Regioselective synthesis of isoxazole-mercaptobenzimidazole hybrids and their in vivo analgesic and anti-inflammatory activity studies

Article abstract of DOI:10.1016/j.bmcl.2012.12.101

Regioselective synthesis of isoxazole-mercaptobenzimidazole hybrids and their efficiency in in vivo analgesic and anti-inflammatory activity was described. A comparison of structure-activity relationship for there compounds was also emphasized.

Full text of DOI:10.1016/j.bmcl.2012.12.101

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1306–1309
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Regioselective synthesis of isoxazole–mercaptobenzimidazole
hybrids and their in vivo analgesic and anti-inflammatory activity
studies
b
Shravankumar Kankala a, , Ranjith Kumar Kankala , Prasad Gundepaka c,d, Niranjan Thota e,
⇑
Srinivas Nerella a, Mohan Rao Gangula a, Hanmanthu Guguloth a, Mukkanti Kagga d, Ravinder Vadde a,
,
⇑
Chandra Sekhar Vasam c,
⇑
a Department of Chemistry, Kakatiya University, Warangal, India
b Department of Pharmaceutics, Blue Birds College of Pharmacy, Warangal, India
c Department of Chemistry, Satavahana University, Karimnagar, India
d Centre for Pharmaceutical Science, Institute of Science and Technology, JNTU, Hyderabad, India
e Department of Chemistry, Royal Institute of Technology (KTH), Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Regioselective synthesis of isoxazole–mercaptobenzimidazole hybrids and their efficiency in in vivo anal-
gesic and anti-inflammatory activity was described. A comparison of structure–activity relationship for
there compounds was also emphasized.
Received 17 October 2012
Revised 18 December 2012
Accepted 28 December 2012
Available online 9 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Isoxazole–benzimidazole hybrids
1,3-Dipolar cycloaddition
N-Heterocyclic carbene
Analgesic activity
Anti-inflammatory activity
Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the
most widely prescribed drug categories against various inflamma-
tion mediated diseases, such as arthritis, rheumatism as well as to
relieve the aches and pain of daily life.1–8 Inflammation is the non-
specific protective mechanistic action of the immune system, local
biological response of vascular and supporting elements in the tis-
sues at injury to harmful stimuli, resulting in the formation of pro-
tein-rich exudates. These exudates mainly include inflammatory
mediators such as prostaglandin and histamine, which are respon-
sible for the clinical sign and manifests it as swelling (tumor). In
this context, the NSAIDs mainly act by lowering the prostaglandin
production through inhibition of the enzyme cyclooxygenase-
2.9,10,4
Generally, in designing new bio-active agents for various thera-
peutic areas, besides the development of completely new agents,
there is another approach involving the synthesis of hybrid mole-
cules.3,11–18 In the present study, we aim at designing and develop-
ing of new NSAIDs of hybrid molecules through the combination of
different azole pharmacophores in one structure. Indeed this con-
cept allows the fine tuning of electronic effects in the hybrid struc-
ture, provides synergistic effect, to deduce structure–activity
relationship (SAR) to improve the bio-potency. Azole heterocycle
(imidazole, triazole, pyrazole, oxazole, isoxazole etc.) is an impor-
tant structural motif in several naturally occurring bio-mole-
cules19–25 and have been used as privileged scaffolds to
synthesize selective drugs of interest in numerous therapeutic
areas including HIV-RT inhibitor,26 anti-cancer,27 anti-ulcer,28,29
anti-microbial,30,31 antihistamine,32 anthelmintic,33,34 antioxi-
dant,35,36 antihypertensive,37 anti-viral38 and anticoagulant
properties.39
This manuscript describes a facile route for the regioselective
synthesis of N-isoxazole-bound 2-mercaptobenzimidazole hybrids
by readily obtainable materials via catalytic nitrile oxide-alkyne
1,3-dipolar cycloaddition and the in vivo screening of the resultant
cycloadducts by analgesic and anti-inflammatory activities.
We have employed some newly synthesized 2-mercaptobenz-
imidazole derived terminal alkynes as partners to nitrile oxide in
cycloaddition to obtain 3,5-disubstiuted isoxazole bound 2-mercap-
tobenzimidazole hybrid molecules. The new terminal alkynes that is
N-propargyl 2-mercaptobenzimidazoles were obtained in a three
step synthesis (Scheme 1). Firstly, the 2-mercaptobenzimidazoles
⇑
Corresponding authors.
E-mail address: vasamcs@yahoo.co.in (C.S. Vasam).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.12.101

