antioxidants

Review
Medicinal Profile, Phytochemistry, and
Pharmacological Activities of Murraya koenigii
and Its Primary Bioactive Compounds
Rengasamy Balakrishnan 1 , Dhanraj Vijayraja 2 , Song-Hee Jo 1 , Palanivel Ganesan 3 ,
In Su-Kim 1, * and Dong-Kug Choi 1,3, *
1 Department of Applied Life Sciences and Integrated Bioscience, Graduate School, Konkuk University,
Chungju 27478, Korea; [email protected] (R.B.); [email protected] (S.-H.J.)
2 Department of Biochemistry, Rev. Jacob Memorial Christian College, Ambilikkai 624612, Tamilnadu, India;
[email protected]
3 Department of Integrated Bio Science and Biotechnology, College of Biomedical and Health Science,
Nanotechnology Research Center, Konkuk University, Chungju 27478, Korea; [email protected]
* Correspondence: [email protected] (I.S.-K.); [email protected] (D.-K.C.)




Received: 13 December 2019; Accepted: 13 January 2020; Published: 24 January 2020


Abstract: The discovery of several revitalizing molecules that can stop or reduce the pathology of
a wide range of diseases will be considered a major breakthrough of the present time. Available
synthetic compounds may provoke side effects and health issues, which heightens the need for
molecules from plants and other natural resources under discovery as potential methods of replacing
synthetic compounds. In traditional medicinal therapies, several plant extracts and phytochemicals
have been reported to impart remedial effects as better alternatives. Murraya koenigii (M. koenigii)
belongs to the Rutaceae family, which is commonly used as a medicinally important herb of Indian
origin in the Ayurvedic system of medicine. Previous reports have demonstrated that the leaves, roots,
and bark of this plant are rich sources of carbazole alkaloids, which produce potent biological activities
and pharmacological effects. These include antioxidant, antidiabetic, anti-inflammatory, antitumor,
and neuroprotective activities. The present review provides insight into the major components of
M. koenigii and their pharmacological activities against different pathological conditions. The review
also emphasizes the need for more research on the molecular basis of such activity in various cellular
and animal models to validate the efficacy of M. koenigii and its derivatives as potent therapeutic agents.

Keywords: Murraya koenigii; antioxidant; bioactive compounds; pharmacological activity;

traditional medicine

1. Introduction
Presently, huge numbers of people in developing countries depend on medicinal plants for
healthcare, skin care, economic benefits, and cultural development. For centuries, medicinal plants
have been widely used in traditional medicine in countries like India, China, Germany, Thailand, etc. [1].
The World Health Organization (WHO) projected that 80% of the population relies on traditional
medicine, which is clearly elucidated by the 19.4 billion USD global revenue for herbal remedies in
2010 [2]. Moreover, the demand for traditional medicinal plants is increasing; for instance, the market
for medicinal plants is expanding at an annual rate of 20% in India. Likewise, in China, 30% to
50% of the total medicinal consumption is from preparations of traditional medicine [3]. Nearly
76.7% of the citizens of Thailand have reported mainly using traditional herbal medicine for their
primary healthcare [4]. Around 90% of the German population uses natural remedies for certain health
issues [5]. Therefore, the medicinal plants used in traditional medical treatments are significant in both

Antioxidants 2020, 9, 101; doi:10.3390/antiox9020101 www.mdpi.com/journal/antioxidants

Antioxidants 2020, 9, 101 2 of 28
Antioxidants 2020, 9, 101 2 of 30

developing and industrialized countries. countries. ThisThis is is clearly

clearly demonstrated
demonstrated by by the
the worldwide
worldwide market
market for
traditional medicine. This This market
market continues to gradually increase [6].
Murraya koenigii (M. koenigii)
koenigii) (L) Spreng (Family: Rutaceae) Rutaceae) is is usually
usually known
known as as “curry
“curry leaves”.
leaves”.
The tropical and subtropical regions in the world have large distributions of M. koenigii [7]. Among
the 14 global species belonging
belonging to the genus of Murraya, only two, M. koenigii and M. paniculate, are
available
available in India. M. M. koenigii
koenigii isis more
more important
important due due to its huge spectrum of traditional medicinal
properties. ForFor centuries,
centuries, thisthis plant
plant has has been
been used
used in in diverse
diverse forms
forms andand holds
holds aa place
place of pride in
Indian Ayurvedic medicine, known as “krishnanimba” “krishnanimba” [8]. Different Different parts
parts ofof M. koenigii, such as its
leaves, root, bark, and fruit, are known to promote promote various
various biological
biological activities.
activities. Aromatic bioactive
constituents in the the leaves
leavesof ofM.M.koenigii
koenigiiretain
retaintheir
theirflavor
flavorandand other
other qualities,
qualities, even
even after
after drying
drying [9–
[9–14].
14]. M. koenigii
M. koenigii leaves
leaves are slightly
are slightly bitterbitter in taste,
in taste, pungent
pungent in smell,
in smell, andand weakly
weakly acidic.
acidic. TheyTheyareare used
used as
as antihelminthics,
antihelminthics, analgesics,
analgesics, digestives,and
digestives, andappetizers
appetizersininIndian
Indiancookery
cookery[15,16].
[15,16]. The
The green leaves
of M. koenigii are used in treating piles, inflammation, itching, fresh cuts, dysentery, bruises, and
edema.
edema. TheThe roots
roots areare purgative
purgative to to some extent. They They areare stimulating
stimulating and and used
used for
for common
common body
aches. The
The bark
bark is is helpful
helpful in treating snakebites [17–20]. The The essential
essential oiloil extracted
extracted from M. koenigii
leaves is reported
reportedto topossess
possessanti-oxidative,
anti-oxidative,hepatoprotective
hepatoprotective [21–24],
[21–24], antimicrobial,
antimicrobial, antifungal
antifungal [25–
[25–27],
27], anti-inflammatory,
anti-inflammatory, and nephroprotective
and nephroprotective activitiesactivities
in animal in models
animal[28–30].
modelsThe [28–30]. The medicinal
medicinal properties
properties
of M. koenigiiof M.
have koenigii
been have been accredited
accredited to several to severalconstituents
chemical chemical constituents
of different ofcarbazole
different carbazole
alkaloids
alkaloids
and other and other important
important metabolites, metabolites,
like terpenoids,like terpenoids, flavonoids,carbohydrates,
flavonoids, phenolics, phenolics, carbohydrates,
carotenoids,
carotenoids,
vitamins, andvitamins,
nicotinicand acidnicotinic acid from
from different parts different
of the M. parts of the
koenigii M. koenigii plant.
plant.
In recent years, greater attention has been paid to the use of M. koenigii in traditional medicines
and home remedies. On On the
the other
other hand,
hand, limited
limited studies
studies have
have been
been conducted
conducted for evaluating the
pharmacological
pharmacological and andmedicinal
medicinal efficacy
efficacy of M.
of koenigii in promoting
M. koenigii in promotinghealthhealth
benefits and curing
benefits and disease
curing
[31–36]. This review will discuss the traditional medicinal use of
disease [31–36]. This review will discuss the traditional medicinal use of M. koenigii and its M. koenigii and its bioactive
compounds, highlighting their pharmacological effects. This review aims to present a well-managed
summary
summary and possible recommendation
recommendation on on existing
existing studies
studies to provide information regarding the
current reports
reports that
that can
candirect
directfuture
futureresearch.
research.Therefore,
Therefore,instead
insteadofofdiscussing
discussing a few
a few selected
selected studies
studies in
in a specific
a specific timetime interval,
interval, the present
the present review review will discuss
will discuss and previous
and cover cover previous and existing
and existing major
major studies
studies on M.related
on M. koenigii koenigiito related
the topics to chosen.
the topics Thechosen. The phytochemical
details, like details, like phytochemical screening,
screening, identification,
identification,
and pharmacologicaland pharmacological
activities, willactivities, will be systematically
be systematically categorized,
categorized, compared, andcompared,
summarized. and
summarized.
We hypothesized We hypothesized
that, through all that,
of through all ofathese
these efforts, goodefforts,
summary a good summary on pharmacological
on pharmacological activities that
activities that could
could initiate futureinitiate future with
perspectives perspectives
the utmost withclarity
the utmost
couldclarity could be produced.
be produced.
The pharmacological activities of M. koenigii are discussed in detail in Figure Figure 1.
1.

Figure 1. Pharmacological activities of Murraya koenigii.

Figure 1. Pharmacological activities of Murraya koenigii.

2. Murraya koenigii (M. koenigii)

Antioxidants 2020, 9, 101 3 of 28

2. Murraya koenigii (M. koenigii)

2.1. Traditional Uses of M. koenigii

Essential oils and fresh leaf powder of M. koenigii are useful in seasoning food items and
preparing ready-to-eat foods. Owing to the higher antimicrobial activities of the essential oil from
leaf extracts [37,38], this oil can also be used as perfume and flavor agents in traditional practice.
Fresh curry leaves are boiled with a coconut oil mixture until they are reduced to a black residue to
produce an excellent hair tonic for retaining a normal hair tone and improving hair growth. Curry
leaves have a traditional use, either whole or in parts, as antidiarrheal, antifungal, blood purifying,
anti-inflammatory, and anti-depressant agents [39–41].

2.2. Medicinal Uses of M. koenigii

M. koenigii has numerous disease remedial activities, for instance, different parts of the plant,
such as the leaves, roots, and bark, can be prepared as tonics for inducing digestion and flatulence or
as antiemetics [25,42]. After decoction, the leaves become bitter to the taste and are helpful in reducing
fever. The juice of the root is given to manage renal pains [43]. The leaves and roots can be given as an
anthelmenticku, analgesic, cure for piles, body heat reducer, and thirst quencher and are also helpful in
reducing inflammation and itching. They are also useful in managing leucoderma and blood disorders.
When eaten raw, the green leaves can offer a cure for dysentery, and when they are boiled in milk,
the paste has good application prospects for curing poisonous bites and eruptions [44].

