A rational design, synthesis, characterization, and antihypertensive activities of some new substituted benzimidazoles

Article abstract of DOI:10.1007/s00044-012-0462-7

A series of 5-substituted benzimidazoles were designed, synthesized, and evaluated for in vivo antihypertensive activity by acute renal hypertension on guinea pig. All the compounds of the series elicit remarkable activity in comparison to standard drug (losartan). The activity is found to be relatively better in substituted alkylamino group at 5-position of benzimidazole. The maximum activity that is almost equipotent with losartan is observed with four compounds DR-13, DR-14, DR-15, and DR-16.

Full text of DOI:10.1007/s00044-012-0462-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:4622–4632
DOI 10.1007/s00044-012-0462-7
ORIGINAL RESEARCH
A rational design, synthesis, characterization,
and antihypertensive activities of some new substituted
benzimidazoles
•
Anurekha Jain Rajesh Sharma S. C. Chaturvedi
•
Received: 27 June 2012 / Accepted: 31 December 2012 / Published online: 17 January 2013
Ó Springer Science+Business Media New York 2013
Abstract A series of 5-substituted benzimidazoles were
designed, synthesized, and evaluated for in vivo antihyper-
tensive activity by acute renal hypertension on guinea pig.
All the compounds of the series elicit remarkable activity in
comparison to standard drug (losartan). The activity is found
to be relatively better in substituted alkylamino group at
5-position of benzimidazole. The maximum activity that is
almost equipotent with losartan is observed with four com-
pounds DR-13, DR-14, DR-15, and DR-16.
organ damage. This led to development of new class of
drugs that target both BP and related structural and func-
tional abnormalities of the heart and blood vessels. Renin
angiotensin system (RAS) (Ferrario, 1990) is the most
direct, precise, complete, specific, and effective approach to
antagonize AngII at its receptor site. These drugs have
proved that, by lowering the BP effectively, they are better
tolerated than other classes of drugs and are devoid of side
effects such as dry cough and angioedema caused by non-
specific action of ACE inhibitors (Cockcroft et al., 1993).
Carini et al. (1991) proposed a structure–activity relation-
ship (SAR) of AT1 receptor antagonist, which suggested that
the activity is improved by the presence of a biphenyl group
of losartan, able to fit into a third hydrophobic pocket; a
tetrazole group or an acidic isostere at the ortho position of
the biphenyl group able to interact with basic residue of the
AT1 receptor; a short alkyl chain at the 2 position of the
heterocyclic, for the efficient binding to the receptor and
which could fit into a second lipophilic pocket in the AT1
receptor; a heterocyclic ring, to act as an acceptor in a
hydrogen-bonding interaction with the receptor; and a
moiety hydroxyl methyl group of losartan, which is capable
of a hydrogen-bonding interaction with the AT1 receptor.
Bulky substituents on to the losartan, like chlorine atom,
could occupy a large hydrophobic cavity in the AT1 recep-
tor. This pharmacophore feature can be best exemplified by
the extremely potent benzimidazole antagonist CV-11194
(Naka and Kubo, 1999), and Telmisartan which is clinically
used AngII antagonist. Numerous datasets reported in the
literature were subjected to QSAR analysis for the purpose
of designing novel angiotensin II receptor antagonists
(Balasubramanian et al., 2007; Belvisi et al., 1996; Datar
et al., 2004a, b; Kurup et al., 2001; Pandya and Chaturvedi,
2004, 2005; Pandya et al., 2001; Yan et al., 2007; Yoo et al.,
1999; Jain and Chaturvedi, 2008, 2009a, b).
Keywords Hypertension ꢀ Benzimidazole ꢀ
Angiotensin II antagonist ꢀ Acute renal hypertension
Introduction
Hypertension is the most common cardiovascular disease
which in fact, affects about half of all people belonging to
age group 65 and above and the cause for this disease is not
specific (**Hardman et al. 2001). The failure to reduce risk
of cardiovascular disease (CVD) in hypertensive patients
relates partially to the failure of conventional antihyperten-
sive drugs like adrenergic blockers (e.g., atenolol, propana-
lol, etc.) and diuretics to cause crucial pathophysiological
mechanism of blood pressure (BP) elevation and target
A. Jain (&)
B. R. Nahata College of Pharmacy, Mandasur 458001, MP, India
e-mail: anurekha_jain@yahoo.com;
anurekha_jain71@rediffmail.com
R. Sharma
School of Pharmacy, DAVV, Indore, MP, India
S. C. Chaturvedi
Aurbindo college of Pharmacy, Indore, MP, India
123

Med Chem Res (2013) 22:4622–4632
4623
Bali et al. (2005) reported on the basis of previous study
that extension of chemical group at 5-position may occupy
either L3 pocket or some additional pocket in the receptor to
increase antihypertensive activity. It was also hypothesized
that further extension at nitrogen atom of NO2 group with
substituents (like alkyl amino group) may strengthen the
binding interactions through lipophillic and/or H-bonding
interactions with pocket L3 or L4. Shah et al. (2008) and
Kaur et al. (2008) exploited the 5-position of benzimidazole
with the syntheses of carboxaamido and sulfonyl groups and
reported compounds which are more active than or equally
active as Candesartan. Kohara et al. (1996) reported that the
5-oxo-1,2,4-oxadiazole and its thio analog are lipophillic
bioisosteric replacement for the tetrazole unit, and that their
derivatives exhibit enhanced activity and oral bioavailabil-
ity. Kubo et al. (1993a) studied 2-substitution on benzene
ring of the bezimidazoles with the various substituents.
2-Alkyl benzimidazole-based AT1 receptor antagonist
bearing N-phenylpyrrole moiety at position 1 was also
studied by Jin et al. (2007), Among the different substituents,
a lipophilic group with H-bond-accepting capabilities
(acylureas) at 6-position (Ries et al., 1993) and carboxylic
function at 7-position of benzimidazole nucleus has been
found to be favorable for AngII antagonism. Further, a linear
butyl chain and an ethoxy group are required at position 2 in
6-substituted benzimidazole and in benzimidazole-7-car-
boxylic acid derivatives, respectively.
survey have all the expected structural features: a benz-
imidazole ring is attached to a biphenyl nucleus, which
is attached to an acidic fragment. The acidic fragment is
a –tetrazole group present in all the designed 16 com-
pounds—from DR-1 to DR-16.
