Synthesis of biphenyl derivatives as ACE and α-amylase inhibitors

Article abstract of DOI:10.1007/s00044-013-0574-8

Angiotensin converting enzyme (ACE) and α-amylase inhibitors were synthesized using 4′-(bromomethyl)-biphenyl-2-carbonitrile 1 and various cyclic secondary amines (a-h). The nitrile group appended to biphenyl was converted into tetrazole 3a-3h and the tet

Full text of DOI:10.1007/s00044-013-0574-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0574-8
ORIGINAL RESEARCH
Synthesis of biphenyl derivatives as ACE and a-amylase inhibitors
•
Gangadhar Yamanappa Meti Ravindra Ramappa Kamble
•
•
Dharesh Bhimaraya Biradar Sheetal Babu Margankop
Received: 18 December 2012 / Accepted: 4 March 2013
Ó Springer Science+Business Media New York 2013
Abstract Angiotensin converting enzyme (ACE) and a-amy-
lase inhibitors were synthesized using 40-(bromomethyl)-biphe-
nyl-2-carbonitrile 1 and various cyclic secondary amines (a–h).
The nitrile group appended to biphenyl was converted into
tetrazole 3a–3h and the tetrazole was ring transformed into
1,3,4-oxadiazole derivatives 4a–4h. Some of the compounds
have exhibited significant ACE and a-amylase inhibition.
patients. Biphenyl is the key moiety in all the saratans
(Kumar et al., 2010; Wang et al., 2011; Hadizad et al.,
2009, Zupancic et al., 2010; Park et al., 2010; Larsen et al.,
1994) which are angiotensin II receptor antagonists useful
in the treatment of hypertension, heart diseases, heart
attack, and bladder diseases (Fig. 1).
Tetrazole functions as a carboxylic acid bioisostere
which can impart greater metabolic stability and increased
absorption relative to the carboxylic acid. It has a similar
pKa to CO2H group and as part of a drug molecule it offers
the potential of a longer in vivo half-life. Its negative
charge delocalizes over all four nitrogens which translate
into derivatives with a higher clog P and thus better oral
bioavailability and cell penetration. Additionally, the four
nitrogen atoms offer a greater opportunity for H-bond
donor/acceptor interactions and the p-electron system of
the aromatic ring can have additional hydrophobic inter-
actions, both of which can provide strong receptor binding
and applications as antihypertensive, antiallergic, antibi-
otic, and anticonvulsant agents (Myznikov et al., 2007;
Mavromoustakos et al., 1999; Toney et al., 1998; Sherif
Rostom et al., 2009; Mulwad et al., 2008; Upadhyaya
et al., 2004; Mohite et al., 2010; Bhaskar and Mohite,
2010; De Souza et al., 2005). 1,3,4-Oxadiazole derivatives
have been found to exhibit diverse pharmacological prop-
erties such as antimicrobial, anti-HIV (Ingole et al., 2007;
El-Emam et al., 2004), anti-tubercular (Franski, 2005),
anti-malarial (Kagthara et al., 1999), analgesic (Reddy
et al., 1997), anti-inflammatory (Amir et al., 2007), anti-
convulsant (Khan et al., 2001), hypoglycemic (O’Neal
et al., 1962), antifungal (Mishra et al., 2005), and other
biological properties such as genotoxic (Maslat et al.,
2002) and lipid peroxidation inhibition (Farghaly et al.,
2000). It was envisaged that if two pharmacophores linked
together would generate novel molecular templates which
Keywords Biphenyl ꢀ Tetrazole ꢀ 1,3,4-Oxadiazole ꢀ
ACE ꢀ a-Amylase
Introduction
Special attention is required during the management of
hypertension in diabetes. The presence of hypertension in
diabetic patients substantially increases the risks such as
coronary heart disease, stroke, nephropathy, and retinopa-
thy. When hypertension coexists with diabetes, the risk of
cardiovascular disease is increased by 75 % (Patel, 1985;
Sowers et al., 2001). In view of this, angiotensin convert-
ing enzyme (ACE)-inhibitors and angiotensin II receptor
blockers have many benefits in diabetic hypertensive
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-013-0574-8) contains supplementary
material, which is available to authorized users.
G. Y. Meti ꢀ R. R. Kamble (&) ꢀ D. B. Biradar ꢀ
S. B. Margankop
Department of Studies in Chemistry, Karnatak University,
Dharwad 580003, India
e-mail: kamchem9@gmail.com
123

Med Chem Res
Chemistry
N
The reaction of 40-(bromomethyl)-biphenyl-2-carbonitrile
1 with cyclic secondary amines (a–h) in presence of
anhydrous K2CO3 in acetone afforded 2a–2h. The com-
pounds 2a–2h when refluxed with sodiumazide and tri-
ethylamine hydrochloride in toluene gave tetrazole 3a–3h.
The tetrazole ring of compounds 3a–3h was ring trans-
formed into 1,3,4-oxadizole (4a–4h) which was achieved
by refluxing with acetic anhydride (Scheme 1). The
mechanism of ring transformation of tetrazoles to 1,3,4-
oxadiazoles is depicted in Scheme 2 (Koldobski et al.,
1981). It involved the initial acetylation of 2H-tetrazole
3a–3h which further undergoes the ring opening followed
by elimination of a molecule of nitrogen to form a carbene.
Carbene then undergoes insertion across the carbonyl
group to form 1,3,4-oxadiazole derivatives 4a–4h.
N
O
nBu
N
N
N
N
Cl
N
nPr
COOH
OH
N
N
N
N
N
N
COOH
N
N
H
H
Losartan
Valsartan
Telmisartan
Fig. 1 Angiotensin receptor antagonists (Sartans)
Results and discussion
are likely to exhibit interesting biological properties
(Tegginamath et al., 2013).
