Synthesis and antimicrobial activity studies of some novel substituted phenylhydrazono-1H-tetrazol-5-ylacetonitriles

Article abstract of DOI:10.1007/s00044-009-9177-9

In this study, some substituted phenylhydrazono-1H-tetrazol-5-yl- acetonitriles have been synthesized (2a-o, 2a and 2k are known compounds). The synthesized compounds were characterized by spectroscopic methods [Fourier-transform infrared (FTIR), nuclear magnetic resonance (NMR), mass spectroscopy (MS)]. In addition, antimicrobial activities of synthesized compounds were investigated against Bacillus cereus RSKK 863, Escherichia coli ATCC 3521, Pseudomonas aeruginosa ATCC 2921, and Staphylococcus aureus TP32. These compounds had antimicrobial effect against these bacteria (except for 21). Birkhaeuser Boston 2009.

Full text of DOI:10.1007/s00044-009-9177-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2010) 19:120–126
DOI 10.1007/s00044-009-9177-9
ORIGINAL RESEARCH
Synthesis and antimicrobial activity studies of some
novel substituted phenylhydrazono-1H-tetrazol-5-yl-
acetonitriles
¨
Serkan Yavuz Æ Ozlem Aydın Æ Servet C¸ ete Æ
Ali Dis¸li Æ Yılmaz Yıldırır
Received: 31 October 2008 / Accepted: 10 February 2009 / Published online: 17 March 2009
¨
Ó Birkhauser Boston 2009
Abstract In this study, some substituted phenylhydrazono-1H-tetrazol-5-yl-aceto-
nitriles have been synthesized (2a–o, 2a and 2k are known compounds). The synthesized
compounds were characterized by spectroscopic methods [Fourier-transform infrared
(FTIR), nuclear magnetic resonance (NMR), mass spectroscopy (MS)]. In addition,
antimicrobial activities of synthesized compounds were investigated against Bacillus
cereus RSKK 863, Escherichia coli ATCC 3521, Pseudomonas aeruginosa ATCC 2921,
and Staphylococcus aureus TP32. These compounds had antimicrobial effect against
these bacteria (except for 2l).
Keywords Tetrazole Á Antimicrobial activity Á Antibiotics
Introduction
Tetrazoles are an increasingly popular functionality with wide-ranging applications
(Butler et al., 1996). They have found use in pharmaceuticals as lipophilic spacers
and carboxylic acid surrogates (Herr, 2002), in specialty explosives (Singh et al.,
1980), photography, and information recording systems (Ostrovskii et al., 1999).
Tetrazoles are regarded as biologically equivalent to the carboxylic acid group, and
extensive work on tetrazoles has been carried out in the field of medicinal chemistry
(Meier and Heimgartner, 1994). Tetrazoles have also been used as precursors to
other heterocycles (Moderhack, 1998) and in high-energy compounds (Ostrovskii
et al., 1999). The tetrazole derivatives have been extensively studied due to their
explosive properties and biological importance in agriculture, biochemistry, and
pharmacology (Katritzky and Ress, 1984).
¨
S. Yavuz Á O. Aydın Á S. C¸ ete Á A. Dis¸li Á Y. Yıldırır (&)
Chemistry Department, Faculty of Science and Arts, Gazi University,
Teknikokullar, 06500, Ankara, Turkey
e-mail: yildirir@gazi.edu.tr