Experimental
All the chemicals and reagents used in the syntheses were
of synthetic grade (Merck, National, SD fine, Ranchem,
Lobachem, and Sigma Aldrich). The schemes used for the
syntheses of compounds (DR-1 to DR-16) are shown in
Schemes 1, 2, 3, 4. Melting points were determined by
open capillary method using melting point apparatus model
VMP-DS (manufacturer, Veego Company) and are shown
as uncorrected in Table 1. The time required for comple-
tion of the reaction was monitored by thin layer chroma-
tography that was performed on precoated TLC silica gel
60 F254, 0.2-mm thickness on aluminum sheet, and spots
were exposed in iodine chamber and UV chamber. IR
spectra were recorded on a Shimadzu (8400 S) FTIR
Spectrophotometer. 1H NMR spectra were recorded for the
pure products in DMSO-d6 using a Bruker advance
400 MHz NMR spectrometer from SAIF, Punjab Univer-
sity. The Dart-MS was recorded on a JEOL-AccuTOFJMS-
T100LC mass spectrometer having a Dart (direct analysis
in real time) source by ESI ? method. The elemental
analysis of the synthesized compounds was performed on
elemental analyzer, Heraeus Vario EL III/Carlo Ebra 1108.
Physico-analytic data, and the spectral data of the newly
synthesized compounds are shown in Tables 1 and 2,
respectively.
Keeping in mind the above facts, it was thought
worthwhile to design the novel surrogates of the 5-substi-
tuted benzimidazoles followed by their syntheses and
evaluation of antihypertensive activity based on structure
of AngII AT-1 antagonist with improved pharmacological
profile. The designed compounds on the basis of literature
Scheme 1 Syntheses of starting
materials BMI-1–3 and DR-1
and DR-2. Reagent and
condition: a velaric acid,
phosporus oxychloride, 170 °C;
b DMF, K2CO3, 4-bromo
methyl 20cynobiphenyl, 27 °C;
c ammonium chloride, sodium
azide, 120 °C; d and e Sncl2,
HCl, 70 °C
123

4624
Med Chem Res (2013) 22:4622–4632
solvent was evaporated, and residue was purified by
washing with n-hexane, and by silica gel column chro-
matography and eluting with DCM/ethanol (98:5 v/v) to
give BMI-1 as brown solid. Compound was confirmed by
TLC.
Synthesis of 2-butyl-1-[(20-cynobiphenyl-4-yl)methyl]-1H-
benzimidazole-5-nitro (BMI-2)
43 mmol of BMI-1 was dissolved in 60 mL of DMF
(dimethyl formamide) and stirred vigorously under nitro-
gen atmosphere with 40 mmol of potassium carbonate at
27 °C for 1 h. To the resulting mixture, 43 mmol of
4-bromomethyl 20cynobiphenyl in 60 mL of DMF was
added drop wise with dropping funnel in 1 h. The reaction
was allowed to proceed for further 11 h and solvent
removed under vacuum. Residue was treated with 20 mL
of dilute HCl and extracted with ethyl acetate. The organic
layer was washed with brine solution, distilled water and
dried over anhydrous sodium sulfate. The solvent was
evaporated and a brownish semisolid (BMI-2) was
obtained. BMI-2 was purified by column chromatography
using the mobile phase DCM/ethanol in the ratios of 50:1
and then 25:1. Yellow liquid was obtained.
Scheme 2 Syntheses of DR-5–DR-9. Reagent and condition: alde-
hydes and ethanol
Syntheses
The starting material 2-butyl-5-nitrobenzimidazole (BMI-1),
2-butyl-1-[(20-cynobiphenyl-4-yl) methyl]-1H-benzimida-
zole-5-nitro(BMI-2) and 2-butyl-1-[(20-cyanobiphenyl-4-yl)
methyl]-1H-benzimidazole-5-amino (BMI-3) were prepared
by the described methods given below and characterized by
FTIR and TLC ( Scheme 1).
Synthesis of 2-butyl-1-[(20-cyanobiphenyl-4-yl) methyl]-
1H-benzimidazole-5-amino (BMI-3)
Synthesis of 2-butyl-5-nitrobenzimidazole (BMI-1)
15 mmol of BMI-2 was placed in three-necked RBF and
dissolved in 50 mL of anhydrous ethanol, then acidified
with concentrated HCl (10 mL), and heated to 70 °C under
reflux. To this mixture, 30 mmol of stannous chloride
dihydrates was added with slow stirring for 45 min, and the
reaction conditions were maintained for further 7 h. The
insoluble material was filtered off, and the filtrate was
A solution of 75 mmol of 1,2-diamino-4-nitrobenzene and
85 mmol of valeric acid, and 120 mL of POCl3 was heated
under reflux for 3.5 h. The mixture was then poured in
1.5 L of ice water, the pH was then adjusted to 8–10 by the
addition of concentrated ammonia, and the solution was
then extracted with ethyl acetate. The extract was dried, the
Scheme 3 Syntheses of DR-3
to DR-4. Reagent and
conditions: a acyl chloride;
b sodium azide; ammonium
chloride, 120 °C
123

Med Chem Res (2013) 22:4622–4632
4625
Scheme 4 Syntheses of DR-10
to DR-16. Reagent and
conditions: a alkyl amines,
triethyl amine; b sodium azide,
ammonium chloride, 120 °C
Table 1 Structure and physicochemical data of newly synthesized compounds
Compound code
R1
Molecular formula
Mp (°C)
Yield (%)
Rf value
Analysis calc./found (%)
C
H
N
O
DR-1
DR-2
DR-3
DR-4
DR-5
DR-6
DR-7
DR-8
DR-9
DR-10
DR-11
DR-12
DR-13
DR-14
DR-15
DR-16
NO2
C25H23N7O2
C25H25N7
C27H27N7O
C32H29N7O
C27H27N7
C28H29N7
C29H31N7
C30H33N7
C32H29N7
C26H27N7
C27H29N7
C27H29N7
C29H33N7
C28H31N7
C29H33N7
C32H31N7
160–162
150–152
250–252
270–272
117–119
122–124
130–132
178–180
120–121
120–122
132–134
136–138
142–144
140–142
148–150 °C
148–150
40
38
45
42
51
50
41
52
54
50
49
40
43
45
45
45
0.35
0.42
0.35
0.32
0.22
0.21
0.20
0.24
0.20
0.35
0.34
0.34
0.32
0.33
0.32
0.30
66.20,
70.86,
69.56
72.82
72.12
72.45
72.89
73.21
75.10
71.35
71.80
71.79
72.60
72.20
72.52
74.73
5.08
5.92
5.80
5.53
5.99
6.28
6.52
6.55
5.68
6.20
6.42
6.42
6.92
6.68
6.92
6.02
21.60
23.12
21.02
18.55
21.75
21.12
20.51
19.90
19.12
22.38
21.69
21.68
20.40
21.03
20.40
19.02
7.03
NH2
–
NHCOCH3
NHCOC6H5
CH3CH=N
C2H5CH=N
C3H7CH=N
C4H9CH=N
C6H5CH=N
NHCH3
3.40
3.01
–
–
–
–
–
–
N(CH3)2
–
NHC2H5
–
N(C2H5)2
NHC3H7
–
–
NHC4H9
–
NHCH2C6H5
–
General procedure of syntheses of compounds
from DR-1 to DR-16
concentrated in vacuo. The residue was diluted with water,
basified with 5 % sodium hydroxide solution, and was
extracted with dichloromethane. The extract was washed
with brine and dried over anhydrous MgSO4. Solvent was
removed under vacuum. Product was purified by column
chromatography using DCM/ethanol in ratios of 99:1 and
98:2. A colorless sticky product of benzimidazole inter-
mediate-3 (BMI-3) was obtained.
