like eugenol, 4-allyl-1, 2-diacetoxybenzene, and chavicol pre-
sent in betel leaves extract are found to be responsible for anti-fungal
medicinal activity (Murata et al., 2009; Venkadeswaran et al., 2016).
Ali et al. (2010) reported the major phenolic compounds like
hydroxychavicol (66.55%), eugenol (11.92%), isoeugenol (2.90%) and
4-allyl-1,2-diacetoxybenzene (3.21%) from the optimized ultrasound-
assisted extract of Piper betle leaves using three levels Box–Behnken
design. A maximum extraction yield of 13.71%, 289.05 mg GAE/g
d.w. of TPC, 21.50 mg RE/G d.w. of TFC and 94.99% of was found at
the optimized conditions: 51.60 C of extraction temperature, 78.74%
ethanol concentration and 1:21.85 g/ml of solute to solvent ratio.
Ali, Chong, Mah, et al. (2018) reported some phenolic compounds
like eugenol, hydroxychavicol, isoeugenol, and allylpyrocatechol
3,4-diacetate of dried betel leaves extract that stored in different stor-
age temperature conditions for 6 months. The best stability with
100% retention was found in hydroxychavicol, whereas moderate sta-
bility was found in eugenol and isoeugenol through the entire storage
period. Ali, Lim, and Wahida (2018) also studied ultrasound-assisted
extraction and maceration extraction of Piper betle leaf powder using
ethanol and water as solvents. The results revealed the highest and
lowest phenolic content was found to be 840 mg GAE/g (95% etha-
nol) and 460 mg GAE/g (50% ethanol) along with 200 mg GAE/g
(water), respectively. The Piper betle var. haldia, leaves extract using
chloroform contained 1-n-dodecanyloxy resorcinol and des-
methylenesqualenyl deoxy-cepharadione-A (Atiya et al., 2018). Sarma
et al. (2018) focused on evaluating antioxidant activity of two selected
MADHUMITA ET AL.
varieties of betel leaves (Meetha and Banarasi paan) extract using dis-
tilled water, hexane, acetone, and ethanol as solvent. The results rev-
ealed that among the extracts, ethanolic extract of Banarasi paan had
the highest antioxidant (89.46%).
Besides leaf extract powder, EO extracted by different extraction
methods, and its chemical composition was also presented in Table 2.
The first study describing the composition of EO of Piper betle
L. was carried out by Rimando et al. (1986) and Ghosh and
Bhattacharya (2005). Fourteen chemical constituents namely, 53.1%
of chavibetol, 15.5% of chavibetol acetate, 0.71% of allypyrocatechol
diacetate, 0.48% camphene along with other compounds (methyl
eugenol, eugenol, α-pinene, ß-pinene, α-limonene, safrole, and
1, 8-cineole) were identified. Rawat et al. (1989) studied the identifi-
cation of volatile constituents of EO extracted from five landraces of
betel vine. Fifty-one compounds were isolated, and eugenol was
found to be highest in all landraces. Hydroxychavicol, a phenolic com-
pound, with other compounds of less percentage present in extracted
EO of different varieties were also reported which possess several
activities like antioxidant, biological, and anticarcinogenic activity
(Bhide et al., 1991; Garg & Jain, 1996; Ramalakshmi et al., 2002; San-
kar et al., 1996). Row and Ho (2009) revealed the chemical composi-
tion of betel leaf EO and its fractions that were analyzed by GC–MS.
GC–MS analysis of the crude oil revealed an abundance of
allylphenolic compounds and 36 compounds were identified, rep-
resenting 98.1% of the EO. Among them, 36.2% of eugenol, 16.9%
of chavibetol acetate, 9.4% of 4-allyl phenylacetate and 7.2% of
4-allylphenol were found as major components, comprising 69.7% of
the oil. In another study, because of the presence of eugenol, EO pos-
sesses the antibacterial, antifungal activity, and many pharmacological
activities (Lakshmi & Naidu, 2010; Thurairajah & Rahim, 2007).