S. Kankala et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1306–1309
1307
Table 1
H
R
R
R
NH
NH
N
CS , NaOH
2
aq.ethanol (7:3)
reflux, 100 °C
Results of organo-NHC-catalyzed cycloadditon of terminal alkyne (4a–d) with aryl
2
2
S
nitrile oxides (5a–c)a
N
H
Entry
R
Ar
Product
Yieldb (%)
1a-d
2a-d
NO
68 (3:7)c
92
90
94
92
90
95
92
95
94
92
95
94
2
1
2
3
4
5
6
7
8
H (4a)
4a
4a
4a
Br (4b)
4b
4b
OCH3 (4c)
4c
4c
NO2 (4d)
4d
4-OMeC6H4 (5a)
5a
4-FC6H4 (5b)
4-CNC6H4 (5c)
5a
5b
5c
5a
5b
5c
5a
5b
5c
6a
6a
6b
6c
6d
6e
6f
6g
6h
6i
KOH,
aq.ethanol (1:1)
reflux, 3h
Cl
NO
NO
2
NO
NO
2
2
2
Br
R
N
N
N
S
NO
S
2
K CO
N
2
3
9
H
Acetone
10
11
12
13
3a-d
4a-d
reflux, 5h
6j
6k
6l
R = H (4a), Br (4b), OCH (4c), NO (4d)
3
2
4d
Scheme 1. Synthesis of N-propargyl 2-mercaptobenzimidazoles (4a–d).
a
b
c
All products were characterized by NMR and mass spectral analysis.
Isolated yields after column chromatography.
Without NHC catalyst.
(2a–d) were obtained by the condensation of o-phenylenediamines
(OPDA) (1a–d) with carbon disulphide in presence of NaOH as a
base. The as-synthesized 2a–d were then treated with 2,4-dinitro-
chlorobenzene in the presence of a base to obtain 2-mercaptobenz-
imidazoles 3a–d. N-propargylation of 3a–d has given the terminal
alkynes (4a–d).
Now the terminal alkynes were subjected to cycloaddition reac-
tion with nitrile oxides (5a–c) in the presence of an organo-N-het-
erocyclic carbene (NHC) catalyst to obtain N-isoxazole-bound 2-
mercaptobenzimidazoles (6a–l) (Scheme 2). The in situ generation
and stabilization of aryl nitrile oxides was reported by us
recently.40
IR, 1H/13C NMR, mass and elemental analysis (Experimental Sec-
tion). The absence of 1H NMR signals of terminal alkyne at
d = ꢀ2.10, and emerging of a new signal at d = ꢀ6.30 corresponds
to 4th C–H proton of isoxazole provides a good support for the
cycloaddition to form 3,5-disubstituted isoxazoles. The same fea-
tures are reflected in 13C NMR spectra, where the signal belongs
to terminal carbon of alkyne was disappeared and a new signal be-
longs to 4th C–H ring carbon, was appeared at d = ꢀ99 after
cycloaddition.
All the compounds prepared herein (6a–l) were screened for
their in vivo analgesic and anti-inflammatory activities. These
activities were carried out by measuring the physiological re-
sponses of animals to the thermal and chemical stimuli. For anal-
gesic activity, hot plate method in mice was used41 at a dose of
100 mg/kg b.w (body weight) was performed. These activity re-
sults were compared with standard drug pentazocine (50 mg/kg
b.w). For anti-inflammatory activity, carrageenan induced inflam-
mation on rat hind paw oedema method of Winter et al.,42 in mice
at a dose of 100 mg/kg b.w. was carried out. The percentage inhibi-
tion was determined for synthesized compounds as well as stan-