2-Butyl-1-[[20-(1H tetrazol-5-yl) biphenyl-4-yl] methyl]-
1H benzimidazole-5-nitro (DR-1).
A mixture of 16 mmol of BMI-2, 120 mmol of sodium
azide, and 120 mmol ammonium chloride in 30 mL DMF
123

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Med Chem Res (2013) 22:4622–4632
Table 2 Spectral data of newly synthesized compounds
Compd. FTIR(KBr/cm-1) (observed)
1H NMR (DMSO-d6) (d, ppm)
13C NMR (DMSO-d6) (d,
ppm)
MS
(M?)
DR-1
DR-2
3398 (N–H), 3031 (C–H Ar), 2920 (C–H
aliphatic), 2840 (C–H aliphatic), 1623 (C=N), 2.87 (t, 2H, CH2), 1.59 (qu, 2H, CH2), 1.30
8.47–7.32 (m, 11H, Ar–H), 5.44 (s, 2H, CH2), 160–158, 44–111, 47.51,
35.17, 29.30, 22.41, 14.00
453
1604–1569&1455–1438 (C=C Ar.), 1510
(N=O sym), 1378 (N=O asy), 1122 (C–N)
(sx, 2H, CH2), 0.90 (t, 3H, CH3)
3438, 3398, 3320 (NH2 Asy and sym & N–H 7.98–6.67 (m, 11H, Ar–H), 5.44 (s, 2H, CH2), 160–158, 137, 106, 47.51, 423
(Tetrazole), 3025 (C–H Ar), 2924 (C–H 3.27 (s, 2H, NH2), 2.87 (t, 2H, CH2), 1.59 (qu, 35.1729.30, 22.41, 14.00
aliphatic), 2843 (C–H aliphatic), 1621 (C=N), 2H, CH2), 1.30 (sx, 2H, CH2) 0.90 (t, 3H,
1605–1565 &1478–1438 (C=C Ar.), 1113 (C– CH3)
N)
DR-3
DR-4
DR-5
DR-6
DR-7
3388 (N–H), 3025 (C–H Ar), 2992 (C–H 8.26 (s, 1H, NH), 8.06–7.37 (m, 11H, Ar–H), 170, 160–158, 137–112,
aliphatic), 2840 (C–H aliphatic), 1646 (C=O), 5.44 (s, 2H, CH2), 2.87 (t, 2H, CH2), 2.05 (s, 47.51, 35.17, 29.30 (CH2),
465
527
449
463
477
1621 (C=N), 1606–1552&1478–1434 (C=C
Ar.), 1117 (C–N)
3H, CH3), 1.5 (qu, 2H, CH2), 1.30 (sx, 2H,
CH2), 0.90 (t, 3H, CH3)
23.82 (COCH3), 22.41,
14.00
3388 (N–H), 3025 (C–H Ar), 2992, 2943 (C–H 9.19 (s, 1H, NH), 8.13–7.03 (m, 16H, Ar–H), 166, 160–158, 137–110,
aliphatic), 2840 (C–H aliphatic), 1646 (C=O), 5.44 (s, 2H, CH2), 2.87 (t, 2HCH2), 1.59 (qu, 47.51, 35.17, 29.30,
1621 (C=N), 1606–1552 &1478–1438 (C=C
Ar.), 1117 (C–N)
2H, CH2), 1.30 (sx, 2H, CH2), 0.90 (t, 3H,
CH3)
22.40, 14.00
3383 (N–H), 3015 (C–H Ar), 2986, (C–H 8.0–7.15 (m, 12H, 11ArH&1H, CH=N), 5.44 (s, 164, 160–158, 138–107,
aliphatic), 2808 (C–H aliphatic), 1627 (C=N), 2H, CH2), 2.87 (t, 2HCH2), 1.89 (d, 3H, CH3), 47.51 (CH2), 35.17, 29.30,
1609–1565 &1452–1396 (C=C Ar.), 1123 (C– 1.59 (qu, 2H, CH2), 1.30 (sx, 2H, CH2), 0.90
N) (t, 3H, CH3)
3385 (N–H), 3021 (C–H Ar), 2988, 2954 (C–H 7.98–7.15 (m, 12H, 11HAr–H&1H, CH=N),
22.86, 22.40, 14.00
162, 160–158, 139–107,
aliphatic), 2818 (C–H aliphatic), 1624 (C=N), 5.44 (s, 2H, CH2), 2.87 (t, 2HCH2), 2.19 (qu, 47.51, 35.17, 29.30,
1609–1559 &1452–1421 (C=C Ar.), 1123 (C– 2H, CH2), 1.59 (qu, 2H, CH2), 1.30 (sx, 2H,
N) CH2), 1.01 (t, 3H, CH3) 0.90 (t, 3H, CH3)
26.67, 22.41 (CH2), 14.00
(CH3), 9.0
3386 (N–H), 3010 (C–H Ar), 2978, 2954 (C–H 7.98–7.15 (m, 12H, 11HAr–H& 1H, CH=N),
aliphatic), 2848 (C–H aliphatic), 1644 (C=N), 5.44 (s, 2H, CH2), 2.87 (t, 2HCH2), 2.19 (q,
1605–1569 &1462–1431 (C=C Ar.), 1125 (C– 2H, CH2), 1.66 (Sx, 2H, CH2) 1.59 (qu, 2H,
165, 160–158, 139–107,
47.51, 35.17, 34.74,
29.30, 22.41, 20.75,
14.00, 12.95
N)
CH2), 1.30 (sx, 2H, CH2), 0.94 (t, 3H, CH3)
0.90 (t, 3H, CH3)
DR-8
3378 (N–H), 3022 (C–H Ar), 2975, 2949 (C–H 7.98–7.16 (m, 12H, 11HAr–H& 1H, CH=N),
aliphatic), 2843 (C–H aliphatic), 1638 (C=N), 5.42 (s, 2H, CH2), 2.86 (t, 2HCH2), 2.33 (q,
1611–1561 &1477–1431 (C=C Ar.), 1133 (C– 2H, CH2), 1.56 (m, 4H, CH2, CH2) 1.34 (sx,
165, 160–158, 137–108,
47.51, 35.17, 34.57,
30.00, 29.30, 22.40, 14.00
491
N)
2H, CH2), 1.30 (sx, 2H, CH2), 0.93 (t, 3H,
CH3) 0.90 (t, 3H, CH3)
DR–9 3387 (N–H), 3012 (C–H Ar), 2977, 2949 (C–H 8.66 (s, 1H, CH=N), 7.98–7.16 (m, 16H, Ar–H), 165, 160–158, 139–103,
aliphatic), 2813 (C–H aliphatic), 1628 (C=N), 5.44 (s, 2H, CH2), 2.87 (t, 2HCH2), 1.59 (qu, 47.51, 35.17, 29.30,
511