The compounds 2a–2h have shown a characteristic stretch-
ing band at 2,150–2,220 cm-1 due to the nitrile group. The
protons on the methylene group resonated as singlet in the
range of 3.81–5.20 ppm. The compounds 3a–3h and 4a–4h
with methylene protons spaced between the biphenyl group
and nitrogen heterocycles appeared as a singlet for two
protons in the range of 3.80–5.99 ppm. The remaining pro-
tons in the various heterocycles attached to biphenyl rings
appeared in their respective range. The number of signals in
13C NMR spectra of all the compounds was in consistent with
the number of magnetically non-equivalent carbon atoms.
Also the mass spectral studies indicated the m/z value cor-
responding to the molecular mass of the respective com-
pounds. All these data are provided in the ‘‘Experimental
All the above facts encouraged us to synthesize novel
molecules by reacting 40-(bromomethyl)-biphenyl-2-car-
bonitrile 1 and cyclic secondary amines (a–h). The nitrile
group on the biphenyl moiety was converted into tetrazole
and further ring transformed into 1,3,4-oxadiazole. The
newly synthesized biphenyl derivatives of cyclic secondary
amines appended to tetrazole 3a–3h and to 1,3,4-oxadiaz-
ole 4a–4h were subjected to OSIRIS property explorer to
find out the drug-likeliness and hence drug score values
were calculated to analyze their oral bioavailability. Also,
the title compounds 3a–3h and 4a–4h were subjected to
inhibition of ACE and a-amylase to substantiate the OSI-
RIS property explorer results.
R1
Scheme 1 Protocol for the
synthesis of biphenyl
derivatives
R1
R1
N
N
Br
R2
N
R2
R2
R1 R2
Ac2O
reflux
N
H
NaN3/TEA.HCl
Toluene, reflux
CN
N
N
N
N
K2CO3, Acetone
CN
N
CH3
O
N
H
4a-h
1
2a-h
3a-h
(CH2)2O(CH2)2OH
N
COOH
CH3
N
H
N
O
S
N
N
R1 R2
OC
CO
=
N
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
a
g
c
h
b
d
e
f
123

Med Chem Res
Ar
Ar
Ar
Table 1 Osiris properties of molecules 3a–3h and 4a–4h
N
NH
N
Entry no.
clog P
Drug-likeliness
Drug score
CH3
N
N
N
N
N
NH
N
N
N
N
3a
3b
3c
3d
3e
3f
1.77
2.03
1.74
1.92
2.20
1.62
2.08
2.13
2.82
3.08
2.79
2.97
3.25
2.67
3.13
3.18
2.77
1.81
0.41
3.30
8.54
3.23
1.99
4.67
2.33
1.17
-0.029
2.74
8.02
2.83
1.53
4.29
0.36
0.73
0.62
0.75
0.78
0.75
0.70
0.66
0.33
0.65
0.53
0.70
0.73
0.7
O
3a-h
CH3
Ar
N
N
N
N
N
CH3
Ar
Ar
O
N
N
O
O
CH3
4a-h
3g
3h
4a
4b
4c
4d
4e
4f
N
R1
R2
Scheme 2 Mechanism for ring transformation of tetrazole 3a–3h
into oxadiazole 4a–4h
procedure’’ section. We have recently reported the single
crystal analyses of compound 3g (Meti et al., 2013).
4g
4h
0.63
0.61
Pharmacological assay
converts angiotensin I into angiotensin II. Angiotensin II a
powerful vasoconstrictor which stimulates the aldosterone
secretion. Aldosterone increases reabsorption of Na? from
distal as well as collecting tubule and hence leads to edema
and hypertension. Therefore, ACE is the main target for
reducing the blood pressure in the treatment of hyperten-
sion thus lowering the arteriolar resistance, increasing the
venous capacity, increasing cardiac output, cardiac index,
stroke work, and lowering the renovascular resistance
(Haslett et al., 1999; Chaudhuri, 1993). As per the infor-
mation to the authors, no report is found in which the
angiotensin receptor antagonists (ARB) were used to
inhibit the ACE enzyme. Therefore, in the present work we
have made an effort to use the tetrazole derivatives of
biphenyl attached to various heterocycles viz., the com-
pounds 3a–3h and 4a–4h (ring transformed products of
tetrazole derivatives) which are the structural analogs of
angiotensin II receptor antagonists (sartans) for their
inhibitory activities of ACE.
Molecular Osiris property explorer
A novel molecule is subjected for verification of parame-
ters set by Lipinski’s rule of five to analyze its drug-like-
liness and drug score (Lipinski, 2004; Emami et al., 2011;
Taj et al., 2011, 2012).
The title compounds do not violate the Lipinski rule and
they fall well in the range (Table 1). All the title com-
pounds showed clog P well within the range and also
molecular weights less than 500. The drug-likeliness ran-
ged from -3.01 to 8.54 whereas, the drug score ranged
from 0.23 to 0.78. The drug-likeliness and drug score was
found to be more in tetrazole 3a–3h and decreased after
ring transformation into compounds viz., 1,3,4-oxadizole
derivatives 4a–4h. Interestingly, this observation is in
correlation with the in vitro ACE and a-amylase inhibition
assays.
In vitro ACE inhibition
In view of this, the compounds 3a–3h and 4a–4h were
used in three concentrations viz., 1, 5, and 10 lg to inhibit
the ACE. It was found that the compound 3b (with imid-
azole) exhibited the potent inhibition at 10 lg (80 %).
Also, the compounds 3c (1,2,4-triazole), 3d (piperazine),
and 3e (N-methylpiperazine) have exhibited stronger ACE
inhibition at higher concentration (10 lg) viz., 80, 83, and
92 %, respectively. The remaining compounds did not
show any activity.
