Synthesis of New Tetrazole Derivatives and Their Biological Evaluation

Article abstract of DOI:10.1134/S1070363218080273

An operationally simple and efficient method of synthesis of novel 1,5-disubstituted tetrazoles with high yields from easily accessible 2-(2-benzamido-3-arylacrylamido)acetate under mild conditions is developed. Anticancer and anti-microbial tests of the

Full text of DOI:10.1134/S1070363218080273

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 8, pp. 1726–1733. © Pleiades Publishing, Ltd., 2018.
Synthesis of New Tetrazole Derivatives
and Their Biological Evaluation1
H. A. Solimana*, A. Kalmouchb, H. M. Awadc, and N. A. M. Abdel Wahedd
a Photochemistry Department, National Research Centre, Dokki, Cairo, 12622 Egypt
*e-mail: tarek12_2@yahoo.com
bPeptide Chemistry Department, National Research Centre, Dokki, Cairo, 12622 Egypt
cTanning Materials and Leather Technology Department, National Research Centre, Dokki, Cairo, 12622 Egypt
dChemistry of Natural and Microbial Products Department, National Research Centre, Dokki, Cairo, 12622 Egypt
Received June 27, 2018
Abstract—An operationally simple and efficient method of synthesis of novel 1,5-disubstituted tetrazoles with
high yields from easily accessible 2-(2-benzamido-3-arylacrylamido)acetate under mild conditions is
developed. Anticancer and anti-microbial tests of the new tetrazole derivatives have been carried out.
Keywords: tetrachlorosilane, 1,5-disubstituted tetrazoles, mild conditions, anticancer activity, anti-microbial activity
DOI: 10.1134/S1070363218080273
INTRODUCTION
as the precursors, these upon aminolysis gave the cor-
responding dehydropeptides. Treatment of the amide
bond of dehydropeptide with triazidochlorosilane
(TACS) gave the corresponding tetrazole derivatives.
Tetrazole derivatives are used as cyclo-oxygenase
inhibitors, anti-inflammatory, antiviral, antifungal,
hypoglycemic, and anticancer agents [1]. 1,5-Disub-
stituted tetrazoles (1,5-DSTs) demonstrate activity
towards the cis-amide bond in peptides because they
are isosteres for the cis-amide bond in those [2].
Replacement of the cis-amide bond by tetrazole ring in
peptides enhances their metabolic stability [3].
Cephalosporin and its analogs that are comparable
with penicillin structure and activity are known drugs
containing 1,5-DST moieties [4, 5].
Arylidene derivatives of 2-phenyl-5(4H)-oxazolone
were synthesized according to the developed earlier
method [17], and mixed with amino acid esters hydro-
chloride in the presence of TEA at room temperature.
Accumulation of dehydropeptides started within few
minutes. Refluxing of the reaction mixture made the
process to complete. The free amino acid ester reacted
as a nucleophilic reagent with the carbonyl group of
oxazolone cycle, and the ring cleavage took place leading
to the corresponding dehydropeptide (Scheme 1).
Many compounds containing 1,5-disubstituted tetra-
zoles (1,5-DSTs) demonstrate specific biological
activity, including anti-tubercular [6], anti-inflammatory
[7], antiviral [8], antibiotic [9], and some others
[10, 11]. Various methods of synthesis and
applications of 1,5-disubstituted tetrazoles have been
presented in recent publications [12–16].
Structures of the compounds 2a–2i were confirmed
by spectral data. IR spectra indicated the presence of
two NH groups at ca 3320 and 3218 cm–1 and carbonyl
1
groups at ca 1748 and 1658 cm–1. H NMR spectra
demonstrated two signals in the range of 8.03–
8.90 ppm that disappeared upon D2O exchange with
2NH groups, and one singlet in the range of 3.9–4.3
attributed to CH2 of the amino acid [18].
Inspired by the above, we have synthesized and charac-
terized different tetrazole-dehydropeptides conjugates
and evaluated their anticancer and antimicrobial activity.