1600–1561 &1457–1441 (C=C Ar.), 1122 (C– 2H, CH2), 1.30 (sx, 2H, CH2), 0.90 (t, 3H,
N) CH3)
DR-10 3381 (N–H), 3016 (C–H Ar), 2965, 2916 (C–H 7.98–6.57 (m, 11H, ArH), 5.44 (s, 2H, CH2),
22.41, 14.00
160–158, 138–104, 47.51, 437
aliphatic), 2823 (C–H aliphatic), 1625 (C=N), 3.75 (s, 1H, NH) 2.87 (t, 2HCH2), 2.75 (s, 3H, 37.51, 35.17, 29.30,
1599–1565 &1458–1396 (C=C Ar.), 1123 (C– CH3) 1.59 (qu, 2H, CH2), 1.30 (sx, 2H, CH2), 22.40, 14.00
N)
0.90 (t, 3H, CH3)
DR-11 3385 (N–H), 3021 (C–H Ar), 2988, 2954 (C–H 7.98–6.69 (m, 11H, Ar–H), 5.44 (s, 2H, CH2), 160–158, 142–107, 47.51, 451
aliphatic), 2818 (C–H aliphatic), 1624 (C=N), 3.06 (s, 6H, (CH3) 2 NH), 2.87 (t, 2HCH2),
1609–1559 &1452–1421 (C=C Ar.), 1123 (C– 1.59 (qu, 2H, CH2), 1.30 (sx, 2H, CH2), 0.90
41.00, 35.17, 29.30,
22.41, 14.00
N
(t, 3H, CH3)
DR-12 3383 (N–H), 3015 (C–H Ar), 2986, 2934 (C–H 7.98–6.64 (m, 11H, ArH), 5.43 (s, 2H, CH2),
aliphatic), 2808 (C–H aliphatic), 1627 (C=N), 3.15 (s, 1H, NH) 3.45 (q, 2H, CH2), 2.87 (t,
1599–1528 &1458–1396 (C=C Ar.), 1127 (C– 2H, CH2), 1.59 (qu, 2H, CH2), 1.31 (sx, 2H,
160–158, 138–107, 47.51, 451
37.50, 35.17 29.30, 22.40,
14.00, 13.00
N)
CH2), 1.15 (t, 3H, , CH3) 0.90 (t, 3H, CH3)
DR-13 3386 (N–H), 3015 (C–H Ar), 2986, 2934 (C–H 7.98–6.64 (m, 11H, Ar–H), 5.44 (s, 2H, CH2), 160–158, 129–104, 47.50, 479
aliphatic), 2808 (C–H aliphatic), 1627 (C=N), 3.40 (q, 4H, (CH2) 2 N) 2.87 (t, 2H, CH2),
1599–1565&1458–1396 (C=C Ar.), 1123 (C– 1.59 (qu, 2H, CH2), 1.30 (sx, 2H, CH2), 1.12
46.00, 35.17, 29.30,
22.40, 14.00, 12.00
N)
(t, 6H, (CH3CH2) 2 N), 0.90 (t, 3H, CH3)
123

Med Chem Res (2013) 22:4622–4632
4627
Table 2 continued
Compd. FTIR(KBr/cm-1) (observed)
1H NMR (DMSO-d6) (d, ppm)
13C NMR (DMSO-d6) (d,
ppm)
MS
(M?)
DR-14 3386 (N–H), 3010 (C–H Ar), 2978, 2954 (C–H 7.98–6.61 (m, 11H, ArH), 5.42 (s, 2H, CH2),
aliphatic), 2848 (C–H aliphatic), 1644 (C=N), 3.76 (s, 1H, NH) 3.30 (t, 2H, CH2NH), 2.87 (t, 46.00, 35.17, 29.30,
1605–1569&1462–1431 (C=C Ar.), 1125 (C– 2H, CH2), 1.57 (sx, 4H, CH2), 1.30 (sx, 2H, 22.62, 22.40, 14.00, 11.00
N) CH2), 0.90 (t, 6H, CH3)
160–158, 138–104, 47.51, 465
DR-15 3386 (N–H), 3010 (C–H Ar), 2978, 2954 (C–H 7.96–6.73 (m, 11H, Ar–H), 5.44 (s, 2H, CH2), 160–158, 138–104, 47.51, 479
aliphatic), 2848 (C–H aliphatic), 1634 (C=N), 3.76 (s, 1H, NH) 3.30 (t, 2H, CH2NH), 2.87 (t, 43.85, 35.17, 30.00,
1603–1545&1466–1433 (C=C Ar.), 1122 (C– 2H, CH2), 1.59 (qu, 2H, CH2), 0.89 (t, 6H,
N) CH3)
29.30, 22.41, 20.00, 14.00
DR-16 3385 (N–H), 3021 (C–H Ar), 2988, 2954 (C–H 7.95–7.16 (m, 16H, Ar–H), 5.44 (s, 2H, CH2), 160–158, 139–107, 47.51, 513
aliphatic), 2818 (C–H aliphatic), 1624 (C=N), 4.31 (s, 2H, CH2NH) 3.89 (s, 1H, NH), 2.87 (t, 47.11, 35.17, 29.30,
1609–1559 &1452–1421 (C=C Ar.), 1123 (C– 2H, CH2), 1.59 (q, 2H, CH2), 1.30 (sx, 2H,
CH2), 0.90 (t, 3H, CH3)
22.40, 22.08, 14.00
N)
Conversion of 2-butyl-1-[(20-cyanobiphenyl-4-yl) methyl]-
1H-benzimidazole-5-acetamide(DRIM-3) to 2-butyl-1-
[[(1H-tetrazole-5-yl)biphenyl-4-yl] methyl)]-N-(1H-ben-
zimidazol-5-yl)acetamide (DR-3) A mixture of 0.56 mmol
DRIM-3, 8.4 mmol of sodium azide and 8.4 mmol of
ammonium chloride in 15 mL DMF was stirred at 120 °C
for 3.5 days. The reaction mixture was diluted with water
and acidified to pH 3–4 with 1 N HCl. The precipitate was
collected by filtration, and purified by column chroma-
tography using the mobile phase DCM/ethanol in the ratio
of 98:2 (Scheme 2).
was stirred at 120 °C for 3.5 days. The reaction mixture
was diluted with water and acidified to pH 3–4 with 1 N
HCl. The precipitate was collected by filtration, and
washed with water. Product was purified by column chro-
matography using the mobile phase DCM/ethanol in the
ratio of 98:2.
