Bulky organosilicon compounds based on sulfanyltetrazoles: their synthesis and in vitro antibacterial evaluation

Article abstract of DOI:10.1007/s13738-018-1325-z

The study introduces different organosilicon derivatives incorporating sulfanyltetrazole ring for biological applications. Initially, the sulfanyltetrazole derivatives and halo-analogues (Br, I) were synthesized. Later, selective reaction of tris(trimethylsilyl)methyllithium (TsiLi) in the presence (?46 and 0?°C) and absence (room temperature) of CS₂ with halo-sulfanyltetrazole derivatives yielded new multifunctional sulfanyltetrazole regioisomers with SH, C?=?S, ethynylthio and SiMe₃ groups, respectively. All the synthesized compounds were characterized by IR, ¹H-NMR, ¹³C-NMR spectra and elemental analysis data. The compounds were screened for their antibacterial activities against clinically important gram-positive and gram-negative bacteria using the spectrophotometric microdilution method. The preliminary screening indicated that the organosilicon derivatives incorporating SH and C?=?S (mercapto-silyl-thiones) and silyl-thioalkynes have antibacterial activities, whereas no antibacterial activity was observed on compounds containing (Me₃Si)₃C groups. Of the synthesized compounds, compound 5d showed the best activity against all the tested organisms (3.91–31.25?μg/mL).

Full text of DOI:10.1007/s13738-018-1325-z

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1325-z
ORIGINAL PAPER
Bulky organosilicon compounds based on sulfanyltetrazoles: their
synthesis and in vitro antibacterial evaluation
Mahrokh Baghershiroudi1 · Kazem D. Safa1 · Khosro Adibkia2 · Farzaneh Lotfpour2
Received: 23 September 2017 / Accepted: 9 February 2018
© Iranian Chemical Society 2018
Abstract
The study introduces diferent organosilicon derivatives incorporating sulfanyltetrazole ring for biological applica-
tions. Initially, the sulfanyltetrazole derivatives and halo-analogues (Br, I) were synthesized. Later, selective reaction of
tris(trimethylsilyl)methyllithium (TsiLi) in the presence (−46 and 0 °C) and absence (room temperature) of CS2 with
halo-sulfanyltetrazole derivatives yielded new multifunctional sulfanyltetrazole regioisomers with SH, C = S, ethynylthio
and SiMe3 groups, respectively. All the synthesized compounds were characterized by IR, 1H-NMR, 13C-NMR spectra
and elemental analysis data. The compounds were screened for their antibacterial activities against clinically important
gram-positive and gram-negative bacteria using the spectrophotometric microdilution method. The preliminary screening
indicated that the organosilicon derivatives incorporating SH and C = S (mercapto-silyl-thiones) and silyl-thioalkynes have
antibacterial activities, whereas no antibacterial activity was observed on compounds containing (Me3Si)3C groups. Of the
synthesized compounds, compound 5d showed the best activity against all the tested organisms (3.91–31.25 µg/mL).
Keywords Organosilicon compounds · Sulfanyltetrazole · Mercapto-silyl-thione · Antibacterial activity
Introduction
the drugs which include 1,5-disubstituted sulfanyltetrazole
structures [6].
Five-membered ring heterocyclic derivatives such as tetra-
zoles are valuable intermediates in organic synthesis. In
recent years, tetrazole derivatives are increasingly being
used in medicinal chemistry [1]. Tetrazoles have been widely
used as isoesters of carboxylic acids, and some examples of
them have been reported [2, 3]. Sulfanyltetrazoles are prob-
ably one of the most interesting classes of tetrazoles [4],
and among them, 1,5 and 2,5-disubstituted sulfanyltetrazoles
have gained an increasing interest because of their biological
efects [5]. The cephalosporin class beta-lactam antibiot-
ics as well as latamoxef are the best-known examples of
In recent years, the chemistry of organosilicon com-
pounds has an increasing growth because of the critical role
it plays in many chemical, biochemical transformations and
medicinal applications [7–10]. Increasing interest in organo-
silicon derivatives and a lack of general synthetic procedures
prompted us to focus on the preparation of the sulfanyltetra-
zoles containing organosilicon moieties. In the recent pub-
lications [11–16], we have recently reported organosilicon
heterocyclic compounds containing bulky groups, such as
(RSiMe2)3C– (R = H, Me, Ph), mercapto-silyl-thione and
silyl-protected terminal thioalkyne.
To the best of our knowledge, there are no reports on the
use of organosilicon analogues incorporating sulfanyltetra-
zole ring with antibacterial efects in the literatures. Herein,
we report the synthesis and characterization of a series of
new organometallic silicon-containing compounds based on
a sulfanyltetrazole scafold along with their biological activi-
ties. A series of some novel 2,5-disubstituted sulfanyltetra-
zole derivatives were synthesized and evaluated for their
antibacterial properties. We used the spectrophotometric
microdilution method for screening of antibacterial activ-
ity of the synthesized compounds to determine the minimal
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-018-1325-z) contains
supplementary material, which is available to authorized users.
* Kazem D. Safa
dsafa@tabrizu.ac.ir
1
Organosilicon Research Laboratory, Faculty of Chemistry,
University of Tabriz, Tabriz 51666-14766, Iran
2
Faculty of Pharmacy, Tabriz University of Medical Sciences,
Tabriz 51664, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
inhibitory concentration (MIC) for the tested microorgan-
isms. The method is quick, reproducible and economical in
both time and materials and does not require a high level of
skill, it also worked well with a wide variety of microorgan-
isms and gave more accurate results at low concentrations,
increased sensitivity for small quantities of material, and it
is able to test large number of samples at a time. We found
that the compounds having mercapto-silyl-thiones and silyl-
thioalkynes are biologically active. On the basis of these
results, we later moved to the evaluation of the reaction of
diferent 2,5-disubstituted sulfanyltetrazoles with CS2 and
TsiLi.