2.3. Phytochemistry of M. koenigii

A wide range of phytochemicals have been isolated from the leaves, roots, and stem bark of
M. koenigii. M. koenigii extracts of leaves, root, stem bark, fruits, and seeds have yielded alkaloids,
flavonoids, terpenoids, and polyphenols, as shown in Table 1. The plant leaves contain a substantial
amount of proximate composition; the moisture is 63.2%, protein is 8.8%, carbohydrate is 39.4%,
total nitrogen is 1.15%, fat is 6.15%, total sugars are 18.92%, starch is 14.6%, and crude fiber is 6.8%.
The leaves have been reported as a significant source of several vitamins, such as vitamin A (B-carotene),
with a level of 6.04 ± 0.02 mg/100 g; vitamin B3, (niacin), with a level of 2.73 ± 0.02 mg/100 g; vitamin
B1 (thiamin), with a level of 0.89 ± 0.01 mg/100 g; calcium, with a level of 19.73 ± 0.02 mg/100 g;
magnesium, with a level of 49.06 ± 0.02 mg/100 g; and sodium, with a level of 16.50 ± 0.21 mg/100 g.
The alcohol-soluble extract has a value of 1.82%, ash has a value of 13.06%, acid-insoluble ash has a
value of 1.35%, cold water (20 ◦ C) extractive has a value of 27.33%, and maximum of hot-water-soluble
extractive has a value of 33.45% [15,45]. Wide ranges of carbazole alkaloids, essential oils, terpenoids,
and flavonoids have numerous beneficial roles. Table 2 summarizes the major chemical constituents of
M. koenigii and its pharmacological activities.

Table 1. Phytochemical compounds identified from M. koenigii.

Compound Molecular Formula Plant Part References

Alkaloids
Mahanine C23 H25 NO2 Leaves, stem bark, and seeds [45–49]
Mahanimbine C23 H25 NO Leaves, roots, seeds, and fruits [47–49]
Murrayanol C24 H29 NO2 Leaves, roots, and fruits [47–49]
Koenimbine C19 H19 NO2 Leaves, seeds, and fruits [46–49]
O-Methylmurrayamine A C19 H20 NO2 Leaves [45–48]
Koenigicine C20 H21 NO3 Leaves [45–48]
Koenigine C19 H19 NO3 Leaves and stem bark [47–49]
Murrayone (Coumarine) C15 H14 O4 Leaves [45–48]
Mahanimbicine C23 H25 NO Leaves [45–48]
Antioxidants 2020, 9, 101 4 of 28

Table 1. Cont.

Compound Molecular Formula Plant Part References

Bicyclomahanimbicine C23 H25 NO Leaves [45–48]
Phebalosin C15 H14 O4 Leaves [45–48]
Isomahanimbine C23 H25 NO Leaves and roots [45,46,48]
Koenimbidine C20 H21 NO3 Leaves and roots [45,46,48]
Euchrestine B C24 H29 NO2 Leaves [45,46]
Bismurrayafoline E C48 H56 N2 O4 Leaves [45,46]
Isomahanine C23 H25 NO2 Leaves, seeds, and fruits [45,46,49]
Mahanimbinine C23 H27 NO2 Leaves and seeds [45,46,49]
Girinimbilol C18 H19 NO Leaves [45,46]
Pyrayafoline-d C23 H25 NO2 Leaves and stem bark [45,46,49]
Glycozoline C14 H13 NO Leaves [45,46]
Cyclomahanimbine C23 H25 NO Leaves [45,46]
Isomurrayazoline C23 H25 NO Leaves [45,46]
Mahanimboline C23 H25 NO2 Leaves [49]
Mukonicine C20 H21 NO3 Leaves [49]
Isolongifolene C15 H24 Leaves [49]
Mukonal C13 H9 NO2 Stems [49]
Mukeic acid C14 H11 NO3 Stems [49]
9-Carbethoxy-3-methyl carbazole C16 H15 NO2 Roots and stems [49]
9-Formyl-3-methyl carbazole C14 H11 NO Roots and stems [49]
Murrayazolinol C23 H25 NO2 Stems bark [49,50]
Mahanimbinol C23 H27 NO Stems bark [49,50]
Mukoeic acid C14 H11 NO3 Stem bark [49,50]
Osthol C15 H16 O3 Stem bark [49,50]
Umbelliferone C9 H6 O3 Stem bark [49,50]
Murrayanine C14 H11 NO2 Stem bark [49,50]
Mukoenine-A C18 H19 NO Roots and stem bark [49,50]
Mukoenine-B C23 H25 NO2 Roots and stem bark [49,50]
Mukoline C14 H13 NO2 Roots [49,50]
Mukolidine C14 H11 NO2 Roots and stem bark [49,50]
(M)-murrastifoline-F C28 H24 N2 O2 Roots and stem bark [49,50]
3-Methyl-9H-carbazole-9-carbaldehyde C14 H11 NO Roots [49,50]
Bismahanine C46 H48 N2 O4 Roots and stem bark [49,50]
Bikoeniquinone A C27 H20 N2 O3 Roots and stem bark [49,50]
Bismurrayaquinone C26 H16 N2 O4 Roots and stem bark [49,50]
3-Methylcarbazole C13 H11 N Roots [49]
Murrayafoline A C14 H13 NO Roots [49]
Murrayakonine A C37 H36 N2 O2 Leaves and stems [39]
Murrayakonine B C23 H23 NO2 Leaves and stems [39]
Murrayakonine C C24 H25 NO3 Leaves and stems [39]
Murrayakonine D C23 H25 NO2 Leaves and stems [39]
Girinimbine C18 H17 NO Roots, stem bark, and seeds [49,51]
Murrayacine C18 H15 NO2 Stem and bark [49,51]
Murrayazoline C23 H25 NO Stem and bark [49,51]
Flavonoids
Quercetin C15 H10 O7 Leaves [52]
Apigenin C15 H10 O5 Leaves [52]
Kaempferol C15 H10 O6 Leaves [52]
Rutin C27 H30 O16 Leaves [52]
Catechin C15 H14 O6 Leaves [52]
Myricetin C15 H10 O8 Leaves [52]
4-O-β-d-Rutinosyl-3-methoxyphenyl-
C22 H32 O12 Leaves [53]
1-propanone
1-O-β-d-Rutinosyl-2(R)-ethyl-1-pentanol C19 H36 O10 Leaves [53]
8-Phenylethyl-O-β-d-rutinoside C20 H30 O10 Leaves [54]
Terpenoids
Blumenol A C13 H20 O3 Leaves [53]
Icariside B1 C19 H30 O8 Leaves [53]
Loliolide C11 H16 O3 Leaves [53]
Blumenol A C13 H20 O3 Leaves [53]
 Antioxidants 2020, 9, 101 5 of 28

Table 1. Cont.

Compound Molecular Formula Plant Part References

Icariside B1 C19 H30 O8 Leaves [53]
(−)-Epiloliolide C11 H16 O3 Leaves [55]
(−)-α-pinene C10 H16 Leaves [55]
(−)-β-pinene C10 H16 Leaves [55]
(+)-β-pinene C10 H16 Leaves [55]
(+)-sabinene C10 H16 Leaves [55]
Squalene C30 H50 Leaves and bark [56]
β-sitosterol C29 H50 O Leaves and bark [56,57]

ants 2020, 9, 101 Polyphenols

Selin-11-en-4α-ol C15 H26 O Leaves and bark [56]
2-hydroxy-4-methoxy-3,6-dimethylbenzoic
Antioxidants
Antioxidants 2020,
2020, 9,
9, 101
101 C10 H12 O4 Bark [56]
acid
Table 2. The major bioactive compounds of M. koenigii and its pharmacological activities.

Serial No. Constituent Constituent

Table 2. The major bioactive compounds Structure
of M. koenigii and its pharmacological activities. Activity
Table
Table 2.
2. The
The major
major bioactive
bioactive compounds
compounds of
of M.
M. koenigii
koenigii and
and its
its pharmacological
pharmacological activities.
activities.

SerialSerial
Serial No. No. Constituent
No. Constituent
Constituent Constituent
Constituent Structure
Constituent Structure
Structure Activity Activity
Activity

Cytotoxicity, anti-microbial, and an

1 Mahanine
Cytotoxicity, cancer
Cytotoxicity,
Cytotoxicity, anti-microbial,
anti-microbial, and
and anti-
anti-
11 1 Mahanine
Mahanine
Mahanine anti-microbial, and
cancer
cancer
anti-cancer

Cytotoxicity,
Cytotoxicity, anti-oxidant, anti-micro
2 Mahanimbine anti-oxidant,
anti-diabetic,
Cytotoxicity,
Cytotoxicity, andanti-microbial,
anti-oxidant,
anti-oxidant, hyperlipidemi
anti-microbial,
22 2 Mahanimbine
Mahanimbine
Mahanimbine anti-microbial,
anti-diabetic,
anti-diabetic, and
and hyperlipidemic
hyperlipidemic
anti-diabetic, and
hyperlipidemic

Cytotoxicity,
Cytotoxicity,
anti-oxidant,
Cytotoxicity,
anti-oxidant,
Cytotoxicity, anti-oxidant,
anti-micro
anti-oxidant, anti-microbial,
anti-microbial,
3 33 Isomahanine
Isomahanine
Isomahanine
3 Isomahanine anti-microbial,
anti-diabetic,
anti-diabetic,
anti-diabetic, and and hyperlipidemi
and hyperlipidemic
hyperlipidemic
anti-diabetic, and
hyperlipidemic

44 koenimbine
koenimbine
koenimbine Cytotoxicity
and and
Cytotoxicity
Cytotoxicity and anti-diarrhea
anti-diarrhea
4 4 koenimbine
koenimbine Cytotoxicity and anti-diarrhea
anti-diarrhea
ants 2020, 9, 101

