Molecules 2013, 18, 9049-9060; doi:10.3390/molecules18089049
Olugbenga K. Popoola, Abdulrahman M. Elbagory, Farouk Ameer and Ahmed A. Hussein *
Chemistry Department, University of Western Cape, Private Bag X17, Belleville 7535, South Africa;
E-Mails: firstname.lastname@example.org (O.K.P.); email@example.com (A.M.E.); firstname.lastname@example.org (F.A.)
* Author to whom correspondence should be addressed; E-Mail: email@example.com;
Received: 25 June 2013; in revised form: 20 July 2013 / Accepted: 22 July 2013 /
Published: 29 July 2013
Abstract: The ethno-medicinal approach to drug discovery represents one of the most
important sources of new and safe therapeutic agents to the challenges confronting modern
medicine and daily life. Many of the traditionally important medicinal plants contain active
molecules or ones that serve as precursors to biosynthesised secondary metabolites to
which the biological activity could be attributed. Marrubiin is one such compound and is a
potential valuable compound which exists in high concentrations in many traditionally
important Lamiaceae species which have demonstrated excellent pharmacological
properties with commendably high safety margins. Marrubiin’s attributes include a low
turnover, high stability and little catabolism, which are core characteristics required for
therapeutic compounds and nutraceuticals of economic importance. In addition, marrubiin
is considered a potential substrate for potent active compounds viz; marrubiinic acid, and
marrubenol. The contribution of marrubiin to drug discovery thus needs to be put into
prospective due to its ready availability, high potential applications and ease of
modification. In this short review we highlight the most important chemical and
pharmacological aspects reported on marrubiin since it was discovered.
Keywords: marrubiin; Lamiaceae; biological activity; lead compound; anti-inflammatory
Molecules 2013, 18 9050
Marrubiin is a widely known diterpenoid lactone that constitutes the bitter principle of the
horehound and many other medicinal plants of the family Lamiaceae. It is one of the main constituents
of Marrubium vulgare, Leonotis leonurus and Leonotis nepetifolia , which are used in several
countries to treat different pathologies . According to SciFinder Scholar, there are recently 130
published articles on marrubiin and these cover the chemical and biological aspects associated with the
compound. It is a major constituent of many species of the genus Marrubium (Lamiaceae) and
includes about 97 species found along the Mediterranean and temperate regions of the Eurasian zone.
Subsequent research revealed that marrubiin is the most active diterpenoid responsible for the
therapeutic properties observed from the species Leonotis leonurus [3,4], Phlomis bracteosa ,
Marrubium deserti de Noe , Marrubium vulgare [5,7–19], Marrubium alysson  and Marrubium
thessalum [21,22]. Extensive pharmacological studies have demonstrated that marrubiin displays a
suite of activities inclusing antinociceptive , antioxidant, antigenotoxic , cardioprotective ,
vasorelaxant , gastroprotective , antispasmodic , immunomodulating , antioedematogenic ,
analgesic [10,15], and antidiabetic properties .
Marrubiin was first isolated in Nature from Marrubium vulgare in 1842 and subsequently many
other plants belonging to the same genus as well as some other members of family Lamiaceae  viz;
Leonotis leonurus [4,5], Phlomis bracteosa , Marrubium deserti de Noe , M. vulgare [5,17–19],
M. velatinum [25,26], M. cylleneum [25,26], M. trachyticum , M. globosum , M. anisodon ,
M. sericeum , M. supinum , M. alysson  and M. thassalum [21,22] have been reported to
contain marrubiin. Only a single report mentioned the isolation of marrubiin from Spiraea brahuica
belonging to the family Rosaceae .
3. Physical and Spectroscopic Data 
2-one, 6-[2-(3-furanyl)ethyl]deca-hydro- 6-hydroxy-2a,5a,7-trimethyl-(2aS,5aS,6R,7R,8aR,8bR)-2H-
13(16),14-dien-19-oic acid γ-lactone (8CI); marrubiin (6CI); 15,16-epoxy-6β,9-dihydroxy-8βH-labda-
13(16),14-dien-19-oic acid γ-lactone; NSC 36693. Physical properties and assignment of its
signals are presented in Table 1.
