Synthesis and Evaluation of Some Phenyl Substituted Azetidine Containing 1, 2, 4-triazole Derivatives as Antibacterial Agents

Article abstract of DOI:10.1002/jhet.3357

A novel series of phenyl substituted azetidine containing 1, 2, 4-triazole derivatives 7(a–j) were synthesized and characterized by IR, 1HNMR, 13CNMR, and mass spectroscopy. Synthesized 1, 2, 4-triazole derivatives were subsequently assayed in vitro to investigate their antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli using broth dilution method. Compounds 7c, 7d, and 7e exhibited potent inhibitory activities as compared to standard cefotaxime. Further, fluorescence spectral studies were also carried out to ascertain the antibacterial potential of compound 7c against two bacterial strains, that is, P.?aeruginosa and S.?aureus. In docking studies, all the compounds exhibited good docking scores between ?12.04 and ?11.36?kcal/mol and indicated that compounds could act through inhibition of bacterial DNA gyrase (PDB ID 3U2D). Among all, 7c has shown the maximum docking score and found in agreement to in vitro studies. In conclusion, synthesized 1, 2, 4-triazole derivatives holds substantial caliber to be categorized as antibacterial agents.

Full text of DOI:10.1002/jhet.3357

Month 2018
Synthesis and Evaluation of Some Phenyl Substituted Azetidine
Containing 1, 2, 4-triazole Derivatives as Antibacterial Agents
a
a
b
a
b
Esha Dhall, Sonika Jain, Achal Mishra,
Jaya Dwivedi, *
and Swapnil Sharma
a
Department of Chemistry, Banasthali Vidyapith, Banasthali 304022, India
Department of Pharmacy, Banasthali Vidyapith, Banasthali 304022, India
b
*
E-mail: jayadwivedi@yahoo.co.in
Received March 7, 2018
DOI 10.1002/jhet.3357
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A novel series of phenyl substituted azetidine containing 1, 2, 4-triazole derivatives 7(a–j) were
synthesized and characterized by IR, 1HNMR, 13CNMR, and mass spectroscopy. Synthesized 1, 2,
4
-triazole derivatives were subsequently assayed in vitro to investigate their antibacterial activity
against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli using broth dilution
method. Compounds 7c, 7d, and 7e exhibited potent inhibitory activities as compared to standard
cefotaxime. Further, fluorescence spectral studies were also carried out to ascertain the antibacterial
potential of compound 7c against two bacterial strains, that is, P. aeruginosa and S. aureus. In docking
studies, all the compounds exhibited good docking scores between À12.04 and À11.36 kcal/mol and
indicated that compounds could act through inhibition of bacterial DNA gyrase (PDB ID 3U2D).
Among all, 7c has shown the maximum docking score and found in agreement to in vitro studies.
In conclusion, synthesized 1, 2, 4-triazole derivatives holds substantial caliber to be categorized as
antibacterial agents.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
ability to interact with biomolecular targets [3,4]. The 1, 2,
-triazole nucleus is an important pharmacophore
4
Rapid emergence of resistance in microbial therapy is
becoming a major threat to investigators and physicians,
worldwide. Since last decades, mortality and morbidity
with microbial diseases are continuously increasing and
thus require new therapeutic agents for their effective
treatment. Moreover, multidrug therapy offers a burden
of adverse effects which further worsen the situation in
the recipient [1]. In view of this, there is an urgent need
to develop some new chemical scaffolds with efficacious
and potent antimicrobial activity to combat bacterial
diseases [2].
incorporated in a wide variety of therapeutically important
drugs, and its derivatives have consistently attracted
researchers because of their wide chemical properties,
synthetic versatility, and pharmacological activities such as
antibacterial [5–10], antifungal [11,12], anti-inflammatory
[13,14], antimycobacterial [15], anticonvulsant [16],
antidepressant [16], anti-HIV [17], antitumor [18], and
antiproliferative [19–25].
Azetidine, a four-membered cyclic lactam (β-lactam)
heterocycles, skeleton has been recognized as a useful
building block for the synthesis of large number of key
antibiotics such as the penicillin (I), cephalosporin (II),
clavulanic acid (III), and thienamycine (Fig.1).
1
, 2, 4 Triazoles are nitrogen containing heterocycles
which possess high metabolic stability and offers a unique
©
2018 Wiley Periodicals, Inc.

E. Dhall, S. Jain, A. Mishra, J. Dwivedi, and S. Sharma
Vol 000
Figure 1. Antibiotics containing azetidine nucleus.
Azetidinones have been considered as key structure for
precipitation of interesting biological activities [26].
In recent years, combination of two different active
fragments in single molecule has emerged out as a
reliable strategy which allows efficient binding of
resulting complex on target at multiple sites, so as to
achieve additive or synergistic effects. Such dual-action
drugs or hybrid drugs provide better therapeutic
management and simultaneously reduces the frequency of
development of microbial resistance [27].
In view of exploring this idea, we thought that it could
be interesting to develop libraries of new hybrid
molecules containing bioactive pharmacophores such as
azetidine and 1, 2, 4 triazoles, on this premise, that
their presence in tandem in the same molecular
framework could contribute significantly to produce
novel series of compounds with enhanced antibacterial
activities. Further, molecular docking studies were also
carried out to understand the protein-ligand interaction
in between synthesized compounds and concerned
bacterial proteins.
TLC were prepared with silica gel G and activated at
110°C for 30 min. Iodine vapors were used to develop
the TLC plates. Elemental analyses were performed on a
Vario EL-III analyzer.
Synthesis of ethyl 2-(4-isobutylphenyl)propanoate (2) and
2-(4-isobutyl phenyl)propano-hydrazide (3).
To 10 mL of
0.02 mol ibuprofen solution in ethanol, a few drops of
sulfuric acid were added and refluxed for a period of 18 h.
The mixture was then cooled to room temperature, and
excess of 0.06 mol hydrazine hydrate was added to it and
was further refluxed for a period of 5 h. The product was
concentrated under reduced pressure and cooled. The solid
obtained was washed with cold water and recrystallized
from hot water.
2-(4-Isobutylphenyl)propanoate (2). Yield: 94.87%; M.
P.: 97–99°C; Anal. Calcd for C H O : C, 76.88; H, 9.46;
15 22 5
O, 13.66% Found: C, 76.91; H, 9.41; O, 13.68; FT-IR
(νmax): 2967, 2930 (Asym. aliphatic C-H strech.), 2889
(Aliphatic C-H stretch.), 2872, 2864 (Sym. aliphatic C-H
strech.), 1735 (C=O stretch.), 1597 (Phenyl ring stretch.),
À1
1
1252 (C-O strech.) cm ; H-NMR-7.26-7.24 & 7.04–
7
4
.03 (dd, 4H, Phenyl ring Protons J = 8.0, J = 8.0),
.23–4.18 (q, 2H, OCH2 CH ), 3.78–3.75 (q, 1 H,
À
3
EXPERIMENTAL
Ph-CH–CH -), 2.43–2.41 (d, 2H, -Ph-CH- isopropyl,
3
J = 8.0), 1.85–1.79 (s, 1H, CH – CH–CH3 isobutyl
3
All the chemicals were obtained from Himedia
Chemicals, Mumbai (Maharashtra) India. Melting points
were determined on a Tempo capillary melting point appa-
ratus in open capillary tube and are uncorrected. All FTIR
proton), 1.62–1.61 (d, 3 H, ph-CH-CH , J = 4.0),1.30–
3
1.27 (t, 3H, OCH -CH J = 12.0), 0.92–0.91 (d, 6H
2
3,
methyl protons of isobutyl, J = 4.0).
Synthesis of ethyl 2-(4-isobutylphenyl)propanoate (2) and
À1
spectra were recorded (νmax in cm ) on Bruker Tensor 27
2-(4-isobutyl phenyl)propano-hydrazide (3).
