South African Journal of Botany 112 (2017) 54–69

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South African Journal of Botany

journal homepage: www.elsevier.com/locate/sajb

Review

Bioactive compounds from medicinal plants: Focus on Piper species

E.E. Mgbeahuruike ⁎, T. Yrjönen, H. Vuorela, Y. Holm
University of Helsinki, Faculty of Pharmacy, Division of Pharmaceutical Biosciences, P.O. Box 56, FI-00014, University of Helsinki, Finland

a r t i c l e i n f o a b s t r a c t

Article history: This article reviews new discoveries related to the phytochemistry and biological activities of bioactive
Received 19 October 2016 compounds from Piper species. It outlines the anticancer, anti-parasitic, and antimicrobial activities of Piper
Received in revised form 5 April 2017 species in relation to drug discovery. The use of bioactive compounds from medicinal plants as therapeutic agents
Accepted 11 May 2017
has been an important area in biomedical and natural product research. Piper species are effective medicinal
Available online 24 May 2017
plants used in folk medicine. They have traditionally been used to treat stomach ache, rheumatoid arthritis,
Edited by S Van Vuuren diarrhoea and other general infections, and their efficacy has been attributed to their bioactive compounds.
Bioactive compounds and extracts from Piper species have been examined and found to be of clinical importance
Keywords: for both malignant and non-malignant diseases. They have displayed pronounced efficacy as anticancer,
Alkaloids antitumour and antimicrobial agents in various pharmacological studies. They have been reported to possess
Amides anti-inflammatory, antioxidant, antibacterial, antifungal, and antimalarial activities. The alkaloids piperine,
Anticancer activity piperlongumine, guineensine, chabamide and pellitorine, which have been isolated from most Piper species,
Antimicrobial activity are able to inhibit the growth of cancer cell lines inducing apoptosis and acting as nuclear export inhibitors.
Piperaceae
These bioactive compounds can improve the effectiveness of chemotherapeutic drugs with minimal systemic
toxicity to normal cells in cancer therapy. Pinoresinol, guineensine and other bioactive compounds from
this species exhibited strong antimicrobial efficacy against various microorganisms including pathogenic
Vibrio strains, which are often involved in host cell invasion during Vibrio cholera infection. The anticancer,
antimicrobial and antimalarial properties of Piper species are compiled to support further exploration of their
bioactive compounds for drug discovery. Biomedical and pharmacological discoveries concerning their
anticancer and antimicrobial properties are highlighted here for further clinical applications, which could pave
the way for the proper therapeutic use of bioactive compounds and extracts from this plant species.
© 2017 SAAB. Published by Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
2.1. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
2.2. Inclusion and exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
3. Phytochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
4. Biological activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
4.1. Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
4.1.1. Anticancer activity of isolated compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
4.1.2. Anticancer activity of crude extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
4.2. Antimicrobial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
4.2.1. Antimicrobial activity of isolated compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
4.2.2. Antimicrobial activity of crude extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
4.3. Antimalarial/anti-parasitic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
4.3.1. Anti-parasitic activity of isolated compounds and extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

⁎ Corresponding author.
E-mail addresses: eunice.mgbeahuruike@helsinki.fi (E.E. Mgbeahuruike), Teijo.yrjonen@helsinki.fi (T. Yrjönen), Heikki.vuorela@helsinki.fi (H. Vuorela), Yvonne.holm@helsinki.fi
(Y. Holm).

http://dx.doi.org/10.1016/j.sajb.2017.05.007
0254-6299/© 2017 SAAB. Published by Elsevier B.V. All rights reserved.
 E.E. Mgbeahuruike et al. / South African Journal of Botany 112 (2017) 54–69 55

Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

1. Introduction
Bioactive compounds from Piper species have played a substantial
role as therapeutic agents in drug discovery (Barh et al., 2013).
Piperaceae is a family of plants that contain valuable natural com-
pounds. It comprises the genera Macropiper, Zippelia, Piper, Peperomia
and Manekia (Nascimento et al., 2012). The genus Piper consists of 700
species growing in various parts of the world (Parmar et al., 1997). It
is the largest genus in the family and has numerous medicinal and
traditional uses (Table 1). These species are mostly shrubs, climbing
herbs or trees and are widely distributed in tropical regions such as
Asia, Central and Western Africa, South and Central America, and Pacific
Ocean islands (Parmar et al., 1997; Trindade et al., 2012). Available
images of Piper species most commonly utilized in traditional African
medicine are presented in Fig. 1.
Piper species are often cultivated for their seeds and leaves, which
have the pungent aroma that makes them important spices. Piper
species are consumed for the treatment of various ailments such as
fever, headache, diarrhoea, rheumatism, boils, scabies and stomach
problems (Tsai et al., 2005; Chakraborty and Shah, 2011; Sharkar

Table 1
Piper species and medicinal uses.

Piper species Medicinal/traditional uses References

Piper aborescens Roxb.
Piper acutifolium Ruiz and Pav.
Piper aduncum L.
Piper alatabaccum Trel. and
Yunck
Piper angustifolium Lam.
Piper auritum Kunth
Piper barbatum Kunth
Piper betle L.
Piper boehmeriifolium
(Miq).C.D.C
Piper capense L.F.
Piper chaba Hunter
Piper claussenianum (Miq.)
C. DC.
Piper cubeba L.F
Piper cumanense Kunth
Piper dennisii Trel.
Piper fimbriulatum C. DC.
Piper glabratum Kunth
Piper grande Vahl
Piper guineense Schum and
Thonn
Piper hayneanum C.DC.
Piper hispidum L.
Piper holtonii C.DC.
Piper jacquemontianum Kunth
Piper jericoense Trel. & Yunck
Piper lanceaefolium HBK.
Piper longum L.
Piper marginatum Jacq.
Piper methysticum G.Forst
Piper multiplinervium C.DC.
Piper nigrum L.
Piper obrutum Trel. & Yunck.
Piper ovatum Vahl
Piper pulchrum C.DC.
Piper pyrifolium Vahl.
Piper regnellii (Miq.) C. DC.
Piper retrofractum Vahl
Piper sanvicentense Trel. & Yunck.
Piper sarmentosum Roxb.
Piper sintenense Hatus.
Piper strigosum Trel. & Yunck.
Piper stylosum Miq.
Piper tuberculatum Jacq.
Piper umbellatum L.
Piper xanthostachyum C. DC
Rheumatism, cytotoxic activity and antiplatelet aggregation. Tsai et al. (2005)
Antiseptic, wound healing, vaginal infections, gastritis, skin ulcerations and ailments. De Feo (2003), Svetaz et al. (2010)
Stomach aches, vaginitis, influenza, rheumatism, cough, fever and general infections. Martínez et al. (2003), Céline et al. (2009)
Stomach aches and diarrhoea. Facundo et al. (2005)
Cutaneous leishmaniasis-associated lesions, stomatitis, vaginitis, liver disorders, and Bosquiroli et al. (2015)
antiseptic.
Fever and sore throat. Conde-Hernández and Guerrero-Beltrán (2014)
Headache, stomach pain, dermatitis, disinfectant, and wound treatment. Tene et al. (2007), Calderón et al. (2010)
Cuts, boils, scabies, mouth odour, cough remedy, bronchitis, and nosebleed. Ahmad and Ismail (2003), Chakraborty and
Shah (2011)
Pain alleviation, rheumatism and arthritic conditions. Tang et al. (2010)
Abdominal pain, diarrhoea, and cough. Tekwu et al. (2012)
Pain alleviation, asthma, bronchitis, fever, piles and stomach aches. Parmar et al. (1997), Naz et al. (2012)
Candidiasis and virginal infections. Curvelo et al. (2014)
Renal disorder, gonorrhoea, syphilis, abdominal pain, enteritis and asthma. Ahmad et al. (2012)
Malaria and fever Garavito et al. (2006)
Rheumatic pain and arthritis. Céline et al. (2009)
Pain and antiplasmodial activity. Solís et al. (2005), Calderón et al. (2006a)
Skin ailments, skin ulcerations, wounds and antiseptic. Calderón et al. (2010), Svetaz et al. (2010)
Antiplasmodial activity and leishmaniasis-associated lesions. Calderón et al. (2006a)
Cough remedy, bronchitis, venereal diseases, rheumatism, female infertility, and Parmar et al. (1997), Tekwu et al. (2012),
aphrodisiac. Umoh et al. (2013)
Wound and skin diseases. Bastos et al. (2011)
Wounds and symptoms of cutaneous leishmaniasis, skin ailments, and stomach aches. Parmar et al. (1997), Calderón et al. (2006b),
Svetaz et al. (2010), Chahal et al. (2011)
Treatment for leishmaniasis symptoms. Calderón et al. (2006b, 2010)
Skin ailments, infections, anaemia and body aches. Svetaz et al. (2010), Cruz et al. (2011)
Antiplasmodial and cytotoxic activity. Mesa Vanegas et al. (2012)
Skin infection. López et al. (2002)
Antidote to snake bite, scorpion stings, chronic bronchitis, cough and cold. Chahal et al. (2011)
Anti-inflammatory, snake bites, diseases of the liver and bile duct. Chahal et al. (2011)
Narcotic beverage made from roots is drunk to cure diseases. Parmar et al. (1997), Li et al. (2012)
Stomach aches. Calderón et al. (2006a), Rüegg et al. (2006)
Diarrhoea, fever, cold, colic disorder and gastric conditions. Aziz et al. (2015)
Antiplasmodial and cytotoxic activity. Mesa Vanegas et al. (2012)
Anti-inflammatory and analgesic. Silva et al. (2009)
Treatment of haemorrhagic venom effect from snakebite and antidote for snakebite. Otero et al. (2000)
Diarrhoea and diuretic. Fortin et al. (2002)
Wounds, swellings and skin irritations. Felipe et al. (2006)
Digestive aid, stimulant, carminative, intestinal disorders, and postpartum treatment Muharini et al. (2015)
in women
Anti-tumour and anticancer properties. Taylor et al. (2013)
Toothache, headache, fungal dermatitis, cough, muscle weakness, and pain in the bones. Rukachaisirikul et al. (2004),
Mohamad et al. (2011), Chahal et al. (2011)
Treatment of snake bites and wounds. Chen et al. (2003)
Treatment of symptoms associated parasitosis and leishmaniasis, wounds. Estevez et al. (2007)
Fever and Pain. Salleh et al. (2014)
Antidiuretic, analgesic, sedative, digestive disorders and antidote for snakebites. Bezerra et al. (2015)
Treatment of miscarriages, boils, dermatosis and leucorrhoea. Céline et al. (2009), Calderón et al. (2010)
Treatment of leishmaniasis symptoms. Calderón et al. (2006a)
56 E.E. Mgbeahuruike et al. / South African Journal of Botany 112 (2017) 54–69