5 5 Girinimbine
Girinimbine Anti-tumor Anti-tumor

6 Isolongifolene Anti-oxidant and neuroprotectiv

7 Pyrayafoline D Anti-cancer and anti-bacterial

ants 2020,
ants 2020, 9,
9, 101
101

Antioxidants 2020, 9, 101 6 of 28

55 Girinimbine
Girinimbine Anti-tumor
Anti-tumor
Table 2. Cont.

Serial No. Constituent Constituent Structure Activity

Anti-oxidant and
66 Isolongifolene
6 Isolongifolene
Isolongifolene Anti-oxidant and
Anti-oxidant and neuroprotectiv
neuroprotectiv
neuroprotective

Anti-cancer and
77 Pyrayafoline
7Pyrayafoline D
Pyrayafoline
D D Anti-cancer and
Anti-cancer and anti-bacterial
anti-bacterial
anti-bacterial

Cytotoxicity and
88 Murrayafoline
8 Murrayafoline
Murrayafoline Cytotoxicity
Cytotoxicity and anti-inflammato
and anti-inflammato
anti-inflammatory

99 Murrayazoline Cytotoxicity and

Cytotoxicity and anti-tumor
anti-tumor
9Murrayazoline
Murrayazoline Cytotoxicity and
anti-tumor

ants 2020,
ants 2020, 9,
9, 101
101

10
10 Koenoline
10 Koenoline
Koenoline Cytotoxicity Cytotoxicity
Cytotoxicity

9-formyl-3-methyl
9-formyl-3-methyl
9-formyl-3-methyl
11
11 11 carbazole Anti-oxidant Anti-oxidant
Anti-oxidant
carbazolecarbazole

12 O-Methylmurrayamine Anti-oxidant and

Anti-oxidant and neuroprotectiv
neuroprotectiv
12 O-Methylmurrayamine
12 O-Methylmurrayamine Anti-oxidant and
neuroprotective

13
13 Koenine
Koenine Anti-oxidant
Anti-oxidant
 9-formyl-3-methyl
11 Anti-oxidant
carbazole

Antioxidants 2020, 9, 101 7 of 28

12 O-Methylmurrayamine Anti-oxidant and neuroprotective

Table 2. Cont.

Serial No. Constituent Constituent Structure Activity

13 13 Koenine
Koenine Anti-oxidantAnti-oxidant

14 14 Koenigine
Koenigine Anti-oxidantAnti-oxidant
Antioxidants 2020, 9, 101
Antioxidants
Antioxidants 2020,
2020, 9,
9, 101
101
Antioxidants 2020, 9, 101

15 15
15 15 Mukonicine
Mukonicine
Mukonicine
Mukonicine Anti-oxidant
Anti-oxidant
Anti-oxidant
Anti-oxidant
15 Mukonicine Anti-oxidant

Anti-oxidant,
Anti-oxidant,
Anti-oxidant,anti-microbial,
anti-microbial,
Anti-oxidant, anti-microbial, anti-diabetic,
anti-diabetic,
anti-microbial, anti-diabetic,
16 16
16 16 Mahanimbinine
Mahanimbinine
Mahanimbinine
Mahanimbinine Anti-oxidant,
and
anti-diabetic,
and
anti-microbial,
hyperlipidemic
and
hyperlipidemic
anti-diabetic,
16 Mahanimbinine and hyperlipidemic
and hyperlipidemic
hyperlipidemic

Anti-oxidant,
Anti-oxidant,
Anti-oxidant, anti-microbial,
anti-microbial, anti-diabetic,
anti-microbial, anti-diabetic,
17
17 17 Murrayacinine
Murrayacinine Anti-oxidant, anti-microbial, anti-diabetic,
17 Murrayacinine
Murrayacinine Anti-oxidant,
and
and
anti-microbial,
hyperlipidemic
hyperlipidemic
anti-diabetic,
17 Murrayacinine anti-diabetic,
andand and
hyperlipidemic
hyperlipidemic
hyperlipidemic

Cytotoxicity,
anti-oxidant,
Cytotoxicity,
Cytotoxicity, anti-oxidant, anti-microbial,
anti-oxidant,anti-microbial,
anti-microbial,
18
1818 Mahanimboline
Mahanimboline Cytotoxicity, anti-oxidant,
18 Mahanimboline
Mahanimboline anti-microbial,
anti-diabetic,
anti-diabetic,
Cytotoxicity, and
and hyperlipidemic
hyperlipidemic
anti-diabetic,anti-oxidant, anti-microbial,
and hyperlipidemic
18 Mahanimboline anti-diabetic, andand hyperlipidemic
anti-diabetic,
hyperlipidemic
Antioxidants 2020, 9, 101

19 19 Mukoeic
Mukoeic acid acid Anti-oxidantAnti-oxidant

20 20 Murrayanine
Murrayanine Anti-oxidantAnti-oxidant
Antioxidants 2020, 9, 101 8 of 28

2.4. Bioavailability Study of M. koenigii-Derived Active Constituents

An in vivo pharmacokinetic study revealed that after oral administration of the bioactive
compounds at the rate of 0.1 gm/kg body weight (b.w.), the maximum systemic concentration
(Cmax) of koenimbine was 1.81 ± 0.55 µM and koenidine was 2.82 ± 0.53 µM, and the time required
to reach the maximum concentration was 49.8 ± 8.4 min and 240 ± 0.00 min, respectively [58].
Bhattacharya et al. demonstrated the bioavailability of mahanine—another important bioactive
compound of M. koenigii—in mice through blood serum estimations based on high-performance liquid
chromatography (HPLC) analysis. Mahanine, at a dose of 100 mg/kg of body weight, was found to
take 60 min to reach the maximum concentration in blood serum [59].

3. Molecular Mechanism and Activities of M. koenigii

3.1. Antioxidants
Reactive oxygen species (ROS), such as singlet oxygen (O2 ), hydrogen peroxide (H2 O2 ),
the superoxide anion (O2 •− ), and the hydroxyl radical (•OH), are often generated as byproducts of
cellular metabolic reactions and exogenous induction. These ROS create homeostatic imbalances, which
lead to the generation of oxidative stress, which in turn, induces cell death and tissue injury [60]. ROS in
elevated levels can damage biomolecules such as nucleic acids, proteins, and lipids [61]. Even though
the antioxidant defense systems like enzymatic antioxidants and non-enzymatic antioxidants are
functioning, uncontrolled ROS accumulation during the life cycle promotes the development of
age-dependent diseases, like cancer, atherosclerosis, arthritis etc. [62]. Natural antioxidants from
plant sources have been considered a promising therapy for the prevention and treatment of these
diseases, especially neurodegenerative disorders, cardiovascular diseases, cancer, and other conditions.
Various natural bioactive compounds, such as mahanine, mahanimbine, isolongifolene, koenimbine,
girinimbine, isomahanine, koenoline, and O-methylmurrayamine, are present in M. koenigii and exhibit
remarkable antioxidant properties [63,64].
The leaf extracts of M. koenigii have high antioxidant activities [65]. Rao et al. evaluated the
antioxidant activities of water and an ethanol extract of M. koenigii assessed by the, α-diphenyl-β-
picrylhydrazyl (DPPH) free radical scavenging assay, with quercetin as a positive control. The ethanolic
extract of M. koenigii showed an 80% scavenging activity, which was similar to the activities exhibited
by the control antioxidant compound quercetin [66]. Gupta et al. evaluated the antioxidant activities
of acetone, alcohol, and aqueous extracts of M. koenigii by the DPPH free radical scavenging assay, with
ascorbic acid as a positive control. The extracts of M. koenigii exhibited activities with an half-maximum
effective concentration (EC50 ) value of acetone of 81.81 ± 19.92 at 4.7 µg/mL, alcohol of 79.80 ± 18.68 at
4.1 µg/mL, and aqueous extract of 62.82 ± 13.62 at 4.4 µg/mL, which was comparable to the EC50 value
exhibited by ascorbic acid (the positive control), which was 97.13 ± 12.64 at 2.69 µg/mL [67]. Zahin et al.
also evaluated the antioxidant activities of both ethyl acetate and petroleum ether fractions of M. koenigii
through DPPH radical scavenging assay, cupric reducing antioxidant capacity (CUPRAC), and ferric
reducing antioxidant power (FRAP) assays, with ascorbic acid as a positive control. The benzene
fraction of M. koenigii was found to be the most active free radical scavenger, exhibiting an 88.3%
decrease at a concentration of 100 µg/mL, followed by ethyl acetate at 79.5% and petroleum ether at
78.7%, while positive controls of ascorbic acid and butylated hydroxytoluene (BHT) at a concentration
of 100 µg/mL inhibited 93.1% and 86.5% DPPH absorption, respectively. Similarly, the antioxidant
activity created by reducing activity and CUPRAC assays indicated the highest reducing potential in
the benzene fraction, followed by petroleum ether and ethyl acetate. The activity was greater than that
of ascorbic acid and on par with that of BHT [68].
Yogesh et al. evaluated the antioxidant activity of berry extracts of M. koenigii by DPPH free
radical scavenging activity and reducing power assays. The results indicated that an M. koenigii
berry extract is a powerful free radical scavenger compared to known antioxidants, such as butylated
hydroxytoluene, ascorbic acid, and tannic acid [69]. Tomar et al. evaluated the total antioxidant activity
Antioxidants 2020, 9, 101 9 of 28

of acetone and petroleum ether extracts of younger and older M. koenigii leaves by estimating the
H2 O2 scavenging activity. The acetone extract of old leaves was found to have a maximum activity
at 151.58%, and for young leaves in petroleum ether, the value was 72.23% [70]. Waghmare et al.
evaluated the antioxidant property of fruit extracts of M. koenigii with DPPH free radical scavenging
activity, inhibition of nitric oxide radical (NO) and thiobarbituric acid reactive substances (TBARS)
activity, and reducing power assays, and •OH was also estimated, with vitamin C as a positive control.
The fruit extract of M. koenigii exhibited antioxidant activities, and the EC50 value of the extracts for
the DPPH assay was 2.6 mg/mL; for the NO radical, was 2.9 mg/mL; for TBARS, was 3.1 mg/mL; for
the reducing power assay, was 2.7 mg/mL; and for H2 O2 , was 3.3 mg/mL, which were comparable to
the EC50 value of 5 mg/mL exhibited by the vitamin C positive control [71]. The antioxidant activities
exhibited by the crude extracts of M. koenigii were probably due to the presence of flavonoids and
phenolic derivatives. The above studies revealed that various extracts of M. koenigii display high
antioxidant activity. The studies also indicated the potential for this plant to be a natural source of
strong antioxidant substances that can be used in therapy for human diseases induced by ROS.