Yield:
1
FT-IR spectrometer. H-NMR (proton nuclear magnetic
8
9.56%; M.P.: 214–216°C; Anal. Calcd for C H N OS:
1
4 21 3
resonance) spectrum were recorded at 300 MHz, after dis-
C, 60.18; H, 7.58; N, 15.04; O, 5.73; S, 11.48% Found:
C, 60.16; H, 7.56; N, 15.01; O, 5.76; S, 11.50%; FT-IR
solving in a suitable solvent (dimethyl sulfoxide, CDCl , or
3
À1
D O) on Bruker Avance II 400 MHz, USA FT-NMR spec-
2
(ν in cm ): 3363 (Asym. N-H stretch.), 3354 (Sym. N-H
trometer using tetramethylsilane as internal standard and
stretch.), 2964, 2933 (Asym. aliphatic C-H strech.), 2886
chemical shifts (δ) are reported in parts per million
(Aliphatic C-H strech.), 2874, 2866 (Sym. aliphatic C-H
13
À1
(ppm). C NMR was also recorded on Bruker Avance II
strech.), 1646 (C=O stretch.), 848 (C=S strech.) cm
;
1
FT-NMR spectrometer at frequency of 100 MHz. The spin
multiplicities are indicated by symbols, s (singlet), d (dou-
blet), t (triplet), q (quartet), m (multiplet), and br (broad).
Mass spectra were recorded on waters UPLC-TQD mass
spectrometer using electrospray ionization (ESI) technique.
The purity of the compounds was ascertained by thin layer
chromatography (TLC) and elemental analysis. Plates for
H-NMR 8.12 (s, 1 H, CO-NH-NH ), 7.25–7.23 & 7.05–
2
7.03 (dd, 4H, Phenyl Ring Protons J = 8.0, J = 8.0),
3
.53–3.50 (q, 2H, -Ph-CH-CH -), 2.43–2.41 (d,2H, -Ph-
3
CH-isopropyl J = 8.0), 2.15 (s, 1 H, s, 2H, CO -NH-
NH ), 1.85–1.79 (s, 1H, CH –CH–CH isobutyl proton),
2
3
3
1
.28–1.26 (d, 3H, ph–CH–CH J = 8.0), 0.92–0.91 (d,
3
6H, methyl protons of isobutyl J = 4.0).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
1, 2, 4-Triazole Derivatives as Antimicrobial Agents
Synthesis of potassium salt of 2-[2-(4-isobutyl phenyl)
propanoyl] hydrazine carbodithioate (4).
was filtered, washed with ice cold water, dried, and
recrystallized in methanol.
To a solution
of ibuprofen acid hydrazide in ethanol, (0.02 mol)
carbon disulphide was added and followed by alcoholic
KOH (0.015 mol) dropwise. The reaction mixture was
stirred for about 4 h. Then, reaction mixture was
diluted with ether (50 mL) and separated solid with dry
ether 50 mL, and separated solid was filtered washed
with dry ether to obtained potassium salt in quantitative
yield.
4-(Benzylidene-amino)-5-[1-(4-isobutyl-phenyl)-ethyl]-2,4-
dihydro-[1,2,4]triazole-3-thione (6a). Yield: 67.23%; M.P.:
188–189°C; Anal. Calcd for C21H N S: C, 69.20; H,
24 4
6.64; N, 15.37; S, 8.80% Found: C, 69.23; H, 6.66; N,
À1
1
5.34; S, 8.78%; FT-IR (ν in cm ): 3471.10 (N-H
strech.), 3083 (Aromatic C-H strech.), 2965 (Asym.
aliphatic C-H strech.), 2875 (Sym. aliphatic C-H
strech.), 1659 (C=O strech.), 1599 (C=N stretch.), 1505
(Phenyl ring stretch.), 1389 & 1368 (Sym C-H isobutyl
Yield: 79.14%; M.P.: 228–230°C; Anal. Calcd for
C H N O: C, 70.87; H, 9.15; N, 12.72; O, 7.26%
À1
1
bending), 1248 (C-N strech.) cm ; H-NMR (CDCl
ppm): 8.48 (s, 1H, Ph-CH=N), 7.83–7.51 (m, 5H, p-
)
1
3 20 2
3
(
Found: C, 70.85; H, 9.12; N, 12.74; O, 7.29%; FT-IR
À1
(
ν in cm ): 3373 (Asym. N-H stretch.), 3344 (Sym.
Phenyl ring proton), 7.24–7.03 (dd, 4H, ibuprofen
aromatic ring protons), 7.01 (s, 1H, NH triazole ring
proton), 4.26–4.23 (q, 1H, Ph-CH- CH3 at triazole
linkage), 2.44–2.42 (d, 2H, isopyopyl), 1.85–1.79 (m,
1H, isopyopyl), 1.69–1.67 (d, 3H, Ph-CH- CH at
3
triazole linkage), 0.92–0.91 (d, 6H, isopropyl methyl
N-H stretch.), 2967, 2936 (Asym. aliphatic C-H
strech.), 2889 (Aliphatic C-H strech. o), 2872, 2864
(
(
(
Sym. aliphatic C-H strech.), 1638 (C=O stretch.), 846
À1
1
C=S strech.) cm ; H-NMR 8.56 (s, 2H, NH ), 7.99
2
s, 1 H, CO-NH), 7.26–7.24 & 7.05–7.03 (dd, 4 H,
Phenyl Ring Protons, J = 8.0, J = 8.0), 3.54–3.51 (q,
H, Ph-CH-CH -), 2.45–2.43 (d, 2 H-Ph-CH- isopropyl
protons).
4
-[(2-Chloro-benzylidene)-amino]-5-[1-(4-isobutyl-phenyl)-
1
3
ethyl]-2,4-dihydro-[1,2,4]triazole-3-thione (6b).
Yield:
J = 8.0), 2.01 (s, 1H, s = C-NH), 1.85–1.77 (s, 1 H,
CH À CH-CH isobutyl proton), 1.28–1.26 (d, 3 H, Ph
5
9.61%; M.P.: 239–242°C; Anal. Calcd for C H ClN S:
21
23
4
3
3
C, 63.22; H, 5.81; Cl, 8.89; N, 14.04; S, 8.04% Found: C,
-
CH-CH J = 8.0), 0.94–0.92 (d, 6H, methyl protons of
3
6
3.25; H, 5.79; Cl, 8.92; N, 14.02; S, 8.02%; FT-IR (ν in
isobutyl J = 8.0).
Synthesis of 4-amino-5[(4-isobutylphenyl-1)ethyl]-1,2,4-
triazole-3thiol (5). The potassium carbothioate salt was
refluxed with (0.03 mol) of hydrazine hydrate in
À1
cm ): 3472 (N-H strech.), 3082 (Aromatic C-H strech.),
2
964 (Asym. aliphatic C-H strech.), 2875 (Sym. aliphatic
C-H strech.), 1655 (C=O strech.), 1596 (Phenyl ring
stretch.), 1252 (C-N strech.), 1079 (Aromatic C-Cl stretch.)
methanol until evaluation of H S ceased (6–8 h). Further,
2
À1
1
cm ; H-NMR (CDCl ) (ppm): 8.46 (s, 1H, Ph-CH=N),
mixture was neutralized with dilute HCL and then poured
in to the crushed ice and kept in the fridge for overnight.
The solid was filtered, washed with ice cold water, dried,
and recrystallized in methanol.
3
7
.76–7.75 & 7.52–7.51 (dd, 4H, phenyl ring protons,
J = 4.0, J = 4.0), 7.46–7.37 (m, 4H, p- Phenyl ring
protons),7.25–7.22 (dd, 4H, ibuprofen aromatic ring
protons, J = 12), 7.01 (s, 1H, NH triazole ring proton),
4.26–4.22 (q, 1H, Ph-CH- CH
2.41 (d, 2H, isopropyl, J = 12.0), 1.86–1.78 (m, 1H,
isopropyl),1.69–1.67 (d, 3H, Ph-CH- CH at triazole
Yield: 65.83%; M.P.: 184–186°C; Anal. Calcd for
C H N S: C, 60.84; H, 7.29; N, 20.27; S, 11.60%
at triazole linkage), 2.44–
1
4 20 4
3
Found: C, 60.86; H, 7.26; N, 20.25; S, 11.63%; FT-IR (ν
À1
in cm ): 3393 (Asym. N-H stretch. of NH ), 3384, 3371
3
2
(
Sym. N-H stretch of NH & NH.), 2962, 2935 (Asym.
linkage, J = 8.0), 0.93–0.91 (d, 6H, isopropyl methyl
2
aliphatic C-H strech. of CH & CH ), 2891 (Aliphatic C-
protons J = 8.0).
3
2
H strech.), 2869, 2861 (Sym. aliphatic C-H strech.), 1695
4-[(4-Chloro-benzylidene)-amino]-5-[1-(4-isobutyl-phenyl)-
À1
1
ethyl]-2,4-dihydro-[1,2,4]triazole-3-thione
(6c).