Fig. 1. Examples of Piper species illustrating the differences between the species. A1 and A2: Piper guineense leaves and seeds (photo: Eunice Mgbeahuruike); B1: Piper nigrum seeds
(photo: Eunice Mgbeahuruike); B2: Piper nigrum plant (photo: Ghosh et al., 2014); C1 and C2: Piper longum plant and fresh fruit (photo: Khushbu et al., 2011); C3: Piper longum dried
fruits (photo: Kumar et al., 2011); D: Piper aduncum densely invading a road in Borneo (photo: Padmanaba and Sheil, 2014); E: Piper ovatum leaves (photo: Vishal et al., 2014);
F: Piper sarmentosum leaves (photo: Hussain et al., 2012); G: Piper betle leaves (photo: Shah et al., 2016).

et al., 2013; Umoh et al., 2013; Aziz et al., 2015). They are also effective
in the treatment of respiratory diseases (Mohamad et al., 2011). Piper
species have gastrointestinal and hepatoprotective effects (Kumar
et al., 2010). Moreover, antioxidant and anti-inflammatory activities of
the extracts of Piper species have been widely reported (Vaghasiya
et al., 2007; D. Sarkar et al., 2008; Sarkar et al., 2013). Piper species
could serve as alternatives to synthetic anti-inflammatory drugs, as
research has demonstrated that synthetic anti-inflammatory drugs
such as NSAIDs and steroids are often associated with adverse effects
(Van den Worm et al., 2001; Tapiero et al., 2002) when compared
to natural compounds. More research should be conducted on the
bioactive compounds from Piper species as pharmaceutical agents. The
crude extracts of most Piper species have been reported to display
inhibitory activity against numerous microorganisms and cancer cell
lines. However, the bioactive compounds responsible for most of these
activities have not yet been isolated, as most reports have been based
on crude plant extracts. In recent years, there has been considerable
interests in the phytochemistry and medicinal properties of Piper
species (Gundala et al., 2014; Wang et al., 2014), and the uses of Piper
species in pest control and as insecticides (Okonkwo, 2005; Scott
et al., 2008), and the need to further explore piperamides in drug
discovery has also been recognised (Roersch, 2010; Nascimento et al.,
2012). The medicinal uses, phytochemistry, pharmacological activities
and therapeutic uses of Piper species and their chemical constituents
are of significant importance to researchers (Srinivasan, 2007; Kumar
et al., 2010; Roersch, 2010). The aim of this review is to compile and
summarize the numerous new discoveries concerning the anticancer,
antimicrobial and anti-parasitic activities of Piper species in relation to
drug discovery. It describes and outlines the phytochemistry and
biological activities of Piper species and their bioactive compounds.
 E.E. Mgbeahuruike et al. / South African Journal of Botany 112 (2017) 54–69
2. Methods
2.1. Search strategy
The searches for this review were conducted in the databases
Scopus, Web of Science, SciFinder and Google Scholar. Articles
published from the year 1995 till 2016 were used for the review with
some inclusion and exclusion criteria. The search terms included
“anticancer screening of Piper species”, “antimicrobial analysis of Piper
species”, “Piper species and anticancer activity” “Piper species and anti-
microbial activity” “antimalarial properties of Piper species” “anticancer
activity of bioactive compounds from Piper species” and “antimicrobial
activity of bioactive compounds from Piper species”. Major references
from some of the articles were also further searched for additional
information.
2.2. Inclusion and exclusion criteria
Based on the number of articles accessed, some inclusion and exclu-
sion criteria were applied so as to include the most relevant articles in
this review. Only articles published in English were considered. Finally,
135 articles were included and 10 articles were excluded. Publications
that extensively examined the efficacy of the bioactive compounds
and extracts of Piper species were included. Moreover, those reporting
in vitro and in vivo experiments using animal models were all included.
3. Phytochemistry
Piper species are rich in bioactive compounds (Table 2) and serve as
a reservoir for drug discovery. Bioactive compounds such as amides,
alkaloids, flavonoids, tannins, saponins, glycosides, terpenoids and
phenolic compounds have been widely reported to be present in the
seeds, leaves, and stem bark of Piper species (Scott et al., 2005, 2008;
Tang et al., 2010; Vadlapudi and Kaladhar, 2012). The pharmacological
activities of steroids, terpenes, chalcones, dihydrochalcones, and
essential oils from Piper species indicate that they can serve as health
promoting and pharmaceutical agents (Parmar et al., 1997). Phenolic
compounds such as flavonoids, phenolic acids, tannins, stilbenes and
lignans are present in Piper species. These groups of compounds,
which often contains aromatic rings with hydroxyl groups, naturally
occur in most plants. Flavonoids are mainly characterized by two
benzene rings A and B which are linked through a heterocyclic pyrane
ring. Flavonoids from Piper species are classified as flavones or
isoflavones based on the position of the benzenoid ring. Phenolic
compounds have been widely reviewed and reported to have beneficial
effects on human health such as anticancer, antimicrobial, and
antimutagenic properties (Huang et al., 2009). Phenolic acids such
as vanillic, caffeic, ferulic, protocatechuic, and rosmarinic acid are
present in Piper species (Chandra et al., 2015). Moreover, most Piper
species contain flavonoids such as quercetin, kaempferol, apigenin and
luteolin. Phenolic compounds such as 5–O-caffeoylquinic acid, 4-p-
coumaroylquinic acid, 5-p-coumaroylquinic acid, chavibetol and
hydroxychavicol are additionally present in Piper species (Ferreres
et al., 2014). Numerous other physiologically active compounds have
been isolated from Piper species, most of which have been examined
and confirmed to be biologically active compounds and potential targets
for drug discovery (Bezerra et al., 2005; Felipe et al., 2006; Bezerra et al.,
2007; Bodiwala et al., 2007). Lignans and neolignans isolated from Piper
species are pharmaceutical agents in drug discovery. These optically
bioactive compounds have prospects for use as anti-leishmanial agents
(Bodiwala et al., 2007). Amides and alkaloids are present in Piper
species, these amides which are often referred to as piperamides are
present in large quantity in their fruits (Bezerra et al., 2007; Bokesch
et al., 2011). Most Piper species contain alkaloids, which have strong
efficacy in cancer treatment, as documented in the literature (Bezerra
et al., 2005, 2006; Niu et al., 2015). They are of great importance as
57
therapeutic agents in drug discovery because of pharmacological
discoveries concerning their bioactive compounds.
4. Biological activities
Piper species have various applications in folk medicine.
Extracts from these plants are of great importance because of their
ethnopharmacological properties (Kuete et al., 2011; Abe and Ohtani,
2013; Kuete et al., 2013). The efficacy of Piper extracts as anticancer,
antimalarial and antimicrobial agents are promising and have been
widely reported (Bezerra et al., 2006; Braga et al., 2007; Atjanasuppat
et al., 2009).
4.1. Anticancer activity
Cancer is a disease that is difficult to combat, and therefore often
results in death. Secondary metabolites isolated from plants have been
widely used as chemopreventive agents in cancer treatment. More
than 70% of anticancer drugs are of natural origin (Cragg and
Newman, 2013). It has been observed that most anticancer compounds
have “drug-like” properties and good pharmacokinetic profiles (Ntie-
Kang et al., 2014), and this justifies the search for anticancer lead
compounds from natural products of plant origin. Bioactive compounds
from Piper species have cancer fighting properties (Table 3) (Bezerra
et al., 2005, 2006). They have effects on cancer cells and can serve as
chemopreventive agents in malignant growth (Kuete et al., 2011,
2013; Iwamoto et al., 2015). Bioactive compounds and crude extracts
from Piper species have been widely reported to have inhibitory effects
on tumour cell lines and could be potential sources of new anticancer
drugs (Bezerra et al., 2006; Jyothi et al., 2009; Bokesch et al., 2011;
Ferreira et al., 2014). The extracts from these plants have antiprolifera-
tive and chemopreventive activity against malignant diseases (Gundala
and Aneja, 2014; Gundala et al., 2014). The efficacy of Piper species as
anticancer agents has been attributed to the presence of numerous
piperamides and other bioactive compounds (Bezerra et al., 2006;
Gong et al., 2014).
4.1.1. Anticancer activity of isolated compounds
Amides and alkaloids are the main constituents of Piper species that
suppress the growth of cancer cell lines (Bezerra et al., 2005). Bioactive
compounds from Piper species have been reported to serve as chemo-
therapeutic agents in the treatment of malignant growth (Table 3)
and infectious diseases (Bezerra et al., 2006; Mohamad et al., 2011;
Gong et al., 2014). Piperine (1), responsible for the pungent aroma in
Piper species, has been reported to suppress and inhibit tumour growth
and lung metastasis in mice (Lai et al., 2012). It has been demonstrated
to be an antitumour compound because of its effectiveness against
numerous cancer cells and tumour cell lines (Choi et al., 2007; Hwang
et al., 2011; Kim et al., 2012). Chavicine (2) and 4-5dihydroperine
(3) have memory enhancing and antimalarial properties respectively
(Scott et al., 2005; Iqbal et al., 2016), and should therefore be investigat-
ed for anticancer properties. Pipernonaline (4), a bioactive compound
present in P. longum displayed activity against human prostate cancer
PC-3 cells and inhibited the growth of androgen independent PC-3
and androgen dependent LNCaP prostate cells in a dose-dependent
(30–90 μM) and time-dependent (24–48 h) manner (Lee et al., 2013).
It was observed that this growth inhibition was as a result of sub-G1
and G0/G1 accumulation. It was reported that pipernonaline did not
change the expression of proapoptotic bax and antiapoptotic bcl-2
proteins but up-regulated the cleavage of procaspase-3/PARP. It was
concluded that pipernonaline exhibits apoptotic properties through
the production of reactive oxygen species, which causes the disruption
of mitochondrial function and Ca2+ homeostasis. Alkaloids and amides
(5, 6, 7, 8) isolated from P. boehmeriaefolium have anti-proliferative
activity (Tang et al., 2010). In vitro evaluation of the cytotoxicity of
amide alkaloids from P. boehmeriaefolium against the proliferation of
58 E.E. Mgbeahuruike et al. / South African Journal of Botany 112 (2017) 54–69