The activity of rennin–angiotensin–aldosterone system is
to be reduced to maintain the blood pressure. This is so
because rennin a protein which is released from the kidney
cells produces another protein, angiotensin which induces
the adrenal gland to produce aldosterone. This system is
activated in response to fall in blood pressure as well as
problems with salt–water balance of the body by decreas-
ing sodium ion concentration in the kidney. In this situation
rennin cuts off all aminoacids except the first ten residues
of angiotensin (decapeptide). These ten residues are known
as angiotensin I. ACE further removes two residues and
It is quite interesting to note that the compounds 4a–4h
did not show any ACE inhibition at all the concentrations.
This has obviously indicated that tetrazole moiety is a
requirement for the biphenyl derivatives to exhibit the
123

Med Chem Res
Fig. 3 a-Amylase inhibition by tetrazoles 3a–3h and oxadiazoles
4a–4h
Fig. 2 ACE inhibition by tetrazoles 3a–3h and oxadiazoles 4a–4h
inhibition. The inhibitory potencies of the compounds
on Shimadzu Japan QP2010 S model spectrometer. The
elemental analyses data were obtained from Heraus CHN
rapid analyzer. Chemicals were purchased from Aldrich
and used without purification.
3a–3h and 4a–4h are represented in Fig. 2.
In vitro a-amylase inhibition
The compounds 3a–3h and 4a–4h were also evaluated for
their inhibitory effects against a-amylase to analyze the
possible use of these compounds as antihyperglycemic
agents. All the compounds were tested at three concen-
trations viz., 100, 250, and 500 lg. It was observed that the
tetrazole derivatives with the heterocycles 1,3-thiazolidine-
2,5-dione (3a), imidazole (3b), 1,2,4-triazole (3c), pipera-
zine (3d), and N-methylpiperazine (3e) have exhibited
excellent inhibition of a-amylase and hence the activity of
this enzyme is restricted only to 35.84–41.62 % as com-
pared to control (100 %). Thus, the hydrolysis of starch is
decreased in presence of these compounds at 500 lg dose
level. However, the compounds 3g and 3h with morpholine
and piperidine-4-carboxylic acid moieties, respectively, did
not show significant activities. 1,3,4-Oxadizole derivatives
4a–4h did not exhibit considerable a-amylase inhibition.
Hence, the activity of this enzyme was more at all the
concentration (compared to control) as represented in the
bar graph in Fig. 3.
General procedure for the preparation of compounds
(2a–2h)
A mixture of 40-(bromomethyl)-biphenyl-2-carbonitrile 1
(1.0 mol), cyclic secondary amines (a–h, 1.1 mol), and
anhydrous K2CO3 (1.4 mol) in acetone (25 ml) were stir-
red for 24 h at 27–30 °C and the reaction was monitored by
TLC. After completion of reaction, acetone was evaporated
and poured into water, stirred well and extracted with
DCM. DCM layer was washed with water and dried over
anhydrous sodiumsulphate to get yellowish powder which
was recrystallized using acetone–water mixture (yield
60–75 %).
40-[(2,4-Dioxo-1,3-thiazolidin-3-yl)methyl]biphenyl-2-
carbonitrile (2a)
Pale yellow powder, mp. 134–135 °C. IR (KBr): 1750 (S–
C=O), 1681(N–C=O), 2228(CN) cm-1; 1H NMR (300 MHz,
DMSO-d6): d 3.85 (s, 2H, CH2), 4.71 (s, 2H, CH2), 7.32 (d,
2H, J = 6.9 Hz, ArH), 7.41 (d, 2H, J = 6.9 Hz, ArH),
7.51–7.65 (m, 4H, ArH); 13C NMR (300 MHz, DMSO-d6): d
33.7, 44.7, 110.8, 118.0, 127.5, 128.9, 129.1, 132.7, 133.5,
135.3, 137.9, 144.5, 171.0, 171.5; MS (m/z, 70 eV): 308, 282,
280, 255, 234, 209, 206, 192, 181, 167, 102, 91, 77; Anal.
Calcd. For C17H12N2O2S: C, 66.22; H, 3.92; N, 9.08 %.
Found: C, 66.20; H, 3.87; N, 9.11 %.
Experimental procedure
Chemistry
Melting points were determined in open capillaries. FTIR
spectra were recorded in KBr pellets on a Perkin-Elmer
Paragon 1000 PC spectrometer. The 1H NMR spectral
analyses were carried out in Bruker Avance-300 spec-
trometer (300 MHz) and 13C NMR spectral analyses were
carried out in Bruker-400 (400 MHz) instrument using
TMS as an internal standard. Mass spectra were recorded
40-(1H-Imidazol-1-yl-methyl)-biphenyl-2-carbonitrile (2b)
Colorless crystals, mp. 212–214 °C; IR (KBr): 2220 (CN
stretching), 3040, 1550 cm-1; 1H NMR (300 MHz, CDCl3,):
123

Med Chem Res
d 5.18(s, 2H, CH2), 6.95 (d, 1H, imidazole C5-H), 7.05 (d, 1H,
imidazole C4-H), 7.20 (d, 2H, ArH), 7.45 (d, 2H, ArH),
2.06 (t, 4H, piperazine CH2), 2.32 (t, 4H, piperazine CH2),
3.44 (s, 2H, CH2), 3.56–3.80 (m, 8H, CH2), 7.35–7.80 (m,
8H, ArH); 13C NMR (300 MHz, CDCl3): d 52.20 (N–CH2),
53.22 (N–CH2), 55.41, 61.25, 63.62 (CH2), 69.32, 72.64,
110.31, 127.6, 128.9, 129.0, 129.4, 129.7, 135.4, 135.7,
135.9, 137.20, 148.90; MS (m/z, 70 eV): 366, 321, 277, 99;
CHN Analysis: Calculated for C22H27N3O2: C, 72.30; H,
7.40; N, 11.52. Found: C, 72.28; H, 7.38; N, 11.49.