3.2. Oxidative Stress

Chemical species with one or more unpaired electrons are called free radicals. In biological
systems, the term “free radicals” refers to reactive oxygen species (ROS). Major ROS include O2 •− ,
H2 O2 , and •OH [72]. In addition to ROS, reactive nitrogen species (RNS), including peroxynitrite
(NO3 − ), NO, and S-nitrosothiols, also contribute to the generation of oxidative stress. Both ROS and
RNS arise as intermediates in several metabolic processes and are specifically produced as part of the
cellular defense against invasive pathogens. Free radicals also regulate many processes, including
cellular growth, glucose metabolism, and proliferation [73].
Apart from certain beneficial effects, free radicals induce various deleterious effects. In a
non-specific manner, ROS can react on significant biomolecules, which leads to deleterious effects like
a loss of enzyme activity, genetic mutations and permeability alterations in the cell membrane, and
RNS-induced protein S-nitrosylation [74]. Because DNA is constantly attacked by the free radicals,
around 75,000 to 100,000 DNA damage events might occur in each cell per day. •OH is the most
reactive species and interacts with all biological molecules, including the C-8 position of guanine to
form 8-hydroxyguanine, which is one of the most frequently found oxidized bases in DNA [75].
An increase in the free radical concentration in the body can cause subsequent oxidative and
cellular damage to lipids, proteins, RNA, and DNA [76]. The leaf extract of M. koenigii has recently
been shown to possess potential antioxidant activity and protection against oxidative stress induced in
diabetes [77]. The aqueous leaf extract of M. koenigii has been shown to reduce lipid peroxidation and
decrease cellular damage, thereby protecting the liver from ethanol-induced toxicity [31]. Khan et al.
reported the antioxidant effect and preventive effect of curry leaves in cadmium-induced oxidative
stress, cardiac tissue damage, and alterations in normal cardiac functions in rats [78]. Mitra et al.
reported the heavy metal chelating activity of an M. koenigii leaf extract. They found that there was a
significant decrease in the tissue cadmium level when the rats were pre-treated with the M. koenigii leaf
extract before cadmium administration [79].

3.3. Mitochondrial Dysfunction

Mitochondria are the primary source of high-energy metabolism within the cell. Mitochondria are
known as the powerhouse of the living cell. Mitochondria also regulate calcium homeostasis and play a
role in scavenging free radicals and controlling programmed cell death and/or the apoptosis-signaling
pathway [80]. Mitochondrial damage leads to reduced adenosine triphosphate (ATP) production,
increased ROS generation, impaired calcium buffering, damage to mitochondrial DNA (mtDNA),
an altered mitochondrial morphology, and alterations in mitochondrial fission and fusion. All these
events eventually lead to cell death [81]. It is currently believed that the majority of ROS are
generated by mitochondrial complexes I and III, likely due to the release of electrons by NADH and
Antioxidants 2020, 9, 101 10 of 28

dihydroflavine-adenine dinucleotide (FADH2 ) into the electron transport chain (ETC). Mitochondrial
dysfunction is a characteristic of all chronic diseases and aging. It is characterized by a loss of efficiency
in the ETC, as well as reductions in the synthesis of high-energy molecules [82]. These diseases include
neurodegenerative diseases like Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic
lateral sclerosis, multiple sclerosis, Huntington’s disease, cardiovascular diseases, auto-immune
diseases, diabetes, and others [83,84].
Mitochondria, as essential organelles, have a noteworthy role in the viability of neuronal cells.
Excess ROS formation is due to complex I inhibition inducing impairments in the mitochondrial
membrane potential (MMP) and the pro-apoptotic members are believed to permeabilize the outer
mitochondrial membrane due to the formation of oligomeric pores, which permits the release
of apoptogenic molecules from the intermembrane space. Recent studies have evaluated the
neuroprotective activities of isolongifolene and structurally similar compounds, such as girinimbine,
murrayazoline, and O-methylmurrayamine A isolated from M. koenigii. By using different in vitro
assays, a study reported that the above bioactive compounds exhibited the ability to restore the MMP
levels and repair the mitochondrial damage [85–87].

3.4. Inflammation
Tissue injury, cell damage, infections due to pathogens, and alterations in biochemicals lead to a
biological response called inflammation. In neurological disorders, the important components involved
in inflammatory processes are believed to be mast cells, ependymal cells, microglia, astrocytes, and
macrophages [88]. Microglia, a type of neuronal support cell acting as resident macrophages located
throughout the brain by changing their morphology, actively respond to inflammation and participate
in removing damaged neurons and pathogens. An ethanol extract from M. koenigii leaves showed
significant analgesic and anti-inflammatory activity when explored using carrageenan-induced hind
paw edema in albino rats [89]. Another study also confirmed the anti-inflammatory activity of an
M. koenigii leaf extract in carrageenan-induced paw edema [90]. Additionally, the study recognized the
analgesic activity of curry leaves with several experimental models. M. koenigii leaf extracts effectively
attenuate the pain which is induced by an intraperitoneal injection of acetic acid and subplantar
injection of formalin in mice, and the analgesic effect was elucidated with the writhing responses and
pain responses in the late phase. Furthermore, it was reported that higher concentrations (20 and
40 mg/kg, per os (p.o.)) reduced the early-phase inflammatory responses induced by formalin [91].
Khurana et al. evaluated the in vitro and in vivo efficacy of a hydroalcoholic extract of M. koenigii
curry leaves rich in carbazole alkaloids against lipopolysaccharide (LPS)-induced inflammation in
RAW 264.7 cells. The activity of inflammatory cytokines interleukin 1 beta (IL-1β), interleukin-6
(IL-6), tumor necrosis factor (TNF-α), and p65-NFκB was significantly reduced by the hydroalcoholic
extract of M. koenigii. In addition, the hydroalcoholic extract of M. koenigii reduced the expression
of nitrotyrosine (NT), myeloperoxidase (MPO), IL-1β, intercellular adhesion molecule 1 (ICAM-1),
and cyclooxygenase (COX-2), and increased the expression of Nrf2 [92]. Iman et al. evaluated the
anti-inflammatory activity of an extract of M. koenigii and its bioactive compound girinimbine against
lipopolysaccharide/interferon-gamma-induced RAW 264.7 cells. The girinimbine showed reduced
levels of NO overproduction and pro-inflammatory cytokine levels IL-1β and TNF-α in the peritoneal
fluid. These findings strongly suggest that girinimbine could act as an anti-inflammatory agent by
suppressing inflammation [85]. Another study also confirmed the anti-inflammatory activity of an
M. koenigii leaf extract. Bioactive compounds like murrayakonine A, O-methylmurrayamine A, and
mukolidine were reported for their efficiency in inhibiting TNF-α and IL-6 release in LPS-induced
inflammation in human peripheral blood mononuclear cells (PBMCs) [39]. The above studies have
shed light on the mechanism of the anti-inflammatory activity of M. koenigii leaves and their active
compounds, which are comparable to nonsteroidal anti-inflammatory drugs (NSAIDs).
Antioxidants 2020, 9, 101 11 of 28

3.5. Apoptosis
Apoptosis is a physiological programmed cell death mechanism which is essential for the flawless
growth and development of organisms. Furthermore, it is a lively physiological course causing the
self-destruction of cells that comprises lethal biochemical and morphological changes in the nucleus
and cytoplasm. During cellular strain like oxidative stress and DNA damage, the process of apoptosis
can arise, particularly in cells with high proliferation rates and a high expression of pro-apoptotic
genes [93]. Intrinsic and extrinsic pathways regulate apoptosis, but both pathways are associated and
the molecules involved in those pathways can influence one another.
Previous findings have demonstrated that an M. koenigii extract and its primary active compounds
regulate multiple signaling pathways, including phosphatidylinositol 3 kinase (PI3K)/protein kinase
B (AKT), mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK).
M. koenigii and its primary active compounds exert complementary effects on oxidative stress and the
alteration of proteins [94,95]. They are associated with mitochondrial-mediated apoptotic pathways.
Murrayazoline and O-methylmurrayamine were shown to induce the downregulation of Akt/mTOR,
suggesting downstream targeting of the cell survival pathway and an ability to potentiate the antitumor
activity of D.L. Dexter (DLD-1) colon cancer cells; interestingly, this inhibition of the Akt/mTOR pathway
could possibly activate the intrinsic apoptotic program [86]. Mahanine and isomahanine derived from
M. koenigii leaves exert anticancer effects on oral squamous cell carcinoma cells via the induction of
microtubule-associated protein 1 light chain 3, type II (LC3B-II), and cleaved caspase-3, suggesting the
inhibition of autophagic flux [96]. In human leukemic cells, Mahanine was reported to induce apoptosis
by interrupting signal transfer between Apo-1/Fas signaling and the Bid protein and via mitochondrial
pathways in humans [59]. Recently, it was reported that girinimbine, a carbazole alkaloid isolated from
M. koenigii, inhibited the growth of and induced apoptosis in human hepatocellular carcinoma cells
(HepG2) [97]. In addition, Xin et al. reported that girinimbine inhibited ovarian cancer cell proliferation
in a dose-dependent manner. It also inducted apoptosis and cell cycle arrest due to inhibition of the
PI3K/AKT/mTOR and Wnt/b-catenin signaling pathways [98].
The alkaloid koenimbin found in M. koenigii was shown to extend pro-apoptotic activities in
MCF-7 cancer cells by inhibiting glycogen synthase kinase-3 beta (GSK-3β). Koenimbin induces
apoptotic cell death, phosphorylation, the accumulation of β-catenin, and the activation of nuclear
factor-κB (NF-kB) in cancers. Moreover, koenimbin suppresses the expression of various anti-apoptotic
genes involved in the regulation of cell proliferation and apoptosis [99]. Koenimbine has also been
reported to trigger caspase activation, induce the release of cytochrome c, decrease the anti-apoptotic
proteins, and increase the pro-apoptotic proteins, and all of these events lead to intrinsic apoptotic
pathway activation [99]. Another study demonstrated that pyrayafoline-D and murrafoline-I isolated
from M. koenigii could induce apoptosis in HL-60 cells. The same study also induced the loss of
mitochondrial membrane potential and the subsequent activation of caspase-9/caspase-3, leading to
the activation of apoptotic pathways [100].