General procedure for alkyl bromination of sulfa‑
nyltetrazole derivatives (3a–4e)
1,4-Dibromobutane (3.0 mmol) was added to a solution of
the sulfanyltetrazole derivatives (1 mmol) and anhydrous
K2CO3 (3.0 mmol) in acetone (25 ml). The reaction mix-
ture was stirred for 24 h at 25 °C. After completion of the
reaction, monitored by TLC, the solvent was distilled of
in a vacuum. The residue was treated with water (20 ml),
and the reaction product was extracted with ethyl acetate
(3 × 10 ml). The organic layer was dried over Na2SO4, and
the solvent was concentrated in vacuum.
General procedure for the synthesis of iodobu‑
tyl‑sulfanyltetrazole
Experimental
Chemicals were either purchased from Merck or synthe-
sized in our laboratory. Commercial reagent and solvents
were used without further purifcation. The IR spectra were
recorded on a Bruker Tensor 270 spectrometer using KBr
disks. 1H and 13C NMR spectra were recorded on a Bruker
FT-400 MHz spectrometer at room temperature (400 MHz
for 1H; 100 MHz for 13C) with CDCl3 as solvent. Elemen-
tal analyses were performed on an Elementar Vario EL III
instrument. The optical density was quantifed at 600 nm by
an enzyme-linked immunoabsorbent assay (ELISA) reader
(BioTek, Winooski, USA).
Iodobutyl-sulfanyltetrazoles were obtained by addition of
sodium iodide (1.1 eq) to bromobutyl-sulfanyltetrazole in
boiling dry acetone.
General procedure for the synthesis of mer‑
capto‑silyl‑thione‑substituted sulfanyltetrazole
derivatives (5a–5e)
To a stirred solution of (Me3Si)3CLi (1 mmol) in 15 mL
THF, CS2 (1.2 mmol) in 2 ml THF was added at − 46 °C
(cyclohexanone/N2) under argon atmosphere. The mixture
is stirred for 5 min and then iodobutyl-sulfanyltetrazole
derivative (1 mmol) in 10 ml THF was added at this tem-
perature and the stirring was continued (− 46 °C → 0 °C)
to the end of the reaction that followed by TLC. The mix-
ture is poured into water and extracted with CH2Cl2. The
organic layer was washed with water, dried with Na2SO4
and fltered. The solvent was evaporated and the residue
was purifed by preparative TLC on silica gel using n-hex-
ane–ethyl acetate, 6:1 as eluent to give the product.
Preparation of tris(trimethylsilyl)methyllithium,
(Me3Si)3CLi, in THF
The reagent was prepared according to the procedure
described in the literature [17].
General procedure for preparation of sulfanyltetra‑
zoles (2a–2e)
The sulfanyltetrazole derivatives were synthesized accord-
ing to the procedure described in the literature [18] with
some modifcation. Starting materials were synthesized
using published methodologies [19–22]. Thiocyanate com-
pound (1.0 mmol) was added to a suspension of sodium
azide (1.3 mmol) and tetrabutylammonium chloride (TBAC)
(1.3 mmol) in toluene (3 mL). The reaction mixture was
stirred at 90 °C for 2–6 h until completion, as determined
by thin-layer chromatography (TLC). After cooling, the
reaction mixture was extracted with water (5 mL). To the
aqueous layer, concd HCl was added dropwise to precipitate
the sulfanyltetrazole product. After fltration, the solid was
washed with HCl 4 M, and after drying, it was recrystal-
lized from appropriate solvent. The characterization data are
described in supporting information.
1‑Mercapto‑6‑(5‑(pentylthio)‑2H‑tetrazol‑2‑yl)‑1,1‑bis(trim
ethylsilyl)hexane‑2‑thione (5a)
A yellow sticky solid; yield 82%. FT-IR (KBr, cm−1): 3436,
2953, 2921, 2849, 1453, 1405, 1365, 1248, 1148, 1028,
835 cm−1. 1H NMR (400 MHz, CDCl3, ppm): δ = 0.17 (s,
18H, SiMe3), 0.90 (t, 3H, J = 7.1 Hz, CH3), 1.30–1.44 (m,
4H, 2CH2), 1.71–1.83(m, 4H, 2CH2), 2.13–2.20 (m, 2H,
CH2), 3.16 (t, 2H, J = 7.4 Hz, S-CH2), 3.19 (bs, 1H, S–H),
3.38 (t, 2H, J = 7.1 Hz, CH2-C(SiMe3)2S), 4.60 (t, 2H,
J = 6.9 Hz, N-CH2). 13C NMR (100 MHz, CDCl3, ppm):
δ = −1.06 (SiMe3), 12.92, 21.16, 24.68, 26.52, 28.31,
29.85, 31.12, 38.43, 51.71, 54.08, 162.26, 214.31. Anal.
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Journal of the Iranian Chemical Society
calcd. for C18H38N4S3Si2: C, 46.71; H, 8.28; N, 12.10; S,
2‑((2‑(6‑Mercapto‑5‑thioxo‑6,6‑bis(trimethylsilyl)
hexyl)‑2H‑tetrazol‑5‑yl)thio)‑1‑phenylethan‑1‑one (5e)
20.78%. Found: C, 46.85; H, 8.19; N, 12.18; S, 20.59%.
