Semisynthetic hybrids of boswellic acids: A novel class of potential anti-inflammatory and anti-arthritic agents

Article abstract of DOI:10.1007/s00044-015-1331-y

A series of hybrid molecules 7-13 of boswellic acid (BA)/11-keto-β-boswellic acid (KBA) 1/2 with well-known anti-inflammatory drugs (i.e. aspirin, naproxen, ibuprofen and cinnamic acid) have been synthesized and evaluated for their anti-inflammatory and a

Full text of DOI:10.1007/s00044-015-1331-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1331-y
ORIGINAL RESEARCH
Semisynthetic hybrids of boswellic acids: a novel class of potential
anti-inflammatory and anti-arthritic agents
•
Devdutt Chaturvedi Parmesh Kumar Dwivedi Amit K. Chaturvedi
•
•
•
Nisha Mishra H. H. Siddiqui Virendra Mishra
•
Received: 17 January 2014 / Accepted: 20 January 2015
Ó Springer Science+Business Media New York 2015
Abstract A series of hybrid molecules 7–13 of boswellic
acid (BA)/11-keto-b-boswellic acid (KBA) 1/2 with well-
known anti-inflammatory drugs (i.e. aspirin, naproxen,
ibuprofen and cinnamic acid) have been synthesized and
evaluated for their anti-inflammatory and anti-arthritic
activities. Two of hybrid compounds 8 and 11 bearing
naproxen and BA/KBA unit have displayed promising anti-
inflammatory and anti-arthritic activities than the standard
drugs.
Introduction
Boswellia serrata is a type of deciduous tree grows in
Africa and Asia (Han, 1994). The gum resin extract of
Boswellia serrata has found to represent a promising anti-
inflammatory herbal remedy, using as a folk medicine to
cure inflammatory and arthritic diseases (Safayhi and Sai-
ler, 1997). Boswellic acids (BAs), belongs to the ursane
group of pentacyclic triterpenoids, are the unique and
major constituents from the gum resin of Boswellia serrata,
which includes 11-keto-b-acetyl-11-keto-b-boswellic acid
(AKBA), 11-keto-boswellic acid (KBA), b-boswellic acid
(BA) and acetyl-b-boswellic acid (ABA) (Fig. 1) (Shah
et al., 2009; Safayhi et al., 1992; Altmann et al., 2002; Liu
et al., 2002). In recent years, various derivatives of BAs
and their semisynthetic analogues have been displayed
wide of spectrum of potential biological activities such as
anti-inflammatory (Singh and Atal, 1986; Ammon, 2006;
Singh et al., 2007, 2008a), anticancer (Pang et al., 2009;
Khan et al., 2011; Chashoo et al., 2011a; Kaur et al., 2011;
Kumar et al., 2012; Takahashi et al., 2012; Chashoo et al.,
2011b), anti-arthritic (Sharma et al., 1989; Reddy and
Dhar, 1987; Khanna et al., 2007), anti-ulcer (Gupta et al.,
1997; Singh et al., 2008b), anti-asthma (Gupta et al.,
1998), anti-hepatitis (Safayhi et al., 1991), antimicrobial
(Raja et al., 2011), inhibition of NO production (Golbabaei
et al., 2013), and peritumoral brain oedema (Sun et al.,
2013) etc. However, they have gained a great deal of
attention in recent past owing to their anti-inflammatory
and antiarthritic activities. Various inflammatory disorders
are thought to be regulated through transcription of various
inflammatory cytokines, such as IL-1, IL-2, IL-6, IL-8 and
TNF-a, as well as genes encoding cyclooxygenase-II, nitric
oxide synthase, immunoreceptors, cell adhesion molecules,
haematopoietic growth factors and growth factor receptors
Keywords Triterpenoids ꢀ Boswellic acids conjugates ꢀ
Anti-inflammatory activity ꢀ Anti-arthritic activity
Dedicated to Dr. Nitya Anand, Former Director, CDRI on the
occasion of his 90th birthday.
D. Chaturvedi (&) ꢀ P. K. Dwivedi
Laboratory of Medicinal Chemistry, Amity Institute of
Pharmacy, Amity University Uttar Pradesh, Lucknow Campus,
Lucknow 226028, UP, India
e-mail: devduttchaturvedi@gmail.com;
dchaturvedi@lko.amity.edu
P. K. Dwivedi ꢀ H. H. Siddiqui
Faculty of Pharmacy, Integral University, Lucknow 226026,
UP, India
A. K. Chaturvedi
Department of Chemical Sciences, GLA-University,
Mathura 281406, UP, India
N. Mishra ꢀ V. Mishra
Department of Biomedical Sciences, B. S. A. P. G. College,
Mathura 281004, UP, India
123

