Bulletin of Faculty of Pharmacy, Cairo University xxx (2017) xxx–xxx

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Bulletin of Faculty of Pharmacy, Cairo University

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Review Paper

Umbelliferone: Sources, chemistry and bioactivities review

Ofentse Mazimba
Botswana International University of Science and Technology, Palapye, Botswana

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

Article history: Umbelliferone is a 7-hydroxycoumarin that is a pharmacologically active agent. It is widely distributed
Received 16 March 2017 within the Rutaceae and Apiaceae (Umbelliferae) families and is efficiently extracted using methanol.
Received in revised form 2 May 2017 Umbelliferone is a fluorescing compound used as a sunscreen agent. It is synthesized using the
Accepted 10 May 2017
Pechmann condensation reaction of resorcinol and formyl acetic acid. Biosynthetically it is synthesized
Available online xxxx
using the phenylpropanoid pathway. Umbelliferone is a synthon for other coumarins and heterocycles
with improved biological activities. In the Literature modest antibacterial and antifungal activities are
Keywords:
reported with MIC values of 500–1000 lg/mL, but exhibited good E. coli anti-biofilm formation.
Umbelliferone
Anti-bacterial
Umbelliferone shows good inhibitions of DPPH, hydroxyl, superoxide anion and ABTS radicals. Other
Anti-tumor reported activities are anti-inflammatory, anti-hyperglycaemic, molluscicidal and anti-tumor activities.
Cytotoxicity Ó 2017 Publishing services provided by Elsevier B.V. on behalf of Faculty of Pharmacy, Cairo University.
Synthesis This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-
Biosynthesis nd/4.0/).

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Isolation and sources of UMB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Physical characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2. Sources and extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Biosynthesis of umbelliferone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Bioactivities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Anti-bacterial and anti-fungal activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2. Antioxidant properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2.1. Radical scavenging and metal chelation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2.2. Lipid peroxidation and enzyme activity inhibitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3. Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4. Anti-cancer and toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.5. Molluscicidal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.6. Fluorescent probe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Chemical synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Abbreviations: UMB, Umbelliferone; EI-MS, Electron Impact Mass Spectrometry; NMR, Nuclear Magnetic Resonance; UV/Vis, Ultraviolet–Visible; HPLC-UV, High
Performance Liquid Chromatography Coupled to Ultraviolet Detector; HP-TLC, High Performance Thin Layer Chromatography; Rf, retention factor; PAL, phenylalanine
ammonia lyase; TAL, tyrosine amino lyase; C4H, 4-cinnamic acid hydroxylase; DGC, diglucoside of 2,4-dihydroxycinnamic acid; CoA, coenzyme A; F60 H, feruloyl CoA-60
hydroxylase; U6P, Umbelliferone 6-prenyltransferase; GGT, gamma glutamyl transferase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline
phosphatase; AChe, acetylcholinesterase; CFU, Colony Forming Unit; DPPH, 2, 2-diphenyl-1-picrylhydrazyl; ABTS+, 2,2-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid
radical cation; NADH, nicotinamide adenine dinucleotide; IC50, 50% inhibitory concentration; LC50, 50% lethal concentration; EC50, 50% effective concentration; MIC, minimum
inhibitory concentration; MRSA, methicillin resistant Staphylococcus aureus; ARP, antiradical power; MTT, 3-(4,5-Dimethyl thiazol-2-yl)-5-diphenyl Tetrazolium Bromide;
AAPH, 2,20 -azobis(2-amidinopropane) dihydrochloride; TBA, thiobarbituric acid; DNA, deoxyribonucleic acid; COX, cyclooxygenase; HFD, high fructose diet; STZ,
streptozotocin; HCC, hepatocellular carcinoma; A-549, Human Small Lung Carcinoma; HT-29, Human Colon Carcinoma; Hela, Human Cervical Carcinoma; RPMI, Human
Nasal Septum Carcinoma; Hep G2, Human Liver Carcinoma.
Peer review under responsibility of Faculty of Pharmacy, Cairo University.
E-mail address: mazimbao@biust.ac.bw

http://dx.doi.org/10.1016/j.bfopcu.2017.05.001
1110-0931/Ó 2017 Publishing services provided by Elsevier B.V. on behalf of Faculty of Pharmacy, Cairo University.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: O. Mazimba, Umbelliferone: Sources, chemistry and bioactivities review, Bulletin Facult Pharmacy Cairo Univ (2017),
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2 O. Mazimba / Bulletin of Faculty of Pharmacy, Cairo University xxx (2017) xxx–xxx

