Phytochemistry Letters 9 (2014) 4650

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Phytochemistry Letters
journal homepage: www.elsevier.com/locate/phytol

New antileishmanial sesquiterpene coumarins from Ferula narthex

Boiss
Shumaila Bashir a, Mahboob Alam a, Achyut Adhikari b,*, Ram Lal (Swagat) Shrestha c,
Sammer Yousuf b, Bashir Ahmad d, Shama Parveen b, Akhtar Aman a, M. Iqbal Choudhary b,e
a

Department of Pharmacy, University of Peshawar, Khyber Pakhtunkhwa, Pakistan

H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
Amrit Science Campus, Tribhuvan University, Kathmandu, Nepal
d
Centre of Biotechnology and Microbiology, University of Peshawar, Khyber Pakhtunkhwa, Pakistan
e
Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21412, Saudi Arabia
b
c

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 6 July 2013
Received in revised form 27 March 2014
Accepted 7 April 2014
Available online 19 April 2014

Two new sesquiterpene coumarins, fnarthexone (1) and fnarthexol (2), along with three known
coumarin derivatives, conferol (3), conferone (4) and umbelliferone (5), were isolated from the plant
Ferula narthex Boiss. The structures of the compounds 15 were elucidated using modern spectroscopic
techniques. The structure of compound 3 was unambiguously deduced by the single-crystal X-ray
diffraction technique. Compounds 14 were tested for in vitro leishmanicidal activity and promising
results were obtained. Conferol (3) was found to be the most potent with IC50 value of 11.51  0.09 mg/mL.
2014 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.

Keywords:
Sesquiterpene coumarins
Ferula narthex Boiss
Antileishmanial

1. Introduction
The genus Ferula belongs to the family apiaceae, which
comprises 170 species, and is distributed throughout the world,
including Pakistan, Afghanistan, Iran and India (Bakshi et al., 1999).
Ferula narthex Boiss., locally known as Raw, is found in various
regions of Pakistan such as Gilgit, and Chitral (Kamari, Damusar,
Chillim, Gudai, Astore and the hills of Majini Harai) (Shinwari and
Gilani, 2003). Local people use this plant for the treatment of
cough, asthma, toothache, gastric problems and constipation. The
gum resin of Ferula narthex is used for the treatment of hysteria,
frequent abortion, whooping cough and scorpion sting (Khan et al.,
2011; Srinivasan, 2005; Mahendra and Bisht, 2012). Both the
extracts and pure compounds from this plant exhibited anticancer
(Saleem et al., 2001), antidiabetic (Iranshahy and Iranshahi, 2011)
and anti-fertility effects (Kalita et al., 2011). Several bioactive
classes of secondary metabolites have been isolated from genus
Ferula, such as sesquiterpenes, sesquiterpenes coumarins and
sulfur containing compounds (Appendino et al., 1993; Iranshahi
et al., 2010a,b; Buddrus et al., 1985; Bandyopadhyay et al., 2006).

* Corresponding author. Tel.: +92 21 4824924; fax: +92 21 4819018.

E-mail addresses: adhikarimine@yahoo.com, palpaliachyut@yahoo.com
(A. Adhikari).