Yield:
5.35%; M.P.: 255–257°C; Anal. Calcd for
C H ClN S: C, 63.22; H, 5.81; Cl, 8.89; N, 14.04; S,
(
C=O stretch.), 1258 (C-N), 849 (C=S strech.) cm ; H-
6
NMR 7.25–7.23 and 7.05–7.03 (dd, 4H, Phenyl Ring
Protons J = 8.0, J = 8.0), 7.01 (s, 1H, NH in triazole
21 23
4
8
8
.04% Found: C, 63.24; H, 5.83; Cl, 8.86; N, 14.01; S,
.06%; FT-IR (ν in cm ): 3477 (N-H strech.), 3089
ring), 4.23–4.20 (q, 1H, Ph-CH-CH ), 2.44–2.42 (d, 2H,
3
À1
-
Ph- CH- isopropyl J = 8.0), 2.14 (s, 2H, NH ), 1.85–
2
(Aromatic C-H strech.), 2965 (Asym. aliphatic C-H
1
.79 (s, 1H, CH3 CH-CH isobutyl proton),1.68–1.66
À 3
(d, 3H, Ph-CH-CH J = 8.0), 0.92–0.91 (d, 6H, methyl
strech.), 2878 (Sym. aliphatic C-H strech.), 1656 (C=N
stretch.), 1599 (Phenyl ring stretch.), 1256 (C-N strech.),
3
protons of isobutyl J = 4.0).
Synthesis of 4-{[-(1Z)(substituted phenyl)methylene]
À1
1
1
079 (Aromatic C-Cl stretch.) cm ; H-NMR (CDCl )
3
amino}5-[2-(4-isobutyl phenyl]-1,2,4-triazole-3-thiol (6a–j).
The aromatic aldehyde (0.01 mol) was added to the
solution of triazoles (0.01 mol) in glacial acetic acid
(ppm): 8.49 (s, 1H, Ph-CH=N), 7.77–7.75 & 7.52–7.51
(dd, 4H, o and p Phenyl ring protons J = 8.0, J = 4.0),
7.24–7.22 & 7.05–7.04 (dd, 4H, ibuprofen aromatic ring
protons, J = 8.0, J = 4.0), 7.02 (s, 1H, NH triazole ring
proton), 4.26–4.21 (q, 1H, Ph-CH- CH3 at triazole
10 mL, and mixture was refluxed for 24 h. Then, mixture
was cooled and poured in to the ice cold water. The solid
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. Dhall, S. Jain, A. Mishra, J. Dwivedi, and S. Sharma
Vol 000
À1
1
linkage), 2.44–2.41 (d, 2H, isopropyl J = 12.0), 1.85–1.80
m, 1H, isopropyl J = 20.0), 1.69–1.66 (d, 3H, Ph-CH-
CH3 at triazole linkage J = 12.0), 0.92–0.91 (d, 6H,
(C-N strech.), cm ; H-NMR (CDCl ) (ppm):8.52 (s, 1H
3
(
proton at Phenyl ring near nitro substitution), 8.46 (s, 1H,
Ph-CH=N), 8.22–8.20 & 8.14–8.12 (dd, 4H, Phenyl ring
protons J = 8.0, J = 8.0), 7.77–7.73 (m, 3H, Phenyl ring
protons), 7.24–7.22 & 7.05–7.04 (dd, 4H, ibuprofen
aromatic ring protons J = 8.0, J = 4.0), 7.02 (s, 1H, NH
triazole ring proton), 4.26–4.22 (q, 1H, Ph-CH- CH at
triazole linkage), 2.43–2.41 (d, 2H, isopropyl J = 8.0),
1.85–1.78 (m, 1H, isopropyl J = 28), 1.68–1.66 (d, 3H,
Ph-CH- CH at triazole linkage J = 8.0), 0.93–0.91 (d,
6H, isopropyl methyl protons J = 8.0).
4-[(2-Methoxy-benzylidene)-amino]-5-[1-(4-isobutyl-phenyl)-
ethyl]-2,4-dihydro-[1,2,4]triazole-3-thione
9.27%; M.P.: 191–193°C; Anal. Calcd for C H N OS:
C, 66.97; H, 6.64; N, 14.20; O, 4.06; S, 8.13% Found: C,
6.98; H, 6.67; N, 14.22; O, 4.02; S, 8.11%; FT-IR (ν in
isopropyl methyl protons J = 4.0).
4
-[(2-Bromo-benzylidene)-amino]-5-[1-(4-isobutyl-phenyl)-
ethyl]-2,4-dihydro-[1,2,4]triazole-3-thione (6d).
Yield:
8.74%; M.P.: 247–250°C; Anal. Calcd for
C H BrN S: C, 56.88; H, 5.23; Br, 18.02; N, 12.64; S,
5
3
2
1
23
4
7
7
.23% Found: C, 56.90; H, 5.25; Br, 18.04; N, 12.61; S,
.20%; FT-IR (ν in cm ): 3468 (N-H strech.), 3084
À1
3
(Aromatic C-H strech.), 2965 (Asym. aliphatic C-H
strech.), 2875 (Sym. aliphatic C-H strech.), 1666 (C=N
stretch.), 1603 (Phenyl ring stretch.), 1393 & 1369 (Sym
C-H isobutyl bending), 1254 (C-N strech.), 1042
(6g).
Yield:
6
22 26
4
À1
1
(
(
(
(
(
Aromatic C-Br stretch.), cm
;
H-NMR (CDCl3)
6
ppm):8.46 (s, 1H, Ph-CH=N), 7.72–7.70 & 7.58–7.56
dd, 4H, phenyl ring proton J = 8.0, J = 8.0), 7.46–7.41
m, 4H, p- Phenyl ring protons), 7.24–7.22 & 7.05–7.03
dd, 4H, ibuprofen aromatic ring protons J = 8.0,
À1
cm ): 3478 (N-H strech.), 3087 (Aromatic C-H strech.),
965 (Asym. aliphatic C-H strech.), 2875 (Sym. aliphatic
2
C-H strech.), 1664 (C=N stretch.), 1385 & 1364 (Sym
C-H isobutyl bending), 1258 & 1047 (C-O strech.), 1247
J = 8.0), 7.00 (s, 1H, NH triazole ring proton), 4.26–4.22
q, 1H, Ph-CH- CH at triazole linkage), 2.44–2.42 (d,
À1
1
(
C-N stretch.), cm ; H-NMR (CDCl ) (ppm): 8.46 (s,
(
3
3
1
4
7
H, Ph-CH=N), 7.72–7.70 (d, 2H, J = 8.0),7.58–7.56 (m,
H, p- Phenyl ring protons J = 8.0), 7.27–7.22 (q, 1 H),
.12–7.10 & 7.05–7.03 (dd, 4H, ibuprofen aromatic ring
2
1
H, isopropyl J = 8.0), 1.86–1.78 (m, 1H, isopropyl),
.69–1.67 (d, 3H, Ph-CH- CH3 at triazole linkage
J = 8.0) 0.92–0.90 (d, 6H, isopropyl methyl protons
J = 8.0).
protons J = 8.0, J = 8.0), 7.01 (s, 1H, NH triazole ring
proton), 4.26–4.24 (q, 1H, Ph-CH- CH3 at triazole
4
-[(4-Bromo-benzylidene)-amino]-5-[1-(4-isobutyl-phenyl)-
ethyl]-2,4-dihydro-[1,2,4]triazole-3-thione (6e).
Yield:
linkage), 3.83 (s, 3H, OCH
2.43–2.41 (d, 2H, isopropyl J = 8.0), 1.86–1.79 (m, 1H,
isopropyl), 1.68–1.66 (d, 3H, Ph-CH- CH at triazole
3
protons at phenyl ring),
6
2.16%; M.P.: 259–261°C; Calculated for C H BrN S:
2
1
23
4
C, 56.88; H, 5.23; Br, 18.02; N, 12.64; S, 7.23% Found:
3
C, 56.91; H, 5.25; Br, 18.04; N, 12.61; S, 7.19%; FT-IR
linkage J = 8.0), 0.93–0.92 (d, 6H, isopropyl methyl
protons J = 4.0).