7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction The EI-MS (rel. intensity) spectra showed peaks at m/z 162 [M]+
(77), 134 (100), 106 (28), 105 (24) and 78 (30) [13,14,23]. The frag-
Umbelliferone is a coumarin widely spread in plants and is a mentation pattern features the loss of one molecule of carbon
benzopyrone in nature. The coumarin name originates from ‘Cou- monoxide leading to the peak at m/z = 134 followed by a loss of
marou’, the vernacular name for the tonka bean (Dipteryx odorata a second molecule of CO or a formyl radical (CHO) giving the peaks
Willd, Fabaceae), from which coumarins were isolated in 1820 at m/z = 106 and 105 respectively [20,24].
[1]. The umbelliferae family is inclusive of economically important
herbs such as sanicle, alexanders, angelica, asafoetica, celery,
2.2. Sources and extraction
cumin, fennel, parsley and giant hogweed. The name Umbellifer-
one on the other hand was derived from the umbelliferae family
Umbelliferone has been reported from the CHCl3, ethyl acetate
of plants, and the latter were named for their umbrella-shaped
and methanol crude extracts and the hexane soluble fraction of
inflorescences [1,2]. The main feature for Apiaceae (Umbelliferae)
the methanol extract. Silica gel column chromatography eluted
is the inflorescence gathered within the compound umbels, a
with n-hexane and ethyl acetate or CHCl3/MeOH solvent mixtures
parasol-like inflorescence. The plant-derived phenolic coumarins
of increasing polarity were employed for the fractionation and iso-
have been purported to play a role as dietary antioxidants because
lations. The extraction efficiency of MeOH was reported to increase
of their consumption in the human diet in fruits and vegetables,
when the MeOH concentration increased from 10 to 80%, extract-
while umbelliferone (UMB) has also been reported to have antiox-
ing increasing amounts of coumarin, 1.5–1.8 g/100 g dry extract
idant properties [3] UMB is used as a sunscreen agent and optical
(25 °C), which dropped to 0.6 g/100 g dry extract at 100% MeOH.
brightener in textiles [4,5]. UMB is a 7-hydroxycoumarin that is a
The optimal ratio of plant matter (in grams) to solvent volume
pharmacologically active agent. By virtue of its structural simplic-
was 1:15, which had 1.7 g/ 100 g dry extract UMB content [25].
ity UMB has been generally accepted as the parent compound for
Successful separations were reported using high speed counter
the more complex coumarins and is widely used as a synthon for
current chromatography solvent system n-hexane/ethyl acetate/
a wider variety of coumarin-heterocycles [6,7].
methanol/water (4:6:4:6, v/v) with a partition coefficient (K) value
In light of the considerable importance of umbelliferone (UMB)
of 0.64 [23]. The HPLC-UV (254 nm) analysis of umbelliferone con-
in synthesis and its pharmacological properties, this review was
tent in n-hexane/ethyl acetate (6:4 v/v) fraction from the ethyl
undertaken in an effort to summarize the available literature about
acetate extract on ODS C18 column using acetonitrile-water linear
this bioactive natural product and its analogues. The review will
gradient elution at 0.6 mL/min the retention time was reported to
detail the recent studies on the chemistry and bioactivity of
be 10 min. The Edgeworthia chrysantha umbelliferone crude extract
UMB. The paper present the occurrence, isolation, characterization
content was 6.89% [23]. Umbelliferone from the tubers of Ipomoea
and application of UMB in synthetic operations. The biological
properties associated with UMB and its analogues with a focus
on their potential antioxidant applications are also examined. Table 1
TLC chromatogram Rf values using different solvent mixtures.

2. Isolation and sources of UMB Solvent Ratio v/v Rf

Chloroform /methanol 97:3 0.74
2.1. Physical characteristics 9:1 0.35
Chloroform/formamide 1:1 0.43
Benzene/acetone 9:1 0.39
Umbelliferone yellowish-white crystals are slightly soluble in
Benzene/chloroform 1:1 0.04
hot water, but have good solubility in ethanol [8]. UMB molecular Toluene, ethylformate/formic acid 5:4:1 0.59
formula is C9H6O3 and the needle crystals recrystallized from chlo- Toluene:ethyl acetate, 1:1 1:1 0.50
roform melts at 224–227 °C [9,10]. The dimensions of a single crys- Toluene/chloroform/acetone 8:5:7 0.67
tal grown by the cryostat process are 5.4 mm  4.2 mm  1.85 mm Toluene/chloroform/acetone/acetic acid 8:5:7:0.4 0.67

[11]. The optimized geometry is planar and the OH group lies on Data Refs. [19–22].
the same plane as the whole molecule [12].
The IR spectra of UMB shows bands at 3165 (Ar-OH), 1715–
1690 and 1628–1603 (lactone), 1575, 1109 (C@C) and 835 (CH)
cm1. When UMB form strong interactions with hydroxypropyl-a Table 2
-cyclodextrin the IR bands shift to higher wavenumbers [13–15]. NMR data for umbelliferone in CDCl3 and [CD3OD].
The UV spectra (MeOH) knm (log e) shows maxima’s at 339 Position 1
H (400 MHz) dH 13
C
(0.50), 294 (0.36), 242 (0.77) nm [14]. The absorbance maxima in (100 MHz) dC
acid is 325 nm while in alkaline solution it shift to 365 nm. The flu- 2 160.5 [162.6]
orescence excitation maxima in acid and alkali solutions are 330 3 6.16 (1H, d, J = 10.0 Hz) [6.19 (1H, d, J = 9.5 Hz)] 112.0 [112.8]
and 370 nm respectively, while the emission maxima is 460 nm 4 7.87 (1H, d, J = 9.1 Hz) [7.86 (1H, d, J = 9.5 Hz)] 144.2 [144.5]
4a 111.9 [111.9]
[16]. Another report states that umbelliferone shows blue emission
5 7.50 (1H, d, J = 9.1 Hz) [7.46 (1H, d, J = 8.5 Hz)] 129.7 [129.3]
band at kmax = 460–480 nm [17] and a positive test with FeCl3 indi- 6 6.83 (1H, dd, J = 2.7 Hz, 8.2 Hz) [6.87 (1H, dd, 113.2 [113.7]
cated by the deep blue colour [18]. The typical umbelliferone J = 8.5, 2.3 Hz)]
bright blue spot under UV/Vis Rf values reported for authentic 7 161.6 [161.4]
and isolated samples [19–22] are shown in Table 1. 8 6.74 (1H, d, J = 2.7 Hz) [6.78 (1H, d, J = 2.3 Hz] 102.5 [103.0]
8a 156.2 [155.9]
The NMR data for umbelliferone is shown in Table 2 and its
chemical structure is shown in Fig. 1 [9,13,14,23]. Data Refs. [9,13,14,23].