As the main constituent of the genus Ferula, the sesquiterpene

coumarins showed different bioactivities such as being antiinammatory, cytotoxicity and P-glycoprotein (P-gp) inhibitory,
cancer chemopreventive, antibacterial, antileishmanial, and antiviral (Nazari and Iranshahi, 2011). The excellent bio-activity prole
of genus Ferula inspired us in this research work.
Leishmaniasis, common in tropical and sub-tropical regions of
the world, is a protozoal infection caused by the protozoan parasite
of the genus Leishmania. A number of synthetic drugs are used for
chemotherapy of leishmaniasis, many of which are either not very
effective or possess adverse effects addition to being expensive.
Some drugs such as antimony potassium tartrate, also known as
tartar emetic, as well as stibamine, megulamine antimoniate,
sodium stibogluconate etc., cause undesirable effects on the
patients. Failure of and resistance against the available treatment
is also common (Choudhary et al., 2010). Some of the other drugs,
such as amphotericin B and pentamidine, are toxic and lack
adequate efcacy. In this situation, there is a need to develop more
effective and less toxic drugs and topical applications for the
treatment of this common and painful disease.
Different proposed mechanisms have been reported for the
antileishmanial activity of natural products, such as quinone
(Yardley et al., 1996) acting as an antioxidant; indole (Wright and
Phillipson, 1990) analogs, which act on the DNA and the amino acid
metabolism of the parasite; and diterpenes (Nazari and Iranshahi,

http://dx.doi.org/10.1016/j.phytol.2014.04.009
1874-3900/ 2014 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.

S. Bashir et al. / Phytochemistry Letters 9 (2014) 4650

2011), which exerts their effect by activation of the protein kinase

C enzyme and thus interfere with important cellular functions of
the parasite.
It may be possible that the sesquiterpene coumarins may exert
their leishmanicidal effect through affecting the G1 phase of the
cell cycle and thus inducing the process of cell apoptosis. This
supports the hypothesis that sesquiterpene coumarins may also be
useful in the inhibition of cancer cell growth. Further detailed
studies are required to determine its mechanism(s) and possible
clinical utility in the treatment of different cancers.
2. Results and discussion
Compound 1 was isolated as an amorphous white material. The
molecular formula C24H26O4, was deduced with the help of 13C
NMR and HRESI-MS, which showed a pseudo molecular ion [M+H]+
at m/z 379.1899 (Calc. for C24H26O4 + H = 379.1909). The EI MS
Spectrum showed [M]+ at m/z 378, with fragment ions at m/z 105,
119, 175, 203, and 217. Its IR spectrum showed absorption bands at
1711 cm1 (ketone) and 1618 cm1 (aromatic moiety). Ultraviolet
absorptions at 324 and 246 nm indicated the presence of a
coumarin moiety (Su et al., 2000).
Compound 1 (Fig. 1) was identied as a sesquiterpene coumarin
due to the presence of characteristic peaks in the 1H and 13C NMR
spectra (Table 1). The NMR spectra of 1 displayed signals for ve
downeld methines [dH/dC {6.21 (d, J = 9.6 Hz)/113.6, CH-3}, {6.96
(dd, J = 8.4, 2.4 Hz)/113.7, CH-6}, {7.01 (d, J = 2.4 Hz)/102.0, CH-8},
{7.58 (d, J = 8.4 Hz)/130.1, CH-5} and {7.90 (d, J = 9.6 Hz)/144.5,
CH-4}]; and four quaternary carbons at dC 113.5 (C-10), 156.9 (C-9),
162.7 (C-2) and 162.8 (C-7), characteristic for an umbelliferone
moiety containing coumarin (Iranshahi et al., 2010a,b).
Two olenic methines at dH/dC [{6.34 (dd, J = 10.2, 3.0 Hz)/
132.6, CH-60 and {5.77 (d, J = 10.2 Hz)/128.4, CH-70 }], an exocyclic
olenic methylene at dH/dC {5.06 (br s), 5.08 (br s)/113.1, CH2-120 },
an oxygenated methylene at dH/dC {4.38 (dd, J = 10.2, 7.2 Hz), 4.48
(dd, J = 10.2, 3.6 Hz)/67.4, CH2-110 }, and three tertiary methyl
groups at dH/dC [{1.02 s/14.8, CH3-150 }, {1.14 s/26.9, CH3-130 },{1.07
s/21.7, CH3-140 }] were assigned to sesquiterpene moiety. The longrange HMBC interaction of proton signals d 5.06/5.08 (CH2-120 ) and