2-Butyl-1-[[(1H-tetrazole-5-yl) biphenyl-4-yl] methyl)]-1-
H-Benzimidazole-5-amino (DR-2)
10 mmol of DR-1 was placed in three-necked RBF and
dissolved in anhydrous ethanol and acidified with conc.
HCl and heated to 70 °C under reflux. To this mixture,
30 mmol of stannous chloride dihydrates was added with
slow stirring for 45 min, and reaction conditions were
maintained for further 7 h. The mixture was cooled to room
temperature, and the insoluble material was filtered, and
then the solvent was removed under vaccuum. Water was
added, and the pH was adjusted to 7 with 5 % sodium
hydroxide solution. The residue was extracted with
dichloromethane. The extract was washed with brine and
distilled water, and then dried over anhydrous MgSO4.
Solvent was removed under vacuum. Product was purified
by column chromatography using DCM/ethanol.
Synthesis of 2-butyl-1-[[(1H-tetrazole-5-yl) biphenyl-4-yl]
methyl)]-N-(1H-benzimidazol-5-yl) benzamide (DR-4)
Synthesis of 2-butyl-1-[(2-cyanobiphenyl-4-yl) methyl]-1H-
benzimidazole-5-benzamide (DRIM-4) Benzoyl chloride,
1 mmol, was added drop wise from a dropping funnel for
15 min under stirring in an ice-cooled mixture of 1 mmol
of BMI-3 in 10 mL of DCM and 1.5 mmol of Triethyl-
amine in 50 mL RBF. The mixture was then stirred at 0 °C
under nitrogen. After completion of the reaction (moni-
tored by TLC), the reaction mixture was washed with
aqueous NaHCO3 and dried over anhydrous MgSO4.
Evaporation of the solvent was done under vacuum to yield
colorless oil, and the compound was kept for further use in
the next step.
2-Butyl-1-[[(1H-tetrazole-5-yl) biphenyl-4-yl] methyl)]-N-
(1H-benzimidazol-5-yl) acetamide (DR-3)
Conversion of 2-butyl-1-[(20-cyanobiphenyl-4-yl) methyl]-
1H-benzimidazole-5-benzamide (DRIM-4) to 2-butyl-1-
[[(1H-tetrazole-5-yl) biphenyl-4-yl] methyl)]-N-(1H-ben-
2-Butyl-1-[(20-cyanobiphenyl-4-yl) methyl]-1H-benzimida-
zole-5-acetamide (DRIM-3) To a stirred solution of
0.65 mmol of BMI-3 in 4 mL of pyridine, 0.65 mmol of
acetoyl chloride was added slowly at 0 °C. Reaction was
carried out under nitrogen; after stirring for 1 h at 25 °C,
the mixture was poured into ice water (13 mL). The pre-
cipitated solid was filtered off, dried, and kept for use in the
next step (ii).
zimidazol-5-yl)benzamide
(DR-4)
A
mixture
of,
0.65 mmol of DRIM-4,, 9.7 mmol of sodium azide and
9.7 mmol of ammonium chloride in 15 mL DMF was
stirred at 120 °C for 3.5 days. Reaction is also monitored
through TLC, and after completion of reaction, the reaction
123

4628
Med Chem Res (2013) 22:4622–4632
mixture was diluted with water and acidified to attain pH
3-4 with 1 N HCl. The precipitate was collected by filtra-
tion, and purified by column chromatography using the
mobile phase DCM/ethanol in the ratio of 95:5.
methyl iodide in 20 mL of DCM was stirred for overnight
at room temperature with 2 mmol of Triethyl amine. After
completion of the reaction (monitored by TLC), the reac-
tion mixture was evaporated to dryness under reduced
pressure. The residue was dissolved in 5 mL of DCM and
washed with 5 mL of distilled water. The aqueous layer
was washed with 3 9 5 mL fractions of DCM. The col-
lected organic fractions were dried over anhydrous MgSO4,
and the solvent was removed under reduced pressure to
yield the crude sticky product and kept for further use in
the next step.
General scheme of syntheses of compounds
DR-5 to DR-9
To 50 mL of RB Flask fitted with reflux condenser, a
solution of 0.5 mmol of aldehyde in 5 mL of ethanol was
added drop wise to a well-stirred solution of 0.5 mmol of
DR-2 in 15 mL of boiling ethanol. The reaction mixture
was refluxed, and after completion of reaction (monitored
by TLC), the solvent was evaporated under reduced pres-
sure. The solid precipitate produced was filtered off,
washed with dilute ethanol, and purified by recrystalliza-
tion using boiling ethanol, as shown in Scheme 3.
Conversion of 2-butyl-1-[(20-cyanobiphenyl-4-yl) methyl]-
1H-benzimidazole-5-diethyl amine (DRIM-12) to 2-butyl-
1-[[(1H-tetrazole-5-yl)
biphenyl-4-yl]
methyl)]-N,N-
Methyl-1H-benzimidazol-5-amine (DR-11) A mixture of
0.65 mmol of DRIM-11, 9.7 mmol of sodium azide and
9.7 mmol of ammonium chloride in 30 mL DMF was
stirred at 120 °C for 3.5 days. The reaction mixture was
diluted with water and acidified to pH 3–4 with 1 N HCl.
The precipitate was collected by filtration, and purified by
column chromatography using the mobile phase DCM/
methanol in the ratio of 99:1.
2-Butyl-1-[[(1H-tetrazole-5-yl) biphenyl-4-yl] methyl)]-N-
methyl-1H-benzimidazol-5-amine(DR-10)
Synthesis of 2-butyl-1-[(20-cyanobiphenyl-4-yl) methyl]-
1H-benzimidazole-5-methyl amine (DRIM-10) To the
mixture of 2 mmol of BMI-3 and 1 mmol of methyl Iodide
in 20 mL DCM, 2 mmol of triethyl amine was added, and
the final mixture was stirred overnight. Reaction was car-
ried out under nitrogen. After completion of reaction
(monitored by TLC), water was added. The separated
organic layer was washed with brine and water and then
dried over anhydrous MgSO4. Solvent was evaporated
under reduced pressure. Product was purified by column
chromatography using mobile phase DCM:methanol in the
ratio of 99:1, and the remaining colorless sticky residue
was used for further reaction.