Please cite this article in press as: O. Mazimba, Umbelliferone: Sources, chemistry and bioactivities review, Bulletin Facult Pharmacy Cairo Univ (2017),
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 O. Mazimba / Bulletin of Faculty of Pharmacy, Cairo University xxx (2017) xxx–xxx 3

Fig. 1. Umbelliferone chemical structure.

mauritiana were quantified by the HPLC method using water-
acetonitrile mobile phase (77:23) on C-18 RP column, flow rate
1 mL/min and detected at 325 nm. The mean peak area, retention
time of umbelliferone was reported to be 316.1 and 8.9 min
respectively. The HP-TLC method mobile phase was toluene, iso-
propanol and ammonia (8:2:0.1 v/v/v). The mean peak area and
retention factor (Rf) of umbelliferone for HP-TLC method was
reported to be 5940.92 and 0.55 respectively [26]. A 20 min reten-
tion time was reported for the HPLC analysis of umbelliferone from
grapefruit (Citrus paradise) on a C-18 RP column using MeOH/H2O
mobile phase, flow rate 1 mL/min and detecting at 254 nm. 7-
hydroxycoumarin, and a number of its methyl derivatives are
found in plants of the family Umbelliferae. The plant sources of
umbelliferone are listed in Table 3.
The pie chart, Fig. 2 shows the distribution of umbelliferone
amongst the plant families.
3. Biosynthesis of umbelliferone
The phenylpropanoid biosynthetic path way for coumarins syn-
thesis has been discussed in literature. The key steps in the biosyn-
thesis of umbelliferone coumarin are the cinnamic acid synthesis
or para and ortho hydroxylations, trans-cis isomerization of the
double bond and finally lactonization as illustrated in Fig. 3. Cin-
namic acid 2 was derived from phenylalanine 1 by the action of
phenylalanine ammonia lyase (PAL), while para-hydroxy cinnamic
acid (para-coumaric acid) 3 was derived from tyrosine 4 using tyr-
osine amino lyase (TAL). p-Coumaric acid 3 may also be derived

Table 3
The plant sources of umbelliferone.

Plant Family Part/extract Extract content (%) Ref.

Acacia nilotica Mimosaceae Bark-MeOH 0.18I [27]
Angelica decursiva Umbelliferae (Apiaceae) root nr [28]
Aegle marmelos Rutaceae Fruit pulp-EtOH nr [29]
Artemesia tridentata Asteraceae Whole-MeOH nr [30]
Aster praealtus Asteraceae Aerial and roots-DCM 0.01I [31]
Balsamocitrus camerunensis Rutaceae Stem bark-MeOH/DCM 0.03I [32]
Chamomilla recutita Asteraceae Leaves-MeOH 0.009H [33]
Citrus aurantium (Marmalade orange peel) Rutaceae Fruit flesh Nr [34,35]
Unripe fruit nr
Citrus natsudaidai Rutaceae Whole-cold press oil 0.001H [36]
Citrus paradise Rutaceae Water extracted-Fungi infected albedo layer 0.2%H [20,37]
Coriandrum ativum Umbelliferae Aerial-MeOH 0.01I [18]
Diospyros oocarpa Ebenaceae Roots-CHCl3 0.01I [38]
Diplostephium foliosissimum Asteraceae Leaves-MeOH 0.01I [39]
Dystaenia takeshimana Umbelliferae Roots-MeOH 0.0002I [9]
Edgeworthia chrysantha Thymelaeaceae Stem/EtOAc 6.89%H [22]
Edgeworthia gardneri Thymelaeaceae Flowers-EtOAc nr [40]
Eriostemon apiculatus Rutaceae Aerial/CHCl3 0.002I [41]
Ferula communis Umbelliferae Peduncles-MeOH nr [42]
Ferula assafoetida Umbelliferae Rhizomes-MeOH nr [43]
Fructus Aurantii Rutaceae Whole-EtOH nr [18,44]
Glycyrrhiza glabra Fabaceae Rhizomes-MeOH nr [45]
Angelica archangelica (Garden angelica) Umbelliferae Root oil nr [46]
Haplophyllum villosum Rutaceae Aerial/CHCl3 0.41%I [10]
Harbouria trachypleura Umbelliferae Aerial-MeOH 0.1%I [47]
Haplopappus desertzcola Asteraceae Aerial-MeOH/ether (1:1) nr [48]
Haplophyllum patavinum Rutaceae Aerial & Roots-MeOH 2.1I [49]
Hydrangea chinensis Saxifragaceae Leaves- EtOAc 0.002%I [13]
Hydrangea macrophylla Hydrangeaceae Leaves-MeOH/CHCl3 (2:1) 0.3I [50]
Hieracium pilosella Asteraceae Leaves & roots-MeOH 1.5–1.8H [25]
Ipomoea mauritiana Convolvulaceae Tuber- MeOH 0.0007H [26]
Justicia pectoralis Acanthaceae Aerial-Water 50%H [51]
Matricaria recutita (Chamomile) Asteraceae Flowers-MeOH 0.1H [52]
Melicope glabra Rutaceae Stem bark-MeOH 0.005I [14]
Musa spp (banana) Musaceae Flowers-Alcohol nr [53]
Parkinsonia aculeata Fabaceae Leaaves-MeOH nr [54]
Poa huecu Gramineae Whole-MeOH nr [55]
Peucedanum praeruptorum Umbelliferae Roots-pet. ether 2.7I [24]
Picea abies Pinaceae Needles-MeOH 0.0001I [20]
Potentilla evestita Rosaceae Whole-CHCl3 nr [56]
Rhododendron lepidotum Ericaceae Aerial-MeOH 0.01I [57,58]
Stem-MeOH nr
Platanus acerifolia Planataceae Stem-EtOH 0.08H [59]
Selaginella stautoniana Selaginellaceae Whole-Acetone(aq) 0.008I [60]
Saussurea eopygmaea Compositae Whole-pet. ether 0.1I [61]
Stellera chamejasme Thymelaeaceae Roots-EtOH nr [62]
Typha domingensis Typhaceae Aerial-EtOH 0.007I [8,63]

I = isolated; H = HPLC determination; nr: not reported.