47

d 4.38/4.48 (CH2-110 ) with the C-90 (d 52.2) revealed the presence

of a CH2-120 terminal methylene group at C-80 of ring A. Similarly,
the HMBC correlations between the protons of Me-150 (d 1.02) and
the carbons C-10 , C-90 and C-100 resonances at d 34.8, 37.9, and 52.2,
respectively indicated the presence of a C-100 terminal methyl
group. The remaining methyl groups were placed at C-40 , based on
the long-range HMBC correlations between the protons of Me-130
(d 1.14), and Me-140 , (d 1.07) with the carbons C-40 (d 47.5), C-50
(54.9), and C-30 (214.5). The assigned position of an olenic bond
between C-60 and C-70 was supported by a COSY correlation
between H-50 (d 2.64) and H-60 (d 6.34), which in turn coupled to
the olenic proton H-70 (d 5.77) (Fig. 2).
The stereochemistry of compound 1 was determined using the
NOESY technique. NOESY correlations of d 4.48 and 4.44 (H-110 )
with the olenic proton d 5.06 (H-120 ) and d 1.02 (H3-150 ) indicated
the b-orientation of an oxymethylene substituent, attached to C-90 .
The a-orientation of H-90 was supported by the interactions of d
2.64 (H-50 ) with 2.69 (H-90 ) and 1.14 (H3-130 ). The key NOESY
correlations observed in compound 1 are presented in Fig. 3.
Compound 2 was also isolated as a white amorphous material
from the chloroform-soluble part of the crude methanolic extract
of F. narthex Boiss. Its molecular formula C24H30O4 was deduced
with the help of 13C NMR as well as HRESI-MS, and showed a
pseudo molecular ion peak [M+H]+ at m/z 383.2260 (Calc. for
C24H30O4 + H = 383.2222). The EI MS spectrum showed [M]+ at m/z
382 with fragment ions at m/z 203, 147, 119 and 55. Its IR spectrum
exhibited absorption bands for the hydroxyl (3534 cm1) and
aromatic (1613 cm1) functionalities. Ultraviolet absorptions at
325 and 243 nm indicated the presence of a coumarin moiety (Su
et al., 2000).
Compound 2 (Fig. 1) was also found to be a sesquiterpene
coumarin based on characteristic peaks in the 1H and 13C NMR
spectra (Table 1). The 1H and 13C NMR spectra of 2 displayed
characteristics signals of an umbelliferone moiety. For the
sesquiterpene moiety, signals corresponding to an olenic methine
[dH/dC {5.54 (br s)/123.7, CH-70 }] and an oxygenated methine {3.26
(dd, J = 11 and 4.6 Hz) were observed, whereas oxygenated
methylene at dH/dC {3.99 (d, J = 9.0 Hz), 4.14 (d, J = 9.0 Hz)/67.0,
CH2-110 }, and four methyl groups [dH/dC {0.87 s/15.2, CH3-150 },

Table 1
13
C and 1H NMR chemical shift values of compounds 1 and 2 (ppm, CDCl3, 125 and 500 MHz, respectively).
C. No.

2
3
4
5
6
7
8
9
10
10
20
30
40
50
60
70
80
90
100
110
120
130
140
150

dC

dH (J, Hz)

dC

dH (J, Hz)

162.7
113.6
144.5
130.1
113.7
162.8
102.0
156.9
113.5
34.8
36.5
214.5
47.5
54.9
132.6
128.4
144.4
52.2
37.9
67.4
113.1
21.7
26.9
14.8

6.21 d (9.6)
7.90 d (9.6)
7.58 d (8.4)
6.96 dd (8.4, 2.4)

7.01 d (2.4)

2.18, 1.94 m
2.42, 2.72 m

2.64 br d
6.34 dd (10.2, 3.0)
5.77 br d (10.2)

2.69 br m

4.38 dd (10.2,7.2) 4.48 dd (10.2, 3.6)