À1
(
ν in cm ): 3477 (N-H strech.), 3086 (Aromatic C-H
4
-[(4-Methoxy-benzylidene)-amino]-5-[1-(4-isobutyl-phenyl)-
strech.), 2967 (Asym. aliphatic C-H strech.), 2878 (Sym.
aliphatic C-H strech.), 1657 (C=N stretch.), 1603 (Phenyl
ethyl]-2,4-dihydro-[1,2,4]triazole-3-thione
(6h).
Yield:
9
0.45%; M.P.: 180–182°C; Anal. Calcd for C H N OS:
2
2 26 4
ring stretch.), 1388 & 1369 (Sym C-H isobutyl bending),
C, 66.97; H, 6.64; N, 14.20; O, 4.06; S, 8.13% Found: C,
À1
1
254 (C-N strech.), 1048 (Aromatic C-Br stretch.), cm
;
6
6.99; H, 6.66; N, 14.23; O, 4.02; S, 8.10%; FT-IR (ν in
1
H-NMR (CDCl ) (ppm):8.47 (s, 1H, Ph-CH=N), 7.72–
À1
3
cm ): 3476 (N-H strech.), 3082 (Aromatic C-H strech.),
7
.70 & 7.58–7.56 (dd, 4H, Phenyl ring protons J = 8.0,
J = 8.0), 7.24–7.22 & 7.05–7.03 (dd, 4H, ibuprofen
aromatic ring protons J = 8.0, J = 8.0), 7.01 (s, 1H, NH
2
964 (Asym. aliphatic C-H strech.), 2875 (Sym. aliphatic
C-H strech.), 1664 (C=N stretch.), 1390 & 1367 (Sym
C-H isobutyl bending), 1258 & 1043 (C-O strech.), 1248
triazole ring proton), 4.26–4.21 (q, 1H, Ph-CH- CH at
À1
1
3
(
C-N stretch.), cm ; H-NMR (CDCl ) (ppm): 8.45 (s,
3
triazole linkage), 2.44–2.41 (d, 2H, isopropyl J = 12.0),
1
H, Ph-CH=N), 7.85–7.83 (d, 2H, Phenyl ring protons
1.87–1.79 (m, 1H, isopropyl), 1.69–1.66 (d, 3H, Ph-CH-
J = 8.0), 7.25–7.23 (d, 2H, ibuprofen aromatic ring
protons J = 8.0), 7.06–7.04 (d, 4H, Phenyl ring and
ibuprofen aromatic ring protons J = 8.0, 7.01 (s, 1H, NH
CH3 at triazole linkage J = 12.0), 0.92–0.90 (d, 6H,
isopropyl methyl protons J = 8.0).
4
-[(3-Nitro-benzylidene)-amino]-5-[1-(4-isobutyl-phenyl)-
triazole ring proton), 4.26–4.21 (q, 1H, Ph-CH- CH at
3
ethyl]-2,4-dihydro-[1,2,4]triazole-3-thione (6f).
Yield:
triazole linkage), 3.83 (s, 3H, OCH ), 2.44–2.41 (d, 2H,
3
6
3.41%; M.P.: 242–243°C; Anal. Calcd for C H N S:
2
1 23 5
isopropyl J = 12.0), 1.85–1.77 (m, 1H, isopropyl), 1.69–
C, 61.59; H, 5.66; N, 17.10; O, 7.81; S, 7.83% Found: C,
1
.67 (d, 3H, Ph-CH- CH at triazole linkage J = 8.0),
3
6
1.57; H, 5.69; N, 17.14; O, 7.74; S, 7.85%; FT-IR (ν in
0
.92–0.90 (d, 6H, isopropyl methyl protons, J = 8.0).
À1
cm ): 3474 (N-H strech.), 3085 (Aromatic C-H strech.),
4
-[(4-Hydroxy-benzylidene)-amino]-5-[1-(4-isobutyl-phenyl)-
2966 (Asym. aliphatic C-H strech.), 2877 (Sym. aliphatic
ethyl]-2,4-dihydro[1,2,4]triazole-3-thione
(6i).
Yield:
C-H strech.), 1662 (C=N stretch.), 1596 (Phenyl ring
stretch.), 1525 (Asy N=O stretch.), 1389 & 1365 (Sym
C-H isobutyl bending), 1338 (sym N=O strech.), 1246
70.33%; M.P.: 196–199°C; Anal. Calcd for C H N OS:
C, 66.29; H, 6.36; N, 14.72; O, 4.20; S, 8.43% Found: C,
66.32; H, 6.38; N, 14.74; O, 4.16; S, 8.40%; FT-IR (ν in
21 24 4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
1, 2, 4-Triazole Derivatives as Antimicrobial Agents
À1
À1
cm ): 3415 (O-H & N-H strech.), 3082 (Aromatic C-H
strech.), 2961 (Asym. aliphatic C-H strech.), 2872 (Sym.
aliphatic C-H strech.), 1661 (C=N stretch.), 1453 (Asym
CH3 bending), 1384 & 1368 (Sym C-H isobutyl
12.67; O, 3.63; S, 7.29%; FT-IR (ν in cm ): 3468 (N-H
strech.), 3081 (Aromatic C-H strech.), 2960 (Asym.
aliphatic C-H strech.), 2872 (Sym. aliphatic C-H strech.),
1670–2000 (overtone for substitution on aromatic ring),
1766 (C=O strech.), 1657 (C=N stretch.), 1596 (Phenyl
ring stretch.), 1503 (Phenyl C-H out of plane bending),
1466 (CH bending), 1456 (Asym CH bending), 1389 &
À1
1
bending), 1257 (C-N strech.), cm ; H-NMR (CDCl )
ppm):8.47 (s, 1H, Ph-CH=N), 7.78–7.76 & 6.86–6.84
dd, 4H, Phenyl ring protons J = 8.0 & J = 8.0), 7.24–
3
(
(
2
3
7
.22 & 7.06–7.04 (dd, 4H, ibuprofen aromatic ring
1368 (Sym C-H isobutyl bending), 1246 (C-N strech.),
À1
1
protons J = 8.0 & J = 8.0), 7.01 (s, 1H, NH triazole ring
proton), 5.35 (s, 1H, OH proton on Phenyl ring), 4.26–
768 (C-Cl) cm ; H-NMR (CDCl ) (δ, ppm): 7.6–7.2
3
(m, 4H, ibuprofen aromatic ring protons), 7.01 (m, 1H, p-
aromatic ring proton), 5.44–5.42 (d, 1H, azetidine ring
proton at -Cl linkage), 5.09–5.07 (d, 1H, azetidine ring
proton at aromatic linkage), 2.45–2.43 (d, 2H, isopyopyl),
1.89–1.84 (m, 1H, isopyopyl), 1.66–1.64 (d, 6H,
4.22 (q, 1H, Ph-CH- CH at triazole linkage), 2.44–2.41
3
(d, 2H, isopropyl J = 12.0), 1.86–1.78 (m, 1H,
isopropyl), 1.69–1.67 (d, 3H, Ph-CH- CH3 at triazole
linkage J = 8.0), 0.92–0.91 (d, 6H, isopropyl methyl
protons J = 4.0).
13
isopyopyl); C-NMR (CDCl ) (δ, ppm): 185.58 (C=S,
3
4
-[(4-Dimethylamino-benzylidene)-amino]-5-[1-(4-isobutyl-
triazole ring carbon), 163.73 (C=O azetidine ring carbon),
phenyl)-ethyl]-2,4-dihydro-[1,2,4]triazole-3-thione (6j).
Yield: 72.28%; M.P.: 230–232°C; Calculated for
C H N S: C, 67.78; H, 7.17; N, 17.18; S, 7.87%
Found: C, 67.81; H, 7.19; N, 17.16; S, 7.84%; FT-IR (ν
1
56.67 (C=N triazole ring carbon), 143.37–126.23
(aromatic ring carbon), 65.16 (-Cl linked azetidine ring
2
3
29
5
carbon), 60.20 (aromatic linked azetidine ring carbon);
+
m/e (ESI): 432 (M ).
À1
in cm ): 3462 (N-H strech.), 3075 (Aromatic C-H
3-Chloro-4-(2-chlorophenyl)-1-(3-(1-(4-isobutylphenyl)
strech.), 2965 (Asym. aliphatic C-H strech.), 2876 (Sym.
aliphatic C-H strech.), 1657 (C=N stretch.), 1465 (Asym
CH3 bending), 1384 & 1367 (Sym C-H isobutyl
ethyl)-5-thioxo-1H-1,2,4-triazol-4(5H)-yl)azetidin-2-one (7b).