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Fig. 2. Plant families containing Umbelliferone.
Fig. 3. Biosymthesis of Umbelliferone.
directly from cinnamic acid using a P540 dependent enzyme, 4-
cinnamic acid hydroxylase (C4H). The para-hydroxylation is a pre-
requisite for ortho-hydroxylation as has been evidenced through
tracer experiments involving Melilotus officinalis and Lavandula
angustifolia which showed that cinnamate 2 was incorporated into
the coumarin and 7-hydroxycoumarin 10 [64–67]. The next step
involves the ortho hydroxylation of p-coumaric acid 3 to form
2,4-dihydroxycoumaric acid 12. The cinnamate trans-double bond
is stable and cannot lactonize, hence it must isomerize to the cis
form which is unstable. An evidence was presented that shows
the role of glycosides formation to effect the trans-cis isomeriza-
tion. The work reported in vitro transformations of trans-DGC
(diglucoside of 2,4-dihydroxycinnamic acid) 7 to cis-DGC 8 and
the isolation and identification of skimmin 9 (glucoside of umbel-
liferone) from Hydragenea macrophylla leaf extracts. A compound
that hydrolyzes to yield umbelliferone and two molecules of glu-
cose has been reported from Hydragenea macrophylla [68].
The equilibrium of cis-tran mixtures of cinnamic acids 2 with-
out o-hydroxyl or o-glucosyloxy groups lies well towards the
trans-form (65–75%), while in Melilotus alba the o-
glucosyloxycinnamic acid 7 equilibrium was 80–85% towards the
cis-form [69,70]. This stability was attributed to the strong hydro-
gen bonding between the carbonyl group and the glucose 2-
hydroxy group [67]. An enzyme found in Melilotus Alba has been
shown to hydrolyze cis-glucoside (b-glucosidase) 8 to form skim-
min 9 [71,72]. The hydrolysis of glucoside 9 yields umbelliferone
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Fig. 4. Biosynthesis of Umbelliferone and a pathway to linear and angular furano
coumarins.
10. Other studies have shown the role of CoA-esters in the cou-
marin biosynthesis. 4-coumaroyl-CoA yields umbelliferone using
dioxygenase cloned from Arabidopsis [73–75]. 4-Coumaroyl 2-
hydroxylase is a 2-oxoglutarate-dependent dioxygenase enzyme
that was identified from Ruta graveolens and catalyzed the hydrox-
ylation of the activated 4-coumaryl-CoA 11 to produce (E)-2,4-
dihydroxycinnamate 12 that spontaneously forms umbelliferone
10 [76].
Escherichia coli has been utilized as a model microorganism in
synthesizing phenolic compounds. E coli expressing F60 H (Encoding
feruloyl CoA 60 hydroxylase) and 4CL (Encoding 4-coumarate CoA:
ligase) was used for the synthesis umbelliferone and other coumar-
ins [77] as outlined in Fig. 4. The required prephenate was derived
from glucose via several biotransformation which affords
shikimate-3-phosphate (20) and the chorismate (21). Prephanate
(22) was used in the synthesis of tyrosine (4), which was used to
synthesize p-coumaric acid (3). The enzyme 4-coumaroyl-CoA
ligase converts p-coumaric acid into p-coumaric acid-CoA (15).
The ortho hydroxylation of 11 was effected by feruloyl CoA 60 hy-
droxylase (F60 H) and yielded (E)-2,4-dihydroxycinnamate (12) that
spontaneously formed umbelliferone (10) [77]. Glycosyltransferase
rather than glycosidase catalyzed the biotransformation of umbel-
liferone 10 to its 7-O-b-D-glucopyranoside (Skimmin) (9) in the
Panax ginseng root cultures [78].
Umbelliferone (10) is now considered to be the parent com-
pound for the linear and furano-coumarins. Umbelliferone 6-
prenyltransferase (U6P) and umbelliferone 8-prenyltransferase
(U8P) activities have been documented in Apium graveolens, Ruta
graveolens and Ammi majus [73]. The enzymes affords the two
key prenylated intermediates, demethylsuberosin (26) and osthe-
nol (27). Several actions of P540 enzymes leads to the synthesis
of isobergapten (28), Sphondin (29), Pimpenallin (30), Angelican
 O. Mazimba / Bulletin of Faculty of Pharmacy, Cairo University xxx (2017) xxx–xxx
(31), Bergapten (32), Prolaren (33), Isopimpenallin (34), Xantha-
toxin (35) and many other coumarins [75,79]. Esculetin (25) was
synthesized in E. coli by 5-hydroxylation of 2,4-
dihydroxycinnamate-CoA (12), that spontaneously lactonized to
compound (25) [77]. Umbelliferone has also been noted to be a
stress metabolite of the medicinal plant Chamomilla recutita leaves
12 h after abiotic stress elicitation by CuCl2 [32].
4. Bioactivities
Umbelliferone has been shown to exhibit various pharmacolog-
ical activities against various health-related conditions, including
conditions related to pro-oxidants and reactive oxygen species
such as inflammation, degenerative diseases, microbial infections
and cancer cells.
4.1. Anti-bacterial and anti-fungal activities
It is widely thought that some coumarins, including umbellifer-
one and furanocoumarins are phytoalexins that play important
fungicidal roles in plants. The antimicrobial properties of umbellif-
erone isolated from Rhododendron lepidotum were examined
against different bacterial strains at 0.5 McFarland standard. The
minimum inhibitory concentration (MIC) using microdilution
methods were 500 lg/mL against Staphylococcus aureus and Pseu-
domonas aeruginosa, while activity against methicillin resistant S.
aureus (MRSA) and E. coli was shown by MIC value of 1000 lg/
mL [58]. Pure umbelliferone has shown modest antibacterial activ-
ities with inhibition zones (500 lg sample amount) of 1–4 mm
against E coli, P. aeruginosa and Staphylococcus epidermidis. The cou-
marin was inactive against bacterial strains Bacillus subtilis, Micro-
coccus luteus and S. aureus, and against fungal strains Candida
albicans, Saccharomyces cerevisiae and Aspergillus niger [80]. Umbel-
liferone was also assessed using disc diffusion method for activity
against plant phathogenic fungi. It strongly inhibited the growth of
Fusarium culmorum, and was inactive against Heterobasidium anno-
