Vol. 30, No. 2 (2018)
Design, Synthesis, DFT and Molecular Docking Studies of Novel Clip Type-Pyridyltetrazole Analogues 335
O, 14.75; N, 21.53. Found (%): C, 59.03; H, 4.61; O, 14.74;
1H, J = 15.3-7.8 Hz), 7.00-6.93 (m, 2H), 5.64 (d, 1H, J = 6.0
Hz), 5.12-4.83 (m, 3H), 4.57 (d, 2H, J = 5.4 Hz), 4.52-4.46
1
N, 21.58; H NMR (DMSO-d
8
1
6
, 300 MHz): δ 10.40 (s, 1H),
.72 (d, 1H, J = 4.2 Hz), 8.21 (d, 1H, J = 8.1 Hz), 8.06 (td,
H, J = 1.5-7.8 Hz), 7.72-7.53 (m, 4H), 7.19 (d, 1H, J = 8.4
13
(m, 1H), 4.10 (d, 2H, J = 5.1 Hz) ppm. C NMR (DMSO-d ,
6
75 MHz): δ 157.88, 155.10, 150.14, 146.33, 137.59, 130.75,
127.66, 127.16, 125.18, 122.18, 120.51, 111.28, 69.44, 67.55,
58.00, 56.25 ppm; MS: m/z value 328.14 (M+1).
Single-crystal structure determination:A suitable colour-
less single crystal of 3A with dimensions 0.28 mm × 0.26 mm
× 0.14 mm was obtained from methanol solution at room
temperature was mounted on a CryoLoop (Hampton Research
Corp.); (at IIT Hyderabad) with a layer of light mineral oil
and placed in a nitrogen stream at 150(2) K. All measurements
were made on an Oxford Supernova X-calibur Eos CCD detector
Hz), 7.15-6.92 (m, 2H), 5.59 (d, 1H, J = 6 Hz), 5.19 (d, 2H, J
6.6 Hz), 4.48-4.37 (m, 1H), 4.24-4.12 (m, 3H), 4.03 (q, 1H,
=
13
J = 19.2 Hz) ppm; C NMR (DMSO-d
6
, 75 MHz): δ 189.42,
60.66, 152.31, 149.54, 144.34, 138.16, 136.37, 127.40,
25.85, 124.40, 124.33, 120.90, 113.42, 70.07, 67.40, 51.63
1
1
ppm; MS: m/z value 326.13 (M+1).
Compound 3F: yellowish solid, yield: 99 %. m.p.: 84 °C;
Anal. Calc (%). for C16
H
15
N
5
O (325.32): C, 59.07; H, 4.65;
3
O, 14.75; N, 21.53. Found (%): C, 59.01; H, 4.62; O, 14.71;
1
N, 21.50; H NMR (DMSO-d
6
, 300 MHz): δ 10.48 (s, 1H),
α
with graphite-monochromatic CuK (1.54184 Å) radiation,
8
1
4
7
4
=
.75 (d, 1H, J = 3.3 Hz), 8.14 (d, 1H, J = 7.8 Hz), 8.01 (td,
CrysAlisPro, Agilent Technologies, Version 1.171.35.19. The
structures were solved by direct methods (SIR92) and refined
on F2 by full-matrix least-squares using SHELXL-97 [15].
ORTEP-3 was used to draw the molecule.
Computational procedures: The DFT calculations were
performed using the B3LYP three parameter density functional,
which includes Becke’s gradient exchange correction [16] the
Lee,Yang, Parr correlation functional [17] and theVosko, Wilk,
Nusair correlation functional [18]. The geometries of molecules
were fully optimized with respect to the energy using the 6-
31g(d,p) basis set using the Gaussian 09W suite.
Molecular docking studies: Crystal structure of DNA
was downloaded from Protein Data Bank (PDB ID: 453D).
Energy minimized conformations of compound A, B, C and D
were generated in FRee On line druG conformation generation
(FROG) web-server (Frog2 version), which usesAMMOS force
field [19]. The conformation obtained for each of the compound
was used further for docking with DNA. The biomolecule was
prepared for docking usingAutodock tools involved removal of
all water molecules from PDB files, addition of polar hydrogen
atoms and assigning Gasteiger charges to the proteins. Docking
was carried out with Autodock 4.2 Lamarckian Genetic
Algorithm, where DNA was enclosed in the grid defined by
Auto Grid having 0.375 Å spacing. All other docking para-
meters were kept as default. PyMol was used for visualization
and measurement of distances between the atoms of ligand
and the nucleotides of DNA.