Med Chem Res
30
20
Fig. 1 Structures of some
common boswellic acids
29
21
22
19
R2
18
R1
25
11
26
28
14
16
1
4
9
6
2
3
8
27
RO
AcO
2
COOH
24
COOH
23
5
1, R1 = R2 = H, R = H
2, R1 + R2 = O, R = H
3, R1 = R2 = H, R = COCH3
4, R1 + R2 = O, R = COCH3
AcO
6
COOH
(Baeuerle and Henkel, 1994; Baeuerle and Baltimore,
1996; May and Ghosh, 1998). In the search for the therapy
of inflammatory conditions, approaches like optimization
of anti-TNF treatments have also been examined in
inflammatory bowel disease (Ben-Horina et al., 2014).
However, in recent years several structural incorpora-
tions have been carried out in boswellic acid and their
derivatives in order to look for better activity profile. But,
there is still need of a potential anti-inflammatory drug
which could be more potent than the existing drug mole-
cules. In context with our ongoing research towards the
drug discovery research through the design and synthesis of
novel class of natural/semisynthetic/synthetic molecules
(Chaturvedi et al., 2008; Negi et al., 2005), we have
planned to synthesize the hybrid molecules of boswellic
acids along with some of well-known drugs.
safety profile (up to 40 % reduction in ulcerogenic
potential) than the celecoxib (Hassan et al., 2014). Some
synthesized pyrazole amalgamated flavones have dis-
played promising inhibitory profile against both COX-1
and COX-2. It was also summarized that the key factors
involved in interaction with COX-2 active site are keto
and phenolic hydroxyl group (Chavan et al., 2013).
Furthermore, various synthesized prodrugs of ibuprofen
have been evaluated to observe their anti-inflammatory
potential as well. The above-mentioned prodrugs were
found to have potential activity along with significant
non-ulcerogenic effect than standard drug (Dhakane
et al., 2014). It was observed that majority of the hybrid
molecules are more potent than their starting counterpart
drug. Keeping that view in mind, we have designed a
series of hybrid molecules of prototype I and prototype II
generated from b-boswellic acids/11-keto-b-boswellic
acid and various drugs like aspirin, naproxen, ibuprofen
etc. (Figure 2).
In recent years, designing of the hybrid molecules has
gained tremendous attention that has become a focus of
medicinal chemistry (Meunier, 2008). In this approach,
two or more potent drug molecules for a particular dis-
ease are interconnected employing synthetic reactions,
and the resultant hybrid molecule was synthesized
(Thomas et al., 2011). The biological activity profile of
the hybrid molecule was correlated with the original drug
molecules that has employed in their synthesis. In this
context, some synthesized celecoxib analogues displayed
good anti-inflammatory activity along with better gastric
Results and discussion
Chemistry
First, we have synthesized hybrid molecule 3-O-aspirin-b-
boswellic acid 7 through the reaction of acid chloride of
123

Med Chem Res
O
10: R = Aspirin
11: R = Naproxen
12: R = Ibuprofen
13: R = Cinamic acid
7: R = Aspirin
8: R = Naproxen
9: R = Ibuprofen
RO
O
RO
COOH
COOH
Prototype II (10-13)
Prototype I (7-9)
OH
O
O
O
O
OH
O
OH
O
OH
Cinamic acid
Aspirin
Ibuprofen
Naproxen
Fig. 2 Designed prototype I (7–9), prototype II (10–13) and their counterparts
O
OH
O
Cl
O
O
O
O
a
b
1
O
O
14
COOH
O
O
7
Scheme 1 Reaction protocol for the synthesis of 7: a Dry benzene, SOCl2, reflux, 3 h, 90 %; b Dry CH2Cl2, DMAP, 1 h, 95 %
aspirin 14 with b-boswellic acid 1 using catalytic amount
of dimethylaminopyridine (DMAP). The aspirin’s acid
chloride 14 was synthesized from the acid functionality of
aspirin by refluxing it with thionyl chloride in dry benzene
for 3 h (Scheme 1). Subsequently, 3-O-Naproxen-b-bo-
swellic acid 8 was synthesized through the coupling of acid
chloride 15 of naproxen and b-boswellic acid 1 employing
similar procedure (Scheme 2).
3-O-Aspirin-11-keto-b-boswellic acid 10 was synthe-
sized through the coupling of acid chloride of aspirin 14
and 11-keto-b-boswellic acid 2 following similar procedure
(Scheme 4). Subsequently, 3-O-Naproxen-11-keto-b-bo-
swellic acid 11 and 3-O-Ibuprofen-11-keto-b-boswellic
acid 12 were synthesized through the coupling of the acid
chlorides of naproxen 15 and ibuprofen 16, respectively,
employing similar procedure (Schemes 5, 6).
3-O-Ibuprofen-b-boswellic acid 9 was synthesized
through coupling of acid chloride of ibuprofen 16 and
3-O-Cinnamyl-11-keto-b-boswellic acid 13 was syn-
thesized through the coupling reaction of acid chloride of
cinnamic acid 16 with 11-keto-b-boswellic acid 2 follow-
ing similar procedure (Scheme 7).
b-boswellic acid
(Scheme 3).
1
employing similar procedure
123

Med Chem Res
OH
O
Cl
O
O
O
a
b
COOH
1
8
O
15
O
O
Scheme 2 Reaction protocol for the synthesis of 8: a Dry benzene, SOCl2, reflux, 3 h, 91 %; b Dry CH2Cl2, DMAP, 1 h, 95 %
O
O
a
b
1
O
OH
Cl
O
16
9
COOH
Scheme 3 Reaction protocol for the synthesis of 9: a Dry benzene, SOCl2, reflux, 3 h, 89 %; b Dry CH2Cl2, DMAP, 1 h, 94 %
O
OH
O
Cl
O
O
O
O
O
a
b
2
O
O
14
COOH
O
O
10
Scheme 4 Reaction protocol for the synthesis of 10: a Dry benzene, SOCl2, reflux, 3 h, 90 %; b Dry CH2Cl2, DMAP, 1 h, 96 %
Biological evaluation
activity in mice under different intervals of the time
employing ibuprofen as standard drug at 10 mg/kg dose of
each and the % inhibition of oedema after 1, 2, 3, 4 and
24 h has been observed (Table 1; Fig. 3). However,
All the newly synthesized hybrid molecules (i.e. com-
pounds 7–13) were tested for their anti-inflammatory
123