Prakash et al. (2010) investigated the chemical composition and anti-
oxidant properties EO of betel leaves var magahi. Out of 32 constitu-
ents, 63.39% of eugenol and 14.05% of acetyl eugenol were
identified as major components of betel leaf EO. The EO also
exhibited strong antioxidant potential showing IC50 value (3.6 μg/ml)
that was close to 3.2 μg/ml of ascorbic acid, 7.4 μg/ml of butylated
hydroxytoluene (BHT) and 4.5 μg/ml of butylated hydroxyanisole
(BHA), respectively. Moreover, chavibetol was found to be another
organic chemical compound that contributes to its spicy odor,
whereas eugenol as a principal constituent of betel leaf EO possesses
antifungal and anti-inflammatory effects (Akhtar & Naveed, 2012).
Dwivedi and Tripathi (2014) stated that betel leaf EO mainly com-
posed of terpinen-4-ol, safrole, allyl pyrocatechol monoacetate, euge-
nol, eugenol acetate, hydroxyl chavicol, eugenol, cadinene carvacrol,
allyl catechol, p-cymene, caryophyllene, chavibetol, cineole, estragole,
etc. Sugumaran et al. (2011), identified 65 chemical constituents in
betel leaves EO that extracted using the hydro-distillation method.
The predominant chemical constituents were 5-(2-propenyl)- 1,3
benzodioxole (25.67%) followed by eugenol (18.27%) and 2-methoxy-
4-(2-propenyl) acetate-phenol (8.0%). In another study, the major
compounds like 22.0% of chavibetol, 15.8% of estragole, 13.6% of
β-cubebene, 11.8% of chavicol, and 11.3% of caryophyllene were
found in Tamluk Meetha variety of betel leaf EO among 46 identified
MADHUMITA ET AL. 11

TABLE 3 Different biological activities of Piper betle L.

Sl. No. Extraction of Piper betle leaves Activities References

Antimicrobial activity
1 Leaf extract using ethanol Antimicrobial activity using micro-organisms Ali, Lim, and Wahida (2018)
like Escherichia coli, Staphylococcus aureus,
Streptococcus mutans and Streptococcus
salivarius
2 Red betel (Piper crocatum Ruiz & Pav.) Antimicrobial activity using Staphylococcus Hartini, Diaseptana, Putri, and
leaves aureus, Staphylococcus epidermidis or Susanti (2018)
Eschericia coli.
3 Leaf extract Antimicrobial activity using Vibrio Othman, Saad, Yusof, and
alginolyticus Abdullah, (2018)
4 Leaf extract using ethanol (EE), ethylacetate Antimicrobial activity using Staphylococcus Taukoorah et al. (2016)
(EAE), acetone (ACE), and aureus
Dichloromethane (DCME)
5 Leaf extract var ambadi using methanol and Antimicrobial activity using E. coli, Kleb. Jayalakshmi, Raveesha, Murali, and
chloroform pneumoniae, B. subtilis, B. cereus, Salm. Amruthesh (2015)
typhi, Ent. aerogenes and Staph. Aureus
6 Leaf extract Antimicrobial activity using 5 g positive Nouri et al. (2014)
bacteria (Staphylococcus aureus,
Staphylococcus epidermis, Bacillus cereus,
Bacillus subtilis, Listeria monocytogenes)
5 g negative bacteria (Escherichia coli,
Salmonella Typhimurium, Salmonella
enterididis, Kelebsiella pneumonia,
Pseudomonas aerogenosa)
7 Leaf extract by microwave extraction Antimicrobial activity using B. brevis, M. Tan and Chan (2014)
luteus, S. Enteric, P. aeruginosa, S. cohnii
and E. coli
8 Leaf extract using ethanol Antimicrobial activity using Escherichia coli, Hoque et al. (2011)
Vibrio cholera, and Staphylococcus aureus
9 Leaf extract var. Desawari, Desi, Antimicrobial activity using Pseudomonas Agarwal, Singh, Shukla, Waris, and
Bangladeshi, and Jaleswar using cold aeruginosa, Staphylococcus aureus and Gujrati (2012)
aqueous, methanol, ethanol, and ethayl Escherichia coli
acetate
10 Spray dried leaf powder Antimicrobial activity using Escherichia coli, Arawwawala et al. (2011)
Salmonella spp, Staphylococcus aureus,
and Pseudomonas aeroginosa
11 Leaf extract using water, methanol, ethyl Antimicrobial activity using Streptococcus Chakraborthy and Shah (2011)
acetate and petroleum ether pyogenes, Staphylococcus aureus, Proteus
vulgaris and Escherichia coli