Table 2
Chemical structures and biological activities of alkaloids and related compounds from Piper species.

Compounds Species Biological/ References

pharmacological
properties

P. guineense, Anticancer, Bezerra et al. (2005), Choi

P. longum, P. nigrum antimicrobial, et al. (2007), Lai et al.
antimalarial (2012), Umadevi et al.
(2013), Niu et al. (2015)

Piperine (1)
P. nigrum Memory enhancer Xin et al. (2016), Iqbal et al.
(2016).

Chavicine (2)
P. capense, Antimalarial Scott et al. (2005),
P. guineense, Pedersen et al. (2009)
P. nigrum

4, 5-dihydropiperine (3)
P. longum, Anticancer, Lee et al. (2013), Muharini
P. retrofractum antifungal et al. (2015)

Pipernonaline (4)
P. boehmeriaefolium Anticancer Tang et al. (2010)

1-[(4E, 9E)-10-(3,4-methylenedioxyphenyl)-4,9-nonadienoyl]pyrrolidine (5)

P. boehmeriaefolium Anticancer Tang et al. (2010)

1-[(9E)-10-(3,4-methylenedioxyphenyl)-9-decenoyl]pyrrolidine (6)
P. boehmeriaefolium Anticancer Tang et al. (2010)

1-[(2E, 4Z,9E)-10-(3,4methylenedioxyphenyl)-2,4,9-undecatrienoyl] pyrrolidine (7)

P. boehmeriaefolium Anticancer Tang et al. (2010)

1-[(2E, 4Z,8E)-9-(3,4-mehtylenedioxyphenyl)-2,4,8-nonatrienoyl]pyrrolidine (8)

P. betle, Antimicrobial, Barh et al. (2013),
P. retrofractum anticancer Muharini et al. (2015)

Guineensine (9)
P. guineense, Antimalarial Scott et al. (2005)
 E.E. Mgbeahuruike et al. / South African Journal of Botany 112 (2017) 54–69 59

Table 2 (continued)

Compounds Species Biological/ References

pharmacological
properties

P. nigrum

Pipercide (10)
P. cubeba Antileishmanial Bodiwala et al. (2007)

Hinokinin (11)
P. cubeba, Antileishmanial Bodiwala et al. (2007)
P. retrofractum

Cubebin (12)
P. cubeba, Antituberculosis, Rukachaisirikul et al.
P. sarmentosum antileishmanial (2004), Bodiwala et al.
P. retrofractum (2007)

(−)-Sesamin (13)
P. chaba, Anticancer, Rukachaisirikul et al.
P. retrofractum antimicrobial, (2002), Muharini et al.
antimalarial, (2015), Ren et al. (2015)
antituberculosis

(continued on next page)

60 E.E. Mgbeahuruike et al. / South African Journal of Botany 112 (2017) 54–69

Table 2 (continued)

Compounds Species Biological/ References

pharmacological
properties

Chabamide (14)
P. arborescens Anticancer, Tsai et al. (2005)
anti-platelet
aggregation

(+)-Diayangambin (15)
P. arborescens Anticancer Tsai et al. (2005)

(+)-Arborone (16)
P. arborescens Anticancer Tsai et al. (2005)

Piperarborenine C (17)
Piperarborenine D (18) P. arborescens Anticancer Tsai et al. (2005)
Piperarborenine E (19) P. arborescens Anticancer Tsai et al. (2005)
P. arborescens, Anticancer, Tsai et al. (2005), Bezerra
P. guineense, antimicrobial, et al. (2005, 2006, 2008),
P. longum antimalarial, Bodiwala et al. (2007),
antituberculosis Costa-Lotufo et al. (2010),
Raj et al. (2011), Adams
et al. (2012), Kong et al.
(2008), Jyothi et al. (2009),
Lai et al. (2012), Golovine
et al. (2013)
Piperlongumine (20)
P. guineense, Anticancer, Scott et al. (2005), Rao
P. nigrum antimalarial et al. (2011)

Dihydropiperlongumine (21)
P. aduncum Anticancer, Parmar et al. (1997)
antimicrobial

Aduncamide (22)
 E.E. Mgbeahuruike et al. / South African Journal of Botany 112 (2017) 54–69 61

Table 2 (continued)

Compounds Species Biological/ References

pharmacological
properties

P. regnellii Not reported Felipe et al. (2006)

Eupomatenoid-5 (23)
P. regnellii Not reported Felipe et al. (2006)

Eupomatenoid-6 (24)
P. boehmeriaefolium Anticancer Tang et al. (2010)

R = H 3-(4-hydroxy-3, 5-dimethoxyphenyl) propanoylpyrrole (25)

R = Me 3-(3, 4, 5 trimethoxyphenyl) propanoylpyrrole (26) P. boehmeriaefolium Anticancer Tang et al. (2010)
P. regnellii Not reported Felipe et al. (2006)

Conocarpan (27)
P. boehmeriaefolium Anticancer Tang et al. (2010)

1-[(2E, 4Z,6E)-2,4,6-dodecatrienoyl] pyrrolidine (28)

P. cubeba, P. Antituberculosis, Rukachaisirikul et al.
guineense, P. nigrum, antileishmanial (2004), Scott et al. (2005),
P. retrofractum Bodiwala et al. (2007)

Pellitorine (29)
P. boehmeriifolium Anticancer Tang et al. (2010)

(2E, 4E)-N-[4-hydroxy-3-methoxyphenyl)ethyl]-2,4-decadienamide (30)

P. boehmeriifolium Anticancer Tang et al. (2010)

(2E, 4E)-N-[2-(methylsufiny)ethyl)ethyl]-2,4-decadienamide (31)

62 E.E. Mgbeahuruike et al. / South African Journal of Botany 112 (2017) 54–69

Table 3
Piper species with effect on cancer cells.