Med Chem Res
O
OH
O
Cl
O
a
b
O
O
2
O
COOH
15
O
11
O
Scheme 5 Reaction protocol for the synthesis of 11: a Dry benzene, SOCl2, reflux, 3 h, 91 %; b Dry CH2Cl2, DMAP, 1 h, 97 %
O
O
O
a
b
2
O
OH
Cl
O
16
COOH
12
Scheme 6 Reaction protocol for the synthesis of 12: a Dry benzene, SOCl2, reflux, 3 h, 89 %; b Dry CH2Cl2, DMAP, 1 h, 95 %
O
OH
Cl
O
O
a
b
O
16
COOH
O
13
Scheme 7 Reaction protocol for the synthesis of 13: a Dry benzene, SOCl2, reflux, 3 h, 92 %; b Dry CH2Cl2, DMAP, 1 h, 98 %
majority of these hybrid molecules have displayed poten-
tial anti-inflammatory activity than the standard drug ibu-
profen. It was found that compound 8 bearing naproxen
unit with boswellic acid was found to be most potent
among all the compounds as well as many times more
potent than the standard drug ibuprofen employed in this
123

Med Chem Res
Table 1 Percentage inhibition of oedema after 1, 2, 3, 4, and 24 h in mice at 10 mg/kg
Drugs
% inhibition after 1 h % inhibition after 2 h % inhibition after 3 h % inhibition after 4 h % inhibition after 24 h
Compound 7
Compound 8
Compound 9
26.12
56.12
13.12
58.51
88.30
53.90
56.22
59.80
48.45
38.25
36.20
42.53
71.12
44.23
51.30
53.33
39.21
35.91
34.0
37.74
66.10
38.34
47.82
39.20
32.23
27.45
27.23
48.95
63.24
23.34
45.21
30.78
16.46
25.31
10.89
Compound 10 24.90
Compound 11 25.54
Compound 12
Compound 13 18.78
Ibuprofen 5.12
9.65
Fig. 3 Statistical representation
of anti-inflammatory activity
with ibuprofen in mice
Table 2 Percentage inhibition of oedema after 1, 2, 3, 4, and 24 h in rats
Drugs
% inhibition after 1 h % inhibition after 2 h % inhibition after 3 h % inhibition after 4 h % inhibition after 24 h
Compound 8
74.67
86.23
78.28
12.23
24.11
74.23
79.15
67.08
9.85
64.12
60.32
5.34
40.26
38.54
3.89
Compound 11 58.12
BA
11.02
12.82
64.71
11-KBA
Naproxen
14.60
61.12
7.91
4.92
55.45
31.96
study. Furthermore, compound 11 bearing naproxen unit
with 11-keto-b-boswellic acid was also displayed promis-
ing anti-inflammatory activity than the standard drug ibu-
profen. Encouraged by our above-mentioned results, we
further tested these two hybrid compounds 8 and 11 in rats
employing naproxen as a standard drug and their anti-
inflammatory activity was further correlated with boswellic
acid and 11-keto-11-keto-b-boswellic acid under different
intervals of the time employing ibuprofen as standard drug
and the % inhibition of oedema after 1, 2, 3, 4 and 24 h has
been observed (Table 2; Fig. 4). It was observed that
hybrid compound 8 was most potent than the standard drug
123

Med Chem Res
Fig. 4 Statistical representation
of anti-inflammatory activity
with naproxen in rats
naproxen and compound 11 have also been displayed good
activity than the naproxen. It was further concluded that
although boswellic acid and 11-keto-11-keto-b-boswellic
acid are not alone more active; however, their activity
increases while they have been incorporated into the
naproxen unit.
Encouraged by our anti-inflammatory activity in both
mice and rats, we further planned to study the anti-arthritic
activity of these two hybrid compounds 8 and 11
employing naproxen as a standard drug at 10 mg/kg dose
and the % inhibition of arthritis was observed on the dif-
ferent intervals of the time, i.e. 5th, 7th, 11th, 13th day
(Table 3; Fig. 5). It was found that hybrid compound 8 was
most potent than the naproxen. Furthermore, compound 11
was also more potent than the standard drug naproxen. It
was realized from the above-mentioned anti-inflammatory
and anti-arthritic activity that hybrid compound 8 was most
potent and was picked for further studies for anti-inflam-
matory and anti-arthritic activities for the drug develop-
ment study.
Fig. 5 Statistical representation of anti-arthritic activity with
naproxen
500 MHz 1H, 50, 100, and 125 MHz 13C) with TMS as an
internal standard. Chemical shifts are expressed in parts per
million (d ppm); J values are given in Hertz. Reagents and
solvents used were mostly AR grade. Silica gel precoated
aluminium plates from M/s Merck were used for TLC. MS
were recorded on Jeol MSD-300 and Brucker Esquire 3000
GC-Mass spectrometer. Optical rotations were measured
on Perkin-Elmer 241 polarimeter at 25 °C using sodium D
light. Elemental analyses were performed on Elementar
Vario EL-III. Solvents were dried according to the usual
procedures.
Experimental
1H NMR and 13C NMR spectra in CDCl3 were recorded on
Bruker 200, 400 and 500 spectrometers (200, 400, and
Table 3 Percentage inhibition of arthritis on 5th, 7th, 11th, and 13th day at 10 mg/kg dose
Drugs
% age inhibition on 5th day % age inhibition on 7th day % age inhibition on 11th day % age inhibition on 13th day
Compound 8
52.23
68.69
48.54
39.11
59.21
43.56
33.89
48.30
35.44
30.05
Compound 11 28.85
Naproxen 29.87
123