12 Leaf extract using aqueous and ethanol Antimicrobial activity using three garm Kaveti, Tan, Sarnnia, Kuan, and
positive bacteria (acillus subtilis, Baig (2011)
Staphylococcus aureus and Micrococcus
luteus), and two negative bacteria
(Escherichia coli and Pseudomonas
Aeruginosa)
13 Leaf extracts using ethanol and methanol Antimicrobial activity using pathogenic Khan and Kumar (2011)
bacteria namely, Escherichia coli,
Pseudomonas aeruginosa and
Staphylococcus aureus
14 Leaf extract using ethanol Antimicrobial activity using Pseudomonas Datta, Ghoshdastidar, and Singh (2011)
aeruginosa, Klebsiella pneumonia, Proteus
vulgaris and Staphylococcus aureus
15 Leaf extract using water, methanol, ethyl Antimicrobial activity using Chakraborthy and Shah (2011)
acetate and petroleum ether Streptococcuspyogenes, Staphylococcus
aureus, Proteus vulgaris and Escherichia
coli.

(Continues)
12 MADHUMITA ET AL.

TABLE 3 (Continued)

Sl. No. Extraction of Piper betle leaves Activities References

16 Aqueous leaf extract using chloroform Antimicrobial activity using124 fungal Ali et al. (2010)
strains
17 Leaf extract var. magahi Antimicrobial activity using A. flavus Prakash et al. (2010)
18 Leaf extract using methanol Antimicrobial activity using C. albicans, and Row and Ho (2009)
M. pachydermatis
19 Leaf extract using ethanol Antimicrobial activity using Candida albicans Trakranrungsie, Chatchawanchonteera,
(yeast), Microsporum canis, Microsporum and Khunkitti (2008)
gypseum and Trichophyton
mentagrophyte (zoonotic dermatophytes)
20 Leaf extract using aqueous and methanol Antimicrobial activity using10 gram Nair and Chanda (2008)
positive, 12 gram negative bacteria and
one fungal strain, Candida tropicalis
21 Crude aqueous extract Antimicrobial activity using Streptococcus Thurairajah and rahim (2007)
mutans
22 Leaf extract using ether Antimicrobial activity using Aspergillus fIauus Parmar et al. (1998)
23 Cured leaf EO var. Bangla Antibacterial activity using Mycobacterium Madhumita et al. (2019a)
smegmatis, Staphylococcus aureus, and
Pseudomonas aeruginosa
24 Leaf EO var. Meetha Antimicrobial activity using Aspergillus flavus Basak (2018b)
and Penicillium expansum
25 Essential oil of P. betle Antimicrobial activity using E. coli, P. Aumeeruddy-Elalfi, Gurib-Fakim, and
aeruginosa, S. aureus, and Acinetobacter Mahomoodally (2015)
EO of betel leaves Antibacterial activity using E. coli, P. Arambewela, Arawwawala, and
aeruginosa, S. epidermidis, S. aureus, S. Ratnasooriya (2005)
pyogens
Other activities
1 Hot water leaves extract Gastroprotective activity Pradhan et al. (2013)
2 Piper betle plant extract Antifertility activity/ female rats Pradhan et al. (2013)
3 Methanolic extract of betel leaves Analgesic and anti-inflammatory activity Alam et al. (2013)
4 Ethanolic extract of Piper betle leaves Antidepressant activity Meti Vinayak et al. (2012)
5 Aqueous and ethanol extract of betel leaves Antibacterial activity using B. subtilis, S. Kaveti, Tan, Sarnnia, Kuan, and Baig
aureus, and M luteus, E. coli, and P. (2011)
aeeugonisa using agar diffusion method
6 Piper betle spray dried powder Antidiabetic activity for the treatment of Sujatha, Menuka, Rajapaksha, and
type 2 diabetes patients Ariyawansa (2011)
7 Aqueous extract of betle leaves Antioxidative and antihemolytic activity Chakraborthy and Shah (2011)
using microorganisms like Streptococcus
pyogenes, Staphylococcus aureus,
Pseudomonas aeruginosa and E. coli
8 Piper betle leaf infusion Skin antiseptic/pre-surgery cataract Amallia and Sitompul (2009)
patients
9 Crude ethanolic extract of betel leaves Antidermatophytic activity using yeast like Trakranrungsie et al. (2008)
Candida albicans
10 Piper betle leaf extract Antihepatotoxic effect induced liver injury Young et al. (2007)
in a rat model
11 Methanolic extract of the Piper betle Immunomodulatory activity Kanjwani et al. (2006)
12 Petroleum ether and methanol extract of Insect attractant property in a cornfield Yusoff et al. (2005)