Med Chem Res (2010) 19:120–126
121
It has been long been known that 5-substituted-1H-tetrazoles (RCN4H) may serve
as a nonclassical isostere for the carboxylic acid moiety in biologically active
molecules (Burger, 1991; Lipinski, 1986; Singh et al., 1980; Wittenberger, 1994).
The term nonclassical isosterism (used interchangeably with the term bioisosterism)
refers to the concept in which functional groups that have similar physicochemical
properties may be interchangeable, resulting in similar biological properties.
Furthermore, a nonclassical isostere may or may not have the same steric or neither
electronic characteristics, nor even the number of atoms, as the substituent for which
it is used as a replacement (Burger, 1991; Lipinski, 1986; Patani and LaVoie, 1996).
The earliest published methods for the preparation of 5-substituted tetrazoles
were reactions of nitriles with azides (Kadaba, 1973). An interesting report
described the preparation of a few simple 5-(hydroxyphenyl)tetrazoles by the
reaction of aryl nitriles with sodium azide in the presence of boron trifluoride
(Kumar et al., 1996). This is one of the few examples in the literature by which a
Lewis acid was used to generate a hydrazoic acid species in situ. It has long been
known that simple heating of azide salt with nitrile in a solution produces the
corresponding tetrazole (Dimroth and Fester, 1910).
Thus, in continuation of our lasting interest in chemistry and pharmacological
properties of tetrazoles, in the present study, we synthesized a series of 1-H-tetrazol-
5-yl-acetonitrile derivatives having phenylhydrazono substituent and determined
their antimicrobial activities against some microorganisms.
Results and discussion
Chemistry
In this study, some substituted phenylhydrazono-1H-tetrazol-5-yl-acetonitriles were
synthesized (compounds 2a and 2k were published by Fahmy 1986, the other
compounds are novel compounds) and antimicrobial effects of these compounds were
determined against clinically important pathogens. The target compounds, 2a–o, were
synthesized as depicted in Scheme 1.
The purity of the compounds was checked via thin-layer chromatography (TLC)
using various mobile phases. The structures of synthesized compounds (2a–o) were
1
identified on the basis of FTIR, H-NMR, and MS spectral data. Spectral values
NH2
R1
R1
R1
Et3NHCl, NaN3
toluene
CN
N
1) EtONO/HCl,
0-5 °C
CN
CN
R2
N N
H
R2
N N
H
N H
N
C H N , EtONa/EtOH
2)
3
2 2
R2
N
1(a-o)
2(a-o)
Scheme 1 Protocol for synthesis of substituted phenylhydrazono-1H-tetrazol-5-yl-acetonitriles. (a)
R1 = H, R2 = H; (b) R1 = F, R2 = H; (c) R1 = H, R2 = F; (d) R1 = Cl, R2 = H; (e) R1 = H,
R2 = Cl; (f) R1 = Br, R2 = H; (g) R1 = H, R2 = Br; (h) R1 = I, R2 = H; (i) R1 = H, R2 = I; (j)
R1 = CH3, R2 = H; (k) R1 = H, R2 = CH3; (l) R1 = OCH3, R2 = H; (m) R1 = H, R2 = OCH3; (n)
R1 = NO2, R2 = H; (o) R1 = H, R2 = NO2

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Med Chem Res (2010) 19:120–126
support the expected structures. Two CN bands were observed at 2,220–2,260 cm-1
in the FTIR spectra of compounds 1a–o. One of the CN bands disappeared in the
FTIR spectrum of compounds 1a–o when cyano group was converted to tetrazole
ring. In addition, we observed characteristic bands for tetrazole ring and only one
CN band in the IR spectrum of compounds 2a–o. The characteristic NH absorption
bands appeared between 3,120–3,500 cm-1as broad bands due to tautomeric
structure of tetrazole and the Ar-H band occurs at 3,020–3,100 cm-1
.
Antimicrobial activity
The antimicrobial activities of the compounds were determined against four various
bacteria types. Except for compound 2l, other synthesized compounds have
antimicrobial effect against both Gram-positive and Gram-negative bacteria used. In
this study, antimicrobial activities of tetrazole derivates were compared with some
antibiotics. The antimicrobial activities of the synthesized compounds against
Bacillus cereus RSKK 863, Escherichia coli ATCC 35218, Pseudomonas aerugin-
osa ATCC 29212, and Staphylococcus aureus TP32 are tabulated in Table 1.
The results show that tetrazole derivates have an inhibitory effect on the four
microorganism types tested. The highest antimicrobial effect was obtained in the
cases of compounds 2e (21 mm), 2g (20 mm), 2j (20 mm), and 2k (20 mm) against
B. cereus RSKK 863. On the other hand, the antimicrobial effect was not detected
Table 1 Antimicrobial activity of substituted phenylhydrazono-1H-tetrazol-5-yl-acetonitriles expressed
as inhibition zones (50 ll of 1 mg/ml solutions)
Compound Inhibition zone (mm)
Negative
controls
Staphylococcus aureus Methanol
Bacillus Escherichia
cereus (RSKK coli (ATCC
Pseudomonas
aeruginosa (ATCC TP32 (clinical isolate)
29212)
863)
35218)
2a
2b
2c
2d
2e
2f
15
19
19
5
7
14
11
–
9
4
8
5
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
8
10
7
10
8
21
12
20
17
10
20
20
–
10
7
6
3
–
2g
2h
2i
14
7
8
6
5
3
7
9
8
2j
10
10
–
5
4
2k
2l
8
8
–
–
2m
2n
2o
7
10
7
–
–
10
11
4
4
10
5
3
Dash indicates no inhibition