Upon treatment of dehydropeptides 2a–2i with
SiCl4/NaN3 in acetonitrile for 1.5–3 h, the correspond-
ing new derivatives of 1,5-disubstituted tetrazole 3a–3i
were formed (Scheme 2).
RESULTS AND DISCUSSION
In the present study 1,5-disubstituted tetrazole deri-
vatives were synthesized using oxazolone derivatives
The experimental data indicated high efficiency of
the TACS (SiCl4/NaN3) in the process supporting
1 The text was submitted by the authors in English.
1726

SYNTHESIS OF NEW TETRAZOLE DERIVATIVES
1727
Scheme 1. Synthesis of dehydropeptides 2a–2i.
Ar
O
O
H
N
R1
HCl, NH2−CHRCOOR1
N
O
Ar
N
H
TEA−CHCl3
O
R
Reflux
O
O
2a−2i
1a−1i
Ar = 4-ClC6H4 (1a, 1h, 1i, 2a, 2h, 2i), 4-FC6H4 (1b, 2b), 4-OMeC6H4 (1c, 2c), 3,4-di-OMeC6H3 (1d, 2d), 3,4,5-tri-OMeC6H2
(1e, 2e), 4-NO2C6H4 (1f, 2f), 2-thionyl (1g, 2g); R = H, R1 = CH2CH3 (2a–2g), R = H, R1 = CH3 (2h), R = isopropyl, R1 =
CH2CH3 (2i).
Scheme 2. Synthesis of 1,5-disubstituted tetrazole derivatives 3a–3i.
R1
O
R
Ar
Ar
O
O
O
O
H
SiCl4/NaN3
N
N
N
H
N
O
CH3CN
70oC
N
H
O
R
R1
N
N
3a−3i
2a−2i
Scheme 3. A plausible mechanism of formation of 1,5-disubstituted tetrazole.
N+
O
OSi
N−
SiCl4/NaN3
SiCl4/NaN3
N
R
−HN3
≡Si−O−Si≡
Ar
N
Ar
N
R
H
Ar
N
R
B
A
N
N
N
N
Ar
R
3
formation of the products with high yield. IR spectra of
the synthesized compounds 3a–3i contained bands at
3295–3225 cm–1 for one –NH group, and bands in the
ranges of 1759–1740 and 1661–1654 cm–1 attributed to
by TACS accompanied by losing HN3 and giving the
intermediate A which reacts with another mole of
TACS to give B which rearranges into the product 3.
The above was supported by the absence of the
characteristic bands for one NH group and one
1
two carbonyl groups. H NMR spectra demonstrated a
singlet in the range of 8.3-8.9 ppm for NH proton,
which disappeared upon exchange with D2O, and a
signal at 6.0–7.0 ppm (CH=).
1
carbonyl group at 1626 cm–1. In H NMR spectra
signals of an amino acid CH2 group of 2a–2i recorded
at 4.2 ppm were shifted to 5.3 ppm in the spectra
of compounds 3a–3i under the influence of the
neighboring tetrazole ring. An excess of TACS and
A plausible mechanism pathway of the reaction
(Scheme 3) starts with activation of the carbonyl group
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 8 2018

1728
SOLIMAN et al.
Table 1. Experimental data for synthesized derivatives of 1,5-disubstituted tetrazole 3a–3i
Comp. no.
Ar
Product
Time, h
1.5
Yield, %
95
mp, °C
188
3a
Cl
O
O
O
Cl
N
N
H
N
N
N
3b
F
2
80
162
O
O
O
F
N
N
H
N
N
N
MeO
3c
2
93
158
O
O
O
O
N
N
H
N
N
N
3d
2
92
172
O
O
O
O
O
O
O
N
N
N
H
N
N
3e
2
95
164
O
O
O
O
O
O
O
O
O
N
N
N
H
N
N
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SYNTHESIS OF NEW TETRAZOLE DERIVATIVES
1729
Table 1. (Contd.)
Comp. no.