Initially, the common mevalonic acid pathway was proposed for the biosynthesis of terpenoids
including marrubiin [15,32], however, the results of various
C-labelled glucose experiments by
Rohmer were shown to be inconsistent with the expectations based on the mevalonate pathway.
Consequently, the 1-deoxy-D-xylulose-5-phosphate/2-methyl-D-erythritol-4-phosphate (DOX/MEP)
pathway has been proposed as the source of this compound in Nature [32–34]. The experimental data
Molecules 2013, 18 9051
showed the production and accumulation of marrubiin in agreement with this newly discovered
pathway [a non-mevalonate pathway] like in Eubacteria and Gymnospermae [35,36].
Table 1. Physical properties and
H-NMR data of marrubiin .
Physical properties Value NMR data 
Molecular weight 332.43
1.49qt, J= 13.6, 13.2, 3.6
1.44ddd, J=14.4, 13.6, 3.6
2.15ddd, J=14.0, 6.4, 1.6
H 7.22ddt, J=1.7, 1.0, 0.8
0.96d J= 6.4 : 16.6
1.05s : 22.2
* Overlapped signals
Molecular formula C
CAS Registry Number 465-92-9
Molar volume 288 ± 3.0 cm
/mol(20 °C; 760 Torr)
Density 1.152±0.06 g/cm
(20 °C; 760 Torr)
Melting Point ~155–160 °C
Freely Rotatable Bonds 4
H Acceptors 4
H Donors 1
H Donor/ Acceptor sum 5
LogP 3.796±0.414 (at 25 °C)
: +45.68° (acetone, 24 °C), +35.8
, 24 °C)
Pre-furanic (e.g., premarrubiin) and furanic (e.g., marrubiin) labdanoids are widespread in the
family Lamiaceae [38–40]. There are some ambiguities about the natural origin of the furanic
labdanoids which possess a C-9 hydroxyl group and a furan ring in the side chain (like marrubiin)
which are considered by some authors to be the final products in the biosynthetic pathway, while some
others suggest that they are artefacts which arise from their corresponding prefuran labdanoids during
or after the extraction or isolation process, by cleavage of the 9,13-epoxide bridge [41–43].
According to the recent literature , the detection of marrubiin in fresh plant material has been
reported, together with the isolation of pre-furanic mixed with non-related furanic labdanoids [44–47],
and these data indicate the existence of marrubiin as a natural compound inside the living organism
and as an end product of a biosynthetic pathway. The transformation of premarrubiin into marrubiin is
indicative of the comparative instability of the former compound to the more stable furanic form.
Generally, under certain conditions the chemical treatment of 9,13–15,16-diepoxylabdane derivatives
can converted them into the more stable furanic form, and no work has been done to study the effect of
other substitution patterns in the C
systems, however, many prefuranic structures have
been isolated without their corresponding furanic forms [44–47]. The relation between premarrubiin
and marrubiin needs to be investigated in the plant tissues using one of the available advanced
techniques like high field solid-state NMR.
Molecules 2013, 18 9052
5. Chemical Aspects
Marrubiin was isolated in pure form in 1932 by Mercier and Mercier in a yield of 0.4%. The
chemistry of marrubiin commenced in the last century and the molecular formula was established by
Gordin, and its synthesis completed in 1970.
The synthesis of marrubiin (1) was achieved starting from the keto lactone 5 (Figure 1) which was
prepared stereoselectively from the known keto ester 2 via 3 and 4 (Figure 1). Compound 5 on reaction
with Li acetylide followed by reduction gave 6, which gave 7 on treatment with PBr
(Figure 2). The bromide 7 was converted into the furanoepoxide 8 (Figure 2) by a reaction with
3-furanyl lithium followed by epoxidation. The final step, i.e., the conversion of 8 into marrubiin (1)
was achieved by reduction with lithium in ethylamine . Its stereochemistry had been established by
chemical transformations and confirmed by X-ray crystallography in 1982 [6,49].
