Synthesis, Biological Activity, and Molecular Docking Assessment of Some New Sulfonylated Tetrazole Derivatives

Article abstract of DOI:10.1134/S1070363219090202

The designed molecular structures have been subjected to computational analysis for calculating their physicochemical properties and drug likeness. The calculated data indicate that most of the compound possess the bioactivity score in the active zone. Synthetic approach to the target compounds is straightforward and easy to handle. Structures of the new compounds are supported by FT-IR, ¹H, and ¹³C NMR, and mass spectra. Antimicrobial tests of the products against pathogens (S. aureus, S. epidermidis, E. coli, and P. mirabilis) indicate the products as active or highly active. Their cyto-toxicity is determined to be 92–98% at concentration of 3.125 μmol/L. The molecular docking analysis carried out for the target compounds against the receptor Glc-N-6P exhibits low binding energy and various binding sites of those.

Full text of DOI:10.1134/S1070363219090202

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 9, pp. 1851–1858. © Pleiades Publishing, Ltd., 2019.
Synthesis, Biological Activity, and Molecular Docking Assessment
of Some New Sulfonylated Tetrazole Derivatives
a
b
c
M. Arshad *, M. S. Khan , and S. A. A. Nami
a
Department of Basic Sciences, College of Medicine, Shaqra University, Al-Dawadmi, 11911 Saudi Arabia
e-mail: mohdarshad1985@gmail.com
Interdisciplinary Nanotechnology Centre, Aligarh Muslim University, Aligarh, India
*
b
c
Department of Kulliyat, Faculty of Unani Medicine, Aligarh Muslim University, Aligarh, India
Received March 11, 2019; revised August 21, 2019; accepted August 28, 2019
Abstract—The designed molecular structures have been subjected to computational analysis for calculating their
physicochemical properties and drug likeness. The calculated data indicate that most of the compound possess
the bioactivity score in the active zone. Synthetic approach to the target compounds is straightforward and easy to
1
13
handle. Structures of the new compounds are supported by FT-IR, H, and C NMR, and mass spectra.Antimicrobial
tests of the products against pathogens (S. aureus, S. epidermidis, E. coli, and P. mirabilis) indicate the products
as active or highly active. Their cyto-toxicity is determined to be 92–98% at concentration of 3.125 μmol/L. The
molecular docking analysis carried out for the target compounds against the receptor Glc-N-6P exhibits low bind-
ing energy and various binding sites of those.
Keywords: Sulfonilated tetrazole, computational approach, synthesis, characterization, biological screening
DOI: 10.1134/S1070363219090202
Tetrazole derivatives are characterized by versatile
biological properties including chemotherapeutic and
anti-cancer effects [1–3]. Earlier we have reported the
synthesis and anticancer potential of novel piperonyl-
tetrazole derivatives [4] and N-(pyrimidine-2-yl)benzene-
sulfonamide derivatives [5, 6]. In the current study we
synthesized some new sulfonylated tetrazole derivatives
with enhanced chemotherapeutic potential.
Molinspration software. The computational assessment
(drug likeness and physicochemical properties) was
performed with the software available online (www.
molinspiration.com), according to the route discussed
in [7–12]. Structure of the molecules were drawn with
ChemDraw Ultra 8.0, and their smile files were gener-
ated with the online available software same as above,
and the parameters like molecular mass, milogP, TPSA,
Natoms, N , NOHNH, Nviolationsn Nrot, Volume, GPCR
ON
EXPERIMENTAL
ligand, Ion channel modulator, Kinase inhibitor, Nuclear
receptor ligand, Protease inhibitor and Enzyme inhibitor
were calculated.
The reagents and solvents were purchased from Sigma
Aldrich and Merck, Germany. The processes were moni-
tored by TLC on pre-coated silica gel aluminium sheets
and visualized under UV light. Melting points were de-
termined on a Melt-Temp instrument. Elemental analysis
was carried out on a Heraeus Vario EL III analyzer. FTIR
spectra were recorded on a Perkin-Elmer model 1600 FT-
Synthesis of benzene-1,4-dicarbonitrile. The mix-
ture of (Z,Z)-benzene-1,4-diylbis(N-hydroxymethani-
mine) with 20 mL of acetic anhydride was refluxed.
Upon completion of the reaction the reaction mixture was
poured into ice cold water. The precipitate was filtered
off and dried under vacuum, purified by column chro-
matography using hexane–chloroform. Brown crystals,
1
13
IR RX1 spectrophotometer. H and C NMR spectra were
measured on a BrukerAvance 300 MHz spectrometer us-
–1
yield 85%. FT-IR spectrum, ν, cm : 2955 (CH-Ar), 2222
ing DMSO-d as a solvent and TMS as a standard. Mass
6
1
(
CN). H NMR spectrum, δ, ppm: 7.123–7.169 d (2H,
spectra were measured on a Micromass Quattro II triple
quadrupole mass spectrometer. The antibacterial study
was carried out under laminar flow, and percent viability
of the cells was recorded by ELISA.The bioactivity score
and the physicochemical properties were calculated by
Ar-H), 7.540–7.582 d (2H, Ar-H).
Synthesis of 5,5'-benzene-1,4-diylbis(1H-tetrazole).
The mixture of equimolar amounts of benzene-1,4-
dicarbonitrile, sodium azide and zinc bromoide water
1
851

1852
ARSHAD et al.
solution, and 40 mL of isopropyl alcohol (10 mL) was
refluxed refluxed. 5,5'-Benzene-1,4-diylbis(1H-tetrazole)
was filtered off and dried under vacuum. Creamy-white
124.38 (Ar-C), 125.19 (Ar-C), 125.93 (Ar-C), 125.27
(Ar-C), 126.15 (Ar-C), 126.71 (Ar-C), 126.37 (Ar-C),
127.08 (Ar-C), 127.30 (Ar-C), 127.41 (Ar-C), 159.08
(C–N), 160. 93 (C–N), 164.31 (C=N), 166.20 (C=N).