betel leaves
13 Ethanolic extract of Piper betle leaf Radioprotective activity Bhattacharya et al. (2005)

compounds (Basak & Guha, 2015). Agarwal and Gupta (2018) rev- leaves and GC–MS analysis revealed the presence of valuable com-
ealed an improved microwave extraction (modified microwave oven pounds which possess antioxidant, anti-inflammatory, anti-bacterial
with Clevenger apparatus) method for the distillation of EO from betel and antifungal activities. Also, Karak et al. (2018) reported the
MADHUMITA ET AL.
chemical composition, enzyme inhibitory and cytotoxic properties of
seven local varieties of betel leaves such as Bangla, Bagerhati, Man-
ikdanga, Meetha, Kalibangla, Chhaanchi and Ghanagete. Eugenol
(23.60%) and eugenol acetate (35.77%) were found to be highest
among 45 EO constituents with good cytotoxic properties and
β-glucuronidase inhibitory properties. Moreover, Madhumita, Guha,
and Nag (2019a, 2019b) worked on the EO of cured betel leaf (var.
Bangla) extracted by the HD method and found 33 volatile com-
pounds, representing 98.41% of EO.
3.2 | Biological activities
3.2.1 | Antimicrobial activity
Several studies have been conducted aiming at its various antimicrobial
activities of Piper betle L. as shown in Table 3. The EO, extracted from
betel leaves, possesses strong antimicrobial activities that reduce the
adherence of early dental plaque bacteria (Punuri, Sharma, Sibyala,
Tamuli, & Utpal, 2012). Eugenol, an important compound extracted
from Piper betel exhibited strong antifungal activity against Aspergillus
fIavus (Parmar et al., 1998). The extracts of the betel vine parts (stalks
and stems) and the EO extracted by leaves also exhibited strong anti-
fungal activity and found to be effective at 450 μg/ml concentration
(Bandyopadhyay, Pal, Bhattacharya, Ray, & Roy, 2006). Moreover, the
aqueous and methanolic Terminalia catappa L., Manilkara zapota L. and
Piper betel L. leaf extract were selected to analyze the antibacterial
activity against some selected microorganisms that are described in
Table 3 and the methanolic extract was found to be more effective to
inhibit the microbial strains (Nair & Chanda, 2008). Trakranrungsie
et al. (2008) worked on the antimicrobial activity of crude ethanolic
extracts of betel leaves against some zoonotic dermatophytes like
Microsporum canis, Microsporum gypseum, and Trichophyton men-
tagrophyte and the yeast-like Candida albicans. The results of the anti-
microbial activity analysis revealed that betel leaves extract exhibited
more effective antifungal properties having an antioxidant activity of
average IC50 values that ranged from 110.44 to 119.00 lg/ml. Row and
Ho (2009) studied the antimicrobial activity of EO and solvent extract
(methanolic and aqueous extracts) of P. betle against the selected
yeasts like C. chromatography-mass, and M. pachydermatis using disk
diffusion method. The methanolic and aqueous extracts, along with EO,
exhibited strong activity against the yeasts. Prakash et al. (2010) inves-
tigated the antifungal activity of magahi variety of betel leaf EO. The
minimum inhibitory concentration (MIC) of the EO obtained from betel
leaves was found to be 0.7 μL/ml against A. flavus. The volatile com-
pounds such as propenylphenols, allylpyrocatechol diacetate,
chavibetol, chavibetol acetate, chavicol, and hydroxychavicol, identi-
fied from the chloroform extracted betel leaves extract had a significant
fungicidal effect (Ali et al., 2010). Chakraborthy and Shah (2011) stud-
ied the antibacterial activities of betel leaf extract using water, metha-
nol, ethyl acetate, and petroleum ether as a solvent against the selected
pathogenic bacteria like Streptococcus pyogenes, Staphylococcus aureus,
Proteus vulgaris, and Escherichia coli. The results found that all the
13
extracts exhibited a clear zone of inhibition against all the bacteria