2-Butyl-1-[[(1H-tetrazole-5-yl) biphenyl-4-yl] methyl)]-N-
ethyl-1H-benzimidazol-5-amine (DR-12)
Synthesis of 2-butyl-1-[(20-cyanobiphenyl-4-yl)methyl]-1H-
benzimidazole-5-ethyl amine (DRIM-12) The mixture of
2 mmol of BMI-3 and 1 mmol of ethyl bromide in 20 mL
DCM was stirred overnight to which 2 mmol of triethyl
amine was also added. Reaction was carried out under
nitrogen. After completion of reaction (monitored by
TLC), water was added. The separated organic layer was
washed with brine and water and then dried over anhydrous
MgSO4. Solvent was evaporated under reduced pressure.
Product was purified by column chromatography using
mobile phase DCM: methanol in the ratio of 98:2, and a
colorless semisolid product was obtained and kept for
further use in the reaction.
Conversion of 2-butyl-1-[(20-cyanobiphenyl-4-yl) methyl]-
1H-benzimidazole-5-amine(DRIM-4) to 2-butyl-1-[[(1H-
tetrazole-5-yl)biphenyl-4-yl] methyl)]-N-methyl-1H-benzi-
midazol-5-amine (DR-10) A mixture of 0.5 mmol of
DRIM-10, 7.5 mmol of sodium azide, and 7.5 mmol of
ammonium chloride in 25 mL DMF was stirred at 120 °C
for 3.5 days. The reaction mixture was diluted with water
and acidified to pH 3–4 with 1 N HCl. The precipitate was
collected by filtration, and purified by column chroma-
tography using the mobile phase DCM/methanol in the
ratio of 98:2. (Scheme 4).
Conversion of 2-butyl-1-[(20-cyanobiphenyl-4-yl) methyl]-
1H-benzimidazole-5-ethyl amine (DRIM-12) to 2-Butyl-1-
[[(1H-tetrazole-5-yl) biphenyl-4-yl] methyl)]-N-ethyl-1H-
benzimidazol-5-amine (DR-12) A mixture of 0.65 mmol
of DRIM-12, 9.5 mmol of sodium azide and 9.5 mmol of
ammonium chloride in 25 mL DMF was stirred at 120 °C
for 3.5 days. The reaction mixture was diluted with water
and acidified to pH 3–4 with 1 N HCl. The precipitate was
collected by filtration, and purified by column chroma-
tography using the mobile phase DCM/methanol in the
ratio of 95:5.
2-Butyl-1-[[(1H-tetrazole-5-yl) biphenyl-4-yl] methyl)]-
N,N-dimethyl-1H-benzimidazol-5-amine(DR-11)
Synthesis of 2-butyl-1-[(20-cyanobiphenyl-4-yl) methyl]-
1H-benzimidazole-5-dimethyl amine (DRIM-11) The
mixture of 0.75 mmol of DRIM-10 and 1.0 mmol of
123

Med Chem Res (2013) 22:4622–4632
4629
Synthesis of 2-butyl-1-[[(1H-tetrazole-5-yl) biphenyl-4-yl]
methyl)]-N, N-diethyl-1H-benzimidazol-5-amine (DR-13)
benzimidazol-5-amine (DR-14) A mixture of 0.5 mmol of
DRIM-14, 7.5 mmol of sodium azide and 7.5 mmol of
ammonium chloride in 10 mL DMF was stirred at 120 °C
for 3.5 days. After completion of reaction, the reaction
mixture was diluted with water and acidified to pH 3-4 with
1 N HCl. The precipitate was collected by filtration, and
purified by column chromatography using the mobile phase
DCM/methanol in the ratio of 95:5.
Synthesis of 2-butyl-1-[(20-cyanobiphenyl-4-yl) methyl]-
1H-benzimidazole-5-diethyl amine (DRIM-13) The mix-
ture of 0.75 mmol of DRIM-12 and 1.0 mmol of ethyl
bromide in 20 mL of DCM was stirred for overnight at
room temperature with 2.0 mmol of triethyl amine. After
completion of the reaction (monitored by TLC), the reac-
tion mixture was evaporated to dryness under reduced
pressure. The residue was dissolved in 5 mL of DCM and
washed with 5 mL of distilled water. The aqueous layer
was washed with 3 9 5 mL fractions of DCM. The col-
lected organic fractions were dried over anhydrous MgSO4,
and the solvent was removed under reduced pressure to
yield the crude semisolid product, which was kept for
further use in the next step.
2-Butyl-1-[[(1H-tetrazole-5-yl) biphenyl-4-yl] methyl)]-N-
butyl-1H-benzimidazol-5-amine(DR-15)
2-Butyl-1-[(20-cyanobiphenyl-4-yl)ethyl]-1H-benzimida-
zole-5-butylamine (DRIM-15) The mixture of 0.75 mmol
of BMI-3 and 0.75 mmol of butyl bromide in DCM was
stirred overnight with 2 mmol of triethyl amine. After
completion of the reaction (monitored by TLC) the reaction
mixture was evaporated to dryness under reduced pressure.
The residue was dissolved in 5 mL of DCM and washed
with 5 mL of distilled water. The aqueous layer was
washed with 3 9 5 mL fractions of DCM. The collected
organic fractions were dried over anhydrous MgSO4 and
the solvent was removed under reduced pressure to yield
the crude product. The product purified by column chro-
matography using mobile phase DCM: methanol in ratio of
98:2. A sticky transparent mass was obtained for use in a
further step.
Conversion of synthesis of 2-butyl-1-[(20-cyanobiphenyl-4-
yl)methyl]-1H-benzimidazole-5-diethyl amine (DRIM-13)
to Synthesis of 2-Butyl-1-[[(1H-tetrazole-5-yl)biphenyl-4-
yl]methyl)]-N,N-diethyl-1H-benzimidazol-5-amine
(DR-
13) A mixture of 0.65 mmol of DRIM-13, 9.5 mmol of
sodium azide and 9.5 mmol of ammonium chloride in
30 mL DMF was stirred at 120 °C for 3.5 days. The
reaction mixture was diluted with water and acidified to pH
3–4 with 1 N HCl. The precipitate was collected by fil-
tration, and purified by column chromatography using the
mobile phase DCM/methanol in the ratio of 99:1.