A yellow sticky solid, yield 77%. FT-IR (KBr, cm−1):
3433, 3116, 3080, 2955, 2920, 2852, 1685, 1448, 1398,
1368, 1249, 1153, 1027, 835. 1H NMR (400 MHz,
CDCl3, ppm): δ = 0.15 (s, 8 H, SiMe3), 1.73–1.81 (m,
2H, CH2), 2.10–2.15 (m, 2H, CH2), 3.19 (bs, 1H, S–H),
3.41 (t, 2H, J = 7.1 Hz, CH2-C(SiMe3)2S), 4,61 (t, 2H,
J = 6.9, N-CH2), 4.79 (s, 2H, CH2), 7.48–7.52 (m, 2H,
J = 7.7 Hz, ArH), 7.59–7.63 (m, 1H, ArH), 8.00–8.04 (m,
2H, ArH). 13C NMR (100 MHz, CDCl3, ppm): − 1.08,
24.48, 26.12, 39.06, 38.25, 58.73, 54.97, 125.38, 127.45,
127.82, 132.87, 163.32, 192.79, 214.53. Anal. calcd. for
C21H34N4OS3Si2: C, 49.37; H, 6.71; N, 10.97; S, 18.83%.
Found: C, 49.26; H, 6.80; N, 11.08; S, 18.79%.
6‑(5‑(Hexylthio)‑2H‑tetrazol‑2‑yl)‑1‑mer‑
capto‑1,1‑bis(trimethylsilyl)hexane‑2‑thione (5b)
A yellow sticky solid; yield 91%. FT-IR (KBr, cm−1): 3423,
2956, 2927, 2856, 1454, 1401, 1367, 1248, 1151, 1028,
835 cm−1. 1H NMR (400 MHz, CDCl3, ppm): δ = 0.15 (s,
18 H, SiMe3), 0.87 (t, 3H, J = 7.1 Hz, CH3), 1.24–1.31 (m,
4H, 2CH2), 1.41–1.45 (m, 2H, 2CH2), 1.70–1.82(m, 4H,
2CH2), 2.11–2.17(m, 2H, CH2), 3.17 (t, 2H, J = 7.4 Hz,
S-CH2), 3.19 (bs, 1H, S–H), 3.39 (t, 2H, J = 7.1 Hz,
CH2-C(SiMe3)2S), 4.59 (t, 2H, J = 6.9 Hz, N-CH2). 13C
NMR (100 MHz, CDCl3, ppm): δ = −1.06 (SiMe3), 12.91,
21.15, 24.67, 26.51, 27.26, 28.22, 30.77, 31.04, 38.27, 51.57,
54.11, 163.38, 214.28. Anal. calcd. for C19H40N4S3Si2: C,
47.85; H, 8.45; N, 11.75; S, 20.17%. Found: C, 47.98; H,
8.36; N, 11.86; S, 20.10%.
General procedure for the synthesis of silyl‑thio‑
alkyne‑substituted sulfanyltetrazole derivatives
(6a–6e)
6‑(5‑(Benzylthio)‑2H‑tetrazol‑2‑yl)‑1‑mer‑
capto‑1,1‑bis(trimethylsilyl)hexane‑2‑thione (5c)
To a stirred solution of (Me3Si)3CLi (1 mmol) in 15 mL
THF, CS2 (1.2 mmol) in 2 mL THF was added in one por-
tion at 0 °C under an argon atmosphere. The color of the
mixture turned red immediately. The mixture was stirred
for 15 min and then bromobutyl-sulfanyltetrazole deriva-
tive (1 mmol) in a THF solution (10 mL) was added at this
temperature and stirring was continued until the reaction
was completed (TLC). The mixture was poured into water
and extracted with CH2Cl2. The organic layer was washed
with water, dried (Na2SO4) and fltered. The solvent was
removed in a vacuum and the product was purifed by pre-
parative TLC (silica gel, n-hexane–ethyl acetate, 3:1).
A yellow sticky solid; yield 86%. FT-IR (KBr, cm−1): 3445,
2957, 2848, 1593, 1410, 1384, 1331, 1250, 1150, 1029, 835.
1H NMR (400 MHz, CDCl3, ppm): δ = 0.17 (s, 18 H, SiMe3),
1.71–1.76 (m, 2H, CH2), 2.09–2.15 (m, 2H, CH2), 3.18 (bs,
1H, S–H), 3.38 (t, 2H, J = 7.1 Hz, CH2-C(SiMe3)2S), 4.4
(s, 2H, CH2), 4.59 (t, 2H, J = 6.9 Hz, N-CH2), 7.24–7.31(m,
3H, ArH), 7.36–7.39 (m, 2H, ArH). 13C NMR (100 MHz,
CDCl3, ppm): δ = −1.08 (SiMe3), 24.57, 26.45, 33.42,
35.46, 38.35, 51.56, 54.84, 126.60, 127.55, 127.99, 135.49,
162.63, 214.43. Anal. calcd. for C20H34N4S3Si2: C, 49.75;
H, 7.10; N, 11.60; S, 19.92%. Found: C, 49.84; H, 7.07; N,
11.4; S, 19.73%.