sum, Botrytis cinerea, Phytophtora (cactorum), Rhizoctonia solani and
Rhizoctonia uni-nucleate strain (264) [80]. Umbelliferone
(5  103 M) was also completely inactive against S. aureus, Micro-
coccus lysodeicticus, and Bacillus megatherium, E. coli, Aerobacter
aerogenes and Serratia marcescens [81]. Umbelliferone at a concen-
tration of 500 ppm could not inhibit the growth of the following
bacteria, Bacillus ceres, Sarcina lutea, S aureus SG8A, Streptococcus
lactis, Alcalegenes faecalis B170, E. coli ML30, P. aeruginosa 111, Sal-
monella typhimurim Tml, Serrala marcescens, and fungal strains
Zygosaccharomyces spp, Candida spp, Pichia chodati, Hansenula
anomala, Saccharomyces spp, Torula uiilis, Hanseniaspora melligeri,
Aspergilus spp, Penicillium chrysogenum, Rhizopus senti, B. cinerea
and Aliernara spp, while Byssochlamys fulva growth was effectively
inhibited [82]. Umbelliferone isolated from the stem bark of Bal-
samocitrus camerunensis was tested against reference and clinical
microbial strains using broth microdilutions at 1.5  106 CFU/mL.
The MIC values of 512 lg/mL was reported against E. coli, Enter-
obacter aerogenes and Klebsiella pneumoniae. Moderate activity
Table 4
Umbelliferone DPPH radical scavenging activity.
%I IC50 lg/mL %I conc. DPPH conc (mM). (vol./ lL)
**
43.9 520.7 616.75uM 0.1 (2000)
– 810 – 300 (30)
59.6 36.1 50 lg/mL 0.1 (2000)
75 21.7** 31 lM 0.5 (1000)
44.1 22.1 ppm* 100 ppm 1 (1000)
96 14.5–37 50 lg/mL 0.3 (30)
nr: not reported; UMB: Umbelliferone; *different units were used; **units are lM.
Please cite this article in press as: O. Mazimba, Umbelliferone: Sources, chemistry and bioactivities review, Bulletin Facult Pharmacy Cairo Univ (2017),
http://dx.doi.org/10.1016/j.bfopcu.2017.05.001
5
was exhibited against E coli isolate (AG 102; MIC = 256 lg/mL)
and stronger activity was shown against E aerogenes isolated strain
(CM 64; MIC = 128 lg/mL) while the MeOH extracts were inactive.
The isolated umbelliferone was not active (MIC > 512 lg/mL)
against strains of Providencia stuarti, P. aeruginosa and Mycobac-
terium tuberculosis. The minimum bactericidal values were similar
to MIC values except for good activity against E. aerogenes isolated
strain (CM 64; MIC = 256 lg/mL) [32]. Generally umbelliferone
shows no antifungal activities and very weak antibacterial activi-
ties irrespective of the test method and sample purity, except good
activities against E. aerogenes and B. fulva.
Biofilm formation on plants, stainless steel and glass is closely
related to E. coli O157:H7 and biofilm cells are difficult to eradicate
because of their inherent tolerance to physical and chemical
antimicrobial treatments [83]. Phytochemicals with antimicrobial
properties provides good candidates for anti-biofilm activities,
since they can work in synergistic effects with the main line drugs
to overcome the resistive effects of biofilms. Umbelliferone at
50 lg/ml inhibited E. coli O157:H7 biofilm formation by about
90% without affecting bacterial growth [84].
4.2. Antioxidant properties
4.2.1. Radical scavenging and metal chelation
The stable DPPH free radical is an easy and sensitive method for
surveying the antioxidant potential of an antioxidant. The results
reported from several studies evaluating the DPPH scavenging abil-
ity of umbelliferone are shown in Table 4. The UMB DPPH radical
scavenging is concentration dependent and is a moderate radical
inhibition at a concentration of 50 lg/mL, UMB exhibits 59.6% inhi-
bition [27] while ascorbic acid shows 96% DPPH radical inhibition
[85]. The differences in the reports results are mainly due to the
DPPH radical and UMB concentration, the standard conditions that
would enable the right comparison of different studies results are
therefore suggested. DPPH radical concentration: 1 mM, UMB con-
centration range: 5, 25, 50, 75, 100 and 150 lg/mL. The DPPH and
UMB mixed at 1.5:1.5 (v/v) and incubated for 30 and 60 min.
Umbelliferone scavenged hydroxyl radicals at all concentration
(62–310 lM) in a concentration-dependent manner showing the
second order rate constants (Ks = 5.96  109 M1 S1 at 62 lM).
DMSO standard exerted higher competition towards hydroxyl rad-
icals than umbelliferone [86]. Another study reported 63.6% inhibi-
tion of membrane reactive free hydroxyl radical exhibited by
umbelliferone on a site-specific deoxyribose degradation assay
[27]. Umbelliferone inhibited superoxide anion formation on an
assay based on the oxidation of nicotinamide adenine dinucleotide
(NADH) by phenazine methosulphate showing IC50 value of
150 lM compared to ascorbic acid IC50 value of 86 lM. The 2,2-a
zino-bis-3-ethylbenzothiazoline-6-sulphonic acid radical cation
(ABTS+) percentage of scavenging was 68% for umbelliferone and
80% for ascorbic acid. The reciprocal of effective concentration
(EC50), referred to as the antiradical power (ARP) provides a clear
and more direct indicator of the radical scavenging potency of
compound. The ARP value of umbelliferone (16.7) was reported
Time (min) UMB conc. (lg/mL) (vol. lL) UMB source Ref.
**
15 123.5–616.75 (300) G. glabra [45]
30 7.8–500 (170) M. glabra [14]
nr 1–50 (300) M. nilotica [27]
30 6.2–31** (1000) Synthetic [86]
30 10–100 lg* (3000) P. evestita [87]
30 7.8–500 (170) Standard [14,85]
6 O. Mazimba / Bulletin of Faculty of Pharmacy, Cairo University xxx (2017) xxx–xxx
to be higher than that of ascorbic acid (14.9) [86]. The antioxidant
effect based on chelating effect on ferrous ions was reported.
Umbelliferone caused the reduction of the Fe3+/ferricyanide com-
plex to the ferrous form monitored by the formation of Perl’s Prus-
sian blue and bound Fe2+ ions by 58.8% at 200 lg/mL [27].
4.2.2. Lipid peroxidation and enzyme activity inhibitions
Umbelliferone was assessed for the protection b-carotene from
linoleic acid induced bleaching. Linoleic acid is capable of produc-