Yield: 62.15%; M.P.: 265–267°C; Anal. Calcd for
C H Cl N OS: C, 58.10; H, 5.09; Cl, 14.91; N, 11.78;
23
24
2 4
À1
1
bending), 1337 (sec. amine C-N strech.), cm ; H-NMR
CDCl ) (ppm): 8.49 (s, 1H, Ph-CH=N), 7.52–7.50 &
O, 3.37; S, 6.74%; Found: C, 58.13; H, 5.12; Cl, 14.77;
À1
(
N, 11.78; O, 3.39; S, 6.70%; FT-IR (ν in cm ): 3470
3
6
&
.83–6.81 (dd, 4H, o and p Phenyl ring protons J = 8.0
J = 8.0), 7.24–7.22 & 7.06–7.04 (dd, 4H, ibuprofen
(N-H strech.), 3080 (Aromatic C-H strech.), 2961(Asym.
aliphatic C-H strech.), 2872 (Sym. aliphatic C-H strech.),
1670–2000 (overtone for substitution on aromatic ring),
1765 (C=O strech.), 1653 (C=N stretch.), 1598 (Phenyl
ring stretch.), 1503 (Phenyl C-H out of plane bending),
1465 (CH bending), 1457 (Asym CH bending), 1390 &
aromatic ring protons J = 8.0 & J = 8.0), 7.01 (s, 1H, NH
triazole ring proton), 4.26–4.22 (q, 1H, Ph-CH- CH at
triazole linkage), 3.06 (s, 6H, N-CH protons at phenyl
ring), 2.44–2.42 (d, 2H, isopropyl J = 8.0), 1.86–1.79 (m,
3
3
2
3
1
H, isopropyl), 1.69–1.66 (d, 3H, Ph-CH- CH at triazole
1369 (Sym C-H isobutyl bending), 1250 (C-N strech.),
3
À1
linkage J = 12.0), 0.92–0.90 (d, 6H, isopropyl methyl
protons J = 8.0).
1077 (Aromatic C-Cl stretch.), 769 (C-Cl) cm
;
1
H-NMR (CDCl ) (δ, ppm): 7.72–7.26 (m, 4H, ibuprofen
3
Synthesis of 3-chloro-1-(3-(1-(4-isobutylphenyl)ethyl)-5-
thioxo-1H-1,2,4-triazol-4(5H)-yl)-4-substituted
aromatic ring protons), 7.05–7.01 (m, 4H, aromatic ring
protons), 5.44–5.42 (d, 1H, azetidine ring proton), 5.09–
phenylazetidin-2-one (7a–j). A mixture of the compounds
5
.07 (d, 1H, azetidine ring proton), 2.45–2.43 (d, 2H,
(
6a–j, 0.001 mol) in ethanol (10 mL) and chloroacetyl
chloride (0.003 mol) in the presence of triethylamine
0.003 mol) was placed in round bottom flask and
isopyopyl), 1.89–1.84 (m, 1H, isopyopyl), 1.66–1.64 (d,
13
6H, isopyopyl); C-NMR (CDCl ) (δ, ppm): 186.68
3
(
(C=S triazole ring carbon), 165.63 (C=O azetidine ring
refluxed for 4 h. The reaction mixture was filtered while
hot to remove the triethyl amine hydrogen chloride salt
and the filtrate was concentrated to half its volume then
poured onto crush ice with continuous stirring. The
product was filtered, washed with water, and
recrystallized from ethanol. All the synthesized
carbon), 157.77 (C=N triazole ring carbon), 144.55–
126.43 (aromatic ring carbon), 65.86 (-Cl linked azetidine
ring carbon), 60.63 (aromatic linked azetidine ring
carbon); m/e (ESI): 351 (base peak), 474 (M ),
475(M + 1), 476 (M + 2).
+
3-Chloro-4-(4-chlorophenyl)-1-(3-(1-(4-isobutylphenyl)
ethyl)-5-thioxo-1H-1,2,4-triazol-4(5H)-yl)azetidin-2-one (7c).
1
13
derivatives were also confirmed by FTIR, H NMR,
C
Yield: 62.94%; M.P.: 267–269°C; Anal. Calcd for
NMR, and mass spectroscopy method.
3
-Chloro-1-(3-(1-(4-isobutylphenyl)ethyl)-5-thioxo-1H-1,2,4-
C H Cl N OS: C, 58.10; H, 5.09; Cl, 14.91; N, 11.78;
23
24
2 4
triazol-4(5H)-yl)-4-phenyl azetidin-2-one (7a).
Yield:
O, 3.37; S, 6.74%; Found: C, 58.14; H, 5.11; Cl, 14.96;
À1
78.86%;
M.P.
224–226°C;
Anal.
Calcd
for
N, 11.78; O, 3.39; S, 6.77%, FT-IR (ν in cm ): 3475
C H C N OS: C, 62.64; H, 5.71; Cl, 8.04; N, 12.70; O,
(N-H strech.), 3087 (Aromatic C-H strech.), 2963 (Asym.
2
3 25 l 4
3.63; S, 7.27%; found: C, 62.66; H, 5.73; Cl, 8.02; N,
aliphatic C-H strech.), 2875 (Sym. aliphatic C-H strech.),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. Dhall, S. Jain, A. Mishra, J. Dwivedi, and S. Sharma
Vol 000
1
1
670–2000 (overtone for substitution on aromatic ring),
767 (C=O strech.), 1656 (C=N stretch.), 1597 (Phenyl
(C=N stretch.), 1598 (Phenyl ring stretch.), 1504 (Phenyl
C-H out of plane bending), 1466 (CH bending), 1457
2
ring stretch.), 1504 (Phenyl C-H out of plane bending),
(Asym CH bending), 1388 & 1369 (Sym C-H isobutyl
3
1
1
464 (CH bending), 1455 (Asym CH bending), 1389 &
bending), 1252 (C-N strech.), 1045 (Aromatic C-Br
2
3
À1
1
368 (Sym C-H isobutyl bending), 1254 (C-N strech),
stretch.), 775 (C-Cl) cm ; H-NMR (CDCl ) (δ, ppm):
3
À1
1
079 (Aromatic C-Cl stretch.), 772 (C-Cl) cm
;
7.94–7.15 (m, 4H, ibuprofen aromatic ring protons),
7.05–7.01 (m, 4H, aromatic ring proton) 5.44–5.42 (d,
1H, azetidine ring proton), 5.09–5.07 (d, 1H, azetidine
ring proton), 2.45–2.43 (d, 2H, isopyopyl), 2.45–2.43 (d,
2H, isopyopyl), 1.89–1.84 (m, 1H, isopyopyl), 1.66–1.64
1
H-NMR (CDCl ) (δ, ppm): 7.48–7.24 (m, 4H, ibuprofen
3
aromatic ring protons), 7.05–7.01 (m, 4H, aromatic ring
protons), 5.44–5.42 (d, 1H, azetidine ring proton), 5.09–
5.07 (d, 1H, azetidine ring proton), 2.45–2.43 (d, 2H,
13
isopyopyl), 1.89–1.84 (m, 1H, isopyopyl), 1.66–1.64 (d,
(d, 6H, isopyopyl); C-NMR (CDCl ) (δ, ppm): 182.77
3
13
6
H, isopyopyl); C-NMR (δ, ppm): 183.63 (C=S triazole
ring carbon), 165.63 (C=O azetidine ring carbon), 157.77
C=N triazole ring carbon), 143.95–126.23 (aromatic ring
carbon), 65.56 (-Cl linked azetidine ring carbon), 60.23
(C=S triazole ring carbon), 162.33 (C=O azetidine ring
carbon), 154.57 (C=N triazole ring carbon), 140.75–
122.03 (aromatic ring carbon atoms), 62.26 (-Cl linked
azetidine ring carbon), 58.33 (aromatic linked azetidine
(
+
(
(
aromatic linked azetidine ring carbon); m/e (ESI): 351
base peak), 474 (M ), 475(M + 1), 476 (M + 2).
ring carbon atom); m/z (ESI): 91 (base peak), 518(M ),
+
519 (M + 1), 520 (M + 2).
3-Chloro-1-(3-(1-(4-isobutylphenyl)ethyl)-5-thioxo-1H-1,2,4-
triazol-4(5H)-yl)-4-(3-nitrophenyl)azetidin-2-one (7f). Yield:
4
-(2-Bromophenyl)-3-chloro-1-(3-(1-(4-isobutylphenyl)
ethyl)-5-thioxo-1H-1,2,4-triazol-4(5H)-yl)azetidin-2-one (7d).