5‑(Pentylthio)‑2‑(4‑(((trimethylsilyl)ethynyl)thio)
butyl)‑2H‑tetrazole (6a)
1‑Mercapto‑6‑(5‑(phenethylthio)‑2H‑tetrazol‑2‑yl)‑1,1‑bis(t
rimethylsilyl)hexane‑2‑thione (5d)
A yellow sticky solid; yield 85%. FT-IR (KBr, cm−1):
3436, 2953, 2921, 2849, 2088, 1453, 1405, 1365, 1250,
882, 841. 1H NMR (400 MHz, CDCl3, ppm): δ = 0.17 (s,
9 H, SiMe3),), 0.90 (t, 3H, J = 7.1 Hz, CH3), 1.30–1.44
(m, 4H, 2CH2), 1.71–1.83 (m, 4H, 2CH2), 2.13–2.20 (m,
2H, CH2), 2.75 (t, 2H, J = 6.9 Hz, S-CH2), 3.18 (t, 2H,
A yellow sticky solid: yield 82%. FT-IR (KBr, cm−1):
3445, 3029, 2955, 2856, 1648, 1593, 1496, 1448, 1385,
1
1251, 1151, 1029, 838. H NMR (400 MHz, CDCl3,
ppm): δ = 0.16 (s, 18 H, SiMe3), 1.76–1.84 (m, 2H, CH2),
2.13–2.19 (m, 2H, CH2), 3.06 (t, 2H, J = 7.7 Hz, CH2), 3.18
(bs, 1H, S–H), 3.38 (t, 2H, J = 7.1 Hz, CH2-C(SiMe3)2S),
3.42 (t, 2H, J = 7.7, CH2), 4.61 (t, 2H, J = 6.9 Hz, N-CH2),
7.23–7.26 (m, 3H, ArH), 7.29–7.33 (m, 2H, ArH). 13C NMR
(100 MHz, CDCl3, ppm): δ = −1.07 (SiMe3), 24.64, 26.47,
32.31, 35.04, 38.38, 51.66, 54.2, 125.59, 127.51, 127.64,
138.59, 163.06, 213.91. Anal. calcd. for C21H36N4S3Si2: C,
50.76; H, 7.30; N, 11.28; S, 19.36%. Found: C, 50.86; H,
7.25; N, 10.88; S, 19.44%.
J = 7.4 Hz, S-CH2), 4.60 (t, 2H, J = 6.9 Hz, N-CH2). 13
C
NMR (100 MHz, CDCl3, ppm): δ = −1.06 (SiMe3), 12.91,
21.15, 24.67, 26.51, 28.21, 29.77, 31.10, 34.71, 51,62,
92.58, 100.21, 162.26. Anal. calcd. for C15H28N4S2Si: C,
50.52; H, 7.91; N, 15.71; S, 17.98%. Found: C, 50.36; H,
8.07; N, 15.74; S, 17.81%.
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Journal of the Iranian Chemical Society
5‑(Hexylthio)‑2‑(4‑(((trimethylsilyl)ethynyl)thio)
butyl)‑2H‑tetrazole (6b)
ppm): δ = 0.15 (s, 9 H, SiMe3), 1.73–1.8 (m, 2H, CH2),
2.10–2.17 (m, 2H, CH2), 2.73 (t, 2H, J = 6.9, S-CH2), 4.59
(t, 2H, J = 6.9, N-CH2), 4.79 (s, 2H, CH2), 7.49 (m, 2H,
J = 7.7 Hz, ArH), 7.59–7.64(m, 1H, ArH), 8.00–8.03 (m,
2H, ArH). 13C NMR (100 MHz, CDCl3, ppm): 24.59, 26.41,
33.40, 39.01, 51.73, 92.62, 100.21, 1 27.45, 127.82, 132.86,
135.65, 163.32, 192.78. Anal. calcd. for C18H24N4OS2Si: C,
53.43; H, 5.98; N, 13.85; S, 15.85%. Found: C, 53.57; H,
5.89; N, 13.96; S, 15.76%.
A yellow sticky solid; yield 90%. FT-IR (KBr, cm−1): 3423,
2956, 2927, 2856, 2092, 1454, 1401, 1367, 1250, 881,
842. 1H NMR (400 MHz, CDCl3, ppm): δ = 0.15 (s,, 9H,
SiMe3),), 0.87 (t, 3H, J = 7.1 Hz, CH3), 1.24–1.31(m, 4H,
2CH2), 1.41–1.45(m, 2H, CH2), 1.70–1.81(m, 4H, 2CH2),
2.11–2.17 (m, 2H, CH2), 2.74 (t, 2H, J = 6.9 Hz, S-CH2),
3.17(t, 2H, J = 7.4 Hz, S-CH2), 4.59(t, 2H, J = 6.9 Hz,
N-CH2). 13C NMR (100 MHz, CDCl3, ppm): δ = −1.12
(SiMe3), 12.95, 21.42, 24.58, 26.44, 27.24, 28.40, 30.17,
31.04, 33.36, 51.56, 92.59, 100.20, 163.38. Anal. calcd.
for C16H30N4S2Si: C, 51.85; H, 8.16; N, 15.12; S, 17.30%.
Found: C, 51.65; H, 8.25; N, 15.09; S, 17.16%.
General procedure for the synthesis
of tris(trimethylsilyl‑substituted sulfanyltetrazole
derivatives (7a–7e)
Bromobutyl-sulfanyl tetrazole derivative (5 mmol) in 10
mL THF was added to the stirring solution of (Me3Si)3CLi
(5 mmol) in 15 mL THF at room temperature. The mixture
was stirred for another 10 min at room temperature. Comple-
tion of the reaction was monitored by TLC. The mixture was
poured into saturated ammonium chloride solution (50 mL)
and extracted with CH2Cl2 (2 × 20 mL). The organic phase
was washed with water (100 mL) and dried (Na2SO4), and
the solvent was removed in a vacuum to yield a sticky solid.
The product was purifed by preparative TLC (silica gel,
n-hexane–ethyl acetate, 5:1).