–1
crystals, yield 90%. FT-IR spectrum, ν, cm : 3255 (NH),
+
3
312 (NH), 2924 (CH-Ar), 1617 (C=N), 1596 (C=N).
ESI-MS: m/z: 562.94 [M + H] . Found, %: C 42.62, H
1
H NMR spectrum, δ, ppm: 7.470–7.508 d (2H, Ar-H),
2.19, N 19.90. C H Cl N O S . Calculated, %: C 42.64,
20
12
2
8
4 2
7
.431–7.478 d (2H, Ar-H), 10.922 s (1H, NH), 11.145 s
H 2.15, N 19.89.
,5'-Benzene-1,4-diylbis{1-[(4-bromophenyl)
sulfonyl]-1H-tetrazole} (3). White crystals, yield 80%,
(1H, NH).
5
Synthesis of sulfonylated tetrazole derivatives
–
1
(
1–12). The equimolar amounts of 5,5'-benzene-1,4-
mp 118–120°C. FT-IR spectrum, ν, cm : 1029 (SO ,
2
diylbis(1H-tetrazole) and the corresponding sulfonyl
chloride were mixed with NaOH solution (40 mL, 10%)
and refluxed. Upon completion of the process (TLC),
the reaction mixture was poured into ice cold water,
neutralized by dil. HCl, the precipitate of the correspond-
ing compound was filtered off and dried under vacuum,
purified by column chromatography and recrystallized
from methanol.
sym.), 1033 (SO , sym.), 1045 (C–N), 1047 (C–N),
2
1569 (SO , asym.), 1577 (SO , asym.), 1625 (C=N),
2
2
1
1628 (C=N), 2993 (CH-Ar). H NMR spectrum, δ, ppm:
7.71–7.73 d (2H, CH-Ar), 7.92–7.97 d (2H, CH-Ar),
8.23–8.26 d (2H, CH-Ar), 8.42–8.45 d (2H, CH-Ar),
9.01–9.04 d (2H, CH-Ar), 9.06–9.10 d (2H, CH-Ar). C
NMR spectrum, δ, ppm: 119.14 (Ar-C), 119.24 (Ar-C),
120.35 (Ar-C), 121.21 (Ar-C), 121.29 (Ar-C), 122.55
13
(
1
Ar-C), 122.98 (Ar-C), 123.77 (Ar-C), 124.08 (Ar-C),
24.77 (Ar-C), 125.00 (Ar-C), 125.85 (Ar-C), 126.17
(Ar-C), 126.88 (Ar-C), 127.00 (Ar-C), 127.11 (Ar-C),
27.51 (Ar-C), 127.77 (Ar-C), 127.99 (Ar-C), 157.11
5
,5'-Benzene-1,4-diylbis[1-(phenylsulfonyl)-1H-
tetrazole] (1). White crystals, yield 85%, mp 122–124°C.
FT-IR spectrum, ν, cm : 1027 (SO , sym.), 1030 (SO ,
sym.), 1045 (C–N), 1049 (C–N), 1575 (SO , asym.), 1577
–
1
2
2
1
(
2
C–N), 161. 33 (C–N), 165.17 (C=N), 165.27 (C=N).
(
SO , asym.), 1620 (C=N), 1624 (C=N), 2987 (CH-Ar).
2
+
1
ESI-MS: m/z: 650.85 [M + H] . Found, %: C 36.85, H
1
H 1.85, N 17.18.
H NMR spectrum, δ, ppm: 7.72–7.75 d (2H, CH-Ar),
.92–7.98 d (2H, CH-Ar), 8.20–8.25 m (3H, CH-Ar),
.42–8.48 m (3H, CH-Ar), 9.00–9.03 d (2H, CH-Ar),
.09–9.10 d (2H, CH-Ar). C NMR spectrum, δ, ppm:
19.36 (Ar-C), 120.45 (Ar-C), 120.70 (Ar-C), 121.63
Ar-C), 122.02 (Ar-C), 122.31 (Ar-C), 123.01 (Ar-C),
24.13 (Ar-C), 124.30 (Ar-C), 124.67 (Ar-C), 125.12
Ar-C), 125.30 (Ar-C), 125.55 (Ar-C), 126.02 (Ar-C),
26.31 (Ar-C), 126.70 (Ar-C), 127.19 (Ar-C), 127.53
Ar-C), 127.93 (Ar-C), 158.33 (C–N), 160. 82 (C–N),
.88, N 17.21. C H Br N O S . Calculated, %: C 36.83,
7
8
9
1
(
1
(
1
(
20 12 2 8 4 2
1
3
5,5'-Benzene-1,4-diylbis{1-[(3-bromophenyl)-
sulfonyl]-1H-tetrazole} (4). White crystals, yield 83%,
mp 123–125°C. FT-IR spectrum, ν, cm : 1021 (SO ,
sym.), 1041 (SO , sym.), 1051 (C–N), 1059 (C–N),
1561 (SO , asym.), 1573 (SO , asym.), 1627 (C=N),
1633 (C=N), 2990 (CH-Ar). H NMR spectrum, δ, ppm:
7.71–7.73 d (2H, CH-Ar), 7.91–7.93 d (2H, CH-Ar),
8.27–8.29 d (2H, CH-Ar), 8.43–8.50 m (2H, CH-Ar),
–
1
2
2
2
2
1
1
66.91 (C=N), 167.82 (C=N). ESI-MS: m/z: 495.08 [M +
+
13
H] . Found, %: C 48.55, H 2.87, N 22.69. C H N O S .
9.11–9.13 d (2H, CH-Ar), 9.22–9.25 d (2H, CH-Ar). C
20
14
8
4 2
Calculated, %: C 48.58, H 2.85, N 22.6.