Yield: 72.29%; M.P.: 264–257°C; Anal. Calcd for
C H BrClN OS: C, 53.14; H, 4.65; Br, 15.37; Cl, 6.82;
73.95%; M.P.: 247–249°C; Anal. Calcd for
C H ClN O S: C, 56.84; H, 4.98; Cl, 7.30; N, 14.41;
2
3
24
4
23 24
5 3
N, 10.78; O, 3.08; S, 6.17%; Found: C, 53.16; H, 4.68;
O, 9.88; S, 6.60%; Found: C, 56.90; H, 5.01; Cl, 7.27; N,
12.40; O, 9.93; S, 6.55%. FT-IR (ν in cm ): 3472 (N-H
strech.), 3083 (Aromatic C-H strech.), 2964 (Asym.
aliphatic C-H strech.), 2875 (Sym. aliphatic C-H strech.),
1670–2000 (overtone for substitution on aromatic ring),
1768 (C=O strech.), 1665 (C=N stretch.), 1598 (Phenyl
ring stretch.), 1522 (Asy N=O stretch.), 1505 (Phenyl
À1
Br, 15.35; Cl, 6.80; N, 10.76; O, 3.11; S, 6.15%; FT-IR
À1
(
ν in cm ): 3470 (N-H strech.), 3082 (Aromatic C-H
strech.), 2963(Asym. aliphatic C-H strech.), 2874 (Sym.
aliphatic C-H strech.), 1670–2000 (overtone for
substitution on aromatic ring), 1766 (C=O strech.), 1666
(C=N stretch.), 1599 (Phenyl ring stretch.), 1503 (Phenyl
C-H out of plane bending), 1467 (CH bending), 1456
C-H out of plane bending), 1465 (CH bending), 1459
2
2
(
Asym CH bending), 1393 & 1369 (Sym C-H isobutyl
(Asym CH bending), 1387 & 1365 (Sym C-H isobutyl
3
3
bending), 1252 (C-N strech.), 1040 (Aromatic C-Br
bending), 1335 (sym N=O strech.), 1249 (C-N strech.),
À1
1
À1
1
stretch.), 768 (C-Cl) cm ; H-NMR (CDCl ) (ppm) (δ,
772 (C-Cl) cm ; H-NMR (CDCl ) (δ, ppm): 8.18–7.22
3
3
ppm): 7.55–7.16 (m, 4H, ibuprofen aromatic ring
protons), 7.05–7.01 (m, 4H, aromatic ring protons), 5.44–
(m, 4H, ibuprofen aromatic ring protons), 7.05–7.01 (m,
4H, aromatic ring proton) 5.44–5.42 (d, 1H, azetidine ring
proton), 5.09–5.07 (d, 1H, azetidine ring proton),
2.45–2.43 (d, 2H, isopyopyl), 1.89–1.84 (m, 1H,
5
.42 (d, 1H, azetidine ring proton), 5.09–5.07 (d, 1H,
azetidine ring proton), 2.45–2.43 (d, 2H, isopyopyl),
.89–1.84 (m, 1H, isopyopyl), 1.66–1.64 (d, 6H,
13
1
isopyopyl), 1.66–1.64 (d, 6H, isopyopyl);
C-NMR
13
isopyopyl); C-NMR (CDCl ) (δ, ppm): 182.28 (C=S
(CDCl ) (δ, ppm): 188.68 (C=S triazole ring carbon),
3
3
triazole ring carbon), 162.0 3 (C=O azetidine ring
carbon), 154.97 (C=N triazole ring carbon), 140.95–
167.55 (C=O azetidine ring carbon), 158.87 (C=N triazole
ring carbon), 147.57–128.53 (aromatic ring carbon
atoms), 68.64 (-Cl linked azetidine ring carbon), 63.46
(aromatic linked azetidine ring carbon atom); m/e (ESI):
122.83 (aromatic ring carbon), 62.88 (-Cl linked azetidine
ring carbon), 58.83 (aromatic linked azetidine ring
+
+
carbon); m/e (ESI): 91 (base peak), 518 (M ),
351 (base peak), 486 (M ), 487 (M + 1), 488 (M + 2).
3
-Chloro-1-(3-(1-(4-isobutylphenyl)ethyl)-5-thioxo-1H-1,2,4-
5
19(M + 1), 519 (M + 2).
4
-(4-Bromophenyl)-3-chloro-1-(3-(1-(4-isobutylphenyl)
triazol-4(5H)-yl)-4-(2 methoxyphenyl)azetidin-2-one (7g).
Yield: 61.84%; M.P.: 235–238°C; Anal. Calcd for
C H ClN O S: C, 61.20; H, 5.78; Cl, 7.53; N, 11.89;
ethyl)-5-thioxo-1H-1,2,4-triazol-4(5H)-yl)azetidin-2-one (7e).
Yield: 70.63%; M.P.: 256–259°C; Anal. Calcd for
C H BrClN OS: C, 53.14; H, 4.65; Br, 15.37; Cl, 6.82;
24
27
4 2
O, 6.79; S, 6.81%; Found: C, 61.22; H, 5.80; Cl, 7.51; N,
2
3
24
4
À1
N, 10.78; O, 3.08; S, 6.17%; Found: C, 53.17; H, 4.66;
11.86; O, 6.82; S, 6.78%; FT-IR (ν in cm ): 3474 (N-H
Br, 15.35; Cl, 6.80; N, 10.77; O, 3.11; S, 6.15%; FT-IR
strech.), 3089 (Aromatic C-H strech.), 2967 (Asym.
aliphatic C-H strech.), 2878 (Sym. aliphatic C-H strech.),
1670–2000 (overtone for substitution on aromatic ring),
1767 (C=O strech.), 1667 (C=N stretch.), 1599 (Phenyl
ring stretch.), 1505 (Phenyl C-H out of plane bending),
À1
(
ν in cm ): 3474 (N-H strech.), 3088 (Aromatic C-H
strech.), 2965(Asym. aliphatic C-H strech.), 2876 (Sym.
aliphatic C-H strech.), 1670–2000 (overtone for
substitution on aromatic ring), 1765 (C=O strech.), 1655
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
1, 2, 4-Triazole Derivatives as Antimicrobial Agents
1
1
467 (CH bending), 1457 (Asym CH bending), 1385 & bending), 1386 & 1368 (Sym C-H isobutyl bending),
2
3
À1
1
367 (Sym C-H isobutyl bending), 1258 & 1047 (C-O
1253 (C-N strech.), 776 (C-Cl) cm ; H-NMR (CDCl )
3
À1
1
strech.), 1247 (C-N stretch.), 778 (C-Cl) cm ; H-NMR
CDCl ) (δ, ppm): 7.26–7.16 (m, 4H, ibuprofen aromatic
(δ, ppm): 7.26–7.10 (m, 4H, ibuprofen aromatic ring
protons), 7.5–7.01 (m, 4H, aromatic ring proton), 6.70 (s,
1H, OH), 5.44–5.42 (d, 1H, azetidine ring proton), 5.09–
5.07 (d, 1H, azetidine ring proton), 2.45–2.43 (d, 2H,
isopyopyl), 1.89–1.84 (m, 1H, isopyopyl), 1.66–1.64 (d,
(
3
ring protons), 7.05–7.01 (m, 4H, aromatic ring proton),
6
ring proton), 5.09–5.07 (d, 1H, azetidine ring proton),
.97–6.84 (s, 6H, OCH ). 5.44–5.42 (d, 1H, azetidine
3
13
2.45–2.43 (d, 2H, isopyopyl), 1.89–1.84 (m, 1H,
6H, isopyopyl); C-NMR (CDCl ) (δ, ppm): 183.76
3
1
3
isopyopyl), 1.66–1.64 (d, 6H, isopyopyl);
C-NMR
(C=S triazole ring carbon), 163.16 (C=O azetidine ring
carbon), 154.67 (C=N triazole ring carbon), 142.17–
123.13 (aromatic ring carbon atoms), 63.16 (Cl linked
azetidine ring carbon), 58.53 (aromatic linked azetidine
(CDCl ) (δ, ppm): 185.21 (C=S triazole ring carbon),
3
165.76 (C=O azetidine ring carbon), 156.76 (C=N
triazole ring carbon), 145.67–126.57 (aromatic ring
carbon atoms), 66.82 (-Cl linked azetidine ring carbon),
+
ring carbon atom); m/e (ESI): 93 (base peak), 456 (M ),
6
1.26 (aromatic linked azetidine ring carbon atom); m/e
457 (M + 1), 458 (M + 2).