Cancer cells investigated (concentrations) Bioactive compounds/extracts Species References

MCF-7 and MDA-MB-231; Mel-85; SK-MEL-28 Dillapiole P. aduncum Ferreira et al. (2014)
(IC50: 25 μM, 27 μM, 28 μM and 26 μM)
MCF7, H-460 and SF-268 (IC50 b 10 μg/ml) C2H5OH extracts P. barbatum Calderón et al. (2006a)
PC-3 and A549 (IC50: 3.5, and 42 μg/ml) Hydroxychavicol and ethyl P. betle Banerjee and Shah (2014),
acetate extracts Gundala et al. (2014)
Cervical carcinoma HeLa and tumour cell lines (IC50 2.7 μg/ml) Amide alkaloids P. boehmeriifolium Tang et al. (2010)
CCRF-CEM, HL60AR cell, MCF7 and human pancreatic cell lines MeOH extracts P. capense Kuete et al. (2011, 2013)
(IC50: 6.95 μM, 8.16 μM, 11.22 μM and 4.17 μM)
CL-6, Hep-2, HepG2, C32 and HeLa (IC50: 40.74 μM, 18.93 μM and 68. 09 μM) C2H5OH extracts P. chaba Mahavorasirikul et al. (2010)
MCF7 and HT29 cell lines (IC50: 98.64% and 91.59%) Seed extracts P. cubeba Daoudi et al. (2013)
Human pancreatic cell lines (IC50: 8.20 μg/ml) MeOH extracts P. guineense Kuete et al. (2011)
MCF7, H-460 and SF-268 (IC50 b 10 μg/ml) Dichloromethane extracts P. glabratum Calderón et al. (2006b)
MCF7, H-460 and SF-268 (IC50 b 10 μg/ml) Ethanol extracts P. jacquemontianum Calderón et al. (2006b)
OVCAR3, SKOV3, HEK293T, PC-3 cells, G-361, HT-29 and HCT116 Piperlongumin, P. longum Lee et al. (2013), Gong et al. (2014),
(IC50: 16.3 μM, 30–90 μM, 50 or 100 mg kg−1) Pipernonaline and C2H5OH extracts Ovadje et al. (2014)
LNCaP, LAPC-4, C4-2B, DU145 PC-3 and WPMY-1 C2H5OH extracts P. methysticum Li et al. (2012)
(IC50: 6.5 μg/ml, 5.3 μg/ml, 5.4 μg/ml, and 35.7 μg/ml)
HL 60, C32 and HeLa Petroleum ether, Chloroform and P. nigrum Ee et al. (2009)
(IC50: 30 μg/ml, 11 μg/ml and 9.8 μg/ml) C2H5OH extracts
MDA-MB-231, MCF-7, PC-3 and colon cell line HT 29 C2H5OH extracts P. sanvicentens Taylor et al. (2013)
(IC50: 7 μg/ml, 24 μg/ml, 33 μg/ml, and 30 μg/ml)
Cervical cell line HeLa and MCF-7 (IC50: 14.4 μg/ml, and 9.8 μg/ml) Hexane and C2H5OH extracts P. sarmentosum Ee et al. (2009)
UACC-62, MCF-7, HT-29, PC-3786-0, and OVCAR-3 Dichloromethane extracts P. umbellatum Iwamoto et al. (2015)
(inhibition: 0.2 μg/ml, 1.9 μg/ml, 1.2 μg/ml)

IC50 = Half-Maximal Inhibitory Concentration.