ing aqueous free radicals by generating hydrogen peroxide. The
presence of umbelliferone in the M. glabra MEOH extract fractions
helped to neutralize hydroperoxide and inhibited the oxidation of
b-carotene. Umbelliferone showed slight pro-oxidant inhibitory
activity of 44% while the fraction showed 56% inhibition and
the MeOH extracts showed stronger activity at 93% [14]. Umbellif-
erone also exhibited good ability to inhibit lipid peroxidation of
linoleic acid induced by the thermal free radical producer 2,20 -azo
bis(2-amidinopropane) dihydrochloride (AAPH) exhibiting 92%
inhibitory activity. The soybean lipoxygenase was 100% inhibited
at 100 lM, which was an indicator of umbelliferone anti-
inflammatory activity [88]. On the thiobarbituric acid (TBA) assay
where the reaction of TBA with malondialdehyde forms a pink
chromogen, umbelliferone showed inhibition of lipid peroxidation
by about 67.2% at a concentration of 250 lg/ml [27]. The important
cellular targets for radiation induced free radicals are DNA and
membranes, thus an antioxidant that reduces the free radical activ-
ity could be useful as a radioprotector. Human lymphocytes pre-
treated with umbelliferone (124 lM) showed decreased
apoptotic activity, levels of thiobarbituric acid reactive substance
and lipid hydroperoxide and conjugated dienes compared to
gamma-irradiated cells. Umbelliferone pretreatment significantly
inhibited the intracellular reactive oxygen species production in
irradiated lymphocytes at a dose of 1.6 Gy/min for 1 h and restored
mitochondrial membrane potential and inhibited gamma
radiation-induced DNA damage [86,89].
Diclofenac umbelliferone conjugate (Fig. 5) was synthesized for
the purpose of acting as antioxidant promoieties and reduce the
ulcerogenic side effects of diclofenac. Diclofenac is a non-
steroidal anti-inflammatory drug which are known to induce gas-
tric ulcers. The conjugate retained its anti-infammatory activity
using the carrageenan induced rat paw edema model with 16.7%
rat paw volume increase (diclofenac: 15.2 paw vol. increase). The
conjugate antiulcer activity index was low (1.2) compared to
diclofenac activity (5.1 ulcer index) [90]. The umbelliferone antiox-
idant activity and improved physiochemical properties of the con-
jugates resulted in the protection of gastric damage.
Umbelliferone presented a significant antioedema effect in the
carrageenan model but could not decrease the rat paw volume in
the dextran model, showing that it exhibited antinociceptive
effects which involved the nitric oxide system and not the opioid
system [4]. Umbelliferone sourced from Potentilla evestita exhib-
ited strong antinociceptive and anti-inflammatory activities by
inhibiting both peripheral and centrally acting pain mediators
[56]. Umbelliferone exhibited weak tyrosinase inhibitory activity
compared to kojic acid (IC50 = 16.69 mM) [91], while it was reported
to be a competitive inhibitor of alkaline phosphatase and acetyl-
Fig. 5. Diclofenac-Umbelliferone conjugate.
Please cite this article in press as: O. Mazimba, Umbelliferone: Sources, chemistry and bioactivities review, Bulletin Facult Pharmacy Cairo Univ (2017),
http://dx.doi.org/10.1016/j.bfopcu.2017.05.001
cholinesterase [92]. In another report umbelliferone at (100 mM)
showed weak inhibition (3%) activity against human erythrocyte
acetycholinesterase using the Ellman method [93].
Cyclooxygenase (COX-2) plays a role in mediating the inflam-
matory process while COX-1 is a constitutive isoenzyme that reg-
ulates homeostasis. Umbelliferone assayed on SOS chromotest
exhibited antigenotoxic activity exhibited by reducing the induc-
tion factor of hydrogen peroxide by 68.99% and that of 4-
nitroquiniline oxide by 59.71%. In contrast the coumarin isolated
from D. takeshimana showed weak inhibitory cyclooxygenase-2
(COX-2) and 5-lipoxygenase (5-LOX) activity [9]. It exhibited a
good inhibition of COX-2 (95.7%) and COX-1 (56.91%) [45]. The
coumarin isolated from D. takeshima root MeOH extract expressed
COX-2/5-LOX dual inhibitory activity suggesting anti-
inflammatory activity occurring in part via eicosanoids generation
inhibition [94].
Umbelliferone isolated from T. domingensis caused a marked
reduction of cellularity and eosinophil numbers in bronchoalveolar
lavage fluids from asthmatic mice. The coumarin decreased in
mucus production and lung inflammation in an allergic airway
inflammation model induced by ovalbumin administration in mice
[8]. Cytochrome P450 is a heme-containing protein known to cat-
alyze hydroxylation reactions. Umbelliferone is not a preferred
inhibitor of dermal cytochrome P450 1A (CYP1A; <90% inhibition
at 100 lM) activity compared to the flavanoid, hesperetin which
inhibits more than 90% (1 lM) of dermal microsomal CYP1A activ-
ity [95].
4.3. Diabetes
Post-prandial hyperglycaemia is characterized as the earliest
symptom of diabetes hence antihyperglycaemic effects of umbel-
liferone were reported. It inhibited a-glucosidase (IC50 = 7.08 lg/
ml) in a non-competitive mode of inhibition. In the in vitro glyca-
tion assays it prevented each stage of protein glycation and exhib-
ited a potent inhibition on aldose reductase (IC50 = 1.32–0.29 lg/
ml). The ethanol extract of banana flower anti-hyperglycaemic
activity via inhibition of a-glucosidase and antidiabetogenic effect
by inhibition of the polyol pathway and protein glycation was
attributed to the presence of umbelliferone [53]. The peroxisome
proliferator-activated receptors are nuclear fatty acid receptors
that have been implicated to play crucial roles in metabolic dis-
eases such as hyperlipidemia, insulin resistance and diabetes
[96]. The umbelliferone from the ethanol extract of flowers of E.
gardneri were reported to significantly activate PPARc and PPARb
at the maximum fold activation concentrations of 12.5 and
6.25 lg/mL respectively. These activities were 1.78 and 1.92-fold