4. Beneficial Pharmacological Activities of M. koenigii and Its Primary Active Derivatives

4.1. Antifungal Activity

The antifungal activity of M. koenigii has been reported in various studies. For example, the essential
oil of the leaves was reported to possess antifungal activity [18]. The antifungal activity of the leaves of
M. koenigii is due to the presence of phytochemical constituents of complex molecular structures and
diverse action mechanisms, viz. alkaloids, terpenoids, flavonoids, phenolics, tannins, and saponins,
which are known for their antimicrobial properties. Different investigations support the traditional use
of the plant as an antifungal agent. In vitro antifungal activity may explain the use of curry leaves
for the treatment of diarrhea, dysentery, and skin eruptions in folklore medicines [19]. Bioactive
compounds of M. koenigii appreciably hold the ability of mycelial growth inhibition and thereby
promote antifungal activity. The antifungal activity of M. koenigii against a wide range of pathogenic
Antioxidants 2020, 9, 101 12 of 28

fungi has been studied. Penicillium notatum, Aspergillus flavus, Aspergillus niger, Fusarium moniliforme,
Mucor mucedo, Penicillium funiculosum etc., were isolated from infected saplings and spoiled foods
based on alterations of their growth characteristics, mycelial morphology, and spore morphology
(Table 3) [27]. The ethanolic extract of M. koenigii exhibited notable effects on the hyphal morphology;
namely, an increase in branching potential, which resulted in the development of short slender branches
of hyphae with swollen tips. Such effects are usual for any antifungal compound. Bioactive compounds
like girinimbine, murrayanine, marmesin-10 -O-beta-D’galactopyranoside, mahanine, murrayacine,
mukoeic acid, murrayazolinine, girinimbilol, pyrafoline-D, and murrafoline-I are present in stem bark.
Girinimbine, murrayanine, and marmesin-10 -O-beta-D’galactopyranoside have notable anti-fungal
activity [20,101].

4.2. Antibacterial Activity

The unsystematic use of antibiotics promotes the development of multiple drug-resistant
pathogenic strains of bacteria, which are very harmful, and there is a lack of proper treatment
procedures for these ailments. Therefore, the need to search for new antimicrobials remains. Currently,
in addition to antibiotics and chemically-synthesized drugs, curiosity for alternative medicines, such
as natural or herbal medicines, is increasing. They may have fewer side effects or toxicity owing to
their natural sources [102].
Combating microbial infections without side effects is always a tedious process. In this regard,
in addition to classical antibiotics and synthetic drugs, there is an ongoing hunt for potent molecules
from natural herbal medicines [102]. M. koenigii extracts have demonstrated antibacterial effects on
a wide variety of microorganisms. Methanol and ethanol extracts of M. koenigii leaves were found
to be effective against the bacterial strains Escherichia coli (E. coli), Staphylococcus, Streptococcus, and
Proteus. Hence, M. koenigii leaves could be efficiently used as a natural remedy in everyday meals
for the prevention of several bacterial infections [103]. Pyranocarbazoles isolated from M. koenigii
exhibited antibacterial activity on bacterial strains of Staphylococcus aureus and Klebsiella pneumonia [40].
Green synthesized silver nanoparticles (AGNPs) from M. koenigii exhibited therapeutic efficacy against
multidrug resistant MDR bacteria [103]. M. koenigii essential oil showed antibiofilm activity against
Pseudomonas aeruginosa and it was reported that M. koenigii essential oil treatment revealed an 80%
reduction in biofilm formation by P. aeruginosa. Microscopic analyses confirmed the drop in biofilm
formation in Pseudomonas aeruginosa when treated with M. koenigii essential oil. The presence of
antibiofilm substances like spathulenol (5.85%), cinnamaldehyde (0.37%), and linalool (0.04%) was
reported in gas chromatography-mass spectrometry (GCMS) studies [104]. M. koenigii counteraction on
uropathogenic bacteria isolated from clinical samples was reported in a different study [105]. M. koenigii
was tested for its antibiotic action against Mycobacterium species, which was appreciable, like first-line
anti-tuberculosis drugs. M. koenigii half maximal inhibitory concentration ((IC50 ) 400 µg/mL) was
found to be more effective against Mycobacterium smegmatis compared to water extracts and petroleum
ether. An M. koenigii ethanol extract exhibited significant synergistic antibacterial activity against
Mycobacterium smegmatis and Mycobacterium bovis bacillus calmette-guerin (BCG) in combination with
the anti-tuberculosis drug rifampicin [106].
Antioxidants 2020, 9, 101 13 of 28

Table 3. An overview of the pharmacological activities of M. koenigii and its primary bioactive compounds.

Pharmacological Plant
Extract Bioactive Compounds Model Main Finding Reference
Activities Parts
In vitro studies
Essential oil extracted from M. koenigii exhibited activities with
Antifungal Leaves Essential oil − Disc diffusion method MIC in the range of 25.5 to 75 µg/mL against pathogenic fungi [27]
A. niger, F. moniliforme, P. notatum, M. mucedo, and P. funiculosum
Minimum inhibitory concentrations (MIC) of solvent-free
Solvent-free microwave extraction (SFME) and hydro-distilled oil from
Antibacterial Leaves microwave − Soy agar M. koenigii with values of 400 and 600 µg/mL against L. innocua [37]
extraction SFME-essential oil at 300 µg/mL provided 92% inhibition,
indicating its antibacterial potential
Koenine, koenigine, and mahanine extracted from M. koenigii
Koenine, koenigine, and Broth micro-dilution
Antibacterial Leaves Methanol exhibited activities with MIC values of 3.12–12.5 µg/mL against [40]
mahanine assay
bacterial strains S. aureus and K. pneumonia
M. koenigii-AGNPs exhibited inhibitory activity against E. coli
Antibacterial Leaves Aqueous − Agar diffusion assay and S. aureus, with a value of 16 mm for M. koenigii-AgNPs and [18]
15 mm for AgNO3 solution at 100 µg/well
Essential oil extracts of M. koenigii treatment resulted in a
reduction of biofilm formation in P. aeruginosa PAO1. M. koenigii
Antibacterial Leaves Essential oil − Microtiter assay [19]
essential oil may effectively control Pseudomonas biofilms in
indwelling medical device
Ethanol extracts of M. koenigii exhibited activity half maximal
Petroleum ether, Colony-forming unit inhibitory concentration ((IC50 ) of 400 µg/mL) against the
Antibacterial Leaves − [20]
ethanol, and water (CFU) assay mycobacterium smegmatis compared to petroleum ether and
water extracts
Hepatoprotective Leaves Aqueous − Hep G2 cell line M. koenigii leaves preventing alcohol-induced cellular damage [31]
DPPH free radical
Antioxidant Leaves Ethanol − exhibited activities with IC50 values of 21.4–49.5 µg/mL [21]
scavenging assay
TBARS, CAT, SOD, Carbazole alkaloids from M. koenigii extract exhibited activity
Antioxidant Leaves Aqueous − and glutathione with IC50 values of 120 µg/mL in an ethanol-induced [31]
(GSH) assay hepatotoxicity in vitro model
Aqueous/zinc oxide DPPH free radical Zinc oxide nanoparticle-synthesized M. koenigii extract exhibited
Antioxidant Leaves − [64]
nanoparticles scavenging assay activity with an IC50 value of 36.46 µg/mL
Aqueous/zinc oxide ABTS radical Zinc oxide nanoparticle-synthesized M. koenigii extract exhibited
Antioxidant Leaves − [64]
nanoparticles scavenging assay activity with an IC50 value of 11.55 µg/mL
Antioxidants 2020, 9, 101 14 of 28

Table 3. Cont.