5‑(Benzylthio)‑2‑(4‑(((trimethylsilyl)ethynyl)thio)
butyl)‑2H‑tetrazole (6c)
A yellow sticky solid; yield 87%. FT-IR (KBr, cm−1): 3445,
1
2957, 2848, 2089, 1593, 1410, 1384, 1250, 878, 844. H
NMR (400 MHz, CDCl3, ppm): δ = 0.16 (s, 9 H, SiMe3),
1.70–1.77 (m, 2H, CH2), 2.09–2.17(m, 2H, CH2), 2.72
(t, 2H, J = 6.9 Hz, S-CH2), 4.4 (s, 2H, CH2), 4.59(t, 2H,
J = 6.9 Hz, N-CH2), 7.24–7.31(m, 3H, ArH), 7.37–7.39 (m,
2H, ArH). 13C NMR (100 MHz, CDCl3, ppm): δ = −1.07
(SiMe3), 24.57, 26.45, 33.41, 35.46, 51.65, 92.63, 100.19,
126.61, 127.55, 127.99, 135.49, 162.63. Anal. calcd. for
C17H24N4S2Si: C, 54.22; H, 6.42; N, 14.88; S, 17.03%.
Found: C, 54.35; H, 6.36; N, 14.49; S, 17.07%.
2‑(4‑(1,1,1,3,3,3‑Hexamethyl‑2‑(trimethylsilyl)trisilan‑2‑yl)
butyl)‑5‑(pentylthio)‑2H‑tetrazole (7a)
A brown sticky solid, yield 76%. FT-IR (KBr, cm−1): 3067,
1
2954, 2927, 2857, 1457, 1433, 1393, 1254, 841 cm−1. H
5‑(Phenethylthio)‑2‑(4‑(((trimethylsilyl)ethynyl)thio)
butyl)‑2H‑tetrazole (6d)
NMR (400 MHz, CDCl3, ppm): δ = 0.08 (s, 27 H, SiMe3),
0.90 (t, 3H, J = 7.1 Hz, CH3), 1.33–1.50 (m, 8H, 4CH2),
1.61–1.65(m, 2H, CH2), 1.77–1.86 (m, 2H, CH2), 3.35 (t,
2H, J = 7.4 Hz, S-CH2), 4.20 (t, 2H, J = 6.9 Hz, N-CH2).
13C NMR (100 MHz, CDCl3, ppm): δ = 1.66 (SiMe3), 5.12
(C(SiMe3)3), 12.88, 21.15, 24.65, 26.02, 28.68, 30.05, 31.17,
51.54, 162.32. Anal. calcd. for C20H46N4SSi3: C, 52.34; H,
10.10; N, 12.21; S, 6.99%. Found: C, 52.48; H, 10.01; N,
12.31; S, 6.95%.
A yellow sticky solid; yield 75%. FT-IR (KBr, cm−1): 3446,
3028, 2955, 2856, 2091, 1648, 1593, 1496, 1448, 1385,
1249, 879, 841. 1H NMR (400 MHz, CDCl3, ppm): δ = 0.16
(s, 9 H, SiMe3), 1.76–1.84 (m, 2H, CH2), 2.13–2.19 (m,
2H, CH2), 2.75 (t, 2H, J = 6.9 Hz, S-CH2), 3.06 (t, 2H,
J = 7.7 Hz, CH2), 3.42 (t, 2H, J = 7.7, CH2), 4.61 (t, 2H,
J = 6.9 Hz, N-CH2), 7.21–7.26 (m, 3H, ArH), 7.29–7.33 (m,
2H, ArH). 13C NMR (100 MHz, CDCl3, ppm): δ = −1.07
(SiMe3), 24.64, 26.47, 32.31, 33.41, 35.04, 51.66, 92.60,
100.20, 125.59, 127.51, 127.64, 138.59, 163.06. Anal. calcd.
for C18H26N4S2Si: C, 55.34; H, 6.71; N, 14.34; S, 16.41%.
Found: C, 55.23; H, 6.80; N, 14.42; S, 16.23%.
2‑(4‑(1,1,1,3,3,3‑Hexamethyl‑2‑(trimethylsilyl)trisilan‑2‑yl)
butyl)‑5‑(hexylthio)‑2H‑tetrazole (7b)
A brown Sticky solid; yield 56%. FT-IR (KBr, cm−1):
1
3061, 2955, 2920, 2852, 1459, 1381, 1258, 846. H NMR
(400 MHz, CDCl3, ppm): δ = 0.08 (s, 27 H, SiMe3), 0.86 (t,
3H, J = 7.1 Hz, CH3), 1.25–1.32 (m, 6H, 3CH2), 1.44–1.52
(m, 4H, 2CH2), 1.60–1.64 (m, 2H, CH2), 1.77–1.86 (m,
2H, CH2), 3.35(t, 2H, J = 7.4 Hz, S-CH2), 4.60 (t, 2H,
J = 6.9 Hz, N-CH2). 13C NMR (100 MHz, CDCl3, ppm):
δ = 1.67 (SiMe3), 5.14 (C(SiMe3)3), 12.96, 21.46, 24.48,
26.53, 27.27, 28.35, 30.17, 31.19, 51.65, 162.95. Anal.
1‑Phenyl‑2‑((2‑(4‑(((trimethylsilyl) ethynyl)thio)
butyl)‑2H‑tetrazol‑5‑yl)thio)ethan‑1‑one (6e)
A yellow sticky solid; yield 70%. FT-IR (KBr, cm−1): 3433,
3116, 3080, 2955, 2920, 2852, 2090, 1685, 1448, 1398,
1
1368, 1249, 880, 842 cm−1. H NMR (400 MHz, CDCl3,
1 3

Journal of the Iranian Chemical Society
calcd. for C21H48N4SSi3: C, 53.33; H, 10.23; N, 11.85; S,
method according to European Committee on Antimicrobial
Susceptibility Testing (EUCAST) [23].