2-Butyl-1-[(20-cyanobiphenyl-4-yl)methyl]-1H-benzimida-
zole-5-butylamine (DRIM-15) to 2-Butyl-1-[[(1H-tetrazole-
5-yl) biphenyl-4-yl] methyl)]-N-butyl-1H-benzimidazol-5-
amine (Derivative-15) A mixture of 0.5 mmol of DRIM-
15, 7.5 mmol of sodium azide and 7.5 mmol of ammonium
chloride in 10 mL DMF was stirred at 120 °C for 3.5 days.
After completion of reaction which was also monitored
through TLC, the reaction mixture was diluted with water
and acidified to pH 3–4 with 1 N HCl. The precipitate was
collected by filtration, and purified by column chroma-
tography using the mobile phase DCM/methanol in the
ratio of 95:5. White solid product was obtained.
2-Butyl-1-[[(1H-tetrazole-5-yl) biphenyl-4-yl] methyl)]-N-
propyl-1H-benzimidazol-5-amine(DR-14)
2-Butyl-1-[(20-cyanobiphenyl-4-yl)methyl]-1H-benzimida-
zole-5-propyl amine (DRIM-14) To the stirred mixture of
0.8 mmol of BMI-3 and 2 mmol of triethyl amine in 5 mL
of DCM, 1 mmol of Propyl bromide was added and stirred
overnight. After completion of the reaction (monitored by
TLC), the reaction mixture was evaporated to dryness
under reduced pressure. The residue was dissolved in 5 mL
of DCM and washed with 5 mL of distilled water. The
aqueous layer was washed with 3 9 5 mL fractions of
DCM. The collected organic fractions were dried over
anhydrous MgSO4, and the solvent was removed under
reduced pressure to yield the crude product. The product
was purified by Column chromatography using mobile
phase DCM: methanol in ratio of 95:5. A colorless semi-
solid product was obtained for use in a further step.
2-Butyl-1-[[(1H-tetrazole-5-yl)biphenyl-4-yl]methyl)]-N-
benzyl-1H-benzimidazol-5-amine(DR-16)
2-Butyl-1-[(20-cyanobiphenyl-4-yl) methyl]-1H-benzimida-
zole-5-benzylamine (DRIM-16) The mixture of 0.75 mmol
of BMI-3 and 1 mmol of benzyl chloride was stirred over
night in 10 mL of DCM with 2 mmol of triethyl amine.
After completion of the reaction (monitored by TLC), the
reaction mixture was evaporated to dryness under reduced
pressure. The residue was dissolved in 5 mL of DCM and
washed with 5 mL of distilled water. The aqueous layer
was washed with 3 9 5 mL fractions of DCM. The
Conversion of 2-butyl-1-[(20-cyanobiphenyl-4-yl) methyl]-
1H-benzimidazole-5-propyl amine (DRIM-14) to 2-butyl-1-
[[(1H-tetrazole-5-yl) biphenyl-4-yl] methyl)]-N-propyl-1H-
123

4630
Med Chem Res (2013) 22:4622–4632
collected organic fractions were dried over anhydrous
MgSO4, and the solvent was removed under reduced
pressure to yield the crude product. The product was
purified with column chromatography using mobile phase
DCM: methanol in ratio of 97:3. A transparent semisolid
product was obtained for use in a further step.
same as standard. The standard and test compounds were
administered one by one in juggler vein, and response was
observed, i.e., decrease in BP on physiograph paper.
Changes in BP produced by the 16 synthesized compounds
were compared to that of losartan, and three responses of
each sample were taken to obtain mean BP as shown in
Table 3. Data were expressed as mean and standard error
of the mean of three experiments. Data were statistically
compared as repeated measures using one way ANOVA
followed by Dunnet test (Prism Graph pad Trial Version-5).
P \ 0.05 in two-tailed tests was considered significant.
2-Butyl-1[(20-cyanobiphenyl-4-yl) methyl]-1H-benzimida-
zole-5-benzyl amine (DRIM-16) to 2-butyl-1-[[(1H-tetra-
zole-5-yl)biphenyl-4-yl]methyl)]-N-benzyl-1H-benzimida-
zol-5-amine (DR-16) A mixture of 0.5 mmol of DRIM-
16, 7.5 mmol of sodium azide and 7.5 mmol of ammonium
chloride in 10 mL DMF was stirred at 120 °C for 3.5 days.
Reaction was also monitored through TLC and after
completion of reaction, the reaction mixture was diluted
with water and acidified to pH 3-4 with 1 N HCl. The
precipitate was collected by filtration, and purified by
column chromatography using the mobile phase DCM/
methanol in the ratio of 98:2.
Result and discussion
Chemistry
The synthetic scheme employed to synthesize the designed
compounds is outlined in Schemes 1, 2, 3, 4. The com-
pounds were prepared through a series of reactions as
reported. Synthesis of intermediate 5-nitro 2-butyl benz-
imidazole from 4-nitro orthophenyl diamine with valeric
acid (BMI-1)(Ries et al., 1993) followed by alkylation of
BMI-1 in DMF and K2CO3 to BMI-2 (Kubo et al., 1993a),
and then followed by tritylation of cyano to tetrazole to give
DR-1 (Kubo et al., 1993b). Compound DR-1 was subjected
Antihypertensive activity in vivo
In methodology, recordings of BP in anesthetized guinea
pig (700-725 gm) provided by the Institutional Animal
House of B.R. Nahata College of Pharmacy, Mandsaur
(139/F/09/IAEC/BRNCP/08-09/Mandasur) using acute
renal hypertension BP measurement model were carried
out (Hauser et al., 2005; Gilani et al., 2005; Cherinet et al.,
2002).
Table 3 Antihypertensive activity of compounds and reference
compound
The animal was anesthetized by intraperitoneal injection
of mixture of ketamine hydrochloride and xylazine. After
induction of anesthesia, left renal artery was blocked by
means of artery clamp for 45 min. Clamping of the left renal
artery raised the systolic pressure. Then, trachea was cann-
ulated to avoid any disturbance in respiration of animals
during surgery. The jugular vein was cannulated. The
0.5 mL dose of normal saline was given to animal via jugular
vein, and subsequently all test and standard compounds were
given to animal by this route. The carotid artery was cann-
ulated and attached with pressure transducer. A Mercury
manometer, Physiograph (Student physiographic, 3 Chan-
nel, Biodevice by Incolab, Ambala), BP transducer, and
strain gage coupler were used for the study.
S. Compound Mean arterial blood
no. no.