7.52–7.68 (m, 4H, ArH), 7.77 (s, 1H, imidazole C2-H); 13
C
NMR (300 MHz, CDCl3): d 49.13 (CH2), 113.50, 121.21,
126.8, 127.5, 128.7, 129.0, 129.4, 129.7, 135.4, 135.7, 135.9,
137.20, 141.6, 145.23; MS (m/z, 70 eV): 259, 192, 165, 63,
40; CHN Analysis: Calculated for C17H13N3: C, 78.73; H,
5.05; N, 16.22. Found: C, 78.69; H, 5.02; N, 16.20.
40-(4H-1,2,4-Triazol-1-yl-methyl)-biphenyl-2-
carbonitrile (2c)
40-(Morpholin-4-yl-methyl)biphenyl-2-carbonitrile (2g)
Colorless crystals, mp. 75–77 °C, IR (KBr): 2175 (CN
1
stretching), 1500 cm-1; H NMR (300 MHz, CDCl3,): d
Colorless crystals, mp. 240–242 °C; IR (KBr): 2210 (CN
1
stretching), 1500 cm-1; H NMR (300 MHz, CDCl3): d
2.93 (t, 4H, morpholine CH2), 3.8 (s, 2H, CH2), 3.94 (t, 4H,
morpholine CH2), 7.42–7.84 (m, 8H, ArH); 13C NMR
(300 MHz, CDCl3): d 52.02 (N–CH2), 63.72 (CH2), 66.82
(O–CH2), 117.91, 126.8, 128.9, 128.7, 129.0, 129.7, 135.4,
135.7, 135.9, 137.20, 144.69; MS (m/z, 70 eV): 278, 250,
192; CHN Analysis: Calculated for C18H18N2O: C, 77.65;
H, 6.49; N, 10.08. Found: C, 77.64; H, 6.47; N, 10.06.
5.29 (s, 2H, CH2), 7.30 (d, 2H, ArH), 7.50 (d, 2H, ArH),
7.65–7.74 (m, 4H, ArH), 8.50 (s, 2H, triazole C–H); 13C
NMR (300 MHz, CDCl3): d 47.33 (CH2), 110.50, 127.5,
128.8, 128.7, 129.0, 129.4, 129.7, 135.4, 135.7, 135.9,
137.20, 148.61, 152.13; MS (m/z, 70 eV): 260, 192, 68;
CHN Analysis: Calculated for C16H12N4: C, 73.81; H,
4.65; N, 21.63. Found: C, 73.76; H, 4.61; N, 21.61.
1-[(20-Cyanobiphenyl-4-yl-methyl)piperidine-4-carboxylic
acid (2h)
40-(Piperazin-1-yl)-methyl-biphenyl-2-carbonitrile (2d)
Colorless crystals, mp. 190–192 °C, IR (KBr): 2180 (CN
Brown oil, IR (KBr): 3550 (OH), 2225 (CN), 1725 (C=O)
1
1
stretching), 3450 cm-1; H NMR (300, MHz, CDCl3): d
2.12–3.10(m, 8H, piperazineCH2), 3.81(s, 2H, CH2), 7.42(d,
cm-1, H NMR (300 MHz, CDCl3): d 1.95 (m, 4H, CH2),
2.1–2.3 (t, 4H, CH2), 2.69 (m, 1H, CH), 3.42 (d, 2H, CH2),
7.41–7.75 (m, 8H, ArH), 11.5 (bs, 1H, NH); 13C NMR
(300 MHz, CDCl3): d 28.36 (C–CH2), 39.64, 51.54 (N–
CH2), 63.65 (CH2), 119.79, 127.9, 128.7, 129.0, 129.4,
129.7, 135.4, 135.7, 135.9, 137.20, 144.69, 182.39
(COOH); MS (m/z, 70 eV): 320, 276, 192, 251, 84; CHN
Analysis: Calculated for C20H20N2O2: C, 74.94; H, 6.27;
N, 8.77. Found: C, 74.92; H, 6.25; N, 8.74.
2H, ArH), 7.50 (d, 2H, ArH), 7.67–7.80 (m, 4H, ArH); 13
C
NMR (300 MHz, CDCl3): d 45.43 (N–CH2), 52.21 (N–CH2),
63.12 (CH2), 112.00, 120.86, 127.5, 128.5, 128.7, 129.0,
129.7, 135.4, 135.7, 135.9, 137.20, 146.61; MS (m/z, 70 eV):
277, 248 192, 99; CHN Analysis: Calculated for C18H19N3: C,
77.97; H, 6.89; N, 15.17. Found: C, 77.95; H, 6.88; N, 15.14.
40-[(4-Methylpiperazin-1-yl)-methyl]biphenyl-2-
carbonitrile (2e)
General procedure for the preparation of compounds
(3a–3h)
Pale yellow crystals, mp. 50–52 °C, IR (KBr): 3078, 2895,
1
2200 (CN), 1465 cm-1; H NMR (300 MHz, CDCl3): d
A mixture of compounds 2a–2h (4.0 mol), sodiumazide
(4.2 mol) triethylaminehydrochloride (4.2 mol) in toluene
(35 ml) was refluxed for 48 h. The reaction mass was then
cooled to room temperature and extracted with aqueous
NaOH solution (5 %). The pH of aqueous solution was
adjusted to neutral with conc. HCl and crude solid formed
was filtered and washed with distilled water. Recrystalli-
zation using aqueous ethanol gave crystals of 3a–3h (yield
50–55 %).