Figure 1. Synthesis intermediates of marrubiin (compounds 2–5).
Figure 2. Synthesis intermediates of marrubiin (compounds 1, 6–8).
5.2. Structure Modification
There have not been many extensive structure-activity relationship studies made on derivatives of
marrubiin despite its abundance and high pharmacological activity. Opening of the lactone ring using
refluxing potassium hydroxide solution afforded the active marrubiinic acid (9, Figure 3) in a yield of
~70%. Pharmacological studies have shown that marrubiinic acid possesses antinociceptive activity
against the writhing test, with an LD
value of 12 µM/kg, being about 11-fold more active than the
standard drugs (aspirin, paracetamol and morphine) . Marrubenol (10, Figure 3) was obtained from
marrubiinic acid in a yield of 98% after reduction with lithium aluminium hydride. Marrubenol and
marrubiin were both found to elicit contractions evoked by high-KCl solutions in aortic segments
Molecules 2013, 18 9053
thereby showing promise as a vasorelaxant. It was found that blocking the free acidic group of
marrubiinic acid like in the esterified products 11 and 12 (Figure 3) reduced the biological activities,
which indicates the major role of the free carboxylic group in contributing to the observed
Figure 3. Different derivatives of marrubiin (compounds 9–12).
On the other hand, during the course of structural elucidations performed in earliest studies, many
derivatives have been prepared, e.g., compounds 13–17 (Figure 4) without any tests being conducted
to determine their biological activities .
Figure 4. Different derivatives of marrubiin (compounds 13–17).
6. Pharmacological Aspects of Marrubiin
6.1. Toxicity Studies
According to the NIH PubMed website  marrubiin doesn’t demonstrate any cytotoxicity against
66 cancer cell lines, however on the other hand; in vivo experimental studies have documented a LD
of 370 mg/kg body weight, for marrubiin . Recent studies have showed a safety limit up to 100 mg/kg
body weight when injected into mice .
6.2. Antinociceptive Activity
De Jesus et al. have reported on the antinociceptive effects of marrubiin and these were found to be
dose-related. The antinociceptive properties were observed using both the systemic and oral routes and
its action has sustained over a long period. The high potencies observed in the writhing test and
Molecules 2013, 18 9054
formalin induced pain test suggest that marrubiin is acting by some peripheral mechanism. The
antinociception induced by marrubiin was not reversed by naloxone when analyzed in the writhing
test. In the hot-plate test, marrubiin did not increase the latency period of pain induced by the thermal
6.3. Cardioprotective Activity
Although beneficial for cardiomyocyte salvage and to limit myocardial damage and cardiac
dysfunction, the restoration of blood flow after prolonged ischemia exacerbates myocardial injuries.
Several deleterious processes that contribute to cardiomyocyte death have been proposed, including
massive release of reactive oxygen species, calcium overload and hypercontracture development or
leukocyte infiltration within the damaged myocardium. Chemokines are known to enhance leukocyte
diapedesis at the inflammatory sites. The diterpenoid marrubiin from Leonotis leonurus extracts was
found to dampen the hypercoagulable and inflammatory state associated with obesity, therefore
providing a cardioprotective role. It is clear that marrubiin has been reported to manifest its effects as
an anti-inflammatory agent through the suppression of NF-κB signalling pathway. Chemokines recruit
leukocytes to inflammatory sites; an agent that inhibits RANTES possesses cardioprotective action
through its anti-inflammatory property . The marrubiin extract from L. leonurus inhibited the
secretion of RANTES, therefore marrubiin has the potential of being a cardioprotective agent as it
inhibited platelet aggregation, hypercoagulation and the inflammation in vivo. This provided the first
evidence that inhibition of CCL5/RANTES exerts cardioprotective effects during early myocardial
reperfusion, through its anti-inflammatory properties. It was found to dampen the hypercoagulable and
the inflammatory state associated with obesity, thereby providing a cardioprotective role.