,5'-Benzene-1,4-diylbis{1-[(4-chlorophenyl)-
sulfonyl]-1H-tetrazole} (2). White crystals, yield 85%,
NMR spectrum, δ, ppm: 119.77 (Ar-C), 120.19 (Ar-C),
1
(
20.77 (Ar-C), 121.37 (Ar-C), 121.85 (Ar-C), 122.97
Ar-C), 122.41 (Ar-C), 123.35 (Ar-C), 124.11 (Ar-C),
124.65 (Ar-C), 125.18 (Ar-C), 125.77 (Ar-C), 126.35
Ar-C), 126.86 (Ar-C), 127.01 (Ar-C), 127.57 (Ar-C),
27.78 (Ar-C), 127.90 (Ar-C), 127.99 (Ar-C), 150.44
5
–
1
mp 125–127°C. FT-IR spectrum, ν, cm : 1021 (SO ,
2
(
1
sym.), 1028 (SO , sym.), 1043 (C–N), 1044 (C–N),
2
1
1
7
8
9
571 (SO , asym.), 1573 (SO , asym.), 1621 (C=N),
2 2
1
(C–N), 164. 14 (C–N), 166.33 (C=N), 167.22 (C=N).
626 (C=N), 2980 (CH-Ar). H NMR spectrum, δ, ppm:
.72–7.74 d (2H, CH-Ar), 7.92–7.97 d (2H, CH-Ar),
.23–8.25 d (2H, CHAr), 8.42–8.45 d (2H, CH-Ar),
+
ESI-MS: m/z: 650.85 [M + H] . Found, %: C 36.85, H
1
.88, N 17.21. C H Br N O S . Calculated, %: C 36.83,
20 12 2 8 4 2
1
3
H 1.85, N 17.18.
.01–9.05 d (2H, CH-Ar), 9.08–9.11 d (2H, CH-Ar). C
NMR spectrum, δ, ppm: 119.49 (Ar-C), 120.16 (Ar-C),
20.79 (Ar-C), 121.31 (Ar-C), 122.31 (Ar-C), 122.47
Ar-C), 123.75 (Ar-C), 124.35 (Ar-C), 123.91 (Ar-C),
5,5'-Benzene-1,4-diylbis{1-[(4-methylphenyl)-
1
(
sulfonyl]-1H-tetrazole} (5). Creamy crystals, yield 86%,
–
1
mp 120–122°C. FT-IR spectrum, ν, cm : 1030 (SO ,
2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

SYNTHESIS, BIOLOGICAL ACTIVITY, AND MOLECULAR DOCKING ASSESSMENT
1853
sym.), 1033 (SO , sym.), 1055 (C–N), 1061 (C–N),
(Ar-C), 120.72 (Ar-C), 120.99 (Ar-C), 121.10 (Ar-C),
121.58 (Ar-C), 122.11 (Ar-C), 122.59 (Ar-C), 123.55
(Ar-C), 124.13 (Ar-C), 124.90 (Ar-C), 125.30 (Ar-C),
125.82 (Ar-C), 126.15 (Ar-C), 126.88 (Ar-C), 127.00
(Ar-C), 127.10 (Ar-C), 127.52 (Ar-C), 127.69, (Ar-C),
127.95 (Ar-C), 153.33 (C–N), 164.52 (C–N), 167.21
2
1
1
7
8
9
569 (SO , asym.), 1570 (SO , asym.), 1634 (C=N),
2 2
1
639 (C=N), 2989 (CH-Ar). H NMR spectrum, δ, ppm:
.72–7.75 d (2H, CH-Ar), 7.91–7.94 d (2H, CH-Ar),
.27–8.29 d (2H, CH-Ar), 8.43–8.46 d (2H, CH-Ar),
.11–9.15 d (2H, CH-Ar), 9.21–9.25 d (2H, CH-Ar), 2.51
1
3
+
s (3H, CH ), 2.57 s (3H, CH ). C NMR spectrum, δ,
(C=N), 168.11 (C=N). ESI-MS: m/z: 583.00 [M + H] .
3
3
ppm: 25.77 (CH ), 26.17 (CH ), 119.35 (Ar-C), 120.23
Found, %: C 49.39, H 3.285, N 19.18. C H N O S .
3
3
24 22
8
6 2
(
1
(
1
(
1
(
5
Ar-C), 120.77 (Ar-C), 121.30 (Ar-C), 121.85 (Ar-C),
22.21 (Ar-C), 122.78 (Ar-C), 123.30 (Ar-C), 124.08
Ar-C), 124.45 (Ar-C), 125.17 (Ar-C), 125.79 (Ar-C),
26.21 (Ar-C), 126.75 (Ar-C), 127.02 (Ar-C), 127.11
Ar-C), 127.25 (Ar-C), 127.58 (Ar-C), 127.95 (Ar-C),
Calculated, % C 49.48, H 3.81, N 19.23.
5
,5'-Benzene-1,4-diylbis{1-[(4-nitrophenyl)-
sulfonyl]-1H-tetrazole} (8). Yellow crystals, yield 80%,
mp 119–121°C. FT-IR spectrum, ν, cm : 1021 (SO ,
–1
2
sym.), 1036 (SO , sym.), 1051 (C–N), 1055 (C–N),
2
50.91 (C–N), 164. 70 (C–N), 166.55 (C=N), 167.57
1
1
567 (SO , asym.), 1573 (SO , asym.), 1628 (C=N),
2 2
635 (C=N), 2985 (CH-Ar). H NMR spectrum, δ, ppm:
+
C=N). ESI-MS: m/z: 523.11 [M + H] . Found, %: C
1
0.55, H 3.49, N 21.46. C H N O S . Calculated, %:
22 18 8 4 2
7.86–7.789 d (2H, CH-Ar), 7.78–7.80 d (2H, CH-Ar),
.36–8.38 d (2H, CH-Ar), 8.55–8.59 d (2H, CH-Ar),
C 50.57, H 3.47, N 21.44.