Ar
Product
Time, h
Yield, %
90
mp, °C
O2N
3f
1.5
215
O
O
O
NO2
N
N
N
H
N
N
3g
1.5
162
197
S
S
O
O
O
N
N
N
H
N
N
Cl
3h
2
88
O
H
O
O
Cl
N
N
N
N
H
N
Cl
3i
3
80
140
O
O
O
Cl
N
N
H
N
N
N
longer reaction time did not improve the results of
synthesis.
Antimicrobial assay. Agar diffusion medium. The
synthesized compounds 3a–3i were assayed in vitro
for their antimicrobial activity against the pathogenic
microorganisms in DMSO medium. Ciprofloxacin
(5 µg/disc) and nystatin (100 units/disc) were used as
standards for antibacterial and antifungal activity
respectively (Table 3).
In vitro anticancer activity. Nine compounds
were examined in vitro for their antitumor activity
against MCF-7 human breast carcinoma cell line using
the MTT assay. The accumulated cytotoxicity data for
the compounds were compared against the control,
Doxorubicin®. According to the tests the compounds
demonstrated cytotoxicity, which was somewhat dose-
dependent (see the figure). Five compounds 3a–3c, 3e,
3f demonstrated high anticancer activity (Table 2).
According to the tests data, the compounds 3a–3f
demonstrated moderate activity against gram +ve
bacteria (Bacillus subtilis, Staphylococcus aureus) and
gram –ve bacteria (Pseudomonas aeuroginosa).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 8 2018

1730
SOLIMAN et al.
80
70
and neutralized by TEA (1.8 equiv.) in chloroform. To
1
↓
9
a free amino acid ester mixed with chloroform, a
chloroform solution of oxazolone was added dropwise.
After stirring the mixture for 30 min it was refluxed for
3 h. The solvent was evaporated to dryness and the
residue was dissolved in ethyl acetate and washed with
1 N HCl and water. Upon drying the organic layer over
anhydrous MgSO4, the solvent was removed under
reduced pressure and the residue was treated with ether
to obtain the corresponding product as a white powder.
60
50
40
30
20
25
50
100
Concentration, μM
(E)-Ethyl 2-[2-benzamido-3-(4-chlorophenyl)acryl-
amido]acetate (2a). mp 204°C. IR spectrum, ν, cm–1:
3320, 3218, 2973, 1748, 1658. H NMR spectrum, δ,
Dose dependence anticancer activity curves for the
synthesized compounds 3a–3i against MCF-7 human
cancer cells: (1–9) ah1–ah9.
1
ppm: 8.07 br.s (1H, NH), 8.02 d (J = 8.1 Hz, 2H, Ar-H),
7.93 s (1H, NH), 7.70–7.43 m (7H, Ar-H), 6.75 s (1H,
=CH), 4.23 s (2H, CH2), 4.13 q (2H, CH2), 1.29 t (3H,
CH3). 13C NMR spectrum, δ, ppm: 169, 166, 163.5,
133.15, 132.1, 130, 129, 128.7, 127.5, 61, 40.7, 14.10.
Found, %: C 32.10; H 4.55; Cl 9.32; N 7.44. C20H19ClN2O4.
Calculated, %: C 62.10; H 4.95; Cl 9.17; N 7.24.
EXPERIMENTAL
The chemicals used in the study, including TMS,
were purchased from Sigma-Aldrich.
The determined melting points were uncorrected.
IR spectra were recorded for KBr discs on a Mattson
FTIR Spectrophotometer 5000. NMR spectra were
measured on a Bruker 300 MHz spectrometer in
CDCl3. Mass spectra were measured on an Agilent LC-
MS spectrometer (pump quarternary 1200 Series,
quadruple MSD 6110) equipped with LC column in
multimode (ESI+APCI) ion source of MSD. TLC was
carried out on Merck silica gel GF254 plates and
visualized by UV light at 254 nm and iodine.