6.4. Gastroprotective (Anti Ulcer) Activity
The treatment of gastric ulcers includes antacids and antisecretory drugs, mainly antagonists of
histamine-2 receptors and proton pump inhibitors, which block the secretion of gastric acid. These
treatments are effective, but may have many adverse effects, such as hypersensitivity, arrhythmia,
impotence, gynecomastia and hematopoietic disorders. The search for new antiulcer therapies that can
combine efficacy and lower toxicity like M. vulgare a plant used for treating various diseases,
including gastric ulcers  becomes justifiable and warrants examination. The antiulcer activity of
the methanolic extract obtained from leaves of M. vulgare and its main compound, the diterpene
marrubiin, was examined by Paula de Oliveira A. et al. (2011). The gastroprotective activity of
marrubiin was established through in vivo analysis on assays using different protocols (ulcers induced
by ethanol/HCl and indomethacin/bethanecol) in mice . In both models, marrubiin (25 mg/kg)
produced a significant reduction when compared with the control group (p < 0.01). Marrubiin was
found to contribute to an increase in the defensive mechanisms of the stomach through the production
of prostaglandin synthesis  and the stimulation of the bronchial mucosa . It is reported to have
antiarrhythmic properties and may induce the cardiac irregularities. The results also demonstrated that
the gastroprotection by marrubiin is related to the activity of NO and endogenous sulfhydryls, which are
important gastroprotective factors that have vasodilator effects, thereby inhibiting gastric acid secretion.
Pre-treatment with L-NAME revealed that the gastroprotective effect of marrubiin is strongly related to
Molecules 2013, 18 9055
NO synthesis, an important endogenous transmitter released by the endothelial cells when mucosa is
exposed to damaging agents.
6.5. Anti-Diabetic Activity
Leonotis leonurus an indigenous South African plant has been reported to be traditionally used to
cure hypertension . Jao evaluated the aqueous extract for its cardiovascular and hypotensive effects
in rats and observed that the arterial blood pressures and heart rates of normal, anaesthetized
spontaneously hypertensive rats were significantly reduced . It was confirmed that the ethanolic
extract of L. leonurus reduced plasma protein uptake and that marrubiin is responsible for the
stimulation of insulin secretion in 1NS-1 cells of obese rat model. The anti-diabetic activity of
marrubiin was studied in vivo using an obese rat model , which resulted in an increase in respiratory
rate and mitochondrial membrane potential under hyperglycemic conditions. Marrubiin was found to
increase insulin secretion and LDL-cholesterol in this study. In vitro analysis carried out on marrubiin
confirmed the stimulatory index of INS-1 cells cultured under hyperglycemic conditions, and this was
significantly increased in cells exposed to them. Furthermore the insulin and glucose transporter-2
gene expressions were significantly increased by marrubiin . INS-1 cells cultured under
hyperglycaemic conditions increased chronic insulin secretion by 1.5-fold relative to the
normoglycaemic control (NGC) cells (p < 0.05).
6.6. Antispasmodic and Ca
Hussain et al. have demonstrated the antispasmodic potential of marrubiin when administered to
rabbit jejunum. It caused concentration-dependent relaxation and high K (80 mM)-induced
contractions, very similar to that caused by verapamil, indicating that marrubiin exhibits spasmolytic
activity possibly mediated through the Ca
channel blocking action .