5.06 br s, 5.08 br s
1.14 s
1.07 s
1.02 s

161.2
113.0
143.4
128.7
113.1
161.9
101.3
155.9
112.5
23.3
27.2
78.8
38.7
49.3
37.8
123.7
132.2
35.8
53.7
67.0
21.6
14.8
28.0
15.2

6.21 d (9.6)
7.61 d (8.7)
7.33 br d (9.6)
6.81 br d (8.4)

6.78 br S

2.02 m
1.67, 0.95 m
3.26 dd (11, 4.6)

1.25 dd (9.5, 17.5)

2.01 m
5.54 br s

2.20 br s
3.99 d (9.0), 4.14 d (9.0)
1.67 s
0.89 s
0.99 s
0.87

48

S. Bashir et al. / Phytochemistry Letters 9 (2014) 4650

Fig. 1. Structure of compounds 1 and 2.

Fig. 2. Key COSY and HMBC correlations in compounds 1 and 2.

{0.89 s/14.8, CH3-130 }, {0.99 s/28.0, CH3-140 }, {1.67 s/21.6, CH3120 }] clearly indicate the presence of a sesquiterpene moiety. The
absence of a methyl group at C-100 was inferred from COSY
correlations between H-50 (d 1.25) and H-100 (d 2.20), and H2-10 (d
2.02), which was further supported by the HMBC spectrum. The
presence of a methyl group at C-90 was inferred from the HMBC

correlations of Me-150 protons (d 0.87) with quaternary carbon

C-90 (d 35.8) and C-110 methylene (d 67.0). The long-range HMBC
interaction of Me-120 protons (d 1.67) with C-90 (d 35.8) further
supported the same inference. Resonances of H2-110 as AB doublets
{d 3.99 (d, J = 9.0 Hz) and 4.14 (d, J = 9.0 Hz)} instead of a doublet of
doublets as observed in case of compound 1, supported that the

Fig. 3. Key NOESY correlations in compounds 1 and 2.

S. Bashir et al. / Phytochemistry Letters 9 (2014) 4650

49

Boiss. The spectral data of compound 5 was found similar to that of

a synthetic coumarin synthesized and reported by Srivastava and
co-workers (Srivastava et al., 2010).
Compounds 14 were evaluated for their in vitro antiprotozoal
activity against Leishmania major. All compounds showed good
leishmanicidal activity (Table 2).
3. Experimental
3.1. General experimental procedures

Fig. 4. ORTEP diagram of the X-ray structure of compound 3 (H-atoms omitted for
clarity).

vicinal C-90 is a quaternary carbon with the substitution of the Me150 . The HMBC correlations between the Me-120 (d 1.67) and C-80 (d
132.8), C-70 (d 123.7), and C-90 (d 35.8) indicated the presence of an
olenic bond between C-70 /C-80 . This was further supported by the
COSY correlation between the protons H-50 (d 1.25) and H2-60 (d
2.01), which in turn coupled with the olenic proton H-70 (d 5.44).
The stereochemistry in compound 2 was deduced on the basis
of the NOESY correlations. The coupling constant of H-30 (d 3.26 dd,
J = 11.0, 4.6 Hz) supported an axial orientation of H-30 , previously
observed in gumosin (Iranshahi et al., 2010a,b). The NOESY
correlations of d 3.26 (H-30 ) with 0.99 (H3-140 ) and 1.25 (H-50 )
supported the b-oriented H-50 . The a-orientation of H2-110 was
determined by the NOESY interactions of H2-110 (d 3.99/4.14) with
H-100 (d 1.25) and 1.67 (H3-120 ). Key NOESY correlations in
compound 2 are presented in Fig. 3.
All of the spectral data of compound 3 was found to be
unambiguously matched with the reported data for conferol,
previously isolated from Ferula pallida (Su et al., 2000). For the rst
time, single-crystal X-ray diffraction analysis was carried out to
support the reported structure of compound 3. The ORTEP
diagrams (Fig. 4) showed that compound 3 consists of two
trans-fused cyclohexane rings (C10 C50 /C100 and C50 C100 ), attached to the chromen-2-one moiety through an oxymethylene
bridge. Cyclohexane rings C10 C50 /C100 and C50 C100 adopt chair
and half- chair conformations, respectively, with the equatorial
hydroxyl at C30 , and the C70 /C80 olenic bond. All of the bond angles
and bond lengths were within the normal range.
Compound 4 was also identied as a known sesquiterpene
coumarin, previously isolated from Ferula badrakema (Iranshahi
et al., 2009) and this is the rst report of its isolation from F. narthex