3-Chloro-4-(4-(dimethylamino)phenyl)-1-(3-(1-(4-
isobutylphenyl)ethyl)-5-thioxo-1H-1,2,4-triazol-4(5H)-yl)
+
(ESI): 91(base peak), 470 (M ), 472 (M + 1).
3
-Chloro-1-(3-(1-(4-isobutylphenyl)ethyl)-5-thioxo-1H-1,2,4-
triazol-4(5H)-yl)-4-(4 methoxyphenyl)azetidin-2-one (7h).
Yield: 63.54%; M.P.: 239–241°C; Anal. Calcd for
C H ClN O S: C, 61.20; H, 5.78; Cl, 7.53; N, 11.89;
azetidin-2-one (7j).
Yield: 73.45%; M.P.: 215–217°C;
Anal. Calcd for C25H30ClN OS: C, 62.03; H, 6.25; Cl,
5
7.32; N, 14.47; O, 3.31; S, 6.62%; Found: C, 62.06; H,
2
4
27
4 2
O, 6.79; S, 6.81%; Found: C, 61.24; H, 5.80; Cl, 7.51; N,
6.26; Cl, 7.30; N, 14.45; O, 3.33; S, 6.60%; FT-IR (ν in
cm ): 3465 (N-H strech.), 379 (Aromatic C-H strech.),
À1
À1
11.86; O, 6.81; S, 6.78%; FT-IR (ν in cm ): 3472 (N-H
2
962 (Asym. aliphatic C-H strech.), 2874 (Sym. aliphatic
strech.), 3080 (Aromatic C-H strech.), 2961 (Asym.
aliphatic C-H strech.), 2872 (Sym. aliphatic C-H strech.),
C-H strech.), 1670–2000 (overtone for substitution on
aromatic ring), 1762 (C=O strech.), 1654 (C=N stretch.),
1
1
670–2000 (overtone for substitution on aromatic ring),
762 (C=O strech.), 1659 (C=N stretch.), 1599 (Phenyl
1
598 (Phenyl ring stretch.), 1505 (Phenyl C-H out of
2
plane bending), 1468 (CH bending), 1458 (Asym CH3
ring stretch.), 1503 (Phenyl C-H out of plane bending),
bending), 1386 & 1365 (Sym C-H isobutyl bending),
1
468 (CH bending), 1459 (Asym CH bending), 1393
2
3
À1
1
336 (sec. amine C-N strech.), 768 (C-Cl) cm
;
&
1369 (Sym C-H isobutyl bending), 1255 & 1040 (C-
1
À1
1
H-NMR (CDCl ) (δ, ppm): 7.26–7.10 (m, 4H, ibuprofen
3
O strech.), 1245 (C-N stretch.), 778 (C-Cl) cm ; H-
aromatic ring protons), 7.05–7.01 (m, 4H, aromatic ring
NMR (CDCl ) (δ, ppm): 7.26–7.16 (m, 4H, ibuprofen
3
proton), 6.71 (s,1H, NH-CH ), 5.44–5.43 (d, 1H,
3
aromatic ring protons), 7.05–7.01 (m, 4H, aromatic ring
azetidine ring proton), 5.09–5.07 (d, 1H, azetidine ring
proton), 2.45–2.43 (d, 2H, isopyopyl), 1.89–1.84 (m, 1H,
proton), 6.95–6.94 (s, 3H, OCH ), 5.44–5.42 (d, 1H,
3
azetidine ring proton), 5.09–5.07 (d, 1H, azetidine ring
proton), 2.45–2.43 (d, 2H, isopyopyl), 1.89–1.84 (m,
13
isopyopyl), 1.66–1.64 (d, 6H, isopyopyl);
(CDCl ) (δ, ppm): 186.35 (C=S triazole ring carbon),
65.65 (C=O azetidine ring carbon), 156.57 (C=N triazole
C-NMR
13
3
1H, isopyopyl), 1.66–1.64 (d, 6H, isopyopyl);
C-
1
NMR (CDCl ) (δ, ppm): 185.87 (C=S triazole ring
3
ring carbon), 144.38–125.65 (aromatic ring carbon
atoms), 68.74 (-Cl linked azetidine ring carbon), 65.22
carbon), 166.22 (C=O azetidine ring carbon), 156.97
(C=N triazole ring carbon), 146.11–127.17 (aromatic
(
3
aromatic linked azetidine ring carbon atom); m/e (ESI):
51 (base peak), 483 (M ), 484 (M + 1), 485 (M + 2).
ring carbon atoms), 67.22 (-Cl linked azetidine ring
carbon), 62.72 (aromatic linked azetidine ring carbon
+
+
Antibacterial study. In vitro antibacterial activity of
atom); m/e (ESI): 91 (base peak), 470 (M ),
newly synthesized compounds 7(a–i) was assayed using
disc diffusion method. The microbial strains, namely,
Staphylococcus aureus, Pseudomonas aeruginosa, and
Escherichia coli were procured from Microbial Type
Culture Collection, Chandigarh, India. In this method, a
sterile disc (6 mm in diameter) was impregnated with
test compound and was transferred on the Muller–Hinton
agar medium, previously seeded with 0.2 mL of broth
culture of each organism for 24 h. The plates were
incubated at 37°C for 24 h, and after incubation, zone
of inhibition was determined. Dimethyl sulfoxide
impregnated disc was used as a control [28]. Cefotaxime
was used as standard.
4
71(M + 1), 472 (M + 2).
3
-Chloro-4-(4-hydroxyphenyl)-1-(3-(1-(4-isobutylphenyl)
ethyl)-5-thioxo-1H-1,2,4-triazol-4(5H)-yl)azetidin-2-one (7i).
Yield: 75.32%; M.P.: 229–231°C; Anal. Calcd for
C H ClN O S: C, 60.45; H, 5.51; Cl, 7.76; N, 12.26;
O, 7.00; S, 7.02%; Found: C, 60.48; H, 5.53; Cl, 7.72; N,
1
2
3
25
4 2
À1
2.24; O, 7.04; S, 6.99%; FT-IR (ν in cm ): 3495 (O-H
N-H strech.), 3088 (Aromatic C-H strech.), 2965
&
Asym. aliphatic C-H strech.), 2876 (Sym. aliphatic C-H
strech.), 1670–2000 (overtone for substitution on
aromatic ring), 1765 (C=O strech.), 1663 (C=N stretch.),
1
595 (Phenyl ring stretch.), 1505 (Phenyl C-H out of
plane bending), 1464 (CH bending), 1455 (Asym CH3
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. Dhall, S. Jain, A. Mishra, J. Dwivedi, and S. Sharma
Vol 000
Fluorescence study.
P. aeruginosa) and Gram-positive (S. aureus) were
Bacterial strains, Gram-negative
Pymol 1.3 software [32]. In addition, drug-likeness such
as molar weights (MW), lipophilicity (log P), number of
hydrogen bond acceptors (HBA), number of hydrogen
bond donors (HBD), and number of rotatable bonds
(NRB) was also determined using SwissADME
software [33].
(
incubated overnight at 37°C in Luria broth (LB) medium.
After incubation, bacterial culture colonies were adjusted
8
to 10 cfu/mL using 0.5 McFarland standard. The
bacterial culture was centrifuged for 20 min at 2300 rpm
for 3 min and washed thrice with sterilized phosphate
buffered saline (pH 7.4), and supernatant was removed in
each turn to ensure complete removal of medium.
Different concentration of compound 7c (10–200 μg/mL)
was added in respective test tubes containing
RESULTS AND DISCUSSION
Chemistry. Here, we report the synthesis of 1, 2, 4-
triazole condensed azitidine derivatives 7(a–j) by
following Schemes 1 and 2.
8
approximately 10 cfu/mL bacterial sample and incubated
overnight. The fluorescence emission intensities
(
[
excitation 350 nm) were noted after overnight incubation
29,30].
Synthesis was initiated with the reaction of ibuprofen (1)
with ethyl alcohol to obtain corresponding ester (2) which
then reacted to hydrazine hydrate to yield its hydrazone
derivative (3) [34]. The ethanolic solution of hydrazone
Docking studies.