human cervical carcinoma (HeLa cells) revealed inhibitory activity with
(1-[(9E)-10-(3, 4-methylenedioxyphenyl)-9-decenoyl] pyrrolidine
being the most effective compound. Guineensine (9) has been reported
to have an anticancer property (Muharini et al., 2015), while in vitro and
in vivo anticancer properties of pipercide (10), hinokinin (11), cubebin
(12) and (−)-sesamine (13) should be investigated. Chabamide (14),
a bioactive compound from P. chaba has inhibitory activity against
adriamycin-resistant human leukaemia cells (K562/ADR) and K562
cells in a dose-dependent and time-dependent manner (Ren et al.,
2015). The mechanism underlying the cytotoxicity and downregulation
of P-gp expression by chabamide in adriamycin-resistant human leu-
kaemia cells (K562/ADR) was examined, and this alkaloid inhibited
cell proliferation by cell cycle arrest in the G0/G1 phase which led to
an increase in p21 and a decrease in cyclin D1 and CDK2/4/6 protein
expression. The result further indicates that chabamide could regulate
changes in the mitochondrial membrane potential and also increase
the expression of apoptosis-related proteins, such as Bax and
cytochrome c, thereby reducing the protein expression levels of Bcl-2,
caspase-9, caspase-3, PARP-1, and p-Akt. There was inhibition of P-gp
expression as a result of a decrease in reactive oxygen species levels
and this demonstrates that chabamide may be useful as ab anticancer
agent. Although (+)-diayangambin (15) and (+)-arborone (16) are
reported to have anticancer properties (Tsai et al., 2005), more in vivo
experiments are needed to verify this claim. Three amides isolated
from P. arborescens, piperarborenine C (17), piperarborenine D (18),
and piperarborenine E (19), displayed cytotoxic activity against P-388,
HT-29 and A549 cell lines in vitro (Tsai et al., 2005).
Piperlongumine (piplartine) (20), a bioactive compound present in
most pepper species, has been reported to be one of the most effective
natural compounds in cancer therapy, with minimal systemic toxicity
to normal cells (Bodiwala et al., 2007; Bezerra et al., 2008; Costa-
Lotufo et al., 2010; Raj et al., 2011; Adams et al., 2012). This compound
has been reported to inhibit the proliferation of human prostate cancer
cell lines, human leukaemia cells and numerous tumour cell lines
(Kong et al., 2008; Jyothi et al., 2009; Lai et al., 2012; Golovine et al.,
2013). Bezerra et al. (2006, 2007, 2008) have been investigating the
therapeutic potentials of piperlongumine and piperine. This group of
researchers has outlined and emphasized the chemotherapeutic uses
of piperlongumine and piperine and their role as anticancer agents. Pip-
erine and piperlongumine have the ability to improve the effectiveness
of chemotherapeutic drugs (Bezerra et al., 2008). When examining the
in vitro and in vivo effects of the combination of 5-fluorouracil (5-FU)
with piplartine or piperine on tumour cell lines, inhibitory activity was
detected. Tumour cell lines, when incubated with 5-FU in the presence
of piplartine or piperine displayed inhibitory activity. There was an
observed increase in the growth inhibition rate when piplartine or
piperine was combined with 5-FU compared to when they were admin-
istered individually in equal dosages. In vivo analysis conducted on the
same combination revealed a high inhibition rate. Histopathological
analysis of the liver and kidney of the animals demonstrated that the
treatment had mild effects on their kidneys and liver. Leukopenia,
which was observed after 5-FU treatment during haematological
analysis, was reversed by the combined use of piplartine and piperine.
Interestingly, these two bioactive compounds could improve the thera-
peutic potentials of anticancer drugs with minimal effects on normal
cells. Piplartine and piperine administered intraperitoneally for 7 days
at 50 or 100 mg kg−1 day−1 inhibited tumour development in female
Swiss mice transplanted with Sarcoma 180 cells (Bezerra et al., 2006).
The inhibition of the tumour proliferation rate was used to access the
anti-tumour potentials of piplartine. Immunohistochemical assay
results demonstrated a reduction in Ki67 staining in a nuclear antigen
associated with G1, S, G2, and M cell cycle phases, in tumours from
animals treated with piplartine. However, there was no inhibition of
cell proliferation with piperine as observed in Ki67. Histopathological
analysis of the organs demonstrated that piperine was more toxic to
the liver, while piplartine was more toxic to the kidney and led to haem-
orrhage in treated animals, with no effect on the spleen of the animals.
Piperlongumine is effective against human epithelial ovarian cancer
(EOC) lines A2780, OVCAR3, and SKOV3 (Gong et al., 2014). It inhibited
the growth of the three ovarian cancer cell lines after 72 h of exposure.
Interestingly, piperlongumine showed weak activity against human
normal HEK293T. It was further found to induce apoptosis in OVCAR3
ovarian cancer cells when cell apoptosis was assessed by FCM with
Annexin V/PI staining. Different concentrations of piperlongumine,
when applied for 48 h, induced apoptosis in OVCAR3 cells, and
increased numbers of cells in both the early and late stage of apoptosis
were observed at elevated piperlongumine concentrations. The
mechanism of action of piperlongumine in inducing apoptosis was fur-
ther assessed by conducting apoptosis marker cleaved-PARP (C-PARP)
proteins analysis. The levels of C-PARP proteins in OVCAR3 cells were
 E.E. Mgbeahuruike et al. / South African Journal of Botany 112 (2017) 54–69
increased in a dose- and time-dependent manner after treatment with
piperlongumine and this group of researchers attributed the growth
inhibition of ovarian cancer cells by piperlongumine to be a result of
the induction of apoptosis. In mutagenic studies conducted by Bezerra
et al. (2009), piperlongumine was reported to exert a mutagenic effect
on eukaryotic cells.
The mechanism of action of piperlongumine as an inhibitor of
nuclear export through direct interaction of CRM1 with Cys528 has
been reported (Niu et al., 2015). Piperlongumine has been found to
induce the nuclear retention of tumour suppressor proteins and inhibit
the interactions between CRM1 and these proteins, as well as binding to
the conserved Cys528 of CRM1. Piperlongumine inhibited the growth of
Hela cancer cell lines after 24 h of exposure. Further analysis of the
subcellular localization of CRM1 substrates in cells treated with
piperlongumine and further treatment of the cells with either 10 nM
of LMB or 25 μM of piperlongumine resulted in equal distribution
between the cytoplasm and nuclear compartment, which justifies the
role of piperlongumine as a nuclear export inhibitor. Piperlongumine
induced the nuclear retention of the major tumour suppressor proteins
when applied to cancer cell lines. There was an increase in the nuclear
fraction of major tumour suppressor proteins, and this led to the
conclusion that CRM1 inhibition is due to the nuclear retention of
major tumour suppressor proteins, which then leads to the suppression
of cancer cell growth. Examination of the antiproliferative effects of
piperlongumine on human leukaemia cell lines HL-60, K562, Jukart,
and Molt-4 using the trypan blue exclusion method revealed that
piperlongumine did not affect the viability of all human leukaemia cell
lines after an exposure time of 6 h, 9 h, or 12 h, but a rapid inhibition
was observed after 24 h of exposure (Bezerra et al., 2007). This led to
the conclusion that the antiproliferative activity of piperlongumine
could result from the inhibition of DNA synthesis, which was reflected
by a reduction in 5-bromo-2′-deoxyuridine (BrdU) incorporation after
24 h of incubation. Interestingly, there was an increase in the number
of dead cells. Morphological analysis revealed apoptotic morphological
changes in piperlongumine treated cells at the lowest concentration.
Bezerra et al. (2007) argued that piperlongumine has the ability to
suppress leukaemia growth and could be useful in the treatment of
malignant diseases. Piperlongumine has been found to inhibit tumour
cell lines (Bezerra et al., 2005). Piperlongumine inhibited the growth
of Burkitt lymphoma in vitro and could be a potential haematological
agent (Han et al., 2013). In an in vitro evaluation, the combination of
piperine and paclitaxel inhibited the growth of breast cancer cell lines
(Motiwala and Rangari, 2015). Dihydropiperlongumine (21) and
aduncamide (22) have anticancer properties (Parmar et al., 1997; Rao
et al., 2011). However it is interesting to note that the anticancer efficacy
of amide compounds (23), (24) and (27) has not been reported and
should therefore be investigated. Amides (25, 26, 30, and 31) have
antitumour properties (Tang et al., 2010). P. betle contains a bioactive
compounds with strong effect on prostate cancer management
(Paranjpe et al., 2013; Yadav et al., 2014). Hydroxychavicol and its
analogues synthesized from P. betle have been shown to have anti-
proliferative activity against prostate cancer PC-3 cells and cervical
cancer HeLa cells (Yadav et al., 2014). PC-3 cancer cells treated for
48 h with an increasing concentration of hydroxychavicol and its
analogues inhibited prostate cancer cell lines. The hydroxychavicol
analogues were also active against HeLa cells. In vitro cell proliferation
analysis suggests that the methyl ether derivatives at position 3 of
hydroxychavicol are less active when compared to both the hydroxyl
and acylated analogues, suggesting that the methyl structural modifica-
tion compromises the biological activity. In comparing the activities of
the various analogues, it was observed that the presence of the hydroxyl
group also contributed to the inhibitory activity, while the more hydro-
philic compounds with lower distribution coefficients (logD) did not
show promising anticancer profiles. This justifies the potentials of
hydroxychavicol and its analogues as anti-cancer agents. Extracts of
P. betle had strong activity in mice implanted with human prostate
63
xenografts when fed orally (Paranjpe et al., 2013). Piperdine, a bioactive
compound isolated from P. nigrum inhibited HEp2 cells (human epithe-
lial cells of larynx) at a concentration of 5 μg/ml (Reshmi et al., 2010).
This compound has also demonstrated activity against the human
colon carcinoma HT 29 cell line and human liver carcinoma HepG2.
Dillapiole, a bioactive compound present in P. aduncum, has anti-
proliferative activity and could arrest cells at the G0/G1 phase
(Ferreira et al., 2014). The compound has cytotoxic activity against
various tumour cells and can act as a pro-oxidant compound through
the induction of reactive oxygen species (ROS) release in MDA-MB-
231 cells. Dillapiole reduced cell viability in all the tumour cells after
24 h of incubation. When the anticancer effect was evaluated using
MDA-MB-231 cells as a model, and the cells were pre-incubated with
a pan-caspase inhibitor, z-VAD-fmk, and an antioxidant agent, there
was a decrease in the cytotoxic effects of dillapiole on MDA-MB-231
cells with an IC50 value of 63 μM dillapiole for cells pre-treated with
z-VAD-fmk and 82 μM for those pre-treated with Trolox. Reshmi et al.
(2010) argued that dillapiole might have a good mechanism of action
on MDA-MB-231 cells.
Banerjee and Shah (2014) argued that eugenol present in P. betle
extract was responsible for its anti-proliferative activity against a lung
cancer cell line (A549).
Sintenin and other bioactive compounds isolated from P. sintenense
demonstrated activities in vitro against P-388, A549, and HT-29 cell
lines (Chen et al., 2003). While sintenin showed selective cytotoxicity
against the P-388 cell line, sintenpyridone was observed to be the
most cytotoxic compound against the three cancer cell lines P-388,
A549, and HT-29. Interestingly, this bioactive compound was observed
to be more potent against the HT-29 cell line than mithramycin,
which was used as the control. In vitro cytotoxic evaluation of extracts
and bioactive compounds from P. jacquemontianum and P. barbatum
against breast (MCF-7), lung (H-460), and central nervous system
(SF-268) human cancer cell lines revealed that these plants have strong
cytotoxic activity (Calderón et al., 2006b). Three bioactive compounds
isolated from P. barbatum, (2′E.6′E.)-2-farnesyl-1, 4-benzoquinone,
(2′E. 6′E.)-2-farnesylhydroquinone, and dictyochromenol, showed
inhibitory activity with the highest cytotoxic activity against the cell
lines MCF-7 and SF-268. If thoroughly investigated, novel anticancer
agents could be found in Piper species because of the diverse nature of
their bioactive compounds and this could pave the way for a better
and safer cancer therapy and also help to address the problem of
drug-resistant phenotypes.
4.1.2. Anticancer activity of crude extracts
Piper extracts have demonstrated high efficacy in treating various
malignant diseases (Table 3). Out of 310 plant species tested on breast
cancer cell line MCF7, lung cancer cell line H-460 and central nervous
system cancer cell line SF-268, Piper species (P. barbatum and
P. jacguemontianum) were reported to be among the most active plants
(Calderón et al., 2006b). P. sanvicentense was also reported to be one of
the most active plants out of 308 plant extracts screened for effects on
breast cancer MDA-MB-231, prostate cancer PC-3 and human colon
cancer HT29 cell lines (Taylor et al., 2013). Decoctions from Piper
extracts have been reported to exert strong effects on cancer cells
lines (Ee et al., 2009; Kuete et al., 2011; Iwamoto et al., 2015). In vitro
evaluation of the ethanolic fruit extract of Piper chaba demonstrated its
effectiveness against malignant cell lines CL-6 (cholangiocarcinoma),
Hep-2 (laryngeal carcinoma), and HepG2 (hepatocarcinoma), with
lower toxicity against normal renal epithelial cell HRE (Mahavorasirikul
et al., 2010). Root extract from P. methysticum (Kava) displayed activity
against various prostate cancer cell lines (Li et al., 2012). Petroleum
ether and chloroform extracts of P. nigrum showed activity against
leukaemia cell lines, while hexane extracts of P. sarmentosum were
active against cervical cancer cell lines (Mahavorasirikul et al., 2010).
Evaluation of aqueous, methanol, ethyl acetate and petroleum ether
extracts from the leaves of P. betle revealed anti-proliferative activity
64 E.E. Mgbeahuruike et al. / South African Journal of Botany 112 (2017) 54–69