6.78%. Found: C, 53.14; H, 10.31; N, 11.81; S, 6.72%.
A quantity of 100 μl of phosphate-bufered saline (PBS)
was placed in each well of a 96-well plate. A stock solution
(2000 µg/mL) of the synthesized compounds in dimethylsul-
foxide (DMSO) (10% of the fnal volume) was prepared and
sterilized by fltration through a 0.45-µm membrane flter.
100 µl of the tested compounds was added (in triplicate) to
wells in the frst row of the microtiter plate and then serially
diluted along the horizontal axis to obtain a concentration
range of 1000–0.488 µg/mL. Each plate also contained three
wells of inoculated medium, which served as the positive
control; one uninoculated well, PBS with an antimicrobial
agent, was used as the negative control. Also, a control test
with DMSO was conducted to ensure that the solvent did
not afect the growth of the bacteria. Suspension of the
bacteria was prepared in Mueller–Hinton broth (MHB) to
contain approximate 106 colony-forming units (CFU/mL).
Finally, an equal volume of inoculum was then transferred to
a 96-well microtiter plate and thoroughly mixed. The micro-
titer plates were sealed with paraflm and incubated at 37 °C
for 24 h without shaking. The absorbances were measured
with a spectrophotometer at 600 nm. A sharp cutof point
between microbial growth and inhibition was defned as the
MIC [24]. After incubation and reading the optical density
(OD), the diluted cultures were plated on agar medium and
visible growing colonies were confrmed after incubation at
37 °C for 24 h.
5‑(Benzylthio)‑2‑(4‑(1,1,1,3,3,3‑hexame‑
thyl‑2‑(trimethylsilyl)trisilan‑2‑yl)butyl)‑2H‑tetrazole (7c)
A brown Sticky solid; yield 85%. FT-IR (KBr, cm−1):
3302, 2955, 2920, 2853, 1513, 1460, 1405, 1371, 1258,
843 cm−1. 1H NMR (400 MHz, CDCl3, ppm): δ = 0.08 (s,
27 H, SiMe3), 1.32–1.52 (m, 6H, 3CH2), 4.42 (s, 2H, CH2),
4.57 (t, 2H, J = 6.9 Hz, N-CH2), 7.24–7.31(m, 3H, ArH),
7.38 (m, 2H, ArH). 13C NMR (100 MHz, CDCl3, ppm):
δ = 1.68 (SiMe3), 5.12 (C(SiMe3)3), 24.57, 26.45, 35.46,
51.65, 126.60, 127.55, 127.99, 135.49, 162.62. Anal. calcd.
for C22H42N4SSi3: C, 55.17; H, 8.84; N, 11.70; S, 6.69%.
Found: C, 54.94; H, 8.67; N, 11.81; S, 6.71%.
2‑(4‑(1,1,1,3,3,3‑Hexamethyl‑2‑(trimethylsilyl)trisilan‑2‑yl)
butyl)‑5‑(phenethylthio)‑2H‑tetrazole (7d)
A brown Sticky solid; yield 73%. FT-IR (KBr, cm−1): 3447,
2957, 2924, 1630, 1591, 1411, 1384, 1258, 842 cm−1
.
1H NMR (400 MHz, CDCl3, ppm): δ = 0.07 (s, 27H,
SiMe3), 1.30–1.54 (m, 6H, 3CH2), 3.06 (t, 2H, J = 7.7 Hz,
CH2), 3.43 (t, 2H, J = 7.7, CH2), 4.61 (t, 2H, J = 6.9 Hz,
N-CH2), 7.21–7.26 (m, 3H, ArH), 7.29–7.33 (m, 2H, ArH).
13C NMR (100 MHz, CDCl3, ppm): δ = 1.67 (SiMe3),
5.13 (C(SiMe3)3), 24.64, 26.47, 32.32, 35.05, 51.67,
125.59, 127.51, 127.64, 138.59, 163.07. Anal. calcd. for
C23H44N4SSi3: C, 56.04; H, 9.00; N, 11.37; S, 6.50%. Found:
C, 55.93; H, 9.09; N, 11.45; S, 6.58%.
Results and discussion
Chemistry
2‑((2‑(4‑(1,1,1,3,3,3‑Hexamethyl‑2‑(trimethylsilyl)trisi‑
lan‑2‑yl)butyl)‑2H‑tetrazol‑5‑yl)thio)‑1‑phenylethan‑1‑one
(7e)
This study attempted to synthesize organosilicon derivatives
of sulfanyltetrazoles and compare their antibacterial activity.
TsiLi has been shown to be a versatile reagent, leading to
trimethylsilylation reactions with halide-type electrophiles.
In continuation of our research in the feld of organosili-
con compounds, the new organosilyl derivatives of sulfa-
nyltetrazole (5a–7e) were synthesized using its halo-alkyl
derivatives and TsiLi and were screened for their antibacte-
rial activities.
A brown Sticky solid; yield 70%. FT-IR (KBr, cm−1): 3435,
3077, 2944, 2920, 2852, 1684, 1597, 1449, 1395, 1358,
1258, 842. 1H NMR (400 MHz, CDCl3, ppm): δ = 0.08 (s,
27 H, SiMe3), 1.31–1.59 (m, 6H, 3CH2), 4.6 (t, 2H, J = 6.9,
N-CH2), 4.73 (s, 2H, CH2), 7.48–7.52 (m, 2H, ArH),
7.58–7.63 (m, 1H, ArH), 8.00–8.04 (m, 2H, ArH). 13C NMR
(100 MHz, CDCl3, ppm): 1.67 (SiMe3), 5.14 (C(SiMe3)3),
24.58, 26.42, 39.02, 51.62, 125.33, 127.45, 127.82, 132.86,
163.31, 192.77. Anal. calcd. for C23H42N4OSSi3: C, 54.50;
H, 8.35; N, 11.05; S, 6.32%. Found: C, 54.58; H, 8.26; N,
10.8; S, 6.23%.