Med Chem Res
Synthetic procedures
C-26), 23.3 (CH3, C-25), 23.5 (CH2, C-2), 23.8 (CH3,
C-28), 26.8 (CH2, C-11), 28.0 (CH2, C-1), 28.2 (CH2,
C-21), 28.9 (CH2, C-1), 29.2 (CH, C-20), 29.9 (CH, C-19),
30.3 (C-17), 32.1 (CH2, C-7), 33.5 (CH2, C-15), 33.8 (CH2,
C-22), 37.5 (CH2, C-16), 39.6 (C-8), 42.1 (CH, C-5), 45.1
(C-14), 45.8 (C-4), 46.8 (CH, C-18), 48.2 (C-10), 50.7
(CH, C-9), 75.5 (CH, C-3), 121.3 (CH, C-50) 122.6 (CH,
C-12), 124.4 (C-60), 125.2 (CH, C-30), 130.1 (CH, C-20),
136.9 (C-40), 149.3 (C-13), 167.5 (C-70), 172.3 (C-80),
181.9 (C=O, C-24)ppm; ESI-MS (m/z): = 641 [M?Na]?.
Anal. Calc. For C39H54O6: C, 75.69; H, 8.80; Found: C,
75.40; H, 9.09.
General method for the synthesis of acid chloride
To a solution of 1.2 Molar equivalents of NSAID’s in dry
benzene, thionyl chloride (1 ml) and dimethyl-amino-pyr-
idine (1 mg) were added. Then, the reaction mixture was
refluxed for 2–3 h. After completion of refluxing, thionyl
chloride along with benzene was evaporated.
General method for the synthesis of hybrid compounds
(7–13)
Acid chloride formed was dissolved in dry dichlorometh-
ane (10 ml) and then treated with 1 molar equivalent of b-
boswellic acid or 11-keto-b-boswellic acid in presence of
dimethyl-amino-pyridine (1 mg) as a catalyst. After com-
pletion, the product was extracted with dichloromethane.
3-O-Naproxen-b-boswellic acid (8)
3-O-Aspirin-b-boswellic acid (7)
30
29
20
21
22
19
O
O
12
26
1'
13
15
COOH
10'
12'
5'
16
17
11
11'
6'
28
25
9'
8'
2'
14
13'
3'
4'
1
4
9
18
2
3
8
8
27
7'
O
6
O
O
14'
1'
COOH
O
O
7'
2'
8'
9'
3'
4'
1
[a]2D5 = ?43.4 (c = 0.1, CH2C12); H NMR (400 MHz,
CDC13): d = 0.78, 0.88, 0.96, 1.04. 1.14 (m, 21H, 23, 25,
26, 27, 28, 29, 30, –CH3), 1.22, 1.26, 1.36, 1.41, 1.87, 1.93
(m, 18H, CH2 of cyclohexane rings), 1.42, 1.61, 1.63, 1.73,
2.10 (m, 5H, tert. CH of cyclohexane ring), 1.58 (d, 3H,
–CH3, J = 7.1 Hz), 3.95 (s, 3H, –OCH3), 5.07 (bs, 1H,
–CHCO), 5.18 (bs, 1H, H-3), 5.30 (bs, 1H; H-12), 7.07,
7.13 (m, 2H, Harom.), 7.39 (d, 1H, Harom. J = 8.4 Hz), 7.65
(m, 3H, Harom.), 11.2 (br, 1H, COOH)ppm; 13C NMR
(100 MHz, CDC13): d = 13.3 (CH3, C-4), 16.9 (CH3,
C-29), 17.6 (CH3, C-23), 17.7 (CH3, C-130), 17.8 (CH2,
C-6), 19.6 (CH3, C-30), 21.5 (CH3, C-27), 23.2 (CH3,
C-26), 23.8 (CH3, C-25), 26.6 (CH2, C-2), 28.2 (CH3,
C-28), 28.8 (CH2, C-11), 29.2 (CH, C-20), 29.9 (CH,
C-19), 30.3 (C-17), 31.6 (CH2, C-1), 32.1 (CH2, C-7), 33.2
(CH2, C-21), 33.5 (CH2, C-15), 33.8 (CH2, C-22), 37.5
7
6'
5'
1
[a]2D5 = ?58.0 (c = 0.1, CH2C12); H NMR (400 MHz,
CDC13): d = 0.74, 0.86, 0.98, 1.05, 1.19 (m, 21H, 23, 25,
26, 27, 28, 29, 30, –CH3), 1.21, 1.25, 1.36, 1.40, 1.86, 1.92
(m, 18H, CH2 of cyclohexane rings), 1.43, 1.60, 1.63, 1.72,
2.09 (m, 5H, tert. CH of cyclohexane ring), 2.10 (s, 3H,
–COCH3), 4.22 (t, 1H, CH of C3), 5.08 (bs, 1H, H-3), 5.23
(bs, 1H, H-12), 6.82 (m, 2H, Harom., J = 7.29 Hz,
J = 1.64 Hz), 7.41 (m, 1H,
J = 1.6 Hz), 7.83 (m, 1H,
H
arom., J = 7.1 Hz,
H
arom., J = 1.6 Hz,
J = 6.4 Hz), 11.2 (br, 1H, COOH)ppm; 13C NMR
(100 MHz, CDC13): d = 13.4 (CH3, C-4), 16.9 (CH3,
C-29), 17.2 (CH3, C-23), 17.5 (COCH3, C-90), 17.8 (CH2,
C-6), 19.7 (CH3, C-30), 21.3 (CH3, C-27), 21.4 (CH3,
123