Med Chem Res (2010) 19:120–126
123
Table 2 Antimicrobial effect of some antibiotics on the microorganisms
Antibiotics
Inhibition zone (mm)
Bacillus cereus
(RSKK 863)
Escherichia coli
(ATCC 35218)
Pseudomonas aeruginosa
(ATCC 29212)
Erythromycin (15 lg)
Vancomycin (30 lg)
Tetracycline (30 lg)
Fluconazole (30 lg)
Penicillin-G (10 units)
Ampicillin (10 lg)
19
17
17
–
11
–
–
–
–
16
–
–
–
17
9
–
20
–
for 2l against all microorganisms and 2m against P. aeruginosa ATCC29212 and
Staphylococcus aureus TP32. Generally, the p-substituted compounds showed
greater antimicrobial activities than did o-substituted compounds.
It is shown that the compounds have greater antimicrobial effect against Bacillus
cereus than against other microorganisms. It is known that Bacillus cereus is a
Gram-positive bacteria whereas Pseudomonas aeruginosa and Escherichia coli are
Gram-negative bacteria. This observation is attributed to the fact that Gram-positive
bacteria have different cell wall from Gram-negative bacteria.
The antimicrobial effects of some antibiotics were known on the studied
microorganisms (Table 2) (C¸ ete et al., 2007; Katircioglu et al., 2007). The present
observations clearly demonstrate that the synthesized compounds have similar
antimicrobial effect to those antibiotics on the tested microorganisms.
Conclusion
In the present work, some substituted phenylhydrazono-1H-tetrazol-5-yl-acetonitr-
iles were synthesized and their antimicrobial activities were evaluated. All
synthesized compounds demonstrated potent inhibition against all the tested strains
of various microorganisms. At the same time, antimicrobial screenings indicate that
the present compounds have greater antibacterial activities against Gram-positive
bacteria than against Gram-negative bacteria. This study may enhance the usage of
the tetrazole derivates as potential new antibiotics. Further research in this area is in
progress in our laboratory.
Experimental
Chemistry
All aniline derivatives and other chemicals were obtained from Merck. All melting
points were determined in sealed capillaries and are reported uncorrected. FTIR
1
spectra were recorded on a Mattson 1000 spectrometer as KBr pellets. H-NMR