2.25–2.81 (m, 8H, CH2), 2.92 (s, 3H, CH3), 3.81 (s, 2H,
CH2), 7.51 (d, 2H, ArH), 7.68 (d, 2H, ArH), 7.74–7.91 (m,
4H, ArH); 13C NMR (300 MHz, CDCl3): d 46.48 (N–CH3),
52.27 (N–CH2), 54.32 (N–CH2), 63.62 (CH2), 113.0, 126.8,
128.5, 128.7, 129.0, 129.4, 130.7, 135.4, 135.7, 137.20,
146.61; MS (m/z, 70 eV): 291, 192, 99; CHN Analysis:
Calculated for C19H21N3: C, 78.33; H, 7.23; N, 14.42.
Found: C, 78.30; H, 7.23; N, 14.41.
2-[2-{4-(2-Cyanobiphenyl)-methyl-piperazin-1-
yl}ethoxy]ethanol (2f)
5-[2-{4-(2,4-Dioxo-1,3-thiazolidin-3-yl)-methyl}-
biphenyl]-1H-tetrazole (3a)
Pale brown oil, IR (KBr): 3545 (OH), 2220 (CN stretch-
1
Off white solid, mp. 216–218 °C; IR (KBr): 3411 (NH),
ing), 3040, 1500 cm-1; H NMR (300 MHz, CDCl3): d
1749, (S–C=O), 1670 (N–C=O) cm-1
;
1H NMR
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Med Chem Res
1-Methyl-4-{[20-(1H-tetrazol-5-yl)biphenyl-4-yl] methyl}
piperazine (3e)
(300 MHz, DMSO-d6): d 3.72 (s, 2H, CH2), 4.67 (s, 2H,
CH2), 7.12 (d, 2H, J = 8.05 Hz, ArH), 7.36 (d, 2H,
J = 8.05 Hz, ArH), 7.45–7.62 (m, 4H, ArH); 13C NMR
(300 MHz, DMSO-d6): d 35.1 (thiadiazole CH2), 44.2
(CH2), 127.5, 127.7, 128.0, 128.2, 129.3, 129.7, 135.1,
134.5, 135.4, 140.6, 163.5, 165.0, 168.0; MS (m/z): 351,
350, 322, 248, 206, 205, 192, 178, 165, 152, 139, 118, 102,
89, 77, 62, 47, 46, 42; Anal. Calcd. For C17H13N5O2S: C,
58.11; H, 3.73; N, 19.93. Found: C, 58.05; H, 3.68; N,
19.90 %.
Brown crystals, mp. 155–157 °C; IR (KBr): 2988,
1
1642 cm-1; H NMR (300 MHz, DMSO-d6): d 2.35–2.46
(m, 8H, piperazine CH2), 3.56 (s, 2H, CH2), 3.85 (s, 3H,
CH3), 7.5–7.94 (m, 8H, ArH); 13C NMR (300 MHz,
DMSO-d6): d 40.5 (CH2), 51.2, 57.4, 62.0, 127.1, 128.4,
128.7, 128.9, 129.6, 129.9, 135.5, 135.7, 135.8, 136.2,
168.2; MS (m/z, 70 eV): 334, 291, 262, 242, 235, 192, 165,
99, 56, 43; CHN Analysis: Calculated for C19H22N6: C,
68.24; H, 6.61; N, 25.15. Found C, 68.23; H, 6.59; N,
25.13.
5-[40-(1H-Imidazol-1-yl-methyl)biphenyl-2-yl]-1H-
tetrazole (3b)
2-[2-{4-20-(Tetrazol-4-yl)-biphenyl}-piperazin-1-
yl)ethoxy]ethanol (3f)
Pale yellow crystals, mp. 190–192 °C; IR (KBr): 3063,
1
1645 cm-1; H NMR (300 MHz, DMSO-d6): d 5.26 (s,
2H, CH2), 6.64 (1H, s, imidazole C5-H) 6.97 (d, 1H,
imidazole C4-H), 7.38-7.72 (m, 8H, ArH), 7.75 (s, 1H,
imidazole C2-H); 13C NMR (300 MHz, DMSO-d6): d 48.0
(CH2), 120.4, 127.2, 127.9, 128.0, 128.2, 128.5, 129.0,
129.2, 133, 133.2, 133.7, 135.4, 137.0, 166.5; MS (m/z,
70 eV): 301, 235, 207, 178, 165, 152, 63, 44, 40; CHN
Analysis: Calculated for C17H14N6: C, 67.53; H, 4.64; N,
27.83. Found: C, 67.51; H, 4.66; N, 27.82.
Brown crystals, mp. 185–187 °C, IR (KBr): 3515, 3010,
1
1522 cm-1; H NMR (300 MHz, DMSO-d6): d 2.32–2.41
(m, 8H, piperazine CH2), 2.54 (t, 2H, N–CH2–), 3.25 (t,
2H, CH2–O), 3.31 (t, 2H, O–CH2), 3.40 (t, 2H, CH2OH),
3.58 (s, 2H, CH2), 7.15–7.68 (m, 8H, ArH); 13C NMR
(300 MHz, DMSO-d6): d 55.0, 58.0, 59.7, 61.9 (CH2),
62.5, 70.00, 73.5, 127.7, 128.0, 128.2, 128.4, 129.3, 129.4,
134.5, 135.0, 135.1, 135.4, 162.5; MS (m/z, 70 eV): 409,
366, 320, 221, 192, 99, 44, 40; CHN Analysis: Calculated
for C22H28N6O2: C, 64.68; H, 6.87; N, 20.59. Found C,
64.66; H, 6.85; N, 20.60.