Med Chem Res
(CH2, C-16), 39.6 (C-8), 42.1 (CH, C-5), 42.9 (CH, C-20),
45.1 (C-14), 45.8 (C-4), 46.8 (CH, C-18), 48.2 (C-10), 50.7
(CH, C-9), 56.4 (CH3, C-140), 75.5 (CH, C-3), 105.5 (C-80),
119.5 (C-100), 121.3 (CH, C-50), 123.6 (CH, C-12), 123.5
(C-70), 125.9 (C-90), 126.6 (CH, C-120), 127.1 (CH, C-40),
133.7 (CH, C-110), 135.8 (C-30), 154.8 (C-60), 173.5 (C-10),
181.9 (C=O, C-24)ppm; ESI-MS: (m/z): 691 [M?Na]?.
Anal. Calc. For C44H60O5: C, 79.00; H, 9.04; Found: C,
78.67; H, 9.28.
MS: (m/z): 667 [M?Na]?. Anal. Calc. For C43H64O4: C,
80.08; H, 10.00; Found: C, 80.50; H, 9.58.
3-O-Aspirin-11-keto-b-boswellic acid (10)
30
29
20
21
22
19
12
26
3-O-Ibuprofen-b-boswellic acid (9)
O
25
13
15
16
17
11
28
14
1
4
9
18
2
3
8
27
6
O
O
12'
11'
10'
1'
COOH
10
O
O
7'
7'
4'
2'
8'
9'
3'
4'
9'
8'
O
6'
5'
6'
2'
5'
3'
1'
O
COOH
13'
[a]2D5 = ?60.0 (c 0.1, CH2C12); 1H NMR (400 MHz,
CDC13): d = 0.74, 0.86, 0.98, 1.05, 1.19 (m, 21H, 23, 25,
26, 27, 28, 29, 30, –CH3), 1.21, 1.25, 1.36, 1.40, 1.86, 1.92
(m, 16H, CH2 of cyclohexane rings), 1.43, 1.60, 1.63, 1.72,
2.26 (m, 5H, tert. CH of cyclohexane ring), 2.10 (s, 3H,
–COCH3), 4.22 (t, 1H, CH of C3), 5.08 (bs, 1H, H-3),
5.77 (bs, 1H, H-12), 6.82 (m, 2H, Harom., J = 7.29 Hz,
J = 1.64 Hz), 7.41 (m, 1H, Harom., J = 7.1 Hz, J =
1.6 Hz), 7.83 (m, 1H, Harom., J = 1.6 Hz, J = 6.4 Hz),
11.2 (br, 1H, COOH)ppm; 13C NMR (100 MHz, CDC13):
d = 13.4 (CH3, C-4), 16.9 (CH3, C-29), 17.2 (CH3,
C-23), 17.5 (COCH3, C-90), 17.8 (CH2, C-6), 19.7 (CH3,
C-30), 21.3 (CH3, C-27), 21.4 (CH3, C-26), 23.3 (CH3,
C-25), 23.5 (CH2, C-2), 23.8 (CH3, C-28), 28.0 (CH2,
C-1), 28.2 (CH2, C-21), 28.9 (CH2, C-1), 29.2 (CH,
C-20), 29.9 (CH, C-19), 30.3 (C-17), 32.1 (CH2, C-7),
33.5 (CH2, C-15), 33.8 (CH2, C-22), 37.5 (CH2, C-16),
39.6 (C-8), 42.1 (CH, C-5), 45.1 (C-14), 45.8 (C-4), 46.8
(CH, C-18), 48.2 (C-10), 50.7 (CH, C-9), 75.5 (CH, C-3),
121.3 (CH, C-50) 122.6 (CH, C-12), 124.4 (C-60), 125.2
(CH, C-30), 130.1 (CH, C-20), 136.9 (C-40), 149.3 (C-13),
167.5 (C-70), 172.3 (C-80), 181.9 (C=O, C-24), 200.8
(C=O, C-11)ppm; ESI-MS (m/z): 645 [M ? Na]?. Anal.
Calc. For C39H52O7: C, 74.02; H, 8.28; Found: C, 74.50;
H, 8.78.
[a]2D5 = ?23.2 (c 0.1, CH2C12); 1H NMR(400 MHz,
CDC13): d = 0.83, 0.89, 0.92, 0.96, 1.01, 1.11 (21H, 23,
25, 26, 27, 28, 29, 30, –CH3), 0.86 (d, 6H, –CH3 of iso-
propyl group 110and120, J = 3 Hz), 1.22, 1.26, 1.36, 1.41,
1.87, 1.93 (m, 18H, CH2 of cyclohexane rings), 1.43, 1.60,
1.63, 1.72, 2.09 (m, 5H, tert. CH of cyclohexane ring), 1.52
(d, 3H, –CH3-130, b to –COO–, J = 6 Hz), 2.25 (m, 1H,
–CH– of isopropyl group), 2.52 (d, 2H, –CH2-of 90), 3.71
(q, 1H, –CH–CO–), 5.12 (bs, 1H, H-12), 7.11 (d, 2H,
H
arom., J = 6.2 Hz), 7.22 (d, 2H, Harom., J = 6 Hz), 11.30
(br, 1H, OH)ppm; 13C NMR (100 MHz, CDC13): d = 12.4
(CH3, C-4), 16.92 (CH3, C-29), 17.5 (CH3, C-23), 17.3
(CH3, C-130), 17.8 (CH2, C-6), 19.6 (CH3, C-30), 21.5
(CH3, C-27), 21.9 (C-110 and C-120), 23.2 (CH3, C-26),
23.8 (CH3, C-25), 26.6 (CH2, C-2), 28.2 (CH3, C-28), 28.8
(CH2, C-11), 29.2 (CH, C-20), 29.9 (CH, C-19), 30.3 (C-
17), 30.6 (C-100), 31.6 (CH2, C-1), 32.1 (CH2, C-7), 33.2
(CH2, C-21), 33.5 (CH2, C-15), 33.8 (CH2, C-22), 37.5
(CH2, C-16), 39.6 (C-8), 42.1 (CH, C-5), 42.5 (CH, C-20),
44.9 (C-90), 45.1 (C-14), 45.8 (C-4), 46.8 (CH, C-18), 48.2
(C-10), 50.7 (CH, C-9), 75.5 (CH, C-3), 129.1, 129.2 (C-40,
C-50 and C-70, C-80), 123.6 (CH, C-12), 131.8 (C-30), 139.9
(C-60), 173.5 (C=O, C-10), 181.7 (C=O, C-24)ppm; ESI-
123