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Med Chem Res (2010) 19:120–126
spectra were recorded on a Varian Gemini 300 (300 MHz) NMR spectrometer in
dimethyl sulfoxide (DMSO)-d6. Mass spectra measurements were recorded on a
Thermo Finnigan Trace DSQ.
Preparation of phenylazomalononitrile derivatives (1a–o)
A series of substituted phenylazomalononitrile compounds were synthesized from
substituted anilines (C¸ ete et al., 2006).
Preparation of substituted phenylhydrazono-1H-tetrazol-5-yl-acetonitriles (2a–o)
Phenylhydrazono-1H-tetrazol-5-yl-acetonitrile (2a) was prepared by using the
following typical procedure. Suspension of triethylammonium chloride (1.37 g, 0.01
mol) in toluene (20 ml) was prepared in a 250-ml two-necked flask equipped with a
reflux condenser. Then, sodium azide (0.65 g, 0.01 mol) was slowly added
portionwise with stirring. A solution of phenylazomalononitrile (1a) (1.70 g, 0.01
mol) in toluene (25 ml) was slowly added, stirred for 5 min, and then heated to
gentle reflux for 8 h. After cooling the reaction mixture, distilled water (20 ml) was
added, the aqueous layer was separated, the toluene layer was washed with water (3 9
5 ml), and aqueous extracts were collected. Then the aqueous layer (pH 8) was
cooled to 0–5°C, and acidified to pH 3–4 by using dilute HCl while stirring for 10
min. The solid precipitate formed was collected, washed with water, and
recrystallized from ethanol–water. Yield: 92%; m.p. 243–244°C (decomposed)
(Lit. m.p. 245°C, Fahmy 1986); MS(EI) molecular peak (m/z) = 213.49; IR mmax
1
(cm-1) (KBr): N-H: 3390; Ar-H: 3080; C:N: 2250; H-NMR (DMSO-d6) dH:
12.65 (s,1H, NH); 8.03 (s, 1H, NH), 7.54 (m, 5H, Ar-H).
The method for synthesis of 2b–o was the same as that of 2a.
2-Florophenylhydrazono-1H-tetrazol-5-yl-acetonitrile (2b): Yield: 86%; m.p.
264–266°C (decomposed); MS(EI) molecular peak (m/z) = 231.88; IR mmax (cm-1
)
(KBr): N-H: 3290; Ar-H: 3015; C:N: 2210; 1H-NMR (DMSO-d6) dH: 12.65 (s,1H,
NH); 8.03 (s, 1H, NH), 6.90–7.70 (m, 4H, Ar-H). 4-Florophenylhydrazono-1H-
tetrazol-5-yl-acetonitrile (2c): Yield: 91%; m.p. 185–187°C (decomposed); MS(EI)
molecular peak (m/z) = 231.92; IR mmax (cm-1) (KBr): N-H: 3390; Ar-H: 3020;
C:N: 2205; 1H-NMR (DMSO-d6) dH: 12.80 (s,1H, NH); 11.85 (s, 1H, NH), 7.00 (d,
2H, Ar-H), 7.45 (d, 2H, Ar-H). 2-Chlorophenylhydrazono-1H-tetrazol-5-yl-acetoni-
trile (2d): Yield: 86%; m.p. 164–165°C (decomposed); MS(EI) molecular peak
1
(m/z) = 247.36; IR mmax (cm-1) (KBr): N-H: 3400; Ar-H: 3099; C:N: 2230; H-
NMR (DMSO-d6) dH: 13.22 (s, 1H, NH), 8.70 (s, 1H, NH), 7.12–7.85 (m, 4H, Ar-H).
4-Chlorophenylhydrazono-1H-tetrazol-5-yl-acetonitrile (2e): Yield: 92%; m.p. 198–
199°C (decomposed); MS(EI) molecular peak (m/z) = 247.09; IR mmax (cm-1) (KBr):
N-H: 3500; Ar-H: 3098; C:N: 2230; 1H-NMR (DMSO-d6) dH: 13.87 (s, 1H, NH),
12.18 (s, 1H, NH), 7.45 (m, 4H, Ar-H). 2-Bromophenylhydrazono-1H-tetrazol-5-yl-
acetonitrile (2f): Yield: 86%; m.p. 181–182°C (decomposed); MS(EI) molecular peak
(M-H?) (m/z) = 292.49, 294.12; IR mmax (cm-1) (KBr): N-H: 3243; Ar-H: 3100;
C:N: 2250; 1H-NMR (DMSO-d6) dH: 14.12 (s, 1H, NH), 12.17 (s, 1H, NH), 6.81–
7.34 (m, 4H, Ar-H). 4-Bromophenylhydrazono-1H-tetrazol-5-yl-acetonitrile (2g):