5-[40-(4H-1,2,4-Triazol-1-yl-methyl)biphenyl-2-yl]-1H-
tetrazole (3c)
4-{[20-(1H-Tetrazol-5-yl)-biphenyl-4-
yl]methyl}morpholine (3g)
Colorless crystals, mp. 205–207 °C; IR (KBr): 3083, 1955,
1
1095 cm-1; H NMR (300 MHz, DMSO-d6): d 5.33 (s,
2H, CH2), 77.3–7.82 (m, 8H, ArH), 8.5 (s, 2H, triazole H);
13C NMR (300 MHz, DMSO-d6): d 51.60 (CH2), 127.6,
127.8, 129.02, 129.22, 130.56, 131.03, 135.44, 135.82,
138.82, 143.26, 144.27, 151.2, 158.00; MS (m/z, 70 eV):
303, 234, 207, 178, 166, 152, 63, 44; CHN Analysis:
Calculated for C16H13N7: C, 63.35; H, 4.31; N, 32.34.
Found: C, 63.32; H, 4.29; N, 32.32.
Colorless crystals, mp. 200–202 °C, IR (KBr): 2990,
1650 cm-1; 1H NMR (300 MHz, DMSO-d6): d 2.95 (t, 4H,
morpholine N–CH2), 3.74 (s, 4H, morpholine O–CH2),
4.02 (s, 2H, CH2), 7.40–7.84 (m, 8H, ArH); 13C NMR
(300 MHz, DMSO-d6): d 50.0, 55.6, 64.0 (CH2), 126.9,
127.2, 128.2, 128.5, 128.2, 128.7, 129.5, 129.8, 134.3,
135.8, 136.0, 167.0; MS (m/z, 70 eV): 321, 293, 192, 84,
63, 44, 40; CHN Analysis: Calculated for C18H19N5O2: C,
67.25; H, 5.92; N, 21.82. Found: C, 67.26; H, 5.90; N,
21.79.
1-{[20-(1H-Tetrazol-5-yl)biphenyl-4-yl] methyl}
piperazine (3d)
1-{[20-(1H-Tetrazol-5-yl)biphenyl-4-yl] methyl}piperidine-
4-carboxylic acid (3h)
Pale yellow crystals, mp. 182–184 °C; IR (KBr): 3389
1
(NH), 3028, 1658 cm-1; H NMR (300 MHz, DMSO-d6):
d 2.18 (t, 4H, CH2), 2.78 (t, 4H, CH2), 3.85 (s, 2H, CH2),
7.4–7.85 (m, 8H, ArH); 13C NMR (300 MHz, DMSO-d6):
d 48.00 (N–CH2), 53.05 (N–CH2), 60.19 (CH2), 127.20,
128.02, 128.18, 128.25, 129.50, 129.61, 133.05, 134.92,
135.10, 135.81, 162.00; MS (m/z, 70 eV): 320, 280, 250,
192, 154, 89, 63, 44; CHN Analysis: Calculated for
C18H20N6: C, 67.48; H, 6.25; N, 26.27. Found C, 67.47; H,
6.24; N, 26.28.
Pale yellow crystals, mp. 183–185 °C; (IR, KBr): 3455,
3078, 1718 cm-1; 1H NMR (300 MHz, DMSO-d6): d 2.05
(m, 4H, CH2), 2.20–2.35 (t, 4H, CH2), 3.12 (m, 1H, CH),
3.84 (s, 2H, CH2), 7.12–7.64 (m, 8H, ArH), 10.25 (bs, 1H,
OH); 13C NMR (300 MHz, DMSO-d6): d 29.2, 41.7, 51.4,
60.4 (CH2), 127.6, 128.0, 128.2, 128.4, 129.3, 129.4, 134.5,
135.0, 135.1, 135.4, 168.9, 178.00; MS (m/z, 70 eV): 364,
123

Med Chem Res
318, 277, 192, 86, 65, 44, 40; CHN Analysis: Calculated
for C20H21N5O2: C, 66.08; H, 5.81; N, 19.29. Found: C,
66.05; H, 5.82; N, 19.30.
ArH), 7.34–7.58 (m, 4H, ArH)), 8.45 (m, 2H, triazole H);
13C NMR (300 MHz, CDCl3): d 10.23 (CH3), 51.73 (CH2),
122.23, 127.64, 127.98, 128.78, 129.93, 130.79, 131.53,
135.58, 139.33, 140.83, 144.10, 151.25, 163.61 (oxadiazole
C2), 164.02 (oxadiazole C5); MS (m/z, 70 eV): 317, 234,
168, 68; CHN Analysis: Calculated for C18H15N5O: C,
68.09; H, 4.77; N, 22.09. Found C, 68.11; H, 4.75; N,
22.10.
General procedure for the preparation of compounds
(4a–4h)
A mixture of compound (3a–3h, 0.1 mol) and acetic
anhydride (20 ml) were refluxed for 2 h and cooled to
room temperature, poured into ice cold water and kept for
about 10 h at 25–30 °C. The aqueous solution was then
extracted with ethyl acetate (20 ml), washed with water
(50 ml) and distilled to get the crude solid which was
crystallized using aqueous acetone (yield 55–60 %).
1-{[20-(5-Methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-
yl]methyl}piperazine (4d)
Brown crystals, mp. 135–137 °C; IR (KBr): 3515,
1
1650 cm-1; H NMR (300 MHz, CDCl3): d 2.07 (s, 3H,
CH3), 2.74 (t, 4H, piperazine CH2), 2.98 (t, 4H, piperazine
CH2), 3.85 (s, 2H, CH2) 7.2–7.62 (m, 8H, ArH); 13C NMR
(300 MHz, CDCl3): d 10.77 (CH3), 52.79 (HN–CH2),
54.80 (–NCH2), 62.65 (CH2), 127.54, 128.52, 128.97,
129.12, 130.28, 130.82, 131.00, 137.45, 139.07, 141.85,
163.64 (oxadiazole C2), 165.43 (oxadiazole C5); MS (m/z,
70 eV): 334, 251, 246, 224. 192, 97, 83, 44; CHN Analy-
sis: Calculated for C20H22N4O: C, 71.82; H, 6.59; N, 16.79.