(E)-Ethyl 2-[2-benzamido-3-(4-chlorophenyl)acryl-
amido]-3-methylbutanoate (2i). mp 182°C. IR spec-
trum, ν, cm–1: 3332, 3225, 2970, 1740, 1658. 1H NMR
spectrum, δ, ppm: 8.03 s ( 1H, NH), 8.01 d (2H, Ar-H),
8.0 s (1H, NH), 7.70–7.63 m (5H, Ar-H), 7.44 d (2H,
Ar-H), 6.77 s (1H, =CH), 4.2 d (1H, CH), 4.21 q (2H,
CH2), 2.2 m (1H), 1.28 t (3H, CH3), 0.91 d (6H, 2CH3).
13C NMR spectrum, δ, ppm: 173.2, 166.2, 163.5, 133.5,
132.1, 129, 128.8, 127.5, 115.5, 61.5, 61.2, 30.2, 18.5,
14.10. MS: m/z: 428.15 (100.0%), 430.15 (33.0%). Found,
%: C 64.61; H 5.38; Cl 8.67; N 6.23. C23H25ClN2O4.
Calculated, %: C 64.41; H 5.88; Cl 8.27; N 6.53.
General procedure for the synthesis of dehydro-
peptides (2a–2i). In a round bottom flask, an amino
acid ester hydrochloride (1.5 equiv.) was suspended
Table 2. IC50 values for the compounds 3a–3i against
human breast cancer cells
General procedure for synthesis of tetrazole
derivatives (3a–3i). To a mixture of ethyl (or methyl)
2-(2-benzamido-3-arylacrylamido)acetate (5 mmol)
with NaN3 (0.65g, 10 mmol) in 10 mL of acetonitrile
TCS (1.2 mL, 10 mmol) was added at ambient
temperature then the reaction mixture was warmed up
to 50–60°C upon stirring until disappearance of the
starting material, according to TLC. The reaction
mixture was poured into NaHCO3 aqueous solution
and extracted by ethyl acetate. The extracts were dried
over MgSO4, concentrated and cooled down to give
the corresponding pure product.
Compound
IC50, µM
3a
40.2
47.9
44.6
65.3
53.8
53.8
58.7
58.5
84.7
18.6
3b
3c
3d
3e
3f
3g
(Z)-Ethyl 2-{5-[1-benzamido-2-(4-chlorophenyl)
vinyl]-1H-tetrazol-1-yl}acetate (3a). IR spectrum, ν,
3h
1
cm–1: 3225, 3014, 2993, 1740, 1656. H NMR spec-
3i
trum, δ, ppm: 8.67 br.s (1H, NH), 7.76 d (J = 8.1 Hz,
2H, Ar-H), 7.43–7.33 m (7H, Ar-H), 6.77 s (1H, =CH),
Doxorubicin
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SYNTHESIS OF NEW TETRAZOLE DERIVATIVES
1731
Table 3. In vitro antimicrobial activity of compounds 3a–3i according to the agar diffusion methoda
Inhibition zone diameter, mm
Comp.
no.
gram +ve bacteria
gram –ve bacteria
Fungi
Bacillus subtilis Staphylococcus aureus Escherichia coli
Pseudomonas aeuroginosa Candida albicans
3h
3i
15
15
15
17
17
18
18
18
18
14
13
14
16
15
17
16
17
16
13
13
14
15
14
15
14
16
15
14
13
14
15
15
16
16
16
16
11
11
11
12
12
13
13
13
13
3g
3a
3e
3b
3c
3d
3f
a
Highly active (+++) = (inhibition zone ≥ 20 mm); moderately active (++) = (inhibition zone 16–19 mm); slightly active (+) = (inhibition
zone 10–15 mm).
1
5.38 s (2H, CH2), 4.16 q (2H, CH2), 1.21 t (3H, CH3).
13C NMR spectrum, δ, ppm: 166, 164, 147,133.45,
132, 130, 129, 128.4, 127.5, 61, 47.4, 14.12. Found,
%: C 58.53; H 4.21; Cl 8.31; N 16.98. C20H18ClN5O3.