6.7. Antioedematogenic Activity
Marrubiin was evaluated against carregeenan-induced oedema because it is known to be involved in
the release of different inflammatory agents. Its test is highly sensitive to non-steroidal anti-inflammation
drugs, and it has long been accepted as a useful phlogistic tool for investigating new anti-inflammatory
drugs. Marrubiin has significant inhibitory effects on ear oedema. It has been established that kinins
are pro-inflammatory peptides that mediate a variety of pathophysiological responses. These actions
occur through the stimulation of two pharmacologically distinct receptor subtypes viz; B1 and B2. The
fact that there is strong kinin participation in oedematogenic components of the formalin test indicated
that marrubiin reinforces the hypothesis of the role of kinins in the marrubiin anti-inflammatory
actions. However, the inhibitory activity of marrubiin on pro-allergic agents such as serotonin and
histamine was tested with the compound 4880, which has significant inhibitory effects on compound
4880-induced ear oedema, indicating the possible existence of stabilizing mastocyte membranes,
analogous to an allergic status. Marrubiin showed a dose-dependent effect when the oedema was
induced by these agents, suggesting non-specific receptor actions, following the release of serotonin
and histamine. Various pro-inflammatory agonists were tested against marrubiin in oedema
Molecules 2013, 18 9056
development using microvascular extravasation of Evans blue dye. The results demonstrated that
marrubiin presents global inhibitory effects on different phlogistic agents, including histamine, and to
a lesser extent, substance P, participating to a greater or lesser degree in the inflammatory process.
Antioedematogenic activity of marrubiin was analyzed in a model of microvascular leakage in mice
ears. The results as reported by Stulzer show that it exhibits significant and dose-related
antioedematogenic effects. The other phlogistic agonists, such as prostaglandin E2 (PGE2), caused
inhibition of less than 50%. In addition, marrubiin (100 mg/kg) significantly inhibited the
OVO-induced allergic oedema in actively sensitized animals (maximal inhibition 67.6 ± 4%) [2,9].
6.8. Analgesic Activity
Success was obtained in reducing the lactone ring of marrubiin which led to the formation of
marrubiinic acid (9) and two esterified derivatives exhibited significant analgesic effect using the
writhing test in mice. Marrubiinic acid showed higher activity and excellent yield, and its analgesic
effect was confirmed in other experimental models of pain, suggesting its possible use as a new and
useful analgesic agent .
6.9. Anticoagulant and Antiplatelet Activities
Anticoagulant and antiplatelet activities of marrubiin have also been detected. According to
Mnonopi et al. marrubiin was found to significantly prolong activated partial thromboplastin time
(APTT) with fibrin and D-dimer formation being drastically decreased TNF-α and RANTES secretion
were also reduced by the extract and marrubiin when measured in the obese rat model relative to the
controls. Calcium mobilization and TXB2 synthesis were also suppressed . Several diterpenoids
from M. cylleneum and M. velutinum were tested for their cytotoxic effects against various cancer cell
lines and their immunomodulating potential in human peripheral blood mononuclear cells were
standardized. The results showed a differential cytotoxicity of compounds as well as their ability to
improve selected lymphocyte functions .
6.10. Vasorelaxant Potential
The result of Khan et al. revealed that marrubiin present among other constituents from Phlomis
bracteosa exhibited vasodilator action via a combination of endothelium-independent Ca
and endothelium dependent NÃ¹-nitro-L-arginine methyl ester-sensitive nitric oxide-modulating
mechanisms . The crude extracts of the aerial parts of M. vulgare showed appreciable potently in
vitro inhibition of KCl-induced contraction of rat aorta  thereby indicating vasorelaxant properties
in this medicinal plant extract.
Marrubiin exists in high concentrations in many traditionally important Lamiaceae species and has
demonstrated excellent pharmacological properties with high safety margins in different inflammation
models. The low turnover, high stability and little catabolism further indicate its importance and it
Molecules 2013, 18 9057
comparatively, little has been done concerning its chemical modifications and the examination of the
associated bioassay data merits continued chemical investigation.
The authors are grateful to Benjamin Rodriguez (Madrid, Spain) for his valuable discussions during
the preparation of the manuscript.
Conflict of Interests
The authors declare no conflict of interest.
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