Table 2
Antileishmanial activities of extract, fractions and pure compounds.
Fractions/compounds

IC50 (mg/mL)  S.D.

Crude methanolic extract

Hexanes fraction
Chloroform fraction
Ethyl acetate fraction
Butanol fraction
1
2
3
4
Pentamidine (standard drug)

46.78  0.29
6.16  0.46
11.32  0.09
46.78  0.29
47.04  0.02
43.77  0.56
46.81  0.81
11.51  0.09
46.77  0.85
5.09  0.04

The ultraviolet and IR spectra were recorded on Shimadzu UV240 and JASCO A-302 spectrophotometers, respectively. Specic
rotations were measured on a JASCO P-2000 polarimeter. The
HRESI-MS spectrum was recorded on a QSTAR XL LC-MS-MS
(Applied Biosystems) spectrometer. The 1H and 13C NMR spectra
were recorded on Bruker Avance 500 MHz NMR spectrometers.
Column chromatography was performed on silica gel (Kiesegel 60;
70230 mesh) and TLC was carried out on pre-coated silica gel F254
aluminum sheets (0.25 mm thickness). TLCs were analyzed by
spraying with ceric sulphate reagent.
3.2. Plant material
Whole plant material of F. narthex Boiss. was collected from
Chitral, Khyber Pakhtunkhwa, Pakistan, in July 2010. The plant
material was identied by the taxonomy section, Department of
Botany, University of Peshawar and a voucher specimen (BOT
20002) was submitted to the herbarium section of the same
department.
3.3. Extraction and isolation
Plant materials of F. narthex Boiss were air dried in the shade
and nally ground to a powder. The dry powder (8.0 kg) was
extracted by maceration method using methanol as an extraction
solvent at room temperature with daily shaking for 14 days. It was
then ltered and concentrated under vacuum (45 8C) to obtain a
crude methanolic extract (900 g). The crude methanolic extract
was partitioned into n-hexane (70.0 g), chloroform (40.0 g), ethyl
acetate (29.0 g), and butanol (34.0 g) fractions. The chloroform
fraction (40.0) was loaded onto a silica gel column and eluted with
solutions of n-hexanes/ethyl acetate of increasing polarity, to yield
sub-fractions AG. Out of them, fractions D (3.4 g) and E (1.3 g),
eluted at 25% & 35% of EtOAc/n-hexanes mixture, respectively,
were further subjected to repeated silica gel column chromatography. The elution of sub-fraction D using n-hexanes/acetone
yielded compounds 4 (40.0 mg) (5% acetone/n-hexane) and 3
(600 mg) (8% acetone/n-hexane). From sub-fraction E, compounds
2 (24.0 mg) and 5 (80.0 mg) were obtained with the 9% and 15%
acetone/n-hexanes solvent system, respectively. The ethyl acetate
fraction was loaded onto a silica gel column and eluted using
different polarities of n-hexanes/ethyl acetate to yield subfractions AE. Sub-fraction E (400 mg), obtained from 15%
EtOAc/n-hexanes, was further subjected to repeated silica gel
column chromatography and eluted using 15% EtOAc/n-hexanes to
obtain compound 1 (18.0 mg).
3.4. 7-{[(1S,4aS,8aS)-5,5,8a-Trimethyl-2-methylene-6-oxo1,2,4a,5,6,7,8,8a-octahydro-1-naphthalenyl]methoxy}-2H-chromen2-one (1)
White needles, [a]D26 = 27.0 (c 0.2, CHCl3); IR (KBr) nmax 1711
(ketone), 1618 (aromatic) cm1; UV (MeOH) lmax (log e): 324 nm
(4.03) and 246 nm (3.6); EI MS, m/z (rel. int.): 378 [M+] (30.3), 217
(25.9), 203 (48.0), 175 (21.0), 119 (100) and 105 (30). HRESI-MS:

50

S. Bashir et al. / Phytochemistry Letters 9 (2014) 4650

[M+H]+ at m/z 379.1899 (Calc. for C24H26O4 + H = 379.1909), 1H

and 13C NMR spectroscopic data, see Table 1.

and Scientic Studies of Plant Remedies used for the Treatment of

Infectious Skin Disease in Sindh, respectively.

3.5. 7-{[(1S,4aR,6S,8aR)-6-Hydroxy-1,2,5,5-tetramethyl1,4,4a,5,6,7,8,8a-octahydro-1-naphthalenyl]methoxy}-2H-chromen2-one (2)

References

White needles, [a]D26 = 29.8 (c 0.2, CHCl3); IR (KBr) nmax:

3534.8 (OH), 1729.8 (unsaturated ester), 1613 (aromatic) cm1;
UV (MeOH) lmax (log e): 325 nm (4.05) and 243 nm (3.4); EI MS, m/
z (rel. int.): 378 [M+] (30.3), 203 (12.5), 162 (17), 95 (31), 81 (100).
HRESIMS:
[M+H]+
at
m/z
383.2260
(Calc.
for
C24H30O4 + H = 383.2222). 1H and 13C NMR spectroscopic data,
see Table 1.
3.6. Single-crystal X-ray diffraction study of compound 3
The single-crystal X-ray diffraction data were collected on a
Bruker Smart APEX II diffractometer, tted with a CCD detector
(Siemens, 1996). Data reductions were performed using the SAINT
program. The structure was solved by the direct method (Altomare
et al., 1993) and rened by a full-matrix least squares on F2 using
the SHELXTL-PC package (Sheldrick, 1997). The gures were
plotted with the aid of the ORTEP program (Johnson, 1976).
3.7. Crystal data of 3
C24H34O6, Mr = 382.48, Orthorhombic, space group P212121,
a = 6.5950(11) A;
b = 18.3914(19) A;
c = 18.621(2) A;
V = 2110.3(4) A3; Z = 4, rcalc = 1.204 mg/m3, F(000) = 824, m
(MoKa) = 0.71073 A, max/min transmission 0.9936/0.9609, crystal
dimensions 0.50  0.12  0.08, 1.568 < u < 24.998, 12,098 reections were collected, out of which 2164 reections were observed
(Rint = 0.0457). The R values were: R1 = 0.0401, wR2 = 0.0887 for
I > 2s(I), and R1 = 0.0577, wR2 = 0.0990 for all data; max/min
residual electron density: 0.162/0.210 e A83. During renement,
1556 Frederic pairs were merged. Crystallographic data for
compound 3 was deposited in the Cambridge Crystallographic
Data Center. The crystallographic information can directly be
obtained free of charge from the CCDC data center (CCDC 914049).
3.8. In vitro antileishmanial assay
Antileishmanial activity was tested against the promastigote
stage of the leishmania life cycle and was evaluated using the
protocol as described by Choudhary et al. (2006).
Acknowledgements
The authors acknowledge the nancial support of the Pakistan
Academy of Sciences and Education and Literacy Department, Govt.
of Sindh, through research projects entitled, Clinical Trials on
Recently Developed Antileishmanial Agents for Cutaneous Leishmaniasis (PAS Ref: 5-9/PAS/2592), and Survey, Documentation

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