Calculated, %: C 58.33; H 4.41; Cl 8.61; N 17.00.
rum, ν, cm–1: 3225, 2969, 1745, 1659. H NMR spec-
trum, δ, ppm: 8.63 s ( 1H, NH), 8.03 d (2H, ArH), 7.75–
7.63 m (3H, ArH), 7.22–7.00 m (3H, ArH), 6.32 s (1H,
=CH), 5.11 s (2H, CH2), 4.11 q (2H, CH2), 3.83 s (6H,
OCH3), 1.26 t (3H, CH3). 13C NMR spectrum, δ, pp:
166, 163.8, 149.7, 146.5, 133.2, 132.2, 128.8, 127.5,
117.5, 111.0, 106.0, 61, 60, 56, 47.2, 14.1. MS: m/z:
437.17 (100.0%), 438.17 (25.8%). Found, %: C 60.20;
H 5.10; N 15.91. C22H23N5O5. Calculated, %: C 60.40;
H 5.30; N 16.01.
(Z)-Ethyl 2-{5-[1-benzamido-2-(4-florophenyl)vinyl]-
1H-tetrazol-1-yl}acetate (3b). IR spectrum, ν, cm–1:
1
3245, 3014, 2983, 1740, 1656. H NMR spectrum, δ,
ppm: 8.87 br.s (1H, NH), 7.86 d (J = 8.1 Hz, 2H, Ar-
H), 7.53–7.43 m (7H, Ar-H), 6.97 s (1H, =CH), 5.48 s
(2H, CH2), 4.26 q (2H, CH2), 1.31 t (3H, CH3). 13C
NMR spectrum, δ, ppm: 166, 164,162.2, 147,133.25,
132.1, 130.9, 130.4, 129, 127.6, 117.5,106, 61, 47.4,
14.12. MS: m/z: 395.14 (100.0%), 396.14 (23.6%). Found,
%: C 60.85; H 4.79; F, 4.61; N 17.51. C20H18FN5O3.
Calculated, %: C 60.75; H 4.59; F, 4.81; N 17.71.
(Z)-Ethyl 2-{5-[1-benzamido-2-(3,4,5-trimethoxy-
phenyl)vinyl]-1H-tetrazol-1-yl}acetate (3e). IR spec-
trum, ν, cm–1: 3295, 3058, 2969, 1755, 1665. 1H NMR
spectrum, δ, ppm: 8.53 s ( 1H, NH),7.85 d (2H, ArH),
7.66–7.55 m (5H, ArH), 6.95 d (2H, Ar-H), 6.82 s (1H,
=CH), 5.31 s (2H, CH2), 4.21 q (2H, CH2), 3.78 s (6H,
OCH3), 3.72 s (3H, OCH3), 1.06 t (3H, CH3). 13C NMR
spectrum, δ, ppm: 166,1 163.8, 153, 146.5, 133.25,
132.2, 130, 128.8, 127.4, 107.5, 105, 61, 60.5, 56,
47.2, 14.1. MS: m/z: 467.18 (100.0%), 468.18 (27.0%).
Found, %: C 59.00; H 5.29; N 14.68. C23H25N5O6.
Calculated, %: C 59.09; H 5.39; N 14.98.