because of the high concentration of sterols. Also, the crude ethanol
extract of Piper betel showed potent antimicrobial activity against Pseu-
domonas aeruginosa, Klebsiella pneumonia, Proteus vulgaris, and Staphy-
lococcus aureus (Datta et al., 2011). Khan and Kumar (2011) evaluated
the antibacterial properties of Piper betle leaf extracts (ethanolic and
methanolic) against pathogenic bacteria namely, Escherichia coli, Pseu-
domonas aeruginosa, and Staphylococcus aureus. The results revealed
that methanolic extract showed maximum zone of inhibition of 25 mm
against S. aureus, by a zone of 17.5 mm against P. aeruginosa, and
15 mm against E. coli. The methanolic extract was found to be more
effective than ethanolic extract against the used pathogens. Besides
this, three gram-positive bacteria (Bacillus subtilis, Staphylococcus
aureus, and Micrococcus luteus), and two gram-negative bacteria
(Escherichia coli and Pseudomonas aeruginosa) were selected for the
antibacterial activity of aqueous and ethanol betel leaf extracts. Ethanol
extract showed more significant and effective antibacterial activity
than aqueous ones due to the presence of alkaloids, tannins, phenolic
substances, and glycosides, etc. (Kaveti, Tan, Sarnnia, Kuan, and Baig,
2011). Moreover, the antibacterial activities of different varieties of
dried betel leaves (Desawari, Desi, Bangladeshi, and Jaleswar) extracts
were tested against pathogenic bacteria like Pseudomonas aeruginosa,
Staphylococcus aureus, and Escherichia coli using agar well diffusion
method. The dried leaf extracts were obtained by cold aqueous, metha-
nol (80%), ethanol (70%), and ethyl acetate (80%) solvent extraction
method. The results revealed that Bangladeshi and Jaleswar varieties of
betel leaf extract were an effective and good source of herbal drugs
having strong antibacterial activity (Agarwal et al., 2012). Ethanol
extract of betel leaves showed excellent potential to inhibit the growth
of foodborne pathogens such as Escherichia coli, Vibrio cholera, and
Staphylococcus aureus (Hoque et al., 2011). Tan and Chan (2014)
worked on microwave treated A. occidentale, and P. betle leaves to eval-
uate the antibacterial activity against B. brevis, S. enteric, P. aeruginosa,
S. cohnii, M. luteus, and E. coli. The antibacterial activity of treated leaves
against B. brevis, E. coli and S. enteric was found to be stronger than M.
luteus and P. aeruginosa, and remain unchanged against S. cohnii. Nouri
and Nafchi (2014) found that betel leaf extract using four solvents like
ethanol, methanol, acetone, and ethyl acetate exhibited good antimi-
crobial activity against five gram-negative bacteria (E. coli, Salmonella
typhimurium, Salmonella enterididis, Klebsiella pneumonia, Pseudomonas
aeruginosa) and gram-positive bacteria (S. aureus, S. epidermis, B. cereus,
B. subtilis, L. monocytogens) except P. aeruginosa. Additionally, the anti-
microbial properties of EO extracted from P. betle along with other
eight medicinal herbs were studied against 18 microorganisms. P. betle
EO showed a synergistic effect against E. coli and Staphylococcus epider-
mis (Aumeeruddy-Elalfi et al., 2015). Jayalakshmi et al. (2015), studied
antibacterial properties of ambadi variety of methanol and chloroform
betel leaf extract against E. coli, Kleb. pneumoniae, B. subtilis, B. cereus,
Salm. typhi, Ent. aerogenes and S. aureus. Methanol betel leaf extract
showed a good scavenging activity with a strong antibacterial activity
than chloroform extract. Taukoorah et al., 2016 investigated the
antibacterial activities of ethanolic, ethyl acetate, acetone, and dic-
hloromethane extracts from P. betle against six bacterial strains like
14
E. coli, S. aureus, P. aeruginosa, P. acnes, S. epidermis, and S. pyogenes.
Among all the extracts, ethyl acetate and acetone extract exhibited a
strong antibacterial activity against all the selected bacteria except S.