against lung cancer cell line A549, with ethyl acetate extract showing
the highest anti-proliferative activity (Adams et al., 2012). Purified
extracts from P. betle leaves also demonstrated activity against human
prostate cancer cell line PC-3 (Gundala et al., 2014). P. betle which is
locally used in developing countries for the treatment of cough,
displayed anti-proliferative activity against a lung cancer cell line
(Banerjee and Shah, 2014). P. capense showed activity against leukaemia
cell lines and has been found to increase the production of reaction
oxygen species (Kuete et al., 2013).
4.2. Antimicrobial activity
Viral and bacterial infections are health problems that cause
mortalities worldwide. The continuous increase in microbial resistance
to antibiotics is a global problem that urgently needs solution. Microbes
have developed various mechanisms of resistance due to the consump-
tion of antibiotics (Sibanda and Okoh, 2007; Alviano and Alviano, 2009;
Palaniappan and Holley, 2010). In recent years and in most developing
countries, people have resorted to self-medication, which has often
led to increased microbial resistance to the drug. However, the trend
in drug discovery is gradually returning to natural products because of
the constant development of microbial resistance to synthetic drugs
(Harvey et al., 2015). Extracts from Piper species have been reported
to be effective against Gram-positive and Gram-negative bacteria and
could be a potential lead to the discovery of new antimicrobial drugs
(Da Costa et al., 2010; Hussain et al., 2013; Limsuwan and
Voravuthikunchai, 2013). Researchers have demonstrated that plant-
derived antimicrobials often do not induce resistance (Sibanda and
Okoh, 2007; Alviano and Alviano, 2009; Palaniappan and Holley,
2010). Piper species contain alkaloids and other bioactive compounds
that could help to combat infections and solve the problem of increasing
microbial resistance to antibiotics (Vadlapudi and Kaladhar, 2012). Piper
species have anti-helminthic and schistosomicidal activities against
various worms (Atjanasuppat et al., 2009; Carrara et al., 2014). The
isolation of bioactive compounds from these plants could help in
identifying new compounds and could lead to the development of
new natural antibiotics.
4.2.1. Antimicrobial activity of isolated compounds
Microorganisms are susceptible to bioactive compounds from Piper
species (Table 4). Natural compounds from P. betle are effective against
Vibrio cholerae (Barh et al., 2013). Pinoresinol, guineesine, and other
bioactive compounds from P. betle have the ability to bind to and
block the activities of two dual targets of secreted proteins and
membrane-bound enzymes with high specificity. When comparative
proteomic and reverse vaccinology approaches were applied to the
exoproteome and secretome of pathogenic Vibrio strains, two targets
that were found to have a dual target for vaccines and drugs develop-
ment against broad-spectrum Vibrio serotypes were tested against
natural compounds derived from P. betle. These P. betle compounds
were found to be effective against these targets, which are often
involved in host cell invasion during Vibrio cholerae infections (Barh
et al., 2013). Pinoresinol, guineesine, and piperdardine were found to
be the most effective compounds based on the docking results.
Dehydropipernonaline and piperrolein B were effective against the
first target, while chlorogenic acid and eugenyl acetate were active
on the second target, and piperardine and peridine were effective
against both targets. From the docking results obtained based on
the GOLD fitness and Moldock scores, Barh et al. (2013) argued
that since P. betle compounds inhibited these two targets, they could
therefore be better options than conventional antibiotics that are
prescribed for the treatment of cholera and similar infections. Essential
oil from P. claussenianum leaves displayed activity against biofilms
produced by Candida albicans (Curvelo et al., 2014). A novel nerolidol-
rich essential oil derived from P. claussenianum was effective
against the formation, growth and stability of biofilms produced by
C. albicans.

Table 4
Piper species and microorganism susceptible to extracts.

Species Bioactive Microorganisms susceptible to extracts (MIC) References

compound/extracts

P. aduncum MeOH extracts Candida albicans, Cryptococcus neoformans, (MIC: 1.25 mg/ml) Braga et al. (2007)
P. betle C2H5OH and aqueous Streptococcus pyogenes, H. pylori, S. aureus, (MIC: 500 μg/ml, 5 mg/ml Voravuthikunchai and Mitchell (2008), Hussain et al.
extracts and 10 mg/ml) (2013), Limsuwan and Voravuthikunchai (2013)
P. capense MeOH and aqueous Mycobacterium tuberculosis, C. albicans (MIC:512 μg/ml, and 0.56 μg/ml) Tekwu et al. (2012), Steenkamp et al. (2007)
extracts
P. chaba C2H5OH extracts Streptococcus pyogenes (MIC: 1000 μg/ml) Limsuwan and Voravuthikunchai (2013)
P. claussenianum. Nerolidol-rich essential Biofilms from C. albicans Curvelo et al. (2014)
oil (MIC: 0.04 to 0.1%)
P. cubeba MeOH extracts Aspergillus niger, C. albicans, E. coli, P. aeruginosa and S. aureus (MIC: Rukayadi et al. (2013)
12.8 mg/ml, 1.6 mg/ml, 3.2 mg/ml, 6.4 and 1.6 mg/ml for the four
organisms)
P. guineense C2H5OH and MeOH M. tuberculosis, S. aureus, B. subtilis, P. aeruginosa, E. coli. C. albicans, Ngane et al. (2003), Konning et al. (2004), Tekwu et al.
extracts A. niger, A. flavus, S. brevicaulis and T. rubrum (MIC: 256 μg/ml) (2012)
P. hayneanum MeOH extracts S. aureus and C. albicans (MIC: 1.0 to 500 μg/disc) Bastos et al. (2011)
P. lanceaefolium MeOH extracts K. pneumoniae, E. coli, S. faecalis, M. phlei, B. subtilis, S. aureus, Lopez et al. (2001)
P. aeruginosa and C. albicans, (MIC: not measured)
P. nigrum C2H5OH and MeOH S. pyogenes, P. mirabilis, E. coli, P. stutzeri, M. tuberculosis, K. pneumonia, Laikangbam et al. (2009), Karsha and Lakshmi (2010),
extracts A. niger, C. albicans, P. aeruginosa, P. stuartii, E. aerogenes and E. cloacae, Rukayadi et al. (2013), Noumedem et al. (2013),
(MIC: 128 μg/ml, 32 μg/ml and 50–500 ppm) Limsuwan and Voravuthikunchai (2013)
P. ovatum Essential oils and Bacillus subtilis and Candida tropicalis, (MIC: 15.6 μg/ml and 31.2 μg/ml) Silva et al. (2009)
hydroalcoholic extracts
P. pulchrum C2H5OH, hexane and S. aureus Streptococcus β hemolytic, B. areus, P. aeruginosa, E. coli and Rojas et al. (2006)
aqueous extracts C. albicans, (MIC: 0.6 μg/ml)
P. regnellii Hydroalcoholic extracts S. aureus, Bacillus subtilis, P. aeruginosa, E. coli Holetz et al. (2002)
P. sarmentosum Pellitorine, guineensine, S. pyogenes, B. subtilis and S. aureus. M. tuberculosis, (MIC: 25 to 100 μg/ml,
Rukachaisirikul et al. (2004), Atiax et al. (2010),
sarmentosine and 500 μg/ml and 800 μg/ml) Mohamad et al. (2011), Limsuwan and
C2H5OH extracts Voravuthikunchai (2013).
P. stylosum MeOH extract S. aureus, Bacillus subtilis, and E. coli (inhibition zone (mm): 9, 12 and 9 Wiart et al. (2004), Zain et al. (2011)
for the three organisms)
P. tuberculatum C2H5OH extract P. aeruginosa, E. coli, S. aureus (MIC: 10.2 μg/ml) Da Costa et al. (2010)

MIC = Minimal Inhibitory Concentration.