(Z)-Ethyl 2-{5-[1-benzamido-2-(4-methoxyphenyl)-
vinyl]-1H-tetrazol-1-yl}acetate (3c). IR spectrum, ν,
1
cm–1: 3293, 3026, 2962, 1756, 1664. H NMR spec-
trum, δ, ppm: 8,52 s ( 1H, NH), 7.84 d (2H, ArH), 7.56
–7.46 m (5H, ArH), 6.90 d (2H, Ar-H), 6.81 s (1H,
=CH), 5.31 s (2H, CH2), 4.21 q (2H, CH2), 3.78 s (3H,
13
(Z)-Ethyl 2-{5-[1-benzamido-2-(4-nitrophenyl)
vinyl]-1H-tetrazol-1-yl}acetate (3f). IR spectrum, ν,
cm–1: 3238, 3026, 2990, 1741, 1659. 1H NMR
spectrum, δ, ppm: 10.76 s ( 1H, NH), 8.26 d (2H,
ArH), 7.95 d (2H, ArH), 7.66 d (2H, Ar-H), 7.56 t (1H,
Ar-H), 7.53 t (2H, Ar-H), 7.18 s (1H, =CH), 5.46 s
(2H, CH2), 4.00 q (2H, CH2), 1.06 t (3H, CH3). 13C
NMR spectrum, δ, ppm: 166, 165.9, 153.72, 147,
OCH3), 1.06 t (3H, CH3). C NMR spectrum, δ, ppm:
166,1 163.9, 160, 146.5, 133.45, 132, 130, 128.9, 127.4,
117.5, 106, 61, 56, 47.4, 14.12. MS: m/z: 407.16 (100.0%),
408.16 (24.7%). Found, %: C 61.61; H 5.00; N 17.09.
C21H21N5O4. Calculated, %: C 61.91; H 5.20; N 17.19.
(Z)-Ethyl 2-{5-[1-benzamido-2-(3,4-drimethoxy-
phenyl)vinyl]-1H-tetrazol-1-yl}acetate (3d). IR spect-
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1732
SOLIMAN et al.
140.5, 132.62, 132, 130.42, 128.7, 128.5, 127.97, 123.8,
122.5, 62, 48.7, 13.69. MS: m/z: 422.13 (100.0%),
423.14 (22.0%). Found, %: C 56.47; H 4.20; N 19.60;
O 18.99. C20H18ClN6O5. Calculated, %: C 56.87; H
4.30; N 19.90. O 18.94
Memorial Institute medium (RPMI-1640) supple-
mented with 10% heat-inactivated fetal bovine serum
(FBS) and 100 U/mL of both penicillin and
streptomycin in a 5% CO2 humidified atmosphere.
After 24 h the media were removed and a fresh serum-
free media (90 µL/well) were added together with
10 µL of series of compounds or doxorubicin®
(positive control) in DMSO for 48 h. Then, media
were removed, MTT (40 µL of 2.5 mg/mL) was added
to each well and incubated for 4 h. DMSO (200 µL)
were added to solubilized the formazan dye crystals
(purple color). Using a SpectraMax® Paradigm® Multi-
Mode microplate reader, the absorbance was measured
at 590 nm. Each experiment was repeated on three
different days and conducted in triplicate. The relative
cell cytotoxicity was measured according to the
following equation:
(Z)-Ethyl 2-{5-[1-benzamido-2-(thiophen-2-yl)vinyl]-
1H-tetrazol-1-yl}acetate (3g). IR spectrum, ν, cm–1:
1
3295, 3108, 2961, 1750, 1656. H NMR spectrum, δ,
ppm: 8.57 s (1H, NH), 8.05 d (J = 8.1 Hz, 2H, Ar-H),
7.7–7.63 m (4H, Ar-H), 7.01 d (J = 8.1 Hz, 2H, Ar-H),
6.01 s (1H, =CH), 5.48 s (2H, CH2), 4.16 q (2H, CH2),
1.30 t (3H, CH3). 13C NMR spectrum, δ, ppm: 166.1,
163.9, 147, 139, 138, 133.2, 132.1, 130.5, 129, 128,
127.6, 106, 61, 47.4, 14.1. MS: m/z: 383.11 (100.0%),
384.11 (19.8%). Found, %: C 56.18; H 4.27; N 18.07;
S 8.16. C18H17N5O3S. Calculated, %: C 56.38; H 4.47;
N 18.27; S 8.36.