dard drug diclofenac (50 mg/kg b.w). The animal study was
conducted according to the protocol approved by animal ethics
committee, Kakatiya University, India.
In a more detailed explanatory way, the results of the reactions
shown in Scheme 2 are summarized in Table 1. Firstly, the condi-
tions for cycloaddition were optimized by using nitrile oxide (5a)
and terminal alkyne (4a) as model substrates. The cycloaddition
between 5a and 4a studied without a catalyst was so sluggish
(ꢀ16 h) and produced a mixture of two regioisomers of disubsti-
tuted (3,4- and 3,5-) isoxazole (entry 1, 68% of combined mixture
in ꢀ3:7 ratio). In this situation, the cycloaddition between 5a
and 4a performed in the presences of nucleophilic organo-NHC
catalyst (N,N0-ditertiarybutylimidazolium chloride) has enhanced
the reactivity of terminal alkyne and thereby 3,5-disubstituted
isoxazole product (6a) regioselectivity (Table 1, entry 2). After
the synthesis of 6a, we have also studied the catalytic cycloaddi-
tion of terminal alkynes (4b–d) with nitrile oxides (5a–c) and syn-
thesized only 3,5-disubstituted isoxazoles (6b-l) as a sole product
(see Table 1) in a shorter reaction period of ꢀ20 min.
Table 2
The synthesized 2-mercaptobenzimidazole containing 3,5-
disubstituted isoxazole compounds (6a–l) were characterized by
Analgesic activity of tested compounds (100 mg/kg b.w) and pentazocine (50 mg/kg
b.w) The Bold values specify the compounds with superior activity.
Entry
Compound
Reaction time in seconds (X SD)a
1
2
3
4
5
6
7
8
Control
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6.07 0.057⁄⁄⁄
13.28 0.106⁄⁄⁄
13.58 0.134⁄⁄⁄
13.50 0.147⁄⁄⁄
13.80 0.085⁄⁄⁄
13.92 0.093
Cl
NO
NO
NO2
NO2
2
But
N
N
tBu
R
R
H
N
N
N
N
S
S
NHC Precursor
Et3N, DCM, 0-5 °C, 20 min.
2
N
O
Ar
O
13.87 0.093⁄⁄⁄
13.60 0.126⁄⁄⁄
13.65 0.057⁄⁄⁄
13.65 0.102⁄⁄⁄
13.68 0.118⁄⁄⁄
13.80 0.061⁄⁄⁄
13.77 0.061⁄⁄⁄
14.10 0.05⁄⁄⁄
N
Ar
(5a-c)
4a-d
6a-l
9
Ar = 4-OCH3C6H4 (5a), 4-FC6H4 (5b), 4-CNC6H4 (5c)
10
11
12
13
14
R = OCH3, Ar = 4-OCH3C6H4 (6g)
R = H, Ar = 4-OCH3C6H4 (6a)
R = H, Ar = 4-FC6H4 (6b)
R = H, Ar = 4-CNC6H4 (6c)
R = OCH3, Ar = 4-FC6H4 (6h)
R = OCH3, Ar = 4-CNC6H4 (6i)
6l
R = Br, Ar = 4-OCH3C6H4 (6d) R = NO2, Ar = 4-OCH3C6H4 (6j)
Pentazocine
R = NO2, Ar = 4-FC6H4 (6k)
R = NO2, Ar = 4-CNC6H4 (6l)
R = Br, Ar = 4-FC6H4 (6e)
R = Br, Ar = 4-CNC6H4 (6f)
⁄⁄⁄p <0.05. The active compounds are marked in bold letters.
a
Data represent mean values SD (standard deviation) of six mice per group,
NHC Precursor = N,N'-ditertiarybutylimidazolium chloride
shown at the final value for each group (saline, pentazocine and tested compounds)
after 120 min. Data were analyzed using one-way ANOVA followed by Newman–
Keuls multiple comparison test.
Scheme 2. Organo-NHC catalyzed 1,3-dipolar cycloaddition synthesis of isoxazoles
(6a–l).