The processes for the synthesis of target compounds
are shown in Scheme 1. Sulfanyltetrazole derivatives were
prepared with TBAC in very good yields. In general, tau-
tomerism leads to the synthesis of 1,5- and 2,5-disubsti-
tuted sulfanyltetrazole regioisomers bearing halide moie-
ties. These regioisomers could react with a wide range of
nucleophiles such as TsiLi. The resulting crude products
in the same way were used for the synthesis of bulky orga-
nosilicon compounds by reaction with TsiLi and CS2. The
reaction aforded usually in very good yield and in short
Antibacterial activity
The synthesized compounds (5a–7e) were screened in vitro
for their antibacterial activities using the broth microdilution
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Journal of the Iranian Chemical Society
Scheme 1 Synthetic route of the title compounds 2–7. Reagents
and conditions: (i) NaN3, TBAC, toluene, 90 °C, 2–6 h; (ii) K2CO3,
acetone, Br(CH2)4Br, 25 °C, 24 h; (iii) (1) NaI, acetone, refux. (2)
(Me3Si)3CLi, CS2, THF, − 46 °C; (IV) (Me3Si)3CLi, CS2, THF, 0 °C;
(V) (Me3Si)3CLi, THF, rt
times. However, we found that between the two regioi-
somers formed, 2,5-disubstituted sulfanyltetrazoles are
favored to react with TsiLi and only one of the regioiso-
mers was isolated. This can be proved through the 1H and
13C-NMR spectra that the signals for all obtained com-
pounds, which correspond to the 2,5-disubstituted sulfa-
nyltetrazole [25, 26]. It seems that 1,5-regioisomer, espe-
cially at low temperature, does not react or reacts very low.
Using the organolithium reagent TsiLi, a number
of reactions of alkyl halides (Br, I) analogues of sulfa-
nyltetrazoles (5a–6e) with CS2 in two temperatures (0 and
− 46 °C) have been reported, and the reaction with CS2
reagents represented an interesting procedure for obtain-
ing silyl-sulfurated compounds quickly and in very good
yields [14, 27]. As previously described [11, 27], the reac-
tion of TsiLi and CS2 in − 46 °C with alkyl iodides is
faster and has a higher yield. For this reason, iodobutyl-
sulfanyltetrazoles were obtained by addition of sodium
iodide (1.1 eq) to bromobutyl-sulfanyltetrazole derivatives
in boiling dry acetone.
Microbiology
The MICs of the synthesized compounds against a gram-
positive bacterial strain (Staphylococcus aureus PTCC 1112)
and gram-negative bacterial strains (Escherichia coli PTCC
1330, Salmonella typhi PTCC 1609 and Pseudomonas aer-
uginosa PTCC 1074) were determined using the microtiter
assay. For determination of MICs of the synthesized com-
pounds, the ODs of the microtiter plate were read using an
automatic ELISA tray reader at 600 nm. Recorded obser-
vances were then converted to percent and set at 100% of
positive control and at 0% for negative control. All tests
were carried out in triplicate, and the average values were
computed. The breakpoint was detected as a sharp decline
in the absorbance value [24]. Ciprofoxacin was used as a
standard drug.
As presented in Table 1, the highest activity was dis-
played by compound 5d with MIC = 3.91 µg/mL in the case
of S. aureus and MIC = 7.81 µg/mL toward E. coli. The
activity against S. typhi and P. aeruginosa was strong with
MIC = 15.62 µg/mL and 31.25 µg/mL, respectively. The MICs
of compound 5e were 7.81–62.5 µg/mL showed very strong
activity against S. aureus or strong against E. coli and S. typhi.
Compound 6d exhibited strong activity against S. aureus with
MIC = 31.25 µg/mL. The activity of compounds 6c, 6e against
gram-positive bacteria was good with MIC = 62.5 µg/mL.
Also, tris(trimethylsilyl)methyl sulfanyltetrazole deriva-
tives (7a–7e) can be prepared using the bromoalkyl-sul-
fanyltetrazole derivatives at room temperature in good
yields. In view of the presence of certain functional
groups, specifc properties can be expected from totally
new silicon-containing compounds.
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Journal of the Iranian Chemical Society
Table 1 In vitro MIC values (µg/mL) of compounds (5a–7e)
Conclusions
Compound
Microorganism
In summary, we have synthesized bulky silylated hetero-
cycles through a simple method. These new compounds
were characterized by spectral and elemental analyses.
Antibacterial activities of the tested compounds using the
spectrophotometric method were investigated. In addition, a
good correlation between the visual determination of MICs
and the endpoint assigned by OD measurements could be
established. The microbiological results demonstrated that
the antibacterial efects of the compounds depend on the
substituents. Evaluation of antibacterial activity of the sul-
fanyltetrazoles containing mercapto-silyl-thione against both
gram-positive and gram-negative bacteria indicated that they
have antibacterial properties, some of the newly obtained
compounds containing silyl-thioalkyne showed signifcant
antibacterial activity, whereas the compounds contain-
ing (Me3Si)3C groups revealed no activity. Compound 5d
showed the best activity among the tested compounds. We
hope these observations will promote the applications of the
introduced compounds.