activation relative to the vehicle control [40].
Diabetes was induced in adult male albino rats by administra-
tion of streptozotocin (40 mg/kg of body weight) intraperitoneally
and was used to investigate the antihyperglycemic effect of umbel-
liferone. Rats treated with UMB (30 mg/kg of body weight) exhib-
ited a significant effect on glycemic control which was a promising
antihyperglycemic effect that was comparable to glibenclamide
[97]. The effects of umbelliferone on high-fat diet-induced hyper-
triglyceridemia and hyperglycemia in mice were assayed using
high fat diet supplemented with 0.02% (wt/wt) for 12 weeks.
Umbelliferone ameliorated hypertriglyceridemia and hyper-
glycemia partly by improving glucose tolerance (18%), modulating
hepatic lipid metabolism and the antioxidant defense system along
with increasing adiponectin levels (32% increase) [98]. Male Wistar
rats fed a high fructose diet (HFD) (60% fructose or 60% starch)
exhibited significant increases in plasma glucose and insulin levels.
The activities of enzymic antioxidants such as glutathione reduc-
tase and the levels of non-enzymic antioxidants such as vitamin
C and E showed increases in the levels of lipid peroxidative mark-
 O. Mazimba / Bulletin of Faculty of Pharmacy, Cairo University xxx (2017) xxx–xxx
ers in the liver tissues of HFD rats compared to the control group.
The diet supplemented with umbelliferone change all the above
factors to normal and the effective dose was 40 mg/kg body
weight/day [99].
Gamma glutamyl transferase (GGT), aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) are hepatic marker
enzyme whose high levels are associated with later development
of diabetes due to hepatic damage and deficiency of insulin. UMB
decreased the levels (15.3, 9.8 and 22.4% decreases respectively)
of the marker enzymes in streptozotocin (STZ) diabetic rats to near
normalcy. This indicated the protective effect of umbelliferone
against liver cell damage in STZ-diabetic rats [97].
4.4. Anti-cancer and toxicity
An anti-carcinogenic efficacy was reported for umbelliferone
alone and in synergistic activity with 5-fluorouracil as an effective
and potential chemotherapeutic agents against 1,2-
dimethylhydrazine-induced colon carcinogenesis. Umbelliferone
controlled the side effects of 5-fluorouracil [100]. An anticancer
activity against laryngeal cancer cells (RK33 LCC) was reported
by Kielbus and co-workers [101] by reducing their viability and cell
migration.
Umbelliferone isolated from Ferula communis exhibited antitu-
mor activity against liver hepatocellular cell lines at all concentra-
tions (0–50 mM). The activity was established to be via the
induction of apoptosis, cell cycle arrest and DNA fragmentation
[102]. Hepatocellular carcinoma (HCC) are highly malignant
tumors associated with poor patient prognoses, and high rates of
morbidity and mortality and their treatment is limited.
The Sarcoma 180 tumor growth was inhibited with increased
survival time of tumor-bearing mice, this immune-stimulators
activity of the coumarin was also observed in combination with a
lipopolysaccharide [103]. Umbelliferone isolated from Coriandrum
sativum methanol extract was assayed against A-549 (Human
Small Lung Carcinoma), HT-29 (Human Colon Carcinoma), HeLa
(Human Cervical Carcinoma) RPMI (Human Nasal Septum Carci-
noma) and HEp G2 (Human Liver Carcinoma) cell lines for cytotox-
icity test on MTT assay. The cell viabilities were reduced by up to
62.5% at 1000 and 500 lg/ml concentrations compared to controls,
while the test drug amount needed to inhibit cell growth by 50%
was >1000 lg/ml against all cell lines [19].
4.5. Molluscicidal activity
The in vivo and in vitro larvicidal activity of umbelliferone
against the redia and cercaria larva of Fasciola gigantica was
reported to be time and concentration dependent in the year
2011–2012. For the In vitro experiment the highest toxicity after
8 h exposure was reported for months June-August, redia
(LC50 = 0.26–0.30 mg/L) and cercaria (LC50 = 0.09, 0.18 mg/L). The
Scheme 1. Synthesis of umbelliferone fluorescent probe.
Please cite this article in press as: O. Mazimba, Umbelliferone: Sources, chemistry and bioactivities review, Bulletin Facult Pharmacy Cairo Univ (2017),
http://dx.doi.org/10.1016/j.bfopcu.2017.05.001
7
lowest toxicity was observed in November to January
(LC50 = 0.39–0.78 mg/L). In the in vivo treatment of infected Snail
Lymnaea acuminata higher toxicity against redia and cercaria larva
was in May and July, redia (LC50 = 0.93–0.89 mg/L), cercaria
(LC50 = 0.70–0.92 mg/L) while lower LC50 values (2.34–1.53 mg/L)
were reported for the December to February period. Abiotic factors
were noted to be critical factors [104]. High temperate increases
the solubility of umbelliferone, low pH and increased free carbon
dioxides causes more larval mortality. Dissolved oxygen in winter
leads to less mortality of the larvae [92,105,106]. Other umbellifer-
one molluscicidal activities were reported for bait formulations
with attractant amino acid (valine, aspartic acid and alanine).
The bait altered the levels of free amino acid, protein and nucleic
acid in the ovotestis of snail Lymnaea acuminate [107]. A bait feed
made from a combination of umbelliferone and two amino acids
(1:1) caused maximum inhibition of alkaline phosphatase (ALP:
23.57%) and acetylcholinesterase (AChE: 49.48%) in nervous tissue
of L. acuminata exposed to 60% of umbelliferone for 96 h [106].
4.6. Fluorescent probe
The fluorescent property of umbelliferone was used to design a
fluorescent probe for hydrogen peroxide which displayed good
selectivity over other reactive oxygen species, Scheme 1 [108].
5. Chemical synthesis
Umbelliferone is conventionally synthesized using the Pech-
mann condensation reaction of resorcinol and formyl acetic acid
generated in situ from malic acid. Malic acid 38 in the presence