8
13
5
,5'-Benzene-1,4-diylbis{1-[(4-methoxyphenyl)-
8.90–8.94 d (2H, CH-Ar), 9.08–9.11 d (2H, CH-Ar). C
NMR spectrum, δ, ppm: 120.19 (Ar-C), 120.97 (Ar-C),
121.05 (Ar-C), 121.33 (Ar-C), 121.59 (Ar-C), 122.17
(Ar-C), 122.88 (Ar-C), 123.07 (Ar-C), 124.36 (Ar-C),
125.79 (Ar-C), 126.09 (Ar-C), 126.73 (Ar-C), 126.97
(Ar-C), 127.35 (Ar-C), 127.49 (Ar-C), 127.95 (Ar-C),
128.07 (Ar-C), 128.19 (Ar-C), 128.31 (Ar-C), 154.92
(C–N), 163.00 (C–N), 165.19 (C=N), 167.08 (C=N).
sulfonyl]-1H-tetrazole} (6). White crystals, yield 88%,
mp 125–127°C. FT-IR spectrum, ν, cm : 1037 (SO ,
sym.), 1041 (SO , sym.), 1057 (C–N), 1059 (C–N),
1
1
7
8
9
–
1
2
2
572 (SO , asym.), 1575 (SO , asym.), 1637 (C=N),
2 2
1
643 (C=N), 2995 (CH-Ar). H NMR spectrum, δ, ppm:
.74–7.76 d (2H, CH-Ar), 7.92–7.95 d (2H, CH-Ar),
.28–8.29 d (2H, CH-Ar), 8.45–8.47 d (2H, CH-Ar),
.11–9.15 d (2H, CH-Ar), 9.21–9.25 d (2H, CH-Ar), 3.87
+
ESI-MS: m/z: 585.07 [M + H] . Found, %: C 41.13, H
1
3
s (3H, OCH ), 2.89 s (3H, OCH ). C NMR spectrum,
2.04, N 23.41. C H N O S . Calculated, %: C 41.10,
3
3
20 12 10
8 2
δ, ppm: 55.78 (OCH ), 55.98 (OCH ), 120.08 (Ar-C),
H 2.07, N 23.96.
,5'-Benzene-1,4-diylbis{1-[(4-methylsulfonyl-
phenyl)sulfonyl]-1H-tetrazole} (9). Yellow crystals,
3
3
1
(
1
(
20.25 (Ar-C), 120.90 (Ar-C), 121.12 (Ar-C), 121.78
Ar-C), 122.51 (Ar-C), 122.91 (Ar-C), 123.35 (Ar-C),
24.15 (Ar-C), 124.95 (Ar-C), 125.37 (Ar-C), 125.89
Ar-C), 126.30 (Ar-C), 126.76 (Ar-C), 127.99 (Ar-C),
27.02 (Ar-C), 127.12 (Ar-C), 127.25 (Ar-C), 127.62
5
–1
yield 83%, mp 125–127°C. FT-IR spectrum, ν, cm :
037 (SO , sym.), 1040 (SO , sym.), 1057 (C–N), 1065
1
2
2
1
(
(
C–N), 1560 (SO , asym.), 1578 (SO , asym.), 1633
2 2
C=N), 1678 (C=N), 2990 (CH-Ar). H NMR spectrum,
(
1
Ar-C), 153.00 (C–N), 164.19 (C–N), 167.33 (C=N),
68.08 (C=N). ESI-MS: m/z: 555.07 [M + H] . Found,
1
+
δ, ppm: 7.93–7.97 d (2H, CH-Ar), 7.89–7.92 d (2H, CH-
Ar), 8.76–8.79 d (2H, CH-Ar), 8.68–8.71 d (2H, CH-Ar),
%
: C 47.67, H 3.28, N 20.23. C H N O S . Calculated,
22 18 8 6 2
%
: C 47.65, H 3.27, N 20.21.
,5'-Benzene-1,4-diylbis{1-[(4-ethoxyphenyl)-
sulfonyl]-1H-tetrazole} (7). White crystals, yield 81%,
9
.01–9.06 d (2H, CH-Ar), 9.23–9.27 d (2H, CH-Ar), 2.62
1
3
5
s (3H, CH ), 2.54 s (3H, CH ). C NMR spectrum, δ,
3 3
ppm: 25.13 (CH ), 26.94 (CH ), 119.88 (Ar-C), 120.12
3
3
–
1
mp 121–125°C. FT-IR spectrum, ν, cm : 1022 (SO ,
(Ar-C), 120.28 (Ar-C), 121.55 (Ar-C), 121.98 (Ar-C),
122.10 (Ar-C), 122.55 (Ar-C), 123.17 (Ar-C), 123.99
(Ar-C), 124.40 (Ar-C), 125.11 (Ar-C), 125.39 (Ar-C),
126.18 (Ar-C), 126.70 (Ar-C), 127.05 (Ar-C), 127.18
(Ar-C), 127.51 (Ar-C), 127.83 (Ar-C), 127.99, (Ar-C),
151.08 (C–N), 164.79 (C–N), 166.39 (C=N), 167.11
2
sym.), 1037 (SO , sym.), 1055 (C–N), 1063 (C–N), 1579
2
(
(
7
SO , asym.), 1583 (SO , asym.), 1633 (C=N), 1647
2 2
1
C=N), 2999 (CH-Ar). H NMR spectrum, δ, ppm: 7.76–
.78 d (2H, CH-Ar), 7.93–7.96 d (2H, CH-Ar), 8.27–8.29
d (2H, CH-Ar), 8.44–8.47 d (2H, CH-Ar), 9.11–9.15 d
2H, CH-Ar), 9.22–9.24 d (2H, CH-Ar), 1.28-1.33 t (3H,
+
(
(C=N). ESI-MS: m/z: 523.11 [M + H] . Found, %: C
1
3
CH ), 4.11-4.18 q (2H, CH ). C NMR spectrum, δ,
40.64, H 2.80, N 17.23. C H N O S . Calculated, %:
3
2
22 18
8
8 4
ppm: 25.71 (CH ), 55.57 (CH ), 67.35 (O-CH ), 120.10
C 40.61, H 2.79, N 17.22.