Med Chem Res (2010) 19:120–126
125
Yield: 85%; m.p. 215–216°C; (decomposed); MS(EI) molecular peak (m/z) =
1
293.35; IR mmax (cm-1) (KBr): N-H: 3150; Ar-H: 3020; C:N: 2249; H-NMR
(DMSO-d6) dH: 12.84 (s, 1H, NH), 12.60 (s, 1H, NH), 7.25 (d, 2H, Ar-H), 6.71 (d, 2H,
Ar-H). 2-Iodophenylhydrazono-1H-tetrazol-5-yl-acetonitrile (2h): Yield: 86%; m.p.
176–179°C (decomposed); MS(EI) molecular peak (m/z) = 339.17; IR mmax (cm-1
)
(KBr): N-H: 3110; Ar-H: 3030; C:N: 2215; 1H-NMR (DMSO-d6)
dH: 12.75 (s,1H, NH); 11.85 (s, 1H, NH), 7.05–7.35 (m, 4H, Ar-H). 4-Iodophenylhyd-
razono-1H-tetrazol-5-yl-acetonitrile (2i): Yield: 90%; m.p. 224–226°C (decom-
posed); MS(EI) molecular peak (m/z) = 339.14; IR mmax (cm-1
) (KBr):
1
N-H: 3210; Ar-H: 3015; C:N: 2210; H-NMR (DMSO-d6) dH: 12.75 (s,1H, NH);
12.05 (s, 1H, NH), 7.65 (d, 2H, Ar-H), 7.15 (d, 2H, Ar-H). 2-Methylphenylhydrazono-
1H-tetrazol-5-yl-acetonitrile (2j): Yield: 85%; m.p. 195–196°C (decomposed);
MS(EI) molecular peak (m/z) = 227.89; IR mmax (cm-1) (KBr): N-H: 3290; Ar-H:
1
3046; C:N: 2248; H-NMR (DMSO-d6) dH: 12.60 (s, 1H, NH), 7.94 (s, 1H, NH),
7.02–745 (m, 4H, Ar-H), 2.55 (s, 3H, CH3). 4-Methylphenylhydrazono-1H-tetrazol-5-
yl-acetonitrile (2k): Yield: 88%; m.p. 206–208°C (decomposed) (lit. m.p. 207–209°C,
Butler et al., 1992); S(EI) molecular peak (m/z) = 226.55;IR mmax (cm-1) (KBr): N-H:
1
3500; Ar-H: 3050; C:N: 2249; H-NMR (DMSO-d6) dH: 12.90 (s, 1H, NH), 7.67
(s, 1H, NH), 7.32 (d, 2H, Ar-H), 7.15 (d, 2H, Ar-H), 2.56 (s, 3H, CH3).
2-Methoxyphenylhydrazono-1H-tetrazol-5-yl-acetonitrile (2 l): Yield: 89%; m.p.
148–150°C; (decomposed); MS(EI) molecular peak (m/z) = 243.08; IR mmax (cm-1
)
(KBr): N-H: 3120; Ar-H: 3030; C-H: 2965, C:N: 2215; 1H-NMR (DMSO-d6) dH:
12.88 (s, 1H, NH), 9.72 (s, 1H, NH), 6.92–7.68 (m, 4H, Ar-H), 3.91 (s, 3H, CH3).
4-Methoxyphenylhydrazono-1H-tetrazol-5-yl-acetonitrile (2m): Yield: 85%; m.p.
167–169°C; (decomposed); MS(EI) molecular peak (m/z) = 243.21; IR mmax (cm-1
)
(KBr): N-H: 3160; Ar-H: 3025; C-H: 2935, C:N: 2220; 1H-NMR (DMSO-d6) dH:
12.70 (s, 1H, NH), 9.25 (s, 1H, NH), 7.85 (d, 2H, Ar-H), 6.90 (d, 2H, Ar-H), 3.75 (s, 3H,
CH3). 2-Nitrophenylhydrazono-1H-tetrazol-5-yl-acetonitrile (2n): Yield: 82%; m.p.
207–208°C; (decomposed); MS(EI) molecular peak (m/z) = 258.84; IR mmax (cm-1
)
(KBr): N-H: 3290; Ar-H: 3070; C:N: 2220; 1H-NMR (DMSO-d6) dH: 14.46 (s, 1H,
NH), 8.97 (s, 1H, NH), 7.64–8.02 (m, 4H, Ar-H). 4-Nitrophenylhydrazono-1H-
tetrazol-5-yl-acetonitrile (2o): Yield: 86%; m.p. 176–177°C; (decomposed); MS(EI)
molecular peak (m/z) = 259.65; IR mmax (cm-1) (KBr): N-H: 3120; Ar-H: 3040;
1
C:N: 2230; H-NMR (DMSO-d6) dH: 13.02 (s, 1H, NH), 12.60 (s, 1H, NH), 8.72
(d, 2H, Ar-H), 8.17 (d, 2H, Ar-H).
Biology
Material and methods
The bacterial subcultures for Bacillus cereus RSKK 863, Escherichia coli ATCC
35218, Pseudomonas aeruginosa ATCC 29212, and Staphylococcus aureus TP32
were obtained from the Biology Department of Gazi University.
Antimicrobial susceptibilities of all the presently considered pathogenic bacteria
were determined concomitantly by the agar-well diffusion method. Bacterial strains

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Med Chem Res (2010) 19:120–126
were inoculated into nutrient broth (Difco) and incubated at 30 0.1°C for 24 h. In
order to test the antimicrobial effect, substituted phenylhydrazono-1H-tetrazol-5-yl-
acetonitriles and 15 ml Muller–Hinton agar (Merck) were placed in Petri dishes,
which were then inoculated with strains of bacteria by taking 100 ll cell culture
media. This was left to solidify at room temperature for a while and then holes were
made on top with a sterile stick. Solutions (50 ll, 1 mg/ml) were then added to these
holes. Petri dishes were left at 4°C for 2 h. The bacterial cultures were incubated at
34°C for 24 h. At the end of incubation time, the inhibition zones on the bacterial
and yeast nutrient media were measured.
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