H, J = 1.5-7.8 Hz), 7.75-7.64 (m, 2H), 7.56 (dt, 1H, J = 6.6-
.8), 7.26 (d, 1H, J = 8.4 Hz), 7.11 (t, 1H, J = 15-7.5 Hz),
.07-6.87 (m, 1H), 5.78 (d, 1H, J = 6 Hz), 5.10-4.90 (m, 2H),
.59-4.54 (m, 1H), 4.26 (t, 2H, J = 8.4-3.6 Hz), 4.03 (q, 2H, J
13
6.9 Hz), 1.99 (s, 3H) ppm; C NMR (DMSO-d , 75 MHz):
6
δ 189.62, 160.66, 150.13, 146.31, 137.57, 136.37, 127.63,
1
5
25.17, 124.46, 122.33, 120.99, 113.60, 70.08, 67.37, 59.73,
6.03 ppm; MS: m/z value 326.13 (M+1)
Syntheses of 1-[2-(hydroxymethyl)phenoxy]-3-[5-
(
(
pyridin-2-yl)-1H-tetrazol-1-yl]propan-2-ol (3G) and 1-[2-
hydroxymethyl)phenoxy]-3-[5-(pyridin-2-yl)-2H-tetrazol-
2
-yl]propan-2-ol (3H): To a solution of aldehyde 3E or 3F
487 mg, 1.5 mmol) in methanol (25 mL) at 0 °C was added
NaBH (29 mg, 0.75 mmol) and the resultant mixture was
(
4
stirred for 30 min at room temperature. The reaction mixture
was quenched with aqueous ammonium chloride. Methanol
was evaporated under reduced pressure and the compound was
extracted with ethyl acetate (60 mL) and the organic layer
was washed successively with water (50 mL × 3) followed by
brain solution (50 mL). The organic layer was dried over
MgSO and the solvent was evaporated under reduced pressure
4
to get colourless solids 3G and 3H respectively. The solids
were triturated with diethyl ether and utilized without further
purifications.
Compound 3G: Colourless solid, yield: 99 %. m.p.: 141 °C.
Anal. calc. (%). for C16
H
17
N
5
3
O (325.32): C, 58.71; H, 5.23;
O, 14.66; N, 21.39. Found(%): C, 58.69; H, 5.20; O, 14.70;
1
N, 21.38. H NMR (DMSO-d
.5 Hz), 8.22 (d, 1H, J = 7.8 Hz), 8.07 (td, 1H, J = 7.8-1.5
Hz), 7.62 (dt, 1H, J = 6.6-4.8 Hz), 7.38 (d,1H, J = 7.2 Hz),
6
, 300 MHz) : δ 8.74 (d, 1H, J =
RESULTS AND DISCUSSION
4
Synthesis and characterization: The synthetic route was
started from picolinonitrile 1 by following the method published
recently [13] to form the tetrazole 2 and the structure was con-
firmed by comparing the analytical data of 2 with the reported
data. With the compound 2 in hand we tried the reaction of
the same with 0.5 equivalents of epichlorohydrine in dry
7
5
1
5
7
1
5
.19 (t, 1H, J = 14.4-6.9 Hz), 6.93 (q, 2H, J = 16.5-7.5 Hz),
.45 (d, 1H, J = 5.7 Hz), 5.15-5.10 (m, 2H), 5.00 (t, 1H, J =
1.1, 5.4 Hz), 4.53 (d, 2H, J = 5.4 Hz), 4.37-4.29 (q, 1H, J =
1
3
.4 Hz), 4.02 (d, 2H, J = 5.1 Hz) ppm. C NMR (DMSO-d ,
6
5 MHz): δ 154.97, 152.32, 149.66, 144.37, 138.16, 130.69,
27.56, 126.93, 125.81, 124.37, 120.40, 110.99, 69.55, 67.52,
7.89, 51.98 ppm; MS: m/z value 328.14 (M+1)
Compound 3H: Colourless solid, yield: 99 %. m.p.: 132 °C.
Anal. calc. (%) for C16
4.66; N, 21.39. Found(%): C, 58.69; H, 5.20; O, 14.70; N,
1.38. H NMR (DMSO-d , 300 MHz) : δ 8.75 (d, 1H, J = 4.5
Hz), 8.14 (d, 1H, J = 7.8 Hz), 8.01 (td, 1H, J = 7.5-1.5 Hz),
.55 (dt, 1H, J = 6.9-5.1 Hz), 7.21 (d, 1H, J = 7.2 Hz), 7.22 (t,
DMF in the presence of K
2
CO at 70 °C which furnished
3
tetrazoles 3A and 3B and the same reaction with 1.0 equivalents
of epichlorohydrine was afforded tetrazoles 3C and 3D
(Scheme-I). The structure of 3A-3D were readily confirmed
H
17
N O
5 3
(325.32): C, 58.71; H, 5.23; O,
13
1
2
by observing their C NMR which showed chemical shift of
the tetrazole carbon atom appearing at about 152.95 or 164.59
ppm in the 1,5- and 2,5-disubstituted tetrazoles, respectively
[13].
1
6
7