3
2
2
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

1854
ARSHAD et al.
5
,5'-Benzene-1,4-diylbis{1-[(4-sulfanilamidephe-
NMR spectrum, δ, ppm: 150.35 (C–N), 160.19 (C–N),
167.04 (C=N), 168.39 (C=N), 120.19 (Ar-C), 120.85
(Ar-C), 121.19 (Ar-C), 121.90 (Ar-C), 122.41 (Ar-C),
122.71 (Ar-C), 122.90 (Ar-C), 123.77 (Ar-C), 124.71
(Ar-C), 124.97 (Ar-C), 125.32 (Ar-C), 125.77 (Ar-C),
126.81 (Ar-C), 126.95 (Ar-C), 127.00, (Ar-C), 127.08
(Ar-C), 127.16 (Ar-C), 127.50 (Ar-C), 127.89 (Ar-C).
nyl)sulfonyl]-1H-tetrazole} (10). Yellow crystals, yield
9%, mp 135–137°C. FT-IR spectrum, ν, cm : 1038
–
1
8
(
1
(
SO , sym.), 1043 (SO , sym.), 1057 (C–N), 1065 (C–N),
2
2
563 (SO , asym.), 1571 (SO , asym.), 1631 (C=N), 1675
C=N), 2990 (CH-Ar), 3312 (NH ). H NMR spectrum,
δ, ppm: 9.91 s (2H, NH ), 9.96 s (2H, NH ); 9.15–9.19
d (2H, CH-Ar), 9.22–9.25 d (2H, CH-Ar), 8.79–8.81 d
2H, CH-Ar), 8.57–8.59 d (2H, CH-Ar), 7.96–7.99 d (2H,
2 2
1
2
2
2
+
ESI-MS: m/z: 663.09 [M + H] . Found, %: C 39.85, H
(
1.85, N 16.93. C H F N O S . Calculated, %: C 39.88,
22
12
6
8
6 2
1
3
CH-Ar), 7.82–7.86 d (2H, CH-Ar). C NMR spectrum,
H 1.83, N 16.91.
δ, ppm: 120.12 (Ar-C), 120.71 (Ar-C), 120.88 (Ar-C),
Antimicrobial activity. The synthesized compounds
–12 were assessed for antimicrobial activity against
gram positive and negative strains of the pathogens
S. aureus (ATCC-25923), S. epidermidis (ATCC-29887),
E. coli (ATCC-25922), P. mirabilis (ATCC-25933)]. The
tests were carried out by the developed earlier method
1
(
1
(
21.19 (Ar-C), 121.75 (Ar-C), 122.03 (Ar-C), 122.72
Ar-C), 123.19 (Ar-C), 123.79 (Ar-C), 124.37 (Ar-C),
25.33 (Ar-C), 125.69 (Ar-C), 126.27 (Ar-C), 126.59
Ar-C), 127.17 (Ar-C), 127.39 (Ar-C), 127.54 (Ar-C),
27.75 (Ar-C), 127.97 (Ar-C), 150.93 (C–N), 164.37
1
[
1
(
6
C–N), 167.06 (C=N), 168.33 (C=N). ESI-MS: m/z:
53.00 [M + H] . Found, %: C 36.90, H 2.45, N 21.45.
[
13-19]. The pathogens (S. aureus, S. epidermidis,
P. mirabilis, and E. coli) were sub-cultured in nutrient
+
C H N O S . Calculated, %: C 36.81, H 2.47, N 21.46.
20
16 10
8
4
agar medium and left for incubation at 37°C for 24 h. To
5
5
,5'-Benzene-1,4-diylbis{1-[(4-thiomethylphenyl)
yield the suspension of about 10 CFU/Ml, the bacteria
sulfonyl]-1H-tetrazole} (11). Yellow crystals, yield
cells were suspended in the saline solution. The mixture
(10 mL of suspension + 10 mL of sterile antibiotic agar)
was heated to 40°C and poured on the agar plate in a
laminar flow cabinet. To 100 mL of DMSO, was added
1 g of the compound for yielding the stock solution,
one gram of each test compound was added. The 6 mm
diameter paper discs were dipped in the solutions of the
test compounds, diluted to different concentrations, fixed
on agar plate, and incubated for 18 h for determining the
inhibition zone.
–
1
8
0%, mp 129–131°C. FT-IR spectrum, ν, cm : 1025
(
SO , sym.), 1031 (SO , sym.), 1057 (C–N), 1067 (C–N),
2
2
1
1
9
8
7
572 (SO , asym.), 1578 (SO , asym.), 1637 (C=N),
2 2
1
643 (C=N), 2999 (CH-Ar). H NMR spectrum, δ, ppm:
.29–9.32 d (2H, CH-Ar), 9.12–9.16 d (2H, CH-Ar),
.57–8.60 d (2H, CH-Ar), 8.36–8.39 d (2H, CH-Ar),
.92–7.96 d (2H, CH-Ar), 7.77–7.80 d (2H, CH-Ar), 2.51
1
3
s (3H, CH ), 2.57 s (3H, CH ). C NMR spectrum, δ,
3
3
ppm: 25.54 (CH ), 25.88 (CH ), 120.37 (Ar-C), 120.91
3
3
(
1
(
1
(
1
Ar-C), 121.39 (Ar-C), 121.95 (Ar-C), 122.67 (Ar-C),
22.84 (Ar-C), 123.59 (Ar-C), 124.58 (Ar-C), 124.88
Ar-C), 125.82 (Ar-C), 125.86 (Ar-C), 126.57 (Ar-C),
26.88 (Ar-C), 127.14, (Ar-C), 127.23 (Ar-C), 127.51
Ar-C), 127.67 (Ar-C), 127.99 (Ar-C), 150.37 (C–N),
MTT assay. To assess toxicity status of the products
–12, hepatocellular carcinoma Hep G2 cells were har-
vested in DMEM (Dulbecco’s modified Eagle’s medium)
with a mixture of 10% FBS (heat inactivated) with
00 units/mL penicillin, 100 mg/mL streptomycin and
.5 mg/mL amphotericin B) at 37°C. The process was
continued until reaching 80% confluent level. The percent
viability of the cells was tested in accordance with the
developed protocol [20, 21].