Found: C, 71.80; H, 6.61; N, 16.80.
3-{[20-(5-Methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-
yl]methyl}-1,3-thiazolidine-2,4-dione (4a)
Off white solid, mp. 60–62 °C; IR (KBr): 1747 (S–C=O),
1
1673 (N–C=O), 1650, 1485 cm-1; H NMR (300 MHz,
CDCl3): d 1.95 (s, 3H, CH3) 3.72 (s, 2H, CH2), 4.66 (s, 2H,
CH2), 7.12 (d, 2H, J = 8.05 Hz, ArH), 7.35 (d, 2H,
J = 8.05 Hz, ArH), 7.45–7.60 (m, 4H, ArH); 13C NMR
(300 MHz, CDCl3): d 14.3 (CH3), 37.5 (thiadiazole CH2),
46.00 (CH2), 127.8, 128.5, 128.7, 129.0, 129.4, 129.7,
135.4, 135.7, 135.9, 141.6, 167.8 (oxadiazole C2), 169.7
(oxadiazole C5), 171.6 (CO), 173.2 (CO); MS (m/z, 70 eV):
366, 323, 263, 180, 152, 89.49, 44; CHN Analysis: Cal-
culated for C19H15N3O3S: C, 62.45; H, 4.14; N, 11.50.
Found C, 62.40; H, 4.15; N, 11.49.
1-Methyl-4-{[20-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-
4-yl]methyl}piperazine (4e)
Pale yellow crystals, mp. 65–66 °C; IR (KBr): 3535,
1
1665 cm-1; H NMR (300 MHz, CDCl3): d 2.32 (s, 3H,
CH3), 2.76 (t, 4H, piperazine CH2), 2.92 (t, 4H, piperazine
CH2), 3.80 (s, 4H, CH2), 7.55–7.94 (m, 8H, ArH); 13C NMR
(300 MHz, CDCl3): d 15.9 (CH3), 45.0 (N–CH3), 50.7
(CH2), 57.8, 64.2, 126.7, 127.0, 127.2, 127.4, 128.3, 128.5,
133.6, 134.0, 135.4, 135.8, 161.5 (oxadiazole C2), 168.2
(oxadiazole C5); MS (m/z, 70 eV): 348, 265, 249, 192, 98,
44; CHN Analysis: Calculated for C21H24N4O: C, 72.38; H,
6.92; N, 16.10. Found C, 72.35; H, 6.93; N, 16.11.
2-[40-(1H-Imidazol-1-yl-methyl)biphenyl-2-yl]-5-methyl-
1,3,4-oxadiazole (4b)
Pale green crystals, mp. 62–64 °C; IR (KBr): 1650,
1
1485 cm-1; H NMR (300 MHz, CDCl3, d ppm): 2.15 (s,
3H, CH3), 5.25 (s, 2H, CH2), 6.9 (d, 1H, imidazole C5-H),
7.05 (d, 1H, imidazole C4-H), 7.15 (d, 2H, ArH), 7.20 (d,
2H, ArH), 7.32–7.55 (m, 4H, ArH), 7.68 (s, 1H, imidazole
C2-H); 13C NMR (300 MHz, CDCl3): d 9.97 (CH3), 50.3
(CH2), 121.2 (imidazole C5), 125.8, 127.0, 127.1 (imidaz-
ole C4), 127.6, 128.3, 128.6, 129.0, 129.5, 133.0, 135.1,
135.5, 137.8 (imidazole C2), 165.0 (oxadiazole C2), 166.7
(oxadiazole C5); MS (m/z, 70 eV): 317, 275, 242, 220, 155,
68; CHN Analysis: Calculated for C19H16N4O: C, 72.11;
H, 5.08; N, 17.72. Found C, 72.09; H, 5.10; N, 17.69.
2-[2-{4-20-(5-Methyl-1,3,4-oxadiazol-2-yl)-biphenyl}-
piperazin-1-yl)ethoxy]ethanol (4f)
Pale brown crystals, mp. 78–80 °C; IR (KBr): 3515, 3020,
1
1685 cm-1; H NMR (300 MHz, CDCl3): d 2.08 (s, 3H,
CH3), 2.44 (t, 4H, piperazine CH2), 2.68 (t, 4H, piperazine
CH2), 2.92 (t, 2H, N–CH2), 3.14 (t, 2H, CH2O), 3.48 (t, 2H,
OCH2), 3.74 (t, 2H, CH2OH), 3.92 (s, 2H, CH2), 7.46–7.75
(m, 8H, ArH); 13C NMR (300 MHz, CDCl3): d 12.0 (CH3),
52.6, 53.0, 54.8, 60.4, 61.4, 68.8, 72.4, 126.5, 127.6, 128.5,
128.9, 129.2, 129.7, 129.9, 134.6, 135.2, 135.9, 160.7
(oxadiazole C2), 166.7 (oxadiazole C5); MS (m/z, 70 eV):
422, 377, 339, 333, 192, 165, 97, 65, 43; CHN Analysis:
Calculated for C24H30N4O3: C, 68.20; H, 7.12; N, 13.30.
Found: C, 68.18; H, 7.11; N, 13.29.