of acid forms the highly reactive formyl acetic acid 39 and formic
acid. Under acid conditions formyl acetic acid 39 and resorcinol
40 quickly reacts to form intermediate 41. The lactonization of
the intermediate 41 forms umbelliferone 10, Scheme 2. The Pech-
mann reaction of resorcinol 40 and ethyl acetoacetate 42 affords 4-
methylumbelliferone 43 [109–111]. The drawback for the conven-
tional method are long reaction time, salt waste and low yields.
Methoxyumbeliferone 46 was efficiently prepared from the
condensation of methoxyresocinol 44 and ethyl-3,3-
diethoxypropanoate 45 as shown in Scheme 3 [112].
Scheme 2. Conventional synthesis of Umbelliferone.
Scheme 3. Synthesis of methoxyumbelliferrone.
Scheme 4. Synthesis of 8-methylumbelliferone.
8 O. Mazimba / Bulletin of Faculty of Pharmacy, Cairo University xxx (2017) xxx–xxx
Fig. 6. Heterocycles derived from Umbelliferone.
A Pechmann condensation involving 2-methylresorcinol 47,
malic acid 38 and sulfuric acid produced an umbelliferone ana-
logue 48 in Scheme 4. 8-methylumbelliferone 48 exhibited anti-
fungal inhibitory activities against Phytophythora capsici (47.7%),
Botrytis cinerea (28.7%), Alternaria solani (18.6%) and Rhizoctonia
solani (42.4%) at 50 lg/mL [113]. The 8-methyl group could be
responsible for the antifungal activities since umbelliferone was
previously inactive against fungal strains [80].
Umbelliferone has been used as a synthon for various biologi-
cally active heterocycles, Fig. 6.
Umbelliferone when first reduced using Pd-C/H2 and reacted
with 2-methyl-3-butene-2-ol affords decursinol 49 in 41.4% yield
over five steps and xanthyletin 50 [114]. Decursinol has been
reported to show cytotoxic activity, anti-Helicobacter pylori and
strong antinociceptive activities [115]. Incorporation of hydroxyl
benzoic acids 51 and cinnamic acids 52 transformed umbelliferone
into potent mushroom tyrosinase inhibitors. The inhibitory effects
on mushroom tyrosinase activity order was umbelliferone 10
(IC50 = 420 lM), <compound 52 (IC50 = 80.2 lM) < Kojic acid
(IC50 = 16.69 lM) < compound 51 (IC50 = 8.96 lM). The DPPH
activities exhibited were still weak activities (IC50 > 1000 lM)
[91]. The umbelliferone thiadiazole derivatives are non-planar
[116]. Aliphatic groups which were O-attached to the umbellifer-
one structure improved the antifungal activities against Aspergillus
fumigatus and Aspergillus flavus strains. The MIC values were
10 > 2048 lg/mL; 55–57, 64 lg/mL; 58, 128 lg/mL; 59, 16 lg/mL
[117]. The nitro group at position C-6 significantly improved the
antifungal activity, while a methoxy group at the same position
has no effect on the activity. Umbelliferone (IC50 = >20 lg/mL) does
not exhibit a 5a-reductase type 1 inhibitory activity on the
androgen-sensitive human prostatic cancer cell line. The substitu-
tion of alkyl and allyl groups resulted in potent inhibitory activi-
ties. The reported IC50 values were 60: 0.3 lg/mL; 61: 1.7 lg/mL;
62, 63 and 65: 0.2 lg/mL and 64: 0.15 lg/mL [118].
6. Nanoparticles
Lipid nanoparticles [n-hexadecyl palmitate (CP) and glyceril
stearate (GS)] were used to entrap umbelliferone and the hydrody-
namic diameters varied from 120 nm to 220 nm. The
umbelliferone-loaded solid lipid nanoparticles prepared with
Tween 80 surfactant exhibited good entrapment efficiency
(60.70%) and antioxidant property (75%) using chemiluminescence
method involving luminol [119]. Umbelliferone is a weak mono-
protic Brönsted acid that is not fluorescent in acid solutions below
pH = 8. The coumarin in a solution exposed to the UV radiation
exist as singly charged, green fluorescent anion. Thus, a slightly
Please cite this article in press as: O. Mazimba, Umbelliferone: Sources, chemistry and bioactivities review, Bulletin Facult Pharmacy Cairo Univ (2017),
http://dx.doi.org/10.1016/j.bfopcu.2017.05.001
acidic solution has no visible green fluorescence. When aerosols
from the slightly acid and basic (pH = 12) solutions were mixed
a green fluorescence typical of the umbelliferone anion was
reported. This shows that uncharged droplets collide, merge and
produced a product with the expected fluorescent properties
[120] and a narrow distribution of nanoparticle sizes.
7. Conclusion
Umbelliferone is a 7-hydroxycoumarin that is widely dis-
tributed within the plant families of the Rutaceae, Umbelliferae
and Asteraceae. It is synthesized using the Pechmann condensation
reaction of resorcinol, malic acid or ethyl acetoacetates derivatives
in the presence of sulfuric acid or inorganic acid. It is also used as a
synthon for other coumarins and heterocycles. Biosynthetically
umbelliferone is synthesized through the phenylpropanoid path
way. The activities reported against fungal and bacterial strains
are weak to moderate activities (MIC = 250–1000 lg/mL). Antifun-
gal activities against Aspergillus fumigatus and Aspergillus flavus
were improved by O-attached aliphatic group (MIC = 16–64 lg/
mL), while alkyl and allyl groups resulted in potent inhibitory
activities androgen-sensitive human prostatic cancer cell line
(MIC = 0.5–1.7 lg/mL). Umbelliferone shows weak DPPH antioxi-
dant activity and its nanoparticles in Tween 80 surfactant shows
improved antioxidant potency. Umbelliferone exhibits anti-
inflammatory activities where the significant activities were the
protection of DNA against gamma irradiation damage and protec-
tion from the diclofenac side effects. An anti-hyperglycemic effect
was reported on streptozotocin rats. An effective fluorescent probe
for hydrogen peroxide was also reported. Umbelliferone has poten-
tial as a protector against the side effects of anti-inflammatory
agents.
Acknowledgments
The author extends his appreciation to Botswana International
University of Science and Technology Library for access to the
databases.
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