aureus obtaining the lowest MIC value (0.25 μg/μl). Singh et al. (2018)
reported a hydroxychavicol compound present in betel leaf extract that
induces bacterial cell death by DNA damage and inhibition of cell divi-
sion. Moreover, the antimicrobial activity of Piper betle leaf extract was
studied against Vibrio alginolyticus, isolated from Asian sea bass, Lates
calcarifer. The antimicrobial activity was evaluated by the disc diffusion
method, and 100 mg/ml of the extract exerted a significant (p < .05)
effect with the largest inhibition zone (19 mm) compared to other con-
centrations (Othman et al., 2018). Hartini et al. (2018) discussed the
antibacterial activity of betel (Piper betle L.), and red betel (Piper
crocatum) leaves using a paper disk diffusion method, against gram-
positive and gram-negative bacteria. The results revealed that the com-
bination of betel and red betel showed lower antibacterial activity than
betel or red betel alone against Staphylococcus aureus, Staphylococcus
epidermidis, and Eschericia coli. Basak (2018a, 2018b, 2018c) discussed
the modeling effect of betel leaf EO var. Meetha on germination time
of Aspergillus flavus, and Penicillium expansum spore population. Experi-
mental data of the spore germination rate was significantly fitted
(R2 = 0.95%) to the asymmetric model. Minimum inhibitory concentra-
tion for spore germination of A. flavus, and P. expansum was found to be
0.65 and 0.54 μl/ml. Ali, Lim, and Wahida (2018) evaluated and com-
pared the antimicrobial activity of added and without added P.betle
extract in commercially available three types of toothpaste (Colgate
total, Paradontax, and Darlie) against S. aureus, E. coli, S. mutans, and S.
salivarius. Among 95% ethanolic, 50% ethanolic and water extract, the
highest TPC and growth inhibitory effects for the gram-negative E. coli,
with a MIC of 5 mg/ml were found in 95% ethanolic extract. This similar
result was also found by Khan and Kumar (2011), where methanolic
betel leaf extracts showed antimicrobial activity with a MIC of 8.196
and 0.0021 mg/ml for E. coli and S. aureus, respectively. The reason
behind this difference depends on the cellular structure of bacteria hav-
ing a thicker cell wall in gram-positive bacteria and a thinner outer
membrane in gram membrane bacteria. In another study, antimicrobial
activity (antibacterial and antifungal test) of Piper betle extract was
tested using ethanol, distilled water, hexane and acetone solvents
against four pathogens viz. B. subtilis, E. coli, A. niger, and S. cerevisiae.
Among the solvent extracts, ethanolic extract showed maximum inhibi-
tion zone against E. coli followed by S. aureus (Sarma et al., 2018).
3.2.2 | Other biological activities
There are other several biological activities like antioxidant, antican-
cer, antidiabetic, anti-inflammatory, etc., besides antimicrobial activity
(Table 3). Betel leaves contain high amounts of phytochemicals, which
can help fight cancer although betel nuts having the risk of cancer.
Moreover, it can help fight oxidative stress and eliminates free radicals
by which it can prevent cancer (Rai et al., 2011). Ascorbic acid, as an
excellent antioxidant, is very useful to reduce the free radicals in the
body and thus prevents cancer. Extracts of betel leaves have a
MADHUMITA ET AL.
gastroprotective activity which helps in preventing gastric ulcers
(Namburi, Omprakash, and Babu, 2011; Arawwawala et al, 2011).