Pharmacological Plant
Extract Bioactive Compounds Model Main Finding Reference
Activities Parts
In vitro studies
Aqueous/zinc oxide Zinc oxide nanoparticle-synthesized M. koenigii extract exhibited
Antioxidant Leaves − Superoxide assay [64]
nanoparticles activity with an IC50 value of 11.47 µg/mL
Aqueous/zinc oxide Zinc oxide nanoparticle-synthesized M. koenigii extract exhibited
Antioxidant Leaves − H2 O2 Assay [64]
nanoparticles activity with an IC50 value of 54.06 µg/mL
The ethanoic extract of M. koenigii showed an 80% scavenging
DPPH free radical
Antioxidant Leaves Ethanoic − activity, which was similar to the activities exhibited by the [66]
scavenging assay
control antioxidant compound quercetin
The extracts of M. koenigii exhibited activities with an EC50 value
of acetone of 4.7 µg/mL, alcohol of 4.1 µg/mL, and aqueous of
Aqueous, alcohol, DPPH free radical
Antioxidant Leaves − 4.4 µg/mL, which were comparable to the EC50 value of [67]
and acetone scavenging assay
2.6 µg/mL exhibited by ascorbic acid, which was the
positive control
Petroleum ether and Cupric-reducing CUPRAC assays indicated the highest reducing potential in the
Antioxidant Leaves − [68]
ethyl acetate antioxidant capacity benzene fraction, followed by petroleum ether and ethyl acetate
Results showed that for 100 µg/mL, the benzene fraction
Benzene, ethyl
extracted from M. koenigii showed 88.3% free radical scavenging
acetate, acetone, DPPH free radical
Antioxidant Leaves − activity, followed by ethyl acetate (79.5%), petrol ether (78.7%), [69]
methanol, and scavenging assay
acetone (66.1%), methanol (50.7%), and ethanol (53.0%) fractions,
ethanol
respectively, with the positive control being ascorbic acid (93.1%)
DPPH free radical Fruit extracted from M. koenigii exhibited activities with an EC50
Antioxidant Fruits Aqueous − [71]
scavenging assay value of 2.6 mg/mL
Stem
Hexane, chloroform, Girinimbine was shown to significantly inhibit the proliferation
Cytotoxicity bark and Girinimbine MTT assay [85]
and methanol of HT-29 cells with an IC50 value of 4.79 ± 0.74 µg/mL.
roots
Murrayazoline and O-methylmurrayamine A exhibited activities
Murrayazoline and
Cytotoxicity Leaves Ethanol MTT assay with IC50 values of 5.7 and 17.9 mM in both HEK-293 and [86]
O-methylmurrayamine A
HaCaT cell lines, respectively
Isolongifolene exhibited activities at 10 µM, showing a 90%
Cytotoxicity − − Isolongifolene MTT assay [87]
viability in SH-SY5Y cells
M. koenigii methanolic extract exhibited activities with IC50
Cytotoxicity Leaves Methanol − MTT assay [96]
values >400 µg/mL in the CLS-354 cell line
M. koenigii ethanolic extract exhibited activities with an IC50
Cytotoxicity Leaves Ethanol − MTT assay [20]
value of 20 µg/mL in the mouse macrophage RAW 264.7 cell line
Antioxidants 2020, 9, 101 15 of 28

Table 3. Cont.

Pharmacological Plant
Extract Bioactive Compounds Model Main Finding Reference
Activities Parts
Hexane, ethyl Three extracts of M. koenigii exhibited were very active, with
Cytotoxicity Leaves acetate, and − MTT assay values of <1 µg/mL to 2.25 µg/mL, and were thus proved to be [11]
methanol potent cytotoxic activity agents against HeLa cancer cells
In vitro experiments showed murrayakonine A (IC50 10 µM),
Murrayakonine A, Human peripheral
murrayanine (IC50 9.4 µM), and O-methylmurrayamine-A (IC50
Anti-inflammatory Stems Methanol murrayanine, and blood mononuclear [39]
7 µM) against TNF-α, and murrayanine (IC50 8.4 µM) and
O-methylmurrayamine-A cells
methylmurrayamine-A (IC50 8.4 µM) against IL-6, respectively
O-methylmurrayamine A exhibited anti-colon cancer activity
O-methylmurrayamine
Anticancer (Colon) Leaves Ethanol MCF-7 cells through downregulation of the Akt/mTOR survival pathway [86]
5.7–17.9 µM
and activation of the intrinsic pathway of apoptosis
Mahanine increased the expression of LC3B-II, cleaved caspase-3
Anticancer (Oral) Leaves Methanol Mahanine 15 µM CLS-354 cells [96]
proteins, and the inhibition of autophagic flux
Girinimbine was found to be mainly due to the induction of
Stem Ovarian cancer cell
Anticancer (Ovarian) Methanol Girinimbine 10 µM apoptosis and cell cycle arrest due to the inhibition of the [98]
bark line SKOV3/ SV40
PI3K/AKT/mTOR and Wnt/b-catenin signaling pathways
Koenimbin induced apoptosis in MCF7 cells that was mediated
by cell death and regulated the mitochondrial membrane
MCF7 breast cancer potential by downregulating Bcl2 and upregulating Bax, due to
Anticancer (Breast) Leaves Aqueous acetone Koenimbin 4.89 µg/mL [98]
stem cells cytochrome c release from the mitochondria to the cytosol, and
significantly downregulated the Wnt/β-catenin
self-renewal pathway
Koenimbin induced apoptosis through the intrinsic signaling
pathway and suppression of the translocation of cytoplasmic
Prostate cancer stem
Anticancer (Prostate) Leaves Aqueous acetone Koenimbin 3.73 µg/mL NF-κB into the nucleus, in addition to displaying potential for [99]
cells
targeting PCSCs, as affirmed by the prostasphere formation and
Aldefluor assay
Mahanine inhibited the cell migration and invasion and
Anticancer Leaves Methanol Mahanine 7.5 µM Glioma HS 683 cells inhibited cell growth was simultaneous with the suppression of [96]
p-PI3K, p-AKT, and p-mTOR
HepG2, HuCCT1, and Mahanine showed potent cytotoxicity, with increased expression
Anticancer (Liver) Leaves Methanol Mahanine 25 µM [13]
KKU-100 cells levels of MITF balance between the cellular stresses
HeLa (HPV-18) and Mahanine and cisplatin synergistically displayed growth
Anticancer (Cervical) Leaves Methanol Mahanine 8.6 µM SiHa (HPV-16) inhibitory activity in cervical cancer, the inhibition of STAT3 [14]
cell line activation, cell migration, and induced apoptosis
NSCLC cancer cell Mahanine induced the impairment of mTORC2 through rictor
Anticancer (Lung) Leaves Methanol Mahanine 15 µM [22]
line A549 inhibition and the destruction of NSCLC cancer cells
Antioxidants 2020, 9, 101 16 of 28

Table 3. Cont.

Pharmacological Plant
Extract Bioactive Compounds Model Main Finding Reference
Activities Parts
Mahanine synergistically activated the two tumor suppressors
HCT116, HCT116,
Anticancer (Colon) Leaves Methanol Mahanine 0–30 µM PTEN and p53/p73 and can potentially be used in combination [23]
SW480, and Vero
therapy with 5-FU for the treatment of colon carcinoma
Mahanine selectively degraded DNMT1 and DNM T3B via the
PC3 and LNCaP
Anticancer (prostate) Leaves Methanol Mahanine 10 µM ubiquitin-proteasomal pathway in a dose-dependent manner [24]
cell line
upon the inactivation of Akt signaling
Isolongifolene was effectively attenuated in oxidative stress,
Neuroprotective Leaves Methanol Isolongifolene 10 µM SH-SY5Y cells [87]
mitochondrial dysfunction, and apoptosis
O-methylmurrayamine A possibly protects against DNA
Neuroprotective Leaves Methanol O-methylmurrayamine A PC12 cells [35]
damage, apoptosis, and high levels of cell viability
In vivo studies
The oral administration of an M. koenigii leaf extract resulted in a
Antioxidant Leaves Aqueous − Male albino Wistar rat significant reduction in the level of TBARS in both the plasma [61]
(3.64 ± 0.13) and pancreas (53.40 ± 2.13) of diabetic rats
The oral administration of an M. koenigii leaf extract resulted in a
Antioxidant Leaves Aqueous − Male albino Wistar rat significant increase in the level of GSH in both the plasma [77]
(24.16 ± 1.30) and pancreas (19.52 ± 1.09) of diabetic rats
The oral administration of an M. koenigii leaf extract significantly
Antioxidant Leaves Aqueous − Male albino Wistar rat restored the activity of SOD in the pancreas (3.69 ± 0.15) of [77]
diabetic rats
The oral administration of an M. koenigii leaf extract significantly
Antioxidant Leaves Aqueous − Male albino Wistar rat restored the activity of CAT in the pancreas (12.94 ± 0.54) of [77]
diabetic rats
The oral administration of an M. koenigii leaf extract significantly
Antioxidant Leaves Aqueous − Male albino Wistar rat restored the activity of GPx in the pancreas (5.86 ± 0.22) of [67]
diabetic rats
For 200 and 400 µg/mL b.w, the M. koenigii extract showed 80%
Antioxidant Leaves Ethanol − Sprague Dawley rats [10]
inhibited free radical generation and 75% restored GSH levels
Extract exhibited the potential to reduce lipid peroxidation
Antioxidant Leaves Water − Male albino Wistar rat activity in the liver (2.44 ± 0.029) and kidney (2.34 ± 0.09) in [38]
potassium dichromate-induced Wistar rats
Stem
Hexane, chloroform, Girinimbine treatment significantly suppressed the IL-1β and
Anti-inflammatory bark and Girinimbine Adult zebrafish [85]
and methanol TNF-α levels induced by peritoneal fluid mice
roots
Antioxidants 2020, 9, 101 17 of 28

Table 3. Cont.