S. aureus
E. coli
S. typhi
P. aeruginosa
5a
62.5
62.5
15.62
3.91
7.81
125
125
62.5
31.25
62.5
–
62.5
62.5
31.25
7.81
15.62
250
250
125
62.5
125
–
250
250
62.5
15.62
31.25
1000
1000
500
125
250
–
500
500
125
31.25
62.5
–
–
–
500
–
–
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
–
–
–
–
–
–
–
–
–
–
7c
–
–
–
–
7d
7e
–
–
Ciprofoxacin
0.244
0.031
0.122
0.488
– Totally inactive (MIC ≥ 1000 µg/mL)
Acknowledgements This work has been supported by the University
of Tabriz, which is gratefully appreciated.
References
1. C.-X. Wei, M. Bian, G.-H. Gong, Molecules 20, 5528 (2015)
2. M.A. Malik, M.Y. Wani, S.A. Al-Thabaiti, R.A. Shiekh, J. Incl.
Phenom. Macrocycl. Chem. 78, 15 (2014)
Compounds 6a, 6b have shown the same activity. In addi-
tion, compounds 6a–6e except 6d were not active against P.
aeruginosa.
3. R.J. Herr, Bioorg. Med. Chem. 10, 3379 (2002)
4. G. Koldobskii, A. Hrabalek, K. Esikov, Russ. J. Org. Chem. 40,
447 (2004)
Structure–activity relationship
5. G. Karabanovich, J. Roh, O. Soukup, I. Pávková, M. Pasdiorová,
V. Tambor, J. Stolaříková, M. Vejsová, K. Vávrová, V. Klimešová,
Med. Chem. Comm. 6, 174 (2015)
Regarding the antibacterial activity of the tested compounds,
the organosilicon compounds containing (Me3Si)3C (7a–7e)
have no detectable activity against the tested species. In con-
trast, all the sulfanyltetrazoles containing mercapto-silyl-thione
and most of the silyl-protected terminal thioalkynes have
antibacterial properties. The thiol substituent proved to be a
favorite functionality and resulted in a remarkable improve-
ment in antibacterial spectrum. Mercapto-silyl-thiones are
created by rearrangement of CS2 with TsiLi, and the inter-
mediates of this reaction are not stable to separate [27]. In
this respect, compounds with mercapto-silyl-thione substituent
were screened for their antibacterial activities. The antibacte-
rial activity data revealed that the alkyl derivatives 5a, 5b and
6a, 6b with a 5, 6 carbon alkyl side chain present similar anti-
bacterial activity against tested microorganisms. It was shown
that aromatic substituents at the tetrazole-C5 lead to better bio-
logical activity than aliphatic substituents. Generally, the com-
pounds were efective, especially on gram-positive bacteria.
6. R.A. Powers, B.K. Shoichet, J. Med. Chem. 45, 3222 (2002)
7. A. Zablotskaya, I. Segal, Y. Popelis, S. Grinberga, I. Shestakova,
V. Nikolajeva, D. Eze, Appl. Organomet. Chem. 27, 114 (2013)
8. G.A. Showell, J.S. Mills, Drug. Discov. Today 8, 551 (2003)
9. Y. Li, C. de Kock, P.J. Smith, H. Guzgay, D.T. Hendricks, K.
Naran, V. Mizrahi, D.F. Warner, K. Chibale, G.S. Smith, Orga-
nometallics 32, 141 (2012)
10. A.K. Franz, S.O. Wilson, J. Med. Chem. 56, 388 (2013)
11. K.D. Safa, M. Allahvirdinesbat, H. Namazi, Synth. Commun. 45,
1205 (2015)
12. K.D. Safa, M. Allahvirdinesbat, H. Namazi, Mol. Divers. 19, 29
(2015)
13. K.D. Safa, M. Allahvirdinesbat, H. Namazi, P.N. Panahi, C. R.
Chimie. 18, 883 (2015)
14. K.D. Safa, M. Alyari, Synthesis 47, 256 (2015)
15. K.D. Safa, H. Mousazadeh, Synth. Commun. 46, 1595 (2016)
16. M. Allahvirdinesbat, M. Fozi, K.D. Safa, M. Alyari, P.N. Panahi,
A. Niaei, Res. Chem. Intermed. 43, 2653 (2017)
17. B.-T. Gröbel, D. Seebach, Chem. Ber. 110, 852 (1977)
18. S. Vorona, T. Artamonova, Y. Zevatskii, L. Myznikov, Synthesis
46, 781 (2014)
1 3

Journal of the Iranian Chemical Society
19. Z. Benfodda, F. Guillen, H. Arnion, A. Dahmani, H. Blancou,
Heteroat. Chem. 20, 355 (2009)
and Infectious Diseases (ESCMID), Clin. Microbiol. Infect. 9, ix
(2003)
20. A.R. Kiasat, M. Fallah-Mehrjardi, Bull. Korean Chem. Soc. 29,
2346 (2008)
24. K.F. Devienne, M.S.G. Raddi, Braz. J. Microbiol. 33, 166 (2002)
25. G. Ortar, M.G. Cascio, A.S. Moriello, M. Camalli, E. Morera, M.
Nalli, V. Di Marzo, Eur. J. Med. Chem. 43, 62 (2008)
26. P. Bethel, M. Hill, M. Mahon, K. Molloy, J. Chem. Soc. Perkin.
Trans. 1, 3507 (1999)
21. A.H. Schlesinger, D.T. Mowry, J. Am. Chem. Soc. 76, 585 (1954)
22. F.R. Bisogno, A. Cuetos, I. Lavandera, V. Gotor, Green Chem. 11,
452 (2009)
23. European Committee for Antimicrobial Susceptibility Testing
(EUCAST) of the European Society of Clinical Microbiology
27. K.D. Safa, K. Ghorbanpour, J. Organomet. Chem. 745, 214 (2013)
1 3