 E.E. Mgbeahuruike et al. / South African Journal of Botany 112 (2017) 54–69
4.2.2. Antimicrobial activity of crude extracts
Microorganisms are susceptible to Piper extracts. P. nigrum extract
is effective against infections caused by multi-drug-resistant (MDR)
bacteria and enhances the effectiveness of antibacterial drugs
(Noumedem et al., 2013). This extract, when combined with other
antibiotics, has been found to be effective against Gram-negative bacte-
ria and can be used to treat infections caused by multidrug-resistant
pathogens. A methanol extract of P. nigrum inhibited the growth of 29
strains of Gram-negative bacteria such as Providencia stuartii, Pseudomo-
nas aeruginosa, C. pneumoniae, Escherichia coli, Enterobacter aerogenes
and Enterobacter cloacae, including multi-drug-resistant phenotypes.
Further examination of the role of efflux pumps in the susceptibility of
Gram-negative bacteria to the tested plant extract revealed that the
combination of this extract with efflux pump inhibitors could have po-
tential as an anti-bacterial agent for infections caused by multidrug-
resistant bacteria. The plant extract in combination with PAβN was
found to target multidrug resistance efflux pumps, and an increase in
inhibitory activity was observed in 13/14 of the multidrug resistant
Gram-negative species tested (Noumedem et al., 2013). The researchers
argued that a bioactive compound present in this extract acts inside the
bacterial cell and could be the substrate of efflux pumps. A synergistic
effect of this extract with seven antibiotics was observed in 70% of the
tested multidrug-resistant bacteria. This demonstrates that extracts of
P. nigrum contain bioactive compounds that could also act as efflux
pump inhibitors and help to improve the effectiveness of antimicrobial
drugs.
P. nigrum extract is effective against Gram-positive bacteria such as
Staphylococcus aureus, Bacillus cereus and Streptococcus faecalis (Karsha
and Lakshmi, 2010). When the mode of action and the mechanism be-
hind this antibacterial activity was investigated, it was observed that
P. nigrum extract altered the membrane permeability, resulting in the
leakage of UV260 and UV280 absorbing material. Thus the activity was at-
tributed to the loss of control over cell membrane permeability. The
ethanolic extract of the leaves of P. tuberculatum displayed good brine
shrimp larvicidal activity against Artemia salina encysted eggs (Da
Costa et al., 2010). After 24 h of exposure to the treatments, the
extract exhibited toxicity against brine shrimps based on the larval
mortality rate, and the larvicidal activity of this extract was attributed
to the presence of tannins, flavonoids and alkaloids. P. betle, P. nigrum
and P. sarmentosum have activity against an upper respiratory tract
pathogen, Streptococcus pyogenes, which is the major cause of bacterial
pharyngitis (Limsuwan and Voravuthikunchai, 2013). Out of 51 plant
extracts of various species tested, P. betle showed prominent antibacte-
rial activity against S. pyogenes. Further evaluation of this extract on 11
isolates of S. pyogenes obtained from patients with upper respiratory
tract infections revealed moderate activity. P. sarmentosum, widely
consumed in Asia as a spice and staple food, has inhibitory activity
against various strains of Gram-positive and Gram-negative bacteria,
(Atiax et al., 2010; Limsuwan and Voravuthikunchai, 2013).
Evaluation of the antimycobacterial activity of P. guineense and
P. capense demonstrated that they are effective against Mycobacterium
tuberculosis (Tekwu et al., 2012). The efficacy of these extracts against
tuberculosis warrants further investigation of Piper species as anti-
tuberculosis agents. Among the 20 Brazilian medicinal plants evaluated
by Braga et al. (2007), P. aduncum extract showed the highest activity
against Candida albicans and was also found to be effective against
Cryptococcus neoformans, which is the major cause of Cryptococcus
meningitis. P. betle has been widely reported to be effective against
most pathogenic Gram-positive and Gram-negative bacteria (A. Sarkar
et al., 2008; Chakraborty and Shah, 2011). P. hayneanum has wound
healing activity (Bastos et al., 2011). Antimicrobial evaluation of the
leaves, stems and roots extracts of P. hayneanum revealed activity
against Staphylococcus aureus and Candida albicans. The in vivo wound
healing activity of the fractions tested on an infected rat model for
15 days showed that ointment prepared from this plant extract
improved wound healing and contraction. These fractions were
65
effective in rats with dorsal injuries infected with S. aureus and
C. albicans, and could be potential antimicrobial agents. P. longum
extracts demonstrated efficacy in the prevention and treatment of
urolithiasis (Laikangbam et al., 2009) and have been reported to have
anti-quorum sensing activity against Chromobacterium violaceum (Zaki
et al., 2013). Amides (piperovatine and piperlonguminine), essential
oil and hydroalcoholic extracts of P. ovatum displayed activity against
Bacillus subtilis and Candida tropicalis, including clinical strains (Silva
et al., 2009). P. betle has activity against Helicobacter pylori infection,
which causes gastric ulcers (Voravuthikunchai and Mitchell, 2008).
The extract was effective against 20 strains of antibiotic-resistant
H. pylori in a paper disc agar diffusion assay, and these strains were
susceptible to the extracts at a moderate concentration. The efficacy
and inhibitory activity of P. betle in H. pylori infection justifies further
investigation of Piper species as potential anti-bacterial agents that
could be used to treat infections caused by multiple antibiotic-
resistant bacteria.
4.3. Antimalarial/anti-parasitic activity
Malaria is a life-threatening disease that is common in developing
countries and other regions of the world. In general, parasitic diseases
mostly affect people living in rural villages in Africa. Malaria kills
between 1 and 3 million people annually in developing countries
(Fidock et al., 2004). The constant development of resistance to antima-
larial drugs is a health care problem that has necessitated the need
to search for new antimalarial drugs with good efficacy. The anti-
plasmodial efficacy of P. dennisii has been reported in vitro (Céline et
al., 2009). Benzoic acid derivatives from P. glabratum and P. acutifolia
have been reported to be effective against Trypanosoma cruzi and Plas-
modium falciparum (Flores et al., 2008). This demonstrates the need to
further investigate Piper species as antiparasitic agents. Similarly, leish-
maniasis is a tropical disease caused by Trypanosoma species. This infec-
tion, which is difficult to combat, mostly affects people from developing
countries. Calderón et al. (2010) reported the in vitro screening of
the extracts of P. aduncum, P. barbatum, P. acutifolium, and P. dilatatum
on Leishmania mexicana, and Plasmodium falciparum. The anti-
trypanosomal activity of these extracts also showed that they have
activity against Trypanosoma cruzi (Calderón et al., 2010). Braga et al.
(2007) reported the anti-leishmanial activity of P. aduncum. The essen-
tial oils of P. angustifolium have activity against Leishmania infantum,
which causes visceral leishmaniasis (Bosquiroli et al., 2015). Reviewing
the anti-parasitic efficacy of these species will be one of the strategies to
further explore their value as anti-parasitic agents in drug discovery.
4.3.1. Anti-parasitic activity of isolated compounds and extracts
Piper species and their bioactive compounds are effective anti-
leishmanial agents (Table 5) and could be used in the production of a
new anti-leishmanial drugs. Bioactive compounds from P. acutifolium
and P. aduncum are effective against promastigote forms of Leishmania
spp., Trypanosoma cruzi, and Plasmodium falciparum (Flores et al.,
2008). In vitro evaluation of the compounds has yielded promising
results with methyl 3, 4-dihydroxy-5-(3′-methyl-2′-butenyl) benzoate
showing the best leishmanicidal activity against the three Leishmania
species (Leishmania amazonensis, L. braziliensis, and L. donovani) that
were tested. The benzoic acid derivatives methyl 3,4-dihydroxy-5-
(2-hydroxy-3-methylbutenyl)benzoate, methyl 4-hydroxy-3-(2-
hydroxy-3-methyl-3-butenyl)benzoate, and methyl 3,4-dihydroxy-5-
(3-methyl-2-butenyl)benzoate displayed trypanocidal activity. These
compounds showed weak activity when tested against a strain of
chloroquine sensitive Plasmodium falciparum. Braga et al. (2007), in
their search for natural products with anti-leishmanial and antifungal
activity, conducted susceptibility testing on two yeast (C. albicans
ATCC 18804 and C. neoformans ATCC32602) and two Leishmania species
(L. amazonensis and L. chagasi), and found P. aduncum to yield the most
active extracts against C. albicans. Extracts of P. umbellatum, and
66 E.E. Mgbeahuruike et al. / South African Journal of Botany 112 (2017) 54–69

Table 5
Piper species and bioactive compounds as anti-parasitic agents.