Med Chem Res
[M?Na]?. Anal. Calc. For C44H58O6: C, 77.38; H, 8.56;
Found: C, 77.70; H, 8.24.
3-O-Naproxen-11-keto-b-boswellic acid (11)
3-O-Ibuprofen-11-keto-b-boswellic acid (12)
O
12'
O
11'
10'
7'
O
O
9'
8'
O
6'
5'
1'
COOH
11
10'
12'
5'
2'
11'
6'
3'
1'
9'
8'
O
2'
4'
13'
3'
4'
COOH
12
13'
7'
O
14'
[a]2D5 = ?18.0 (c 0.1, CH2C12); 1H NMR (400 MHz,
CDC13): d = 0.83, 0.89, 0.92, 0.96, 1.01, 1.11 (21H, 23,
25, 26, 27, 28, 29, 30, –CH3), 0.86 (d, 6H, –CH3 of iso-
propyl group 110 and 120, J = 3 Hz), 1.22, 1.26, 1.36, 1.41,
1.87, 2.09 (m, 16H, CH2 of cyclohexane rings), 1.43, 1.60,
1.63, 1.72, 2.29 (m, 5H, tert. CH of cyclohexane ring), 1.52
(d, 3H, –CH3–130, b to –COO–, J = 6 Hz), 2.25 (m, 1H, –
CH– of isopropyl group), 2.52 (d, 2H, –CH2– of 90), 3.71
(q, 1H, –CH–CO–), 5.12 (bs, 1H, H-12), 7.11 (d, 2H,
[a]2D5 = ?26.7 (c 0.1, CH2C12); 1H NMR (400 MHz,
CDC13): d = 0.78, 0.88, 0.96, 1.04. 1.14 (m, 21H, 23, 25,
26, 27, 28, 29, 30, –CH3), 1.22, 1.26, 1.36, 1.41, 1.87, 2.26
(m, 16H, CH2 of cyclohexane rings), 1.42, 1.61, 1.63, 1.73,
2.10 (m, 5H, tert. CH of cyclohexane ring), 1.58 (d, 3H, –
CH3, J = 7.1 Hz), 3.95 (s, 3H, –OCH3), 5.07 (bs, 1H, –
CHCO), 5.18 (bs, 1H, H-3), 5.77 (bs, 1H; H-12), 7.07, 7.13
(m, 2H, Harom.), 7.39 (d, 1H, Harom. J = 8.4 Hz), 7.65 (m,
H
arom., J = 6.2 Hz), 7.22 (d, 2H, Harom., J = 6 Hz), 11.30
3H,
H
arom.), 11.2 (br, 1H, COOH)ppm; 13CNMR
(br, 1H, OH)ppm; 13C NMR (100 MHz, CDC13): d = 12.4
(CH3, C-4), 16.92 (CH3, C-29), 17.5 (CH3, C-23), 17.3
(CH3, C-130), 17.8 (CH2, C-6), 19.6 (CH3, C-30), 21.5
(CH3, C-27), 21.9 (C-110 and C-120), 23.2 (CH3, C-26),
23.8 (CH3, C-25), 26.6 (CH2, C-2), 28.2 (CH3, C-28), 29.2
(CH, C-20), 29.9 (CH, C-19), 30.3 (C-17), 30.6 (C-100),
31.6 (CH2, C-1), 32.1 (CH2, C-7), 33.2 (CH2, C-21), 33.5
(CH2, C-15), 33.8 (CH2, C-22), 37.5 (CH2, C-16), 39.6 (C-
8), 42.1 (CH, C-5), 42.5 (CH, C-20), 44.9 (C-90), 45.1 (C-
14), 45.8 (C-4), 46.8 (CH, C-18), 50.7 (CH, C-9), 62.7 (C-
10), 75.5 (CH, C-3), 129.1, 129.2 (C-40, C-50 and C-70,
C-80), 123.6 (CH, C-12), 131.8 (C-30), 139.9 (C-60), 173.5
(C=O, C-10), 181.7 (C=O, C-24), 200.7 (C=O, C-11)ppm;
ESI-MS (m/z): 681 [M?Na]?. Anal. Calc. For C43H62O5:
C, 78.38; H, 9.48; Found: C, 78.78; H, 9.10.
(100 MHz, CDC13): d = 13.3 (CH3, C-4), 16.9 (CH3,
C-29), 17.6 (CH3, C-23), 17.7 (CH3, C-130), 17.8 (CH2,
C-6), 19.6 (CH3, C-30), 21.5 (CH3, C-27), 23.2 (CH3,
C-26), 23.8 (CH3, C-25), 26.6 (CH2, C-2), 28.2 (CH3,
C-28), 29.2 (CH, C-20), 29.9 (CH, C-19), 30.3 (C-17), 31.6
(CH2, C-1), 32.1 (CH2, C-7), 33.2 (CH2, C-21), 33.5 (CH2,
C-15), 33.8 (CH2, C-22), 37.5 (CH2, C-16), 39.6 (C-8),
42.1 (CH, C-5), 42.9 (CH, C-20), 45.1 (C-14), 45.8 (C-4),
46.8 (CH, C-18), 48.2 (C-10), 56.4 (CH3, C-140), 62.7 (CH,
C-9), 75.5 (CH, C-3), 105.5 (C-80), 119.5 (C-100), 121.3
(CH, C-50), 123.6 (CH, C-12), 123.5 (C-70), 125.9 (C-90),
126.6 (CH, C-120), 127.1 (CH, C-40), 133.7 (CH, C-110),
135.8 (C-30), 154.8 (C-60), 173.5 (C-10), 181.9 (C=O,
C-24), 200.8 (C=O, C-11)ppm; ESI-MS (m/z): 705
123