Also, to prevent dental caries, betel leaves have been traditionally
used as a mouth freshener in India and other Southeast Asian coun-
tries. Nowadays, diabetes disorder is becoming common in human
beings. It is a heterogeneous and metabolic disorder of carbohydrate,
lipid and protein metabolism characterized by high blood glucose
levels due to the absolute deficiency of insulin. Due to this deficiency,
body cells do not respond properly to insulin. Therefore, some anti-
diabetic drugs, as a medicine, are used to control the increased blood
glucose level in the body. Some of the researchers reported that the
oral administration of leaf suspension of betel leaf at 75 and 150 mg/kg
of body weight for 30 consecutive days to streptozotocin-induced dia-
betic rats caused a significant decrease in blood glucose and glyco-
sylated hemoglobin levels. Administering betel leaf to diabetic animals
is also reported and in this report, it was found that glucose-
6-phosphatase and fructose-1, 6-bisphosphatase levels decrease in the
liver with an increase of hexokinase levels (Madan et al., 2014).
Betel leaf has a great role in the anti-inflammatory activity which has
been used as a household remedy for the inflammation of the oral
cavity (Dohi, Terada, Anamura, Okamoto, & Tsujimoto, 1989). Anti-
inflammatory is the activity that helps in the treatment of inflammation
or swelling. Inflammation is considered a part of the complex biological
response of vascular tissues to dangerous stimuli such as pathogens,
damaged cells, etc. It is also reported that the ethanolic extracts of betel
leaf possess anti-inflammatory activities at non-toxic concentrations, in
the complete Freund's adjuvant-induced model of arthritis in rats.
Eugenol, a principal compound of betel leaf, also possesses anti-
inflammatory effects in different animal models of studies with
different inflammogens (Azuine, Amonkar, and Bhide, 1991). Besides
eugenol, HC and α-tocopherol, also enhance the levels of Glutathione
(GTH) in mouse skin and liver. This compound acts as an important anti-
oxidant in the human body (Bhide et al., 1991). Due to the presence of
high flavonoid content of betel leaves, the anti-ulcerogenic activity has
also been attributed. Betel leaf extracts can cure gastric ulcers and pep-
tic ulcers (Chaurasia and Johri, 1990). The betel leaf is used as a house-
hold medicine for inflammation alone or with other medicinal plants,
like turmeric and sandalwood paste.
4 | FU T U R E R E S E A RC H
Traditionally, P. betle leaves, treated as medicines having valuable bio-
active compounds, are extensively used in India and elsewhere
because of their low cost and easy accessibility. This can be used as
an additive or individually to treat alcoholism, bronchitis, asthma, lep-
rosy, and dyspepsia. The extract of P. betle leaves contains a large
number of bioactive molecules like polyphenols, alkaloids, steroids,
saponins, and tannins (Chakraborthy and Shah, 2011). Moreover, the
leaf extract has also been reported to exhibit biological capabilities of
detoxification, aromatic, stimulant, carminative, astringent, antiseptic
antioxidative and antimutagenic activities. The principal chemical con-
stituents of P. betle were found to be polyphenols like eugenol,
MADHUMITA ET AL.
chavicol, carvacrol, chevibetol, catechol, and allyl pyrocatechol, and
vitamin C, which were reported to exhibit strong antioxidant activity
(Chakraborthy and Shah, 2011; Pin, Chuah, Rashih, Mazura, &
Fadzureena, 2010). Further, these polyphenols exert their protective
activities through their superior radical scavenging and immune-
modulating potentials (Prabu, Muthumani, & Shagirtha, 2012). P. betle
leaves also contain significant amounts of antioxidants like
hydroxychavicol, eugenol, ascorbic acid, and b-carotene. The leaf pos-
sesses antimicrobial, antifungal, antibacterial, hypotensive, respiratory
depressant, antihelminthic, cardiotonic, antiplatelet, antifertility, anti-
tumor, antiulcer, anti-inflammatory, and radioprotective activities
(Prabu et al., 2012). Betel leaves are credited with several activities
like wound healing, digestive and pancreatic lipase stimulant activities,
which have also been proved in experimental animals (Prabu
et al., 2012). Each compound having the above-mentioned activities,
extracted from the leaves, can be used in various sectors such as food,
cosmetics, perfume, pharmaceutical, etc., and the research is going on.