1
1
2
60.55 (C–N), 167.37 (C=N), 168.15 (C=N). ESI-MS:
+
m/z: 587.08 [M + H] . Found, %: C 45.10, H 3.12, N
1
N 19.10.
9.12. C H N O S . Calculated, %: C 45.04, H 3.09,
22 18 8 4 4
5
,5'-Benzene-1,4-diylbis{1-[(4-trifluoromethyl-
Molecular docking. Molecular docking of the com-
pounds 1–12 was carried out by Auto-dock tools 1.5.6
phenyl)sulfonyl]-1H-tetrazole} (12). Creamy crystals,
yield 85%, mp 126–128°C. FT-IR spectrum, ν, cm :
017 (SO , sym.), 1026 (SO , sym.), 1061 (C–N), 1069
C–N), 1573 (SO , asym.), 1579 (SO , asym.), 1644
2 2
C=N), 1659 (C=N), 2972 (CH-Ar). H NMR spectrum,
–
1
[
22–24]. Chem Draw Ultra 8.0 was used for drawing
1
(
(
2
2
the structures 1–12. The smiles files were generated and
converted to the PDBs by the online smile translator.
1
RESULTS AND DISCUSSION
δ, ppm: 9.11–9.16 d (2H, CH-Ar), 8.98–9.02 d (2H, CH-
Ar), 8.87–8.92 d (2H, CH-Ar), 8.69–8.74 d (2H, CH-Ar),
The four steps synthetic approach to the target
compounds (Scheme 1) started with the reaction
1
3
8
.15–8.19 d (2H, CH-Ar), 7.96–7.99 d (2H, CH-Ar). C
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

SYNTHESIS, BIOLOGICAL ACTIVITY, AND MOLECULAR DOCKING ASSESSMENT
1855
Scheme 1. Synthetic approach to compounds 1–12.
N
N
N
N
N
N
aꢀd
N
S
N
S
OHC
CHO
O
O
O
O
R
R
1ꢀ12
a. NH OH·HCl, NaHCO , H O, reflux; b. Acetic anhydride, H O, reflux;
2
3
2
2
c. NaN , ZnBr , 2-Propanol, H O, reflux; d. Sulfonyl chloride, NaOH, reflux.
3
2
2
R = Ph (1), 4-Cl-Ph (2), 4-Br-Ph (3), 3-Br-Ph (4), 4-CH Ph (5), 4-OCH -Ph (6), 4-OC H -Ph (7),
3
3
2 5
4
-NO -Ph (8), 4-CH SO -Ph (9), 4-NH SO -Ph (10), 4-SCH -Ph (11), 4-OCF -Ph (12).
2 3 2 2 2 3 3
1
of the aldehyde and hydroxylamine hydrochloride
in water which gave (Z,Z)-benzene-1,4-diylbis(N-
hydroxymethanimine). Its following refluxing with acetic
anhydride led to benzene-1,4-dicarbonitrile, cyclization
of which with sodium azide and zinc bromide led to
formation of 5,5'-benzene-1,4-diylbis(1H-tetrazole).
Sulfonylation of the tetrazole intermediate by various
substituted sulfonyl chlorides gave the target compounds
of tetrazole NH in the range of 10.922–11.145 ppm in H
NMR spectra of the products 1–12.
Drug likeness and physicochemical properties of
compounds 1–12. The molecular structures of com-
pounds 1–12 were designed, and their physicochemical
properties and bioactivity score were calculated. The
calculations indicated that all compounds did not have
the molecular weight in accordance with the Lipinski rule
of Five, except the compound 1. The other parameters
including milogP, TPSA, Natoms, Non, Nohnh, Nviola-
tionsn Nrot, and Volume correlated with the Lipinski rule
of Five for active compounds (Tables 1, 2).
1
–12. Structures of the synthesized compounds were
1
13
supported by FT-IR, H and C NMR, and mass spectra.
Completion of the last step of the synthesis was indicated
by the absence of N-H bands in the range of 3255–
–1
3312 cm and disappearance of the characteristic singlet
Table 1. Physicochemical properties of compounds 1–12 and ciprofloxacin
Physicochemical property score
Compound
miLogP
2.750
4.100
4.370
4.320
3.600
2.860
3.610
2.670
0.490
0.140
3.610
4.690
–0.071
TPSA
Natoms
34
MW
nON nOHNH Nviolations Nrotb Volume
1
2
3
4
5
6
7
8
9
1
155.500
155.500
155.500
155.500
155.500
173.970
173.970
247.150
223.790
275.830
155.500
173.970
74.569
494.520
563.410
652.310
652.310
522.570
554.570
582.620
584.510
650.700
652.680
586.710
662.510
331.347
12
12
12
12
12
14
14
18
16
18
12
14
6
0
0
0
0
0
0
0
0
0
4
0
0
2
1
2
2
2
2
2
2
2
2
2
2
2
0
6
6
378.340
405.410
414.110
414.110
411.460
429.430
463.030
425.000
474.320
463.780
447.720
458.900
285.460
36
36
6
36
6
36
6
38
8
40
10
8
40
42
8
0
42
8
11
38
8
1
2
44
10
3
Ciprofloxacin
24
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

1856
ARSHAD et al.