Med Chem Res
ESI-MS (m/z): 623 [M ? Na]?. Anal. Calc. For C39H52O5:
3-O-Cinnamyl-11-keto-b-boswellic acid (13)
C, 77.96; H, 8.72; Found: C, 77.46; H, 9.22.
Biological testing
In vivo anti-inflammatory and anti-arthritic activities
O
Materials and methods
(a) Animals
1. Balb/C mice (8–12 week old, weighing between
18 and 22 mg)
2'
2. Wistar rats (12–16 week old, weighing between
120 and 160 mg)
1'
O
3'
COOH
13
4'
O
Mice and rats were housed in animal house in groups of
5–10 in plastic cages. They were given pellet diet and
libitum during the course of experimentation. Light cycle
was automatically controlled (on at 7.00 am and off at
7.00 pm). Room temperature was regulated at 26 1 °C.
Animals were housed in such conditions for 3–4 days to
become acclimatized.
9'
8'
5'
6'
7'
[a]2D5 = ?26.7 (c 0.1, CH2C12); 1H NMR (400 MHz,
CDC13): d = 0.83, 0.89, 0.92, 0.96, 1.01, 1.11 (21H, 23,
25, 26, 27, 28, 29, 30, –CH3), 1.22, 1.26, 1.36, 1.41, 1.87,
2.09 (m, 16H, CH2 of cyclohexane rings), 1.43, 1.60, 1.63,
1.72, 2.29 (m, 5H, tert. CH of cyclohexane ring), 3.71 (q,
1H, –CH–CO–), 5.77 (bs, 1H, H-12), 5.96 (d, 1H, H-20,
J = 7.0 Hz), 7.09 (d, 1H, H-30, J = 7.0 Hz), 7.14, 7.21,
7.30 (m, 5H, Harom., H-50, 60, 70, 80, 90), 11.30 (br, 1H,
OH)ppm; 13C NMR (100 MHz, CDC13): d = 13.7 (CH3,
C-4), 16.92 (CH3, C-29), 17.5 (CH3, C-23), 17.8 (CH2,
C-6), 19.6 (CH3, C-30), 21.5 (CH3, C-27), 23.2 (CH3,
C-26), 23.8 (CH3, C-25), 26.6 (CH2, C-2), 28.2 (CH3,
C-28), 29.2 (CH, C-20), 29.9 (CH, C-19), 30.3 (C-17), 31.6
(CH2, C-1), 32.1 (CH2, C-7), 33.2 (CH2, C-21), 33.5 (CH2,
C-15), 33.8 (CH2, C-22), 37.5 (CH2, C-16), 39.6 (C-8),
42.1 (CH, C-5), 45.1 (C-14), 45.8 (C-4), 46.8 (CH, C-18),
50.7 (CH, C-9), 62.7 (C-10), 75.5 (CH, C-3), 117.6 (C-20),
123.6 (CH, C-12), 126.2, 127.7, 128.4, 134.9 (C-50 and 90,
80, 60 and 80, 40), 165.5 (C=O, C-10), 181.7 (C=O, C-24),
200.7 (C=O, C-11)ppm; ESI-MS (m/z): 623 [M?Na]?.
Anal. Calc. For C39H52O5: C, 77.96; H, 8.72; Found: C,
77.46; H, 9.22.
(b) Required reagents
1. Carrageenan
2. Normal saline
3. Gum acacia
4. Mycobacterium tuberculosis
(c) Apparatus and equipments
1. Conical flask. Petridish, test tubes, test tube
stands, eppendrofs, beakers, micropipettes, capil-
laries, pestle mortar, spatula, syringe, cannula
2. Screw gauge
3. Volume differential meter
4. Spectrophotometer
(d) Development of rat and mice models for inflammation
and arthritis
The study was conducted in rodents especially in rats
and mice. After 3–5 days acclimatization in animal house,
rats/mice were taken to induce inflammation and arthritis.
Carrageenan-induced mice model
0.76, 0.88, 1.13, 1.18, 1.21, 1.32 (21H, 23, 24, 25, 26,
27, 28, 29, 30, –CH3), 2.35 (bs, 1H, H-9), 5.40 (bs, 1H,
H-3), 5.55 (bs, 1H, H-12), 6.34 (d, 1H, = CHCO,
J = 7.0 Hz), 6.42 (d, 1H,–CH=C–CO–, 7.0 Hz)ppm; 13C
NMR (100 MHz, CDC13): d = 13.7, 17.9, 18.8, 20.9, 21.6,
24.4, 27.9, 29.3, 30.1, 31.3, 34.4, 37.9, 39.7, 41.3, 44.2,
45.5, 47.2, 51.1, 59.4, 60.8, 73.6, 117.6, 118.8, 128.5,
128.8, 129.3, 129.4, 130.7, 130.9, 131.2, 134.4, 134.8,
145.4, 147.6, 165.4, 166.6, 172.4, 182.5, 199.7 ppm;
This test was performed by the most widely and commonly
used technique of Srimal and Dhawan (Srimal and Dha-
wan, 1973). Oedema was induced in mice in groups of 4,
by injecting 25 ll of carrageenan (1 % w/v) solution in
normal saline into sub-planar region of the left hind paw
after 45 min. of drug administration. Paw volume was
measured at 1st, 2nd, 3rd, 4th, and 24th hour after inducing
the inflammation, with the help of screw gauge.
123