Pharmacological Plant
Extract Bioactive Compounds Model Main Finding Reference
Activities Parts
Oral administration of an M. koenigii extract showed the reduced
Anti-inflammatory Leaves Ethanol − Sprague Dawley rats formation of oedema, with values of 43.28%, 59.67%, and 62.29% [30]
induced by carrageenan, histamine, and serotonin in rats
M. koenigii leaves significantly decreased CCl4 -induced
Hepatoprotective Leaves Hydro-ethanolic − Male Wistar rats [16]
hepatotoxic in a time- and dose-dependent manner
M. koenigii extract treatment significantly decreased the renal
Nephroprotective Leaves Aqueous − Male Wistar rats functional markers, like the blood urea nitrogen and [28]
creatinine level
M. koenigii possesses antidiabetic activity and has antioxidant
Anti-Diabetic Leaves Ethanol − Swiss albino mice effects on STZ-NA-induced diabetes mellitus and particularly [10]
significantly decreased the HOMA-IR index
Stem Girinimbine, supplementation specifically, resulted in the
Hexane, chloroform, Zebrafish and Male
Anticancer (Colon) bark and Girinimbine 1.5–100 µg/mL induction of apoptosis, the inhibition of inflammation, and a [85]
and methanol ICR mice
roots significant increase in cell numbers in the G0/G1 phase
M. koenigii aqueous extract has potential for cytotoxicity,
Anticancer (Breast) Leaves Aqueous − Female BALB/c mice anti-inflammatory, and immunomodulatory effects and delays [12]
rather than inhibits tumor formation
M. koenigii is effective in attenuating memory impairment and
Neuroprotective Leaves Methanol − Male albino mice [36]
oxidative stress and prevents abnormal oral movements
M. koenigii supplementation resulted in an improvement of
acetylcholine (ACh) and reduction in acetylcholinesterase
(AChE). In addition, a significant elevation of serum biomarkers,
Neuroprotective Leaves Ethanol − Swiss albino mice [30]
and decline in creatinine, total cholesterol, urea nitrogen, and
glucose levels, ameliorated the hepatic and renal functions in the
normal ageing process
M. koenigii leaves elevated the acetylcholine level in the brain
Male swiss albino and ultimately improved memory impairment. In vitro, it
Neuroprotective Leaves Ethanol − [33]
mice showed BACE1 inhibition and was found to be a
non-competitive inhibitor
Isolongifolene 10 mg/kg Isolongifolene effectively attenuated behavioral impairment and
Neuroprotective Leaves Methanol Male albino Wistar rat [34]
b.w. oxidative stress, acting as an antiaging agent
M. koenigii aqueous leaf extract reduced the despair behavior in
Anti-anxiety and
Leaves Aqueous − Swiss albino mice experimental animal models, suggesting an anti-depressant-like [41]
anti-depressant
activity and also reduced spontaneous locomotor activity
Antioxidants 2020, 9, 101 18 of 28

4.3. Hepatoprotective Effect

Liver diseases are a worldwide concern, and accessible medical treatments have an inadequate
efficacy. Since ancient times, herbs have been used when treating various disease conditions; plant
extracts and natural compounds have significant applications as hepatoprotective agents. The liver is the
site of drug metabolism and the detoxification site of toxic products, and so it is the organ most exposed
to xenobiotics [107]. M. koenigii extended hepatoprotective activity when crude aqueous extracts were
investigated against ethanol-induced hepatotoxicity in experimental animals. M. koenigii was reported
to extend a protective effect in liver impairments in chronic alcoholism and was proved to be effective
in maintaining the enzymatic oxidant status [108]. Water extracts of carbazole alkaloids and tannin of
M. koenigii were explored for their hepatoprotective activity against ethanol-induced hepatotoxicity in
a HepG2 cell line model. They exhibited excellent hepatoprotective activity, maintaining the enzymatic
and non-enzymatic antioxidant level at a near normal value and also maintaining the integrity of the
cells [31]. An M. koenigii hydro-ethanolic leaf extract was reported to attenuate the CCl4 hepatotoxic
effects in rats. M. koenigii-pretreated rats showed a significant decrement in activity levels of hepatic
markers and also maintained the level of enzymatic antioxidants [16].

4.4. Immunomodulatory Activity

The immune system makes a network and regulates processes important for maintaining the
health of an organism by hindering the entry and invasion of microbes. Impairments in the immune
system lead to conditions from chronic inflammation to cancer [109]. In an investigation on the humoral-
and cell-mediated immune response to ovalbumin, the immunomodulatory activity of a methanolic
extract of M. koenigii leaves was evaluated using a carbon clearance test. A considerable increase in the
NO production indicated the increased phagocytic activity of macrophages. The M. koenigii extract
holds promise as an immunomodulatory agent, which acts by stimulating humoral immunity and
the phagocytic function [110]. The M. koenigii leaf extracts were reported to have certain effects in
regulating mice immunology related to oxidative stress metabolism. An M. koenigii leaf extract can
exhibit an immunomodulatory effect through which it can regulate the oxidative stress metabolism in
diabetic mice [111].

4.5. Nephroprotective Activity

M. koenigii has been used as a nephroprotective agent in a diabetic-induced rat model [9].
The M. koenigii leaf extract was found to be efficient in maintaining normal levels of serum creatinine,
blood urea nitrogen, total serum protein, serum Na+ , urine output, urinary creatinine, urinary urea,
total urinary protein, and urinary Na+ . Furthermore, the M. koenigii extract maintained the standard
pattern in in vivo antioxidants, renal myeloperoxidase (MPO) activity, and histopathology of kidneys
against unilateral renal ischemia reperfusion injury. Therefore, the extract of M. koenigii was clearly
demonstrated to be useful in treating kidney disorders in rats [112]. The nephroprotective activity of
M. koenigii was elucidated in experimental investigations, which showed decreased levels of blood
urea nitrogen (BUN), serum creatinine (Cr), and lipid peroxidation (LPO). An M. koenigii extract
is efficient against cyclophosphamide-induced nephrotoxicity, which was clearly revealed through
the maintenance of high levels of glutathione (GSH) and superoxide dismutase (SOD) compared to
the cyclophosphamide-treated group [28]. M. koenigii protective activity has been shown to induce
significant dose-dependent decreases in serum urea and creatinine levels, as well as marked increases
in the levels of plasma antioxidant capacity, in diabetic rats, compared to controls. More noteworthy is
the histological integrity of kidneys, which showed comparable tissue regeneration induced by the
aqueous extract [9].
Antioxidants 2020, 9, 101 19 of 28

4.6. Antidiabetic Activity

Most prominently in developing countries, medicinal plants play a helpful role in managing
diabetes mellitus due to their cost effectiveness. Diabetes mellitus, a metabolic disorder, is becoming
a serious threat to human health. During the past few years, many phytochemicals responsible for
anti-diabetic effects have been isolated from plants. Alkaloids present in the leaves of M. koenigii
have been explored and reported to have inhibitory effects on the aldose reductase enzyme, glucose
utilization, and other enzyme systems for extending anti-diabetic effects [38]. M. koenigii was tested
for the α-glucosidase inhibitory property and was found to inhibit α glycosidase. Alpha-glucosidase
inhibitors are widely used in the treatment of patients with type 2 diabetes [113]. A study reported
that an ethanolic extract of M. koenigii showed a significant reduction in blood glucose levels, and
this effect of reducing blood glucose by M. koenigii is mediated by antioxidant properties and insulin
mimetic effects. In addition, M. koenigii exhibited a profound antioxidant effect by reducing the
malondialdehyde (MDA) level, increasing the GSH level, and significantly decreasing the homeostatic
model assessment (HOMA)-insulin resistance index. On the whole, it is evident that M. koenigii
possesses antidiabetic activity and has antioxidant effects in rats [10].

4.7. Anticancer Activity (In Vivo and In Vitro)

M. koenigii possesses potential secondary metabolites that could be developed as anticancer agents.
In one study, the cytotoxic activity was evaluated for three extracts: hexane, ethyl acetate, and methanol
of M. koenigii leaves against the HeLa cell line. The extracts were reported as being potently cytotoxic
in nature in HeLa cancer cells. These results established the potential of M. koenigii as an anticancer
agent in vitro [11]. Additional evidence for the anticancer activity of M. koenigii has been obtained
from rodent cancer cell lines, as well as different in vivo cancer models [12–14,22–24,114,115]. In an
early study, histopathological evidence showed that M. koenigii extract treatment generated a decline
in neoplasms in the colon [85]. A methanolic extract of M. koenigii was reported to have the ability
to reduce proliferation in breast cancer cell lines [116]. The total alkaloid extracted from M. koenigii
leaves has been shown to have promising cytotoxic activity in breast cancer cells, with an IC50 of
14.4 µg/mL [117]. The anticancer activity of mahanine and isomahanine in human oral squamous cell
carcinoma CLS-354 has also been reported [96].
Girinimbine, another M. koenigii-derived carbazole alkaloid, showed growth inhibitory activity in
human hepatocellular carcinoma and lung cancer cells in vitro [118]. Rutin, quercetin, kaempferol, and
apigenin, present in leaf extracts of M. koenigii, showed the dose-dependent inhibition of endogenous
26S proteasome activity in MDA-MB-231 cells [52]. Therefore, M. koenigii contains remarkable anticancer
compounds, especially mahanine, which has been reported to show anticancer activity targeting
different signaling pathways [46]. Girinimbine, a carbazole alkaloid, has been found to have a good
role in total leukocyte migration and result in an appreciable reduction in pro-inflammatory cytokine
levels. The various activities of M. koenigii against different cancer cell lines are shown in Figure 2.
Antioxidants 2020, 9, 101 20 of 30
23 28