Cytotoxicity = (1 – As/Ab)×100%,
(Z)-Methyl 2-{5-[1-benzamido-2-(4-chlorophenyl)-
vinyl]-1H-tetrazol-1-yl}acetate (3h). IR spectrum, ν,
cm–1: 3234, 3064, 2989, 1747, 1650. 1H NMR
spectrum, δ, ppm: 8.55 s (1H, NH), 7.79 d (2H, Ar-H),
7.56 t (1H, Ar-H), 7.47–7.37 m (4H, Ar-H),7.27 d (2H,
ArH), 6.81 s (1H, =CH), 5.34 s (2H, CH2), 3.73 s
(3H,OCH3). 13C NMR spectrum, δ, ppm: 166.1, 163.8,
146.7,133.5, 132.8, 132, 129, 128.6, 127.5, 106, 51.4,
47.1. MS: m/z: 397.09 (100.0%), 399.09 (32.4%).
Found, %: C 57.16; H 4.00; Cl 8.71; N 17.40.
C19H16ClN5O3. Calculated, %: C 57.36; H 4.05; Cl
8.91; N 17.60.
where As is an absorbance of each sample and Ab is an
absorbance of the blank. The probit analysis using the
SPSS software program (version 20, SPSS Inc.,
Chicago, IL, USA) was used to determine each IC50.
Antimicrobial assay. Antibacterial activity of the
synthesized compounds was tested against Escherichia
coli NRRL B-210 and Pseudomonas NRRL B-23
(gram –ve bacteria), Bacillus subtilis NRRL B-543 and
Staphylococcus aureus NRRL B-313 (gram +ve
bacteria) using nutrient agar medium. The antifungal
activity of these compounds was also tested against
Candida albicans NRRL Y-477 using Sabouraud
dextrose agar medium [22].
(Z)-Ethyl 2-{5-[1-benzamido-2-(4-chlorophenyl)-
vinyl]-1H-tetrazol-1-yl}-3-methylbutanoate (3i). IR
1
spectrum, ν, cm–1: 3276, 3055, 2970, 1743, 1658. H
NMR spectrum, δ, ppm: 8.67 (s,br, 1H, NH), 8.06 d
(2H, Ar-H), 7.73–7.63 m (5H, Ar-H), 7.43 d (2H, Ar-H),
6.27 s (1H, =CH), 4.6 d (1H, CH), 4.21 q (2H,
CH2),2.5 m (1H), 1.29 t (3H, CH3), 092 d (6H, 2CH3);
13C NMR spectrum, δ, ppm:170.2, 164, 146.5,133.15,
132.1, 129, 128.4, 127.5, 72.2, 61.4, 23.2, 17.5, 14.12.
m/z: 453.16 (100.0%), 455.15 (32.0%). Found, %: C
60.56; H 5.13; Cl 7.81; N 05.43. C23H24ClN5O3.
Calculated, %: C 60.86; H 5.33; Cl 7.81; N 15.43.
CONCLUSIONS
We have developed a simple protocol for the
sustainable synthesis of new derivatives of 1,5-
disubstituted tetrazole via the reaction of dehydro-
peptides with TACS under mild conditions. The de-
hydropeptides are synthetized by reaction of arylidene
derivatives of 2-phenyl-5(4H)-oxazolone with amino
acid esters hydrochloride in the presence of triethyl-
amine at room temperature. Tests of anticancer and
anti-microbial activities of the synthesized tetrazole
derivatives indicated moderate to high activity of some
products.
Biological activity. In vitro anticancer activity.
Antitumor activity against the human breast cancer
cells was assessed using the 3-[4,5-dimethyl-2-
thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT)
assay [19–21]. This cancer cell line was purchased
from ATCC (Rockville, MD, USA).
ACKNOWLEDGMENTS
Financial support by National Research Center
(Cairo, Egypt) is gratefully appreciated.
The cells were cultured in a 96-well sterile micro-
plate (5×104 cells per well) at 37°C in Roswell Park
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SYNTHESIS OF NEW TETRAZOLE DERIVATIVES
1733
15. Wittenberger, S., J. Org. Prep. Proced. Int., 1994,
vol. 26, p. 499.
CONFLICT OF INTERESTS
No conflict of interest was declared by the authors.
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