Med Chem Res
Carrageenan-induced rat model
groups of 4, by injecting 25 ll of carrageenan (1 % w/v)
solution in normal saline into sub-planar region of the left
hind paw after 45 min. of drug administration. Paw volume
was measured at 1st, 2nd, 3rd, 4th, and 24th hour after
inducing the inflammation, with the help of screw gauge.
Similarly, Carrageenan-induced model was employed for
rats also. Oedema was induced in rats in groups of 4, by
injecting 100 ll of carrageenan (1 % w/v) solution in
normal saline into the sub-planar region of the left hind
paw after 45 min. of drug administration. Conjugates
formed and ibuprofen were administered orally 45 min.
before the induction of inflammation. Inflammation was
induced in mice by injecting carrageenan (1 % w/v) solu-
tion in normal saline into the sub-planar region of the left
hind paw after. Paw volume was measured on volume
differential meter at 1st, 2nd, 3rd, 4th and 24th hour after
inducing the inflammation. Paw oedema was measured by
using volume differential meter (in rats) and by screw
gauge (in mice). Readings were taken for both injected and
un-injected paw.
Oedema was induced in rats in groups of 4, by injecting
100 ll of carrageenan (1 % w/v) solution in normal saline
into the sub-planar region of the left hind paw after 45 min.
of drug administration. Paw volume was measured on
volume differential meter at 1st, 2nd, 3rd, 4th, and 24th
hour after inducing the inflammation.
Techniques
Swiss albino mice (22–25 g body weight) and male albino
Wistar rats (120–160 g body weight) in groups of 4–6 were
used at room temperature of 26 1C. In acute tests, the
graded dose of test material was administered orally
45 min. before the induction of inflammation. In chronic
tests like in testing anti-arthritic activity, the test materials
were administered once a day and continue till day 13. In
every experiment, one group of animals was kept as control
and given only vehicle, while another group received as
positive standard drug for comparison of activity and
authenticity of the experiment. Paw volume was measured
at different time intervals depending upon the nature of
experiment with the help of volume differential meter or
screw gauge. Mean increase in paw volume and standard
error of the mean each group was calculated, and the
results were expressed as per cent inhibition of oedema as
compared to control group. Drugs were freshly prepared as
fine homogenized suspension in 2 % gum acacia (w/v) for
administration.
Statistical evaluation
The numerical were expressed as Mean SE of difference
between vehicle control and treatment groups, unless
otherwise specified.
%
age inhibition was calculated as:
% inhibi-
tion = (Cm–Tm)/Cm 9 100.
In vivo anti-arthritic activity through mycobacterium-
induced arthritis rat model
Paw oedema measurement
Chronic arthritis in rats was induced by the injection of
0.05 ml (0.5 % w/v) suspension of heat killed Mycobac-
terium tuberculosis, homogenized in liquid paraffin in the
left hind foot paw using the method of (Newbould, 1963).
The administration of test compound was started one day
before the injection of the Mycobacterium tuberculosis and
continued till day 13. The volume of paw was measured on
alternate days and the %age inhibition was determined.
Paw oedema was measured by using volume differential
meter (in rats) and by screw gauge (in mice). Readings
were taken for both injected and un-injected paw.
In vivo anti-inflammatory activity
Balb/C mice (8–12 week old, weighing between 18 and
22 mg) and Wistar rats (12–16 week old, weighing
between 120 and 160 mg) were housed in animal house in
groups of 5–10 in plastic cages. They were given pellet diet
and libitum during the course of experimentation. Light
cycle was automatically controlled (on at 7.00 AM and off
at 7.00 PM). Room temperature was regulated at
26 1 °C. Animals were housed in such conditions for
3–4 days to become acclimatized. The study was con-
ducted in rodents especially in rats and mice. After
3–5 days acclimatization in animal house, rats/mice were
taken to induce inflammation. The test was performed by
the most widely and commonly used technique of (Srimal
and Dhawan, 1973). Oedema was induced in mice in
Conclusion
We have synthesized a series of hybrid molecules of BAs
and 11-KBAs with the various kinds of anti-inflammatory
drugs namely aspirin, naproxen, ibuprofen and cinnamic
acid respectively. Anti-inflammatory activity of these
hybrid compounds were studied in mice and rats under
different intervals of the time. Out of the mentioned
compounds 7–13, compound 8 and 11 were displayed
potential activity. The compound 8 and 11 were further
tested for their anti-arthritic activity out of which
123

Med Chem Res
bronchial asthma: results of a double-blind placebo-controlled
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compound 8 was found to most potent in all the activities
studied in this work. It was concluded that hybrid mole-
cules 8 and 11 containing naproxen unit with boswellic
acid and 11-keto-11-keto-b-boswellic acid was found to
have promising activity. Compound 8 was manifold more
active and thus has been picked for further detailed studies
for anti-inflammatory and anti-arthritic activities for the
drug development study.
Acknowledgments The corresponding author wishes to thank Pro-
Vice Chancellor and Dean, Research (Science and Technology),
Amity University Uttar Pradesh (AUUP), Lucknow Campus, Luc-
know, for his constant encouragement and support for research.
Conflict of interest The authors confirm that there is no conflict of
interest with the commercial identities used inside the manuscript.
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