In India, about 66% of betel leaf production comes from West Ben-
gal out of which 10% of the gross production remains surplus because
of the rainy season, forced marketing (distress-selling), improper pro-
duction method, poor post-harvest handling, packaging, storage, etc.,
(Guha, 2007, 2007b). Waste material, a primary product that is thrown
away or needed to be thrown away, while by-products are secondary
products acquired from a process that can be useful and marketable or
can be used in a secondary process to produce high-added value and
marketable products. Due to the perishable nature of betel leaves, it
cannot store for long term storage. So, in the market the surplus leaves
are thrown away or used as cattle feed; in this case, the shelf life of
leaves should be increased by adopting advanced research techniques.
Moreover, during cultivation, betel vine is affected by different dis-
eases and insects that result in serious loss to the farmers. Also, during
storage and transportation, betel leaves can easily get infected by
microbes, pests, etc. Therefore, waste utilization in processing indus-
tries is one of the important and challenging jobs around the world.
Here the green betel leaves could be of importance as a by-product due
to their abundance and possible utilization as an extract or volatile EO
that obtained by the extraction process. Very few reports are available
about the utilization of leaf extract/ EO that is discussed in the above
section. Given this situation regarding the paucity of research in this
area, we have aimed at its possible utilization by various processes such
as in food application, pharmaceutical industries, cosmetic industries,
etc. The post-harvest losses of betel leaves can be minimized by
adopting advanced preservation methods that can be helpful and appli-
cable in the industrial future. More innovative technology and scientific
research are required to reduce these losses of betel leaves. Most of
the people depend directly or indirectly on each unit operation (produc-
tion, processing, packaging, handling, transportation, and marketing) of
betel leaves in India which adequately justifies its nomenclature as the
“GREEN GOLD OF INDIA.” Depending on the above, each step of betel
leaves operations, the central and state government should jointly take
more appropriate steps for funding various projects and to develop a
Research and Development Board. This can be helpful to stabilize the
prices of betel leaves; to increase the cultivation and export-orient
15
activities, to develop preservation techniques, and to decrease the
waste and by-product utilization, etc. The economy and employment
opportunities will develop if the above-discussed limitations are solved
by the effort of farmers, traders, scientists, technologists, researchers,
administrators, and policymakers, etc. This should include greenhouse
cultivation in industrial scale, product development, cool storage struc-
tures, continuous curing machine, medical aspects, and marketing, etc.
5 | CONC LU SIONS
It is quite evident from the above-discussed review that betel leaves are
an important herbal cash crop from botanical, export potential, economic
status, pharmacological, chemical, and industrial application point of
view. This review paper explored the information of betel leaf and its
products, bioactivity, biological properties, etc. Betel leaf is an abundant
source of phenolic compounds that possess a lot of therapeutic values
and responsible for many health benefits. Therefore, there is a growing
interest to utilize betel leaf extract and EO in various industrial applica-
tions such as food supplements, cosmetic and pharmaceutical industries,
etc. The demand for the bioactive compounds identified from betel
leaves and its derived products is increasing worldwide, which is highly
effective. Furthermore, this review also reports on the recently adopted
extraction methods and characterization, which are highly significant for
the development of the economic value of the product. The isolation,
extraction by common and advanced technologies, and characterization
of bioactive compounds from betel leaves should be considered. Due to
the limited information available in discussed literature focusing on the
proper modern preservation techniques and phytochemical properties
of those treated betel leaves extract used as traditional medicine, future
research should concentrate on the identification of more bioactive com-
pounds. Considering the above discussed biological activities like antimi-
crobial activity, antioxidant activity, antidiabetic, anticancer activity, etc.,
it concludes that betel leaf has tremendous importance which has to
come out as a future green medicine.
ACKNOWLEDG MENTS
The authors are grateful for the support from Indian Institute of Tech-
nology, Kharagpur, West Bengal, India.
CONFLIC T OF INT ER E ST
The authors declare that there are no conflicts of interest.
OR CID
Mitali Madhumita https://orcid.org/0000-0002-1364-2649
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How to cite this article: Madhumita M, Guha P, Nag A. Bio-
actives of betel leaf (Piper betle L.): A comprehensive review
on extraction, isolation, characterization, and biological
activity. Phytotherapy Research. 2020;1–19. https://doi.org/
10.1002/ptr.6715