Table 2. Bioactivity score of the compounds 1–12 and ciprofloxacin
Bioactivity score
Compound
GPCR
ligand
Ion channel
modulator
Kinase
Nuclear
receptor ligand
Protease
inhibitor
Enzyme
inhibitor
inhibitor
–0.05
–0.06
–0.08
–0.10
–0.10
–0.08
–0.16
–0.19
–0.18
–0.18
–0.18
–0.10
–0.07
1
2
3
4
5
6
7
8
9
1
0.06
0.05
–0.16
–0.19
–0.24
–0.26
–0.26
–0.30
–0.42
–0.40
–0.59
–0.59
–0.55
–0.28
–0.04
–0.23
–0.23
–0.29
–0.32
–0.24
–0.22
–0.26
–0.33
–0.29
–0.29
–0.48
–0.22
–0.19
–0.04
–0.07
–0.12
–0.12
–0.09
–0.08
–0.10
–0.14
0.04
0.02
0.00
–0.02
–0.03
0.01
–0.03
–0.03
–0.03
–0.03
–0.11
–0.13
–0.06
–0.06
–0.08
–0.02
0.28
0.02
–0.01
–0.06
–0.01
–0.01
–0.05
0.00
0
0.04
11
0.04
1
2
–0.06
–0.21
Ciprofloxacin
0.12
Antimicrobial activity. The synthesized compounds
–12 were tested for antimicrobial activity against
gram positive and gram negative pathogens (S. aureus,
S. epidermidis, E. coli, and P. mirabilis). All compounds
demonstrated substantial values of activity that were
higher or close to that of ciprofloxacin (Table 3).
MTT assay. The synthesized compounds were tested
according to MTT assay using HepG2 cells. The cells
were cultured in DMEM and the percent viability of
cells was determined. HepG2 Cells were treated by the
solutions of compounds within the concentration range
3.125–100 μmol/L. The determined cyto-toxicity was
concentration dependent (see the figure).
1
Molecular docking. Molecular docking assessment
carried out for compounds 1–12 against Glc-N-6P syn-
thase (PDB: 2VF5) revealed their formation of H-bonds
with the amino acids, including SR 303, CYS 300, SER
3
49, SER 401, VAL 399, ILE 397, GLY 398, THR 302,
ILU 397, GLU 396, THR 352, GLN 348, SER 347, GLU
88. H-Bonding with SER-401 and VAL 399 residues
4
was observed for all compounds. Also H-bonding was
indicated for compounds 1–5, 7 and 11 with SER 303,
for 1, 4, 7, and 8 with CYS 300, for 1, 3, 4, and 6–12
with SER 349, for 2, 10, and 11 with ILE 397, for 2, 5,
9
, and 10 with GLY 398, for 2, 5, 6, 9, 10, and 12 with
THR 302, for 3 and 11 with ILU 397, for 3, 9–11 with
GLU 396, for 6, 8–10, and 12 with THR 352, for 9, 10,
and 12 with GLU 488. Ciprofloxacin was likely to form
H-bonding with VAL 567 and TYR 576. The above data
strongly stimulate further experimental studies.
Percent viability of cells determined for the compounds 1–12
and ciprofloxacin: (1) 3.125, (2) 6.25, (3) 12.5, (4) 25, (5) 50,
and (6) 100 μmol/L.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

SYNTHESIS, BIOLOGICAL ACTIVITY, AND MOLECULAR DOCKING ASSESSMENT
1857
Table 3. Zones of inhibition and the minimum inhibitory concentrations of tetrazole derivatives 1–12 and ciprofloxacin
Zones of inhibition, mm
gram positive gram negative
Minimum inhibitory concentration, μg/mL
gram positive
gram negative
E. coli P. mirabilis
Compound
S.
S.
S. aureus
E. coli
P. mirabilis S. aureus
epidermidis
epidermidis
1
2
3
4
5
6
7
8
9
20.44±0.18 22.53±0.17 23.06±0.14 20.24±0.22
20.90±0.27 22.22±0.22 23.55±0.30 20.58±0.31
20.76±0.17 21.76±0.40 22.11±0.22 19.98±0.17
20.10±0.29 21.22±0.23 22.30±0.19 20.28±0.25
20.31±0.20 22.31±0.33 23.73±0.32 21.14±0.27
21.15±0.35 22.50±0.27 23.98±0.10 20.76±0.35
20.93±0.17 21.29±0.20 21.18±0.20 20.35±0.28
21.76±0.22 21.79±0.19 23.98±0.23 20.88±0.18
21.85±0.30 22.98±0.21 23.77±0.26 20.70±0.17
22.12±0.20 22.85±0.25 23.19±0.50 20.34±0.27
21.12±0.18 21.59±0.43 22.49±0.36 20.55±0.40
21.22±0.20 21.70±0.30 22.88±0.24 20.34±0.38
21.39±0.21 22.87±0.37 23.69±0.81 22.34±0.21
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
3.125
3.125
3.125
3.125
3.125
3.125
3.125
3.125
3.125
3.125
3.125
3.125
3.125
12.5
12.5
12.5
12.5
12.5
6.25
6.25
6.25
6.25
6.25
12.5
12.5
6.25
25
25
25
25
25
12.5
12.5
12.5
12.5
12.5
25
1
0
11
1
2
25
Ciprofloxacin
12.5
CONCLUSIONS
2. Soliman, H.A., Kalmouch, A., Awad, H.M., and Abdel
Wahed, N.A.M., Russ. J. Gen. Chem., 2018, vol. 88,
p. 1726.
A new sequence of twelve sulfonynated analogues of
bis-tetrazole is designed and computationally screened for
physicochemical properties and drug likeness. The readily
synthesized compounds are tested for antimicrobial activ-
ity and cytotoxicity. The tests reveal that all compounds
demonstrate the significant antimicrobial activity with
the low toxic effect.
https://doi.org/10.1134/S1070363218080273
3. Issell, B.F., Cancer Chemother. Pharmacol., 1982, vol. 7,
p. 73.
https://doi.org/10.1007/BF00254525
4. Arshad, M., Bhat, A.R., Pokharel, S., Lee, E.J.,
Athar, F., and Choi, I., Eur. J. Med. Chem., 2014, vol. 71,
p. 229.