Figure 2. Apoptosis induced by M. koenigii bioactive compounds in cancer. Bcl2: B-cell lymphoma 2;
Figure 2.B-cell
Bcl2-XL: Apoptosis induced by M. koenigii
lymphoma-extra-large; P-Bad:bioactive
P plasmidcompounds
araB araA in cancer.
araD; ROS:Bcl2: B-celloxygen
reactive lymphoma 2;
species;
Bcl2-XL: checkpoint
Chk1/2: B-cell lymphoma-extra-large; P-Bad:
kinase; Go/G1: cell cycle P plasmid
phase; araB araA
JAK1: janus kinasearaD; ROS:signal
1; STAT3: reactive oxygen
transducer
species;
and Chk1/2:
activator checkpoint 3;
of transcription kinase; Go/G1: kinase
AKT: protein cell cycle phase;
B (also JAK1:
known janusmTOR:
as AKT); kinasemammalian
1; STAT3: signal
target
transducer
of rapamycin;and activator
P53/p57: of transcription
tumor 3; AKT:
protein; Hsp90: protein
heat shock kinase B (also known as AKT); mTOR:
protein.
mammalian target of rapamycin; P53/p57: tumor protein; Hsp90: heat shock protein.
4.8. Neuroprotective Activity
4.8. Neuroprotective
Supplementation Activity
with M. koenigii leaf extracts has been reported in the management of a wide
spectrum of neurodegenerative
Supplementation diseases,
with M. koenigii like
leaf AD, PD,
extracts hasand
beenothers [30,33–35,41].
reported M. koenigii promotes
in the management of a wide
neuroprotective
spectrum of neurodegenerative diseases, like AD, PD, and others [30,33–35,41]. M. koenigiiit promotes
potential against orofacial dyskinesia induced by resperine. Additionally, stabilizes
the levels of protective
neuroprotective antioxidant
potential against enzymes
orofaciallike SOD, catalase
dyskinesia (CAT),
induced byand GSH, andAdditionally,
resperine. inhibits LPO in it
the forebrain regions of reserpine-treated animals. Furthermore, it has
stabilizes the levels of protective antioxidant enzymes like SOD, catalase (CAT), and GSH, and been shown to significantly
inhibit
inhibitsreserpine-induced
LPO in the forebrain abnormalities in behavior. Similarly,
regions of reserpine-treated treatment
animals. with M.itkoenigii
Furthermore, has beensignificantly
shown to
restored
significantly inhibit reserpine-induced abnormalities in behavior. Similarly, treatment withLPO
the levels of protective antioxidant enzymes (that is, SOD, CAT, and GSH) and inhibited M.
in the forebrain
koenigii significantlyregion when the
restored compared
levels ofwith reserpine,
protective and it also
antioxidant inhibited
enzymes catalepsy
(that is, SOD,induced
CAT, and by
haloperidol [36]. Isolongifolene
GSH) and inhibited (ILF), a region
LPO in the forebrain tricyclicwhen
sesquiterpene
compared of with M.reserpine,
koenigii, has
andbeen reported
it also inhibitedto
render neuroprotective effects against rotenone-induced mitochondrial dysfunction,
catalepsy induced by haloperidol [36]. Isolongifolene (ILF), a tricyclic sesquiterpene of M. koenigii, oxidative stress,
and
has apoptosis
been reported in a cellular
to render model. Cytotoxicity, effects
neuroprotective oxidative stress,rotenone-induced
against and mitochondrial dysfunction
mitochondrial
were also attenuated
dysfunction, oxidative bystress,
ILF inandSH-SY5Y cells,inwhich
apoptosis down-regulated
a cellular Bax and caspases-3,
model. Cytotoxicity, -6, -8, and
oxidative stress, and
-9 expression, and up-regulated Bcl-2 expression. IFL was proved to regulate
mitochondrial dysfunction were also attenuated by ILF in SH-SY5Y cells, which down-regulated Bax p-P13K, p-AKT, and
p-GSK-3 beta expressions
and caspases-3, -6, -8, and [87].
-9 Preclinical
expression,studies have reportedBcl-2
and up-regulated that M. koenigii leaves
expression. IFL wascould enhance
proved to
memory in rats [119]. The possible neuroprotective potential of amethanolic
regulate p-P13K, p-AKT, and p-GSK-3 beta expressions [87]. Preclinical studies have reported that extract of M. koenigii
leaves was exhibited
M. koenigii leaves could in aenhance
two-vessel occlusion
memory (2VO)
in rats rat model
[119]. of partial
The possible global cerebralpotential
neuroprotective ischaemia. of
The Morris water
amethanolic extractmaze
of M. test was implemented
koenigii to assessinthe
leaves was exhibited rats’ cognitive
a two-vessel function
occlusion postoperatively.
(2VO) rat model of
Brain
partialsamples were histopathologically
global cerebral ischaemia. The Morris examinedwaterfor viable
maze testneurons within the CA1
was implemented hippocampal
to assess the rats’
region. Test findings showed that M. koenigii leaves positively
cognitive function postoperatively. Brain samples were histopathologically examined improved memory andfor learning
viable
impairments.
neurons within M.the
koenigii leaf extracts modestly
CA1 hippocampal region. Testimproved
findings memory
showedinthat ratsM.with chronic
koenigii partial
leaves global
positively
cerebral
improved ischemia
memory [120].
andThe various
learning impairments. M. koenigii
activities of M. koenigii against neurotoxicity
leaf extracts modestly areimproved
shown in memory
Figure 3.
in rats with chronic partial global cerebral ischemia [120]. The various activities of M. koenigii against
neurotoxicity are shown in Figure 3.
Antioxidants 2020, 9, 101 21 of 28
Antioxidants 2020, 9, 101 24 of 30

Figure 3. Neuroprotective effect in in vitro and in vivo studies produced by bioactive compounds
Figure 3. Neuroprotective effect in in vitro and in vivo studies produced by bioactive compounds
from M. koenigii. PI3: phosphatidylinositol 3 kinase; GSK3β: Glycogen synthase kinase 3 beta; Ach:
from M. koenigii. PI3: phosphatidylinositol 3 kinase; GSK3β: Glycogen synthase kinase 3 beta; Ach:
Acetylcholine; Bax: Bcl2-Associated X protein.
Acetylcholine; Bax: Bcl2-Associated X protein.
4.9. Radioprotective and Chemoprotective Activity
4.9. Radioprotective and Chemoprotective Activity
A methanolic extract of M. koenigii was demonstrated to render protection in chromosomal damage
A methanolic
against radiation and extract of M. koenigii in
cyclophasphamide was demonstrated
vivo. to render
Radiation leads protection
to a rise in all typesin of
chromosomal
aberrations,
like the fragmentation of chromatids and breakages in chromosomes, rings, and dicentrics.allTreatment
damage against radiation and cyclophasphamide in vivo. Radiation leads to a rise in types of
aberrations,
with like extract
a methanolic the fragmentation of chromatids
of M. koenigii before and breakages
radiation significantly in chromosomes,
reduced the aberrations. rings, and
M. koenigii
dicentrics. Treatment with a methanolic extract of M. koenigii before radiation significantly
can significantly exert bone marrow protection against radiation and cyclophasphamide [121]. reduced
the aberrations. M. koenigii can significantly exert bone marrow protection against radiation and
4.10. Wound Healing[121].
cyclophasphamide Effect
Wound healing is a complex and multifactor process involving numerous biochemical and cellular
4.10. Wound Healing Effect
processes which helps in the restoration of functional and anatomical continuity. M. koenigii leaves
extendWound
wound healing
healingis in
a male
complex andrats
albino multifactor process involving
through significantly numerous
increased wound biochemical and
contraction and
cellular processes
reduced which helps
epithelialization, in the restoration
supporting ofsynthesis
the collagen functional and anatomical
which continuity.
was evident M. koenigii
in histopathological
leaves extend
studies [122]. wound healing in male albino rats through significantly increased wound contraction
and reduced epithelialization, supporting the collagen synthesis which was evident in
5. Conclusions studies [122].
histopathological
The current review summarizes the medicinal uses, phytochemistry, and pharmacological properties
5. Conclusions
of M. koenigii. M. koenigii is a source of several bioactive compounds, including alkaloids, polyphenol,
terpenoids, and flavonoids.
The current M. koenigii and
review summarizes theits medicinal
derivativesuses,
appear to exhibit appreciable
phytochemistry, pharmacological
and pharmacological
activities,
propertieslike anticarcinogenic,
of M. proapoptotic,
koenigii. M. koenigii is a source antiangiogenic, antimetastatic,
of several bioactive compounds,immunomodulatory, and
including alkaloids,
antioxidant properties. The molecular mechanisms underlying these activities of M. koenigii
polyphenol, terpenoids, and flavonoids. M. koenigii and its derivatives appear to exhibit appreciable and its
derivatives are due to their diversified role in combinations of cell signaling pathways
pharmacological activities, like anticarcinogenic, proapoptotic, antiangiogenic, antimetastatic, at multiple
levels in various diseases.
immunomodulatory, M. koenigii and
and antioxidant its derivatives
properties. mitigate mechanisms
The molecular oxidative stress, neurotoxicity,
underlying these
neuroinflammation, neuronal loss, and cognitive dysfunctions. However, like other polyphenols,
activities of M. koenigii and its derivatives are due to their diversified role in combinations of cell
to a certain
signaling extent, M.
pathways koenigii activities
at multiple levels in are limited
various by its M.
diseases. bioavailability
koenigii andand in such conditions,
its derivatives mitigate
enhancement of the
oxidative stress, efficiency should
neurotoxicity, be conducted. Therefore,
neuroinflammation, neuronalfuture
loss, studies need to include
and cognitive more
dysfunctions.
experimental studies on bioavailability and efficiency enhancement in clinical investigations.
However, like other polyphenols, to a certain extent, M. koenigii activities are limited by its
bioavailability and in such conditions, enhancement of the efficiency should be conducted. Therefore,
future studies need to include more experimental studies on bioavailability and efficiency
enhancement in clinical investigations.
Antioxidants 2020, 9, 101 22 of 28

Author Contributions: R.B., writing—original draft preparation; D.V., writing—review and editing; S.-H.J., table
preparation; P.G., validation; I.S.-K., interpreted the figures; D.-K.C., supervision of the review and approval of the
final draft. All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by the Basic Science Research Program through the National Research
Foundation of Korea funded by the Ministry of Education, Science and Technology (NRF-2018R1C1B6005129
and 2020R1A2B5B02002032)
Conflicts of Interest: The authors declare no conflicts of interest.

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