Species Bioactive compounds/extracts Parasite investigated (MIC, IC50) References

P. acutifolium Benzoic acid derivatives Plasmodium falciparum, Trypanosoma cruzi and Leishmania spp. Flores et al. (2008), Calderón et al. (2010)
(IC50 13.8–18.5 μg/ml; 16.4; and 15.6–18.5 μg/ml)
P. aduncum C2H5OH and MeOH extracts P. falciparum, Leishmania mexicana, T. cruzi, Leishmania amazonensis and Braga et al. (2007), Céline et al. (2009),
Leishmania chagasi, (MIC: 1.25 mg/ml; inhibition (mm): 8; IC50 b 10 μg/ml) Calderón et al. (2010),
Mesa Vanegas et al. (2012)
P. angustifoliumEssential oils Leishmania infantum, (MIC: 1.43 μg/ml) Bosquiroli et al. (2015)
P. auritum C2H5OH extracts P. falciparum (IC50 not specified) Mesa Vanegas et al. (2012)
P. capense MeOH extracts P. falciparum (IC50 b 10 μg/ml, IC50 7 μg/ml)) Koch et al. (2005), Kaou et al. (2008)
P. cumanense Ethanol extracts P. falciparum and Plasmodium berghei (IC50 b 1 μg/ml) Garavito et al. (2006)
P. dennisii C2H5OH extracts P. falciparum (IC50 b 10 μg/ml) Céline et al. (2009)
P. fimbriulatum C2H5OH extracts P. falciparum, T. cruzi, L. mexicana and Aedes aegypti (LC100 b 30 μg/ml) Calderón et al. (2006a)
P. glabratum Benzoic acid derivatives P. falciparum, T. cruzi and L. spp. (IC50 15.6, 16.4 and 18.5) Calderón et al. (2010), Flores et al. (2008)
P. grande C2H5OH extracts P. falciparum, T. cruzi, L. mexicana and Aedes aegypti (IC50 b 20 μg/ml) Calderón et al. (2006a)
P. hispidum C2H5OH extracts L. amazonensis (IC50 b 10 μg/ml) Estevez et al. (2007)
P. holtonii C2H5OH extracts P. falciparum, P. berghei, T. cruzi and L. spp. (IC50 b 2.1 μg/ml) Garavito et al. (2006), Calderón et al. (2010)
P. jericoense C2H5OH extracts P. falciparum Mesa Vanegas et al. (2012)
P. marginatum C2H5OH extracts P. falciparum (IC50 not specified) Mesa Vanegas et al. (2012)
P. C2H5OH extracts
multiplinervium P. falciparum, T. cruzi, L. mexicana and Aedes aegypti (IC50 b 20 μg/ml) Calderón et al. (2006a)
P. obrutum C2H5OH extracts P. falciparum (IC50 not specified) Mesa Vanegas et al. (2012)
P. pyrifolium MeOH extracts P. falciparum Kaou et al. (2008)
P. sarmentosum Guineensine, pellitorine, P. falciparum (IC50 6.5 μg/ml and 18.9 μg/ml) Rukachaisirikul et al. (2004)
brachystamide B, sarmentine,
and sermentosine
P. strigosum Ethanol extracts L. amazonensis (IC50 b 10 μg/ml) Estevez et al. (2007)
P. Umbellatum C2H5OH and MeOH extracts P. falciparum, T. cruzi, L. mexicana and Aedes aegypti (inhibition (mm): 40) Calderón et al. (2010), Kaou et al. (2008)
P. xanthostachyum MeOH extracts P. falciparum, T. cruzi, L. mexicana and Aedes aegypti (IC50 b 20 μg/ml) Calderón et al. (2006a)

MIC = Minimal Inhibitory Concentration.

IC50 = Half-Maximal Inhibitory Concentration.
LC100 = Lethal concentration.

P. aduncum showed activity against all the yeasts tested, had no toxic
effects on mammalian cells, and the degree of inhibition observed in
the extracts was attributed to the presence of numerous secondary
metabolites. Essential oils of P. angustifolium could serve as a lead to a
new anti-leishmanial drug (Bosquiroli et al., 2015). An essential oil of
P. angustifolium exhibited in vitro activity against Leishmanial infantum.
The essential oil showed low cytotoxicity against mammalian fibro-
blasts and macrophages at half maximum inhibitory concentrations.
The results based on selective indices, indicated that the essential oil
was 33 and 22 times more toxic against L. infantum than mammalian
cells. In vitro screening of the ethanolic extracts of P. aduncum revealed
activity against a chloroquine-resistant strain of Plasmodium falciparum
(Céline et al., 2009). P. dennisii extracts showed promising
leishmanicidal activity when the viability of Leishmania amazonensis
amastigote stages was assessed by tetrazolium salt reduction (Céline
et al., 2009). The methylene chloride extract of Piper chaba fruits exhib-
ited activity against cercariae of Schistosome worms (Atjanasuppat
et al., 2009). Cubebin and hinokinin, two lignans isolated from
P. cubeba showed strong activity against Leishmania donovani
promastigotes (Bodiwala et al., 2007). In vivo evaluation of the effects
of cubebin and piplartine on amastigotes of Leishmania donovani
in golden hamsters also proved effective. There is little information
on the anti-quorum sensing activity of Piper species (Zaki et al.,
2013), and more efficacy studies should be conducted on the anti-
quorum sensing activity of the major medicinal Piper species (P. betle,
P. aduncum, P. chaba, P. capense, P. guineense, P. cubeba, P. auritum,
P. barbatum, P. glabratum, P. cumanense and P. longum) to find new
lead compounds for anti-pathogenic drugs.
5. Summary
In summary, Piper species have demonstrated strong efficacy against
both malignant and non-malignant diseases. Considering the vast
therapeutic potential of this family of plants, researchers should focus
more on the pharmacological screening of their bioactive compounds
to gain a better understanding of their mechanisms of action as
anticancer and antimicrobial agents. Piperine and piperlongumine are
promising drug candidates, and although various studies have been
conducted on their medicinal properties, a more suitable approach to
understanding their mechanism of action is needed. Chabamide,
pipercide, guineensine and other bioactive compounds from this plant
family, which have been reviewed as therapeutic agents, should be
evaluated and applied in modern therapy. Although numerous studies
have been conducted on Piper species, little information is available on
the antimicrobial activity of the isolated compounds (Table 4). The
gap in knowledge relates to the biological activities of the isolated
compounds and in vivo model anticancer properties of Piper species.
Since P. nigrum extracts are effective against infections caused by
multidrug-resistant bacteria and are capable of enhancing antibacterial
drugs (Noumedem et al., 2013), there is no doubt that isolated
compounds from this species could be potential antibacterial lead
compounds. There is a need for new antimicrobial, antimalarial and
anticancer drugs with good efficacy and low cost. The in vivo and
in vitro anti-tuberculosis efficacy of most Piper species should be further
evaluated (P. betle, P. aduncum, P. chaba, P. umbellatum, P. auritum,
P. barbatum, P. glabratum, P. cumanense, P. acutifolium and P. cubeba).
Although the anti-tuberculosis activity of the extracts of these species
(P. guineense, P. capense, and P. sermentosum) has been assessed and
they have been found to be active (Mohamad et al., 2011; Tekwu
et al., 2012), it would be reasonable to isolate and test their bioactive
compounds as anti-tuberculosis agents. It is interesting to note that little
in vivo data is available on the anticancer activities of Piper species. The
in vivo and in vitro anticancer properties of pipercide, hinokinin and
cubebin have not been reported. Further investigations should be
conducted on the anticancer activities of Piper species using in vivo
models. Reviewing the activity of these extracts on various pathogens
will provide alternative approaches to systematically searching for and
evaluating new bioactive compounds from Piper species. More research
should also be focused on the structural elucidation of Piper species to
identify and isolate new natural bioactive agents; this will help to
address the problem of adverse effects associated with most synthetic
drugs and pave way for better and safer drug therapy. Piper species, if
thoroughly investigated, could also reveal new natural compounds,
which could lead to the production of new natural antibiotic and
 E.E. Mgbeahuruike et al. / South African Journal of Botany 112 (2017) 54–69
antimalarial scaffolds. This would help to combat the menace of cancer,
bacterial infections and malaria, which are life-threatening diseases that
have affected and killed large numbers of people.
Conflict of interest
The authors indicate no potential conflicts of interest.
Acknowledgement
The authors are sincerely grateful to the Faculty of Pharmacy,
Division of Pharmaceutical Biosciences, University of Helsinki for
supporting this work.
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