ACKNOWLEDGMENTS
https://doi.org/10.1016/j.ejmech.2013.11.008
5
. Marc,A.I., Bernard, M., Stephanie, R.,Andrea, S., Gheor-
ghe, C., Valentin, C., and Claudiu, T.S., Bioorg. Med.
Chem., 2004, vol. 12, p. 2717.
The author Dr. MohammadArshad is highly thankful
to Dr. FerasAlMarshad, the Dean College of MedicineAl-
Dawadmi, Shaqra University Kingdom of Saudi Arabia
for his kind cooperation.
https://doi.org/10.1016/j.bmc.2004.03.008
6
. Bhat,A.R.,Arshad,M.,Lee,E.J.,Pokharel,S.,Choi,I.,and
Athar, F., Chem. Biod., 2013, vol. 10, p. 2267.
https://doi.org/10.1002/cbdv.201300009
CONFLICT OF INTEREST
7
. Molinspiration Cheminformatics. Nova ulica, SK-90026
Slovensky Grob, Slovak Republic. [Online] Available
from: http://www. molinspiration.com [Accessed on 3rd
July, 2012].
No conflict of interest was declared by the authors.
REFERENCES
1
. Myznikov, L.V., Hrabalek,A., and Koldobskii, G.I.,
Chem. Heterocycl. Comp., 2007, vol. 43, p. 1.
https://doi.org/10.1007/s10593-007-0001-5
8. Verma, A., Asian Pac. J. Trop. Biomed., 2012, vol. 2,
p. S1735.
https://doi.org/10.1016/S2221-1691(12)60486-9
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 9 2019

1858
ARSHAD et al.
9
. Alodeani, E.A., Arshad, M., and Izhari, M.A., Eur.
J. Pharm. Med. Res., 2017, vol. 4, p. 447.
https://www.ejpmr.com/admin/assets/article_is-
sue/1490961035.pdf.
17. Bushra, R., Shahadat, M., Khan, M.A., Adnan, R., Ar-
shad, M., Rafatullah, M., and Naushad, M., Int. J.
Env. Sci. Technol., 2015, vol. 12, p. 3635.
https://doi.org/10.1007/s13762-014-0726-5
1
0. Alodeani, E.A., Arshad, M., and Izhari, M.A., Eur.
J. Pharm. Med. Res., 2015, vol. 2, p. 296.
18. Nami, S.A.A., Khan, M.S., Arshad, M., Raza, M.A., and
Khan, I., Polym. Adv. Technol., 2017, vol. 28, p. 10.
https://doi.org/10.1002/pat.3846
http://www.ejpmr.com/admin/assets/article_issue/
1
9. Nayab, P.S., Arif, R., Arshad, M., and Rahisud-
din, Heterocyc. Lett., 2015, vol. 5, p. 223.
1
446625932.pdf
1
1. Arshad, M., Russ J Gen Chem., 2018, vol. 88, p. 1886.
https://doi.org/10.1134/S1070363218090207
2. Alodeani, E.A., Arshad, M., and Izhari, M.A., Asian
Pac. J. Trop Biomed., 2015, vol. 5, p. 676.
http://www.heteroletters.org/issue25/PDF/Paper-9.pdf.
0. Gupta, M.K., Neelakantan, TV., Sanghamitra, M.,
Tyagi, R.K., Dinda, A., Maulik, S., Mukhopadhyay, C.K.,
and Goswami, S.K., Antioxid. Redox Signal, 2006, vol. 8,
p. 1081.
2
1
https://doi.org/10.1016/j.apjtb.2015.04.010
1
1
1
3. Arshad, M., Bhat, A.R., Hoi, K.K., Choi, I., and Athar, F.,
https://doi.org/10.1089/ars.2006.8.1081
Chin. Chem. Lett., 2017, vol. 28 p. 1559.
2
2
1. Mosmann, T., J. Immunol. Methods, 1983, vol. 65, p. 55.
https://doi.org/10.1016/0022-1759(83)90303-4
2. Morris, G.M., Goodsell, D.S., Halliday, R.S., Huey, R.,
Hart, W.E., Belew, R.K., Olson, A.J., J. Comput. Chem.,
https://doi.org/10.1016/j.cclet.2016.12.037
4. Kareem, A., Laxmi, Arshad, M., and Nishat, N., J. Photo-
chem. Photobiol. B, 2016, vol. 160, p. 163.
https://doi.org/10.1016/j.jphotobiol.2016.03.030
5. Iram, N., Khan, M.S., Jolly, R., Arshad, M., Alam, M.,
Alam, P., Khan, R.H., and Firdaus, F., J. Photo-
chem. Photobiol. B, 2015, vol. 153, p. 20.
1
998, vol. 19, p. 1639.
https://doi.org/10.1002/(SICI)1096-987X(19981115)19:
4%3C1639::AID-JCC10%3E3.0.CO;2-B
1
2
3. Mouilleron, S., Badet-Denisot, M.A., and Golinelli-Pim-
paneau, B., J. Mol. Biol., 2008, vol. 377, no. 4, p. 1174.
https://doi.org/10.1016/j.jmb.2008.01.077
https://doi.org/10.1016/j.jphotobiol.2015.09.001
6. Nami, S.A.A., Arshad, M., Shakir, M., Khan, M.S.,
Alam, M., Lee, D.U., Park, S., and Sarikavakli, N.,
Polym. Adv. Technol., 2015, vol. 26, p. 1627.
1
24. Trott, O. and Olson, A.J., J. Comput. Chem., 2010, vol. 31,
p. 455.
https://doi.org/10.1002/pat.3591
https://doi.org/10.1002/jcc.21334
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