Total change in systolic
BP (mmHg)
pressure (mmHg)
1
2
Control
149.3 4.055
Standard
(Losartan)
115.5 1.333***
34
3
4
5
6
7
8
9
DR-1
DR-2
DR-3
DR-4
DR-5
DR-6
DR-7
134.0 1.555**
130.0 2.309***
126.7 2.906***
121.3 3.712***
122.0 1.155***
131.3 2.404***
132.0 1.155***
127.0 0.577***
124.7 1.764***
137.3 4.372*
15
19
22
28
27
18
17
27
25
12
29
29
33
32
31
31
10 DR-8
11 DR-9
12 DR-10
13 DR-11
14 DR-12
15 DR-13
16 DR-14
17 DR-15
18 DR-16
This pressure transducer was previously calibrated by
means of mercury manometer, and a calibration pressure
curve was obtained. After attaching the carotid cannula, the
renal artery clamp was removed, which caused a sharp
increase in the BP because of activation of renin angio-
tensin system and rise in the plasma renin level.
120.7 1.764***
120.7 1.764***
116.7 1.764***
117.3 2.404***
118.3 2.848***
118.0 2.000***
Standard losartan solution at a dose of 3 mg/kg was
administrated via jugular vein, and after giving drug dose
the mice were allowed to wait till BP was not reached up to
base line level. Then take responses of test compounds
Statistical analysis: one-way ANOVA followed by Dunnet test
** very significant P \ 0.01, *** highly significant P \ 0.001
123

Med Chem Res (2013) 22:4622–4632
4631
to reduction to make compound DR-2 by reported method
(Jat et al., 2006). DR-2 was converted into to Schiff’s base
DR-5–DR-9 with aliphatic aldehyde. (Mostafa et al., 2007).
Reduction of intermediate BMI-2 with SnCl2/HCl to inter-
mediate BMI-3 was followed by acetylation and alkylation
of BMI-3 with the acyl chloride and alkyl halide (Jason
et al., 2005). Tritylation of cyano to tetrazole gave DR-3,
DR-4, and DR-10–16, respectively. The intermediate was
also purified and ascertained by TLC. All compounds were
purified by crystallization and column chromatography, and
purity was verified by thin-layer chromatography as shown
in Table 1. Structures of the compounds were established
through FTIR, 1HNMR, 13NMR, and Mass spectral analyses.
might be mediated through Renin angiotensin system. The
activity is more in N alkylated at position 5 on benzimid-
azole compound as compared with the Schiffs base and
acylated product at 5-position of benzimidazole. All the
active compounds DR-13, DR-14, DR-15, DR-16 having
ethylamino, propylamino, butyl amino, and benzylamino
substitution at 5-position. However, in compounds DR-13,
DR-14, DR-15, and DR-16, the activity is slightly decreas-
ing with the increasing bulkier group of alkyl/aryl residue.
Shah et al., (2008) report a series of 5-(alkyl and aryl car-
boxamido) derivatives with evaluation for in vitro AngII-
AT1 receptor antagonist and in vivo antihypertensive
activities and suggest that the pharmacological activities
were inversely related to the size of alkyl and aryl substit-
uents. It can be suggested that compounds with lower
alkylamino groups at 5-position of benzimidazole nucleus
demonstrated potent antihypertensive activity.
In vivo antihypertensive activity
Losartan had maximum fall in Systolic Mean Arterial Blood
Pressure (MABP) from
a value of 149 mmHg to
115 mmHg, i.e., 34 mm of Hg. Among these compounds,
maximum fall was seen in compound DR-13, i.e., 33 mmHg
from initial value. While Compounds DR-14, DR-15, and
DR-16 showed a reduction in MABP (32, 31, and 31 mmHg,
respectively, from initial value as shown in Table 3. Hence,
these compounds can be regarded as comparable with
losartan in their antihypertensive action in terms of mini-
mum BP values achieved. Compounds DR-10 and DR-1 had
shown least activity among the all synthesized compounds.
A fall in BP of 19, 18 and 17 mm of Hg was observed in
Compounds DR-2, DR-6, and DR-7, respectively, from
initial value. A significant fall in BP was observed in com-
pounds in DR-11 and DR-12 (29 mm of Hg) from initial
value. Compounds DR-4 and DR-5 were also found to be
active in the same range and showed reduction in BP 28 mm
and 27 mm of Hg, respectively. Compounds DR-3, DR-8,
and DR-9 were also found to be significant in antihyper-
tensive activity and showed fall in BP 22, 27, and 25 mm of
Hg. Compounds DR-1, DR-2, DR-10, DR-6, and DR-7 did
not show comparable value to losartan. However, they
possess antihypertensive effect to some extent. Maximum
lowering of BP is seen with compound DR-13 which showed
a fall of BP about 33 mmHg and this effect is comparable to
the losartan (34 mmHg). Similar activities were shown by
compound DR-14, DR-15, and DR-16 as shown in Table 2.
Antihypertensive activities exhibited by compounds having
the same functional group at 2-position have been found to
be a function of substituent at 5-position.The presence of
amino group has increased the activity substantially over the
other substitution (DR-13DR-16). This suggests that there
are some sites in the receptor pocket, which can interact with
the functional groups at position 5. In renal acute hyper-
tension model, hypertension is increased by the Renin
Angiotensin system because of renal artery blockade. This
study suggests that the BP-lowering effect of the compounds
Conclusions
Novel substituted benzimidazole DR-1DR-16 possessing
nitro, amino, alkyl amino, and acyl groups in position 5
were synthesized in good yield using BMI-1 through BMI-3
as starting materials. The obtained compounds were
evaluated for antihypertensive activity in vivo by acute
renal hypertension model. All tested compounds showed
varied activities. The activity is more in N alkylated at
position 5 on benzimidazole compound as compared with
the Schiffs base and acylated product at 5 position of
benzimidazole. Four compounds 2-Butyl-1-[[(1H-tetrazole-
5-yl) biphenyl-4-yl] methyl)]-N,N-diethyl-1H-benzimida-
zol-5-amine (DR-13), 2-Butyl-1-[[(1H-tetrazole-5-yl)
biphenyl-4-yl]methyl)]-N-propyl-1H-benzimidazol-5-amine
(DR-14),2-Butyl-1-[(1H-tetrazole-5-yl)biphenyl-4-yl]methyl)]-
N-butyl-1H-enzimidazol-5-amine (DR-15), and 2-Butyl-1-
[[(1H-tetrazole-5-yl) biphenyl-4-yl] methyl)]-N-benzyl-1H-
benzimidazol-5-amine (DR-16) can be regarded as compara-
ble with losartan in their antihypertensive action in terms of
minimum BP values achieved. Further, these compounds may
be evaluated in in vitro studies using isolated tissue prepara-
tion, and radioligand assay and acute toxicological studies can
bring a potential drug candidate from this class of compounds.
Acknowledgments The authors thank the Head of the School of
Pharmacy, Devi Ahilya Vishwavidyalaya, for providing the facilities
for carrying out the study, and Mr. B. R. Nahata from the College of
Pharmacy for his help in carrying out biological evaluation.
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