2-Methyl-5-[40-(4H-1,2,4-triazol-1-yl-methyl)biphenyl-2-
yl]-1,3,4-oxadiazole (4c)
Colorless crystals, mp. 80–82 °C; IR (KBr): 3515,
1
1647 cm-1; H NMR (300 MHz, CDCl3): d 2.35 (s, 3H,
CH3), 4.95 (s, 2H, CH2), 7.20 (d, 2H, ArH), 7.42 (d, 2H,
123

Med Chem Res
4-{[20-(5-Methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-
yl]methyl}morpholine (4g)
a-Amylase inhibition assay
The inhibition assay was performed using the chromogenic
DNSA method (Miller, 1959; Sudha et al., 2011). The total
assay mixture (sodium phosphate buffer, 0.05 M,
1,400 ll ? a-amylase 50 ll) along with the title com-
pounds 3a–3h and 4a–4h at concentrations 100, 250, and
500 lg were incubated at 37 °C for 10 min. After pre-
incubation starch solution was added to each tube and
incubated for 15 min. The reaction was terminated with
DNSA reagent, placed on boiling water bath for 5 min,
cooled to RT and absorption was measured at 540 nm. The
control amylase represented 100 % enzyme activity and do
not contain any sample/standard. The maltose liberated was
determined by using standard maltose curve. Activities
were calculated according to the formula
Colorless crystals, mp. 60–62 °C; IR (KBr): 3524,
1
1595 cm-1; H NMR (300 MHz, CDCl3): d 2.07 (s, 3H,
CH3), 2.34 (t, 4H, morpholine CH2), 2.93 (t, 4H, mor-
pholine CH2), 3.90 (s, 2H, CH2), 7.25–7.96 (m, 8H, ArH);
13C NMR (300 MHz, CDCl3): d 11.50 (CH3), 53.3 (CH2),
59.7, 66.8, 127.6, 128.0, 128.2, 128.4, 129.3, 129.4, 134.5,
135.0, 135.1, 135.4, 165.0 (oxadiazole C2), 168.7 (oxadi-
azole C5); MS (m/z, 70 eV): 336, 252, 249, 165, 55; CHN
Analysis: Calculated for C20H21N3O2: C, 71.60; H, 6.28, N,
12.57. Found: C, 71.62; H, 6.25, N, 12.55.
4-{[20-(5-Methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-
yl]methyl}piperidine-4-carboxylic acid (4h)
Activity ¼
Conc: of maltose liberated ꢁ vol: of enzyme used ðmlÞ
Mol: wt: of maltose ꢁ incubation time ðminÞ
ꢁ dilution factor:
Pale yellow crystals, mp. 68–70 °C; IR (KBr): 3490,
3032–3040, cm-1; 1H NMR (300 MHz, CDCl3): d 1.9 (m,
4H, CH2), 2.25 (s, 3H, CH3), 2.30–2.45 (t, 4H, CH2), 3.1
(m, 1H, CH), 3.86 (d, 2H, CH2), 7.24–7.53 (m, 8H, ArH),
11.5 (bs, 1H, OH); 13C NMR (300 MHz, CDCl3): d 10.74
(CH3). 29.2, 41.7, 51.4 (CH2), 60.9, 127.6, 128.5, 128.7,
129.0, 129.8, 130.4, 134.9, 135.6, 136.0, 137.4, 163.9
(oxadiazole C2), 167.5 (oxadiazole C5), 182.0; MS (m/z,
70 eV): 378, 332, 250, 164, 65, 43; CHN Analysis: Cal-
culated for C22H23N3O3: C, 70.00; H, 6.10: N, 11.15.
Found: C, 70.02; H, 6.08: N, 11.13.
The inhibitory property shown by the sample was
compared with that of control and expressed as percent
induction/inhibition. This was calculated according to the
following formula:
Activity of enzyme in presence of sample
% Activity ¼
Control activity
ꢁ 100:
Conclusions
Pharmacological evaluation
At the conclusion of this study, an efficient synthesis
of compounds 3a–3h and further ring transformation into
4a–4h involving ring transformation of tetrazole to
1,3,4-oxadiazole ring is described. The inhibition of ACE and
a-amylase enzyme by diverse library of these compounds
were also evaluated. It was found that some of the tetrazole
derivatives 3b, 3c, 3d, and 3e inhibited the ACE enzyme
effectively. Similarly, in case of a-amylase enzyme inhi-
bition assay, the compounds 3a–3f have inhibited the
enzyme and decreased its activity during starch hydrolysis.
It is interesting to note that the 1,3,4-oxadiazole derivatives
4a–4h did not show any activity against both the enzymes.
ACE inhibition assay (Jimsheena, 2009; Hooper
and Turner, 1987)
The compounds 3a–3h and 4a–4h were tested at three
concentrations viz., 1, 5, and 10 lg, dissolved in assay
buffer [10 mM HEPES buffer containing NaCl (0.3 M) and
zinc sulfate (10 lM) containing kidney cortex plasma
membranes (20 ll, source of ACE] and Hippuryl–His–Leu
(1 mM) as substrate. The compounds were incubated with
the enzyme for 10 min at 37 °C. The substrate was then
added and incubated for 45 min at 37 °C. The reaction was
terminated by the addition of HCl (1 M). The yellow color
developed by the addition of pyridine (100 ll) and ben-
zenesulphonylchloride (50 ll) was measured at 410 nm in
ELISA Plate Reader (iMARK, BIORAD). Compounds
with inhibitory potential block the substrate availability to
the enzyme and thereby cause enzyme inhibition leading to
no formation of yellow color. The inhibition was repre-
sented in the form of percentage over control. Captopril, a
known ACE inhibitor is used as standard.
Acknowledgments We would like to thank the USIC authorities for
their help in carrying out the spectral characterization (FT-IR, 1H
NMR, MS) and NMR Research Centre, IISc, Bangalore for 13C NMR
spectral analyses. We acknowledge the assistance of Biogenics Ltd.,
Hubballi, Karnataka, India for carrying out the pharmacological
properties. The authors acknowledge UGC, New Delhi, Govt. of India
for their financial assistance vide letter no. 37-248/2009 (SR). One of
the authors (GYM) thanks the UGC, New Delhi for Junior Research
Fellowship.
123

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