1308
S. Kankala et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1306–1309
The SAR study was evaluated by changing substituent on 5-po-
sition of benzimidazole and 3-position of isoxazoles as shown in
Table 1 to see the influence electronic effects. Among the 12 com-
pounds investigated for in vivo analgesic activity, when the 5th po-
sition of benzimidazole and 3rd position of substituted aryls of
isoxazoles containing electron withdrawing groups of bromo, flu-
oro, nitro and cyano as in 6e, 6f, 6k and 6l showed superior activity
over the compounds 6a–d and 6g–j that contain atleast one elec-
tron donating group or without any subtituent on benzimidazole
ring.
The activity of the tested compounds 6a–l as well as reference
standard were measured after the administration of carrageenan
inflammation induced in rats. The percent oedema inhibition was
calculated as a regard to saline control group, as depicted in Fig-
ure 2, Table 3. Most of the tested compounds have shown good re-
sults in comparison with standard drug diclofenac. Among all the
compounds investigated, 6e (60.76%) and 6f (58.46%) have shown
potent anti-inflammatory activity, the compounds 6j, 6k and 6l
have shown moderate activity (50.38, 53.07 & 53.07%). However,
all the results were found to be more potent than the standard dic-
lofenac. On the other hand, the compounds 6a, 6g have shown poor
activity.
Figure 1. Analgesic activity of N-isoxazole-bound 2-mercaptobenzimidazoles (6a–
l) by hot plate method.
Further, the efficacious anti-inflammatory activity of these
compounds was analyzed based on the structure–activity relation-
ships considering the basic two structural derivatives: nature of
the group attached to 3-aryl substituted isoxazole ring and nature
of the substituents (functional group) at 5th position of 2-mercap-
tobenzimidazole as described in in vivo analgesic activity.
As observed in in vivo analgesic activity, compounds 6e, 6f, 6k
and 6l that containing electron withdrawing groups on 5th posi-
tion of benzimidazole and 3rd position of substituted aryls of isox-
azoles exhibited greater activity over the compounds that contain
atleast one electron donating group or without any subtituent on
benzimidazole ring.
Figure 2. Anti-inflammatory activity of N-isoxazole-bound 2-mercaptobenzimi-
dazoles (6a–l).
In conclusion, a facile catalytic method for the regioselective
synthesis of 3,5-disubstituted isoxazole bound benzimidazole hy-
brid molecules and their effective analgesic and anti-inflammatory
activities and structure–activity relationship (SAR) was demon-
strated. These hybrid compounds possessing an electron-with-
drawing group displayed higher activity than for compounds
containing electron-donating groups and were found to be more
potent than the standard pentazocine for analgesic and diclofenac
for anti-inflammatory activity.
The analgesic activity of the synthesized compounds (6a–l) was
assessed by hot plate method. According to the structure–activity
relationship (SAR) studies, almost all the compounds have shown
very potent analgesic activity when compared with standard drug
pentazocine. Amongst all the compounds, 6e and 6f with potent
analgesic activity, the compounds 6k and 6l has shown moderate
activity, and was found to be more potent than the standard pen-
tazocine. The remaining compounds 6a–d and 6g–j had shown
poor activity (see Table 2, Fig. 1).
Table 3
Anti-inflammatory activity of the tested compounds (100 mg/kg b.w) and diclofenac (50 mg/kg b.w). The Bold values specify the compounds with superior activity.
Entry
Compound
Paw oedema thickness (mm)
60 min (X SD)
% Oedema inhibition
180 min (X SD)a
% Oedema inhibitionb
1
2
3
4
5
6
7
8
Control
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
2.65 0.10⁄⁄
—
2.60 0.06⁄⁄
—
2.01 0.05
24.15
38.86
29.05
33.58
53.95
52.44
24.15
42.63
24.90
43.39
46.78
45.65
44.52
1.82 0.01
29.99
46.92
44.23
46.15
60.76
58.46
39.61
49.23
42.70
5.38
1.62 0.02⁄⁄
1.88 0.02⁄
1.76 0.06⁄
1.22 0.03⁄⁄⁄
1.26 0.01⁄⁄⁄
2.01 0.13⁄
1.52 0.02⁄⁄
1.99 0.02⁄⁄
1.50 0.04⁄⁄
1.41 0.01
1.38 0.02⁄⁄
1.45 0.05⁄
1.40 0.04⁄
1.02 0.02⁄⁄⁄
1.08 0.04⁄⁄⁄
1.57 0.02⁄
1.32 0.04⁄⁄
1.49 0.02⁄⁄
1.29 0.02⁄⁄
1.22 0.02
9
10
11
12
13
14
53.07
53.07
45.76
6l
1.44 0.03⁄⁄
1.47 0.01⁄⁄⁄
1.22 0.03⁄⁄
1.41 0.04⁄⁄⁄
Diclofenac
a
Data represent mean values SD (standard deviation) of six mice per group and the percent changes versus 60 and 180 min post-carrageenan injection. Data were
analyzed using one-way ANOVA followed by Newman–Keuls multiple comparison test. Significant difference from the control value at p <0.05.
b
Percent oedema inhibition was calculated as regards saline control group and the active compounds are marked in bold letters.

S. Kankala et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1306–1309
1309
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One of the authors S. Kankala is thankful to CSIR, New Delhi for
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Supplementary data
Supplementary data (experimental procedures for 3a–d, 4a–d,
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