In order to understand mode of
interactions of test compound with the target, molecular
docking study was performed using Argus Lab 4.0
docking software [31]. Protein structure of DNA gyrase
was stirred with CS in the presence of basic medium to
2
achieve carbothiaomaides (4) which then cyclized to 1, 2,
4-triazole (5) in the presence of hydrazine hydrate.
Further, these triazole derivatives (5) refluxed with
substituted aldehydes in acidic medium to afford
benzylidine derivatives 6(a–j) [35]. The benzylidine
derivatives reacted with chloroacetyl chloride and in the
presence of triethylamine as base to afford azitidine
derivatives 7(a–j) [36].
(
PDB ID 3U2D) was obtained from the Protein Data
Bank. For 3D molecule development, chem draw ultra
0.0 has been used and structure was saved in.pdb
1
format. In the present study, Argus dock was selected as
docking engine to perform the docking simulation and for
calculation “Dock” was chosen as the calculation type.
The protein–ligand interaction was estimated using
Scheme 1
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
1, 2, 4-Triazole Derivatives as Antimicrobial Agents
À1
The progress of reaction was monitored by TLC method
using silica gel-G stationary phase, ethyl acetate: ethanol
and 1040 cm (Sym. C-O stretch.) for methoxy group;
À1
and 1550 (Asym. N=O stretch.) and 1350 cm (Sym.
(
2:3) as mobile phase and detecting the spots with iodine
vapors.
All the newly synthesized derivatives were also
N=O stretch.) for nitro group substitution.
Antibacterial activity.
Results of antibacterial
screening of synthesized compounds 7(a–j) are
summarized in Table 1. Some of the synthesized
compounds exhibited potent antibacterial activity against
Gram-positive and Gram-negative bacteria. In particular,
compound 7c exhibited potent antibacterial activity
against Gram-negative and Gram-positive bacterial
strains, when compared with standard drug cefotaxime.
The broad-spectrum activity of compound 7e may be due
to the presence of high electron density on phenyl
substituted beta lactam (azetidine) ring along with triazole
nucleus. In addition, it was observed that activity of
synthesized compounds (7c, 7d, and 7e) demonstrated
comparable activity to standard. It is noteworthy that
compounds bearing only triazole nucleus (6a–j) showed
weak antibacterial activity in comparison to compounds
(7a–j) having 1, 2, 4-triazole annulated with azetidine
nucleus. Hence, it can be concluded that incorporation of
azetidine nucleus improves antibacterial activity of
synthesized compounds.
1
13
confirmed by FTIR, H NMR, C NMR, and mass
spectroscopy method. All the synthesized compounds
were characterized by IR, 1H NMR, and mass spectral
techniques. The presence of peak at 1.30–1.27 (t, 3H,
OCH -CH , J = 12.0) and 4.23–4.18 (q, 2H, OCH -CH )
in the H NMR spectrum together with the presence of
strong band of C=O at 1735 cm
confirmed the formation of compound (2). The
formations of compound (3) was ascertained by the
presence of absorption band around 3363 and 3354 cm
in IR corresponding to NH stretching (primary amine)
together with decrease in frequency C=O to 1646 cm
The presence of additional band in region 666 cm
assignable to C=S in IR spectrum of (4) indicated its
formation. Appearance of a singlet at 7.01 ppm (1H, NH
trazole ring) in NMR spectrum and absence of strong
band due to C=O in IR spectrum confirmed the formation
of compound (5). Formation of benzylidine derivatives
2
3
2
3
1
À1
in IR spectrum
À1
À1
À1
.
(
6a–j) were primarily realized by the presence of an
Fluorescence study.
Among all, compound 7c
additional singlet around δ 8.48 ppm (1H, azomethine
exhibited best antibacterial activity in disc diffusion assay
against selected bacterial strains. Further, inhibitory
activity of compound 7c was established using
fluorescence spectral studies against two bacterial strains,
P. aeruginosa and S. aureus. A distinct wavelength
dependent shift of fluorescence for each bacterial strain
indicated that sample 7c exhibited better interaction with
bacterial cell membranes. Notably, Gram-negative
bacteria (P. aeruginosa) exhibited higher fluorescence
intensity as compared to Gram-positive bacteria
(S. aureus) which suggested that compound 7c has better
affinity towards Gram-negative bacterial strain.
Compound 7c caused a concentration dependent decrease
in emission intensities which could be attributed to its
ability to cause alteration in cell surface properties like
lipid compositions and molecular organization etc. (Fig. 2).
group). The presence of absorption band at
À1
1
5
766 cm attributed to C=O, a doublet at δ 5.44–
.42 ppm (1H, azetidine ring), and peaks at 65.16 ppm
(
Cl linked azetidine carbon) and 60.20 ppm (aromatic
1
13
linked azetidine carbon) in there, IR, HNMR, and
C
NMR spectrum, respectively, confirmed the formation of
compounds (7a–j). Further, different substitutions on
phenyl ring were also confirmed through IR bands at
À1
1
1
080–1070 cm for chloro group on aryl ring; 1050–
À1
À1
040 cm
for bromo group; 3500–3300 cm
(O-H
stretch.) for hydroxy group; 1250 (Asym. C-O strech.)
Table 1
Antibacterial activity of test compounds 7(a–j).
Molecular docking study.
DNA gyrase is
a
Zone of inhibition (mm) mean ± SD
representative of topoisomerase family which regulates
the topological state of DNA in cells [37]. It has been
considered as a crucial enzyme for inducing negative
super coiling in DNA replication and its inhibition
ultimately leads to cell death. Owing to its key
biological role, DNA gyrase has been considered as
captivating target for antibacterial drugs [38]. In the
present study, test compounds were docked over
targeted proteins DNA gyrase (PDB ID 3U2D). Among
synthesized compounds 7c, 7d, and 7e showed good
docking score with good molecular interactions. It was
interesting to observe that core structure of all the
compounds was similar; binding site and bonding
S. no. Compound
S. aureus
E. coli
P. aeruginosa
1
2
3
4
5
6
7
8
9
1
1
7a
7b
7c
7d
7e
7f
7g
7h
7i
3.4 ± 0.17
10.1 ± 1.43
13.7 ± 1.51
10.8 ± 1.63
12.4 ± 1.59
4.2 ± 0.15
8.1 ± 0.42
8.8 ± 0.72
6.5 ± 0.32
7.6 ± 0.83
2.1 ± 0.15
9.7 ± 1.52
11.9 ± 1.84
10.1 ± 1.75
10.7 ± 1.42
2.2 ± 0.18
2.5 ± 0.17
2.5 ± 0.16
-
3.2 ± 0.12
16.2 ± 1.92
18.7 ± 1.96
15.9 ± 1.88
17.7 ± 1.82
3.6 ± 0.21
7.1 ± 0.34
7.8 ± 0.39
9.4 ± 0.52
9.3 ± 0.59
17.9 ± 0.93
0
1
7j
-
Cefotqxime 13.3 ± 0.67
12.5 ± 0.89
Bold values highlight the most active compounds in the series against the
target strain.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. Dhall, S. Jain, A. Mishra, J. Dwivedi, and S. Sharma
Vol 000
Figure 2. Fluorescence emission spectra (excitation 350 nm) (a) Pseudomonas aeruginosa and (b) Staphylococcus aureus with different concentration of
compound 7c. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 3. Docking study of compound 7c with PDB ID 3U2D. (Blue color, nitrogen; green color, chlorine; white color, hydrogen; red color, oxygen; and
dark green, sulphur). [Color figure can be viewed at wileyonlinelibrary.com]
Table 2
most active compounds. The other amino acids made a
Molecular docking study (binding energy) data.
cascade to facilitate binding and holding of the test
compounds in the active site of DNA gyrase protein
Compound
Comp. (R2)
Docking score (kcal/mol)
(Fig. 3).
7
7
7
7
7
7
7
7
7
7
a
b
c
d
e
f
g
h
i
H
2-Cl
4-Cl
2-Br
11.13
À11.30
À12.04
À11.36
À11.75
À11.15
À11.01
À10.26
À10.51
À10.24
All compounds showed good docking score (Table 2);
compounds 7c, 7e, and 7d exhibited the considerable
docking score À12.04, À11.75, and À11.36 kcal/mol,
respectively. Compounds 7c (À12.04 kcal/mol) and 7e
4-Br
3-NO2
2-OCH3
4-OCH3
4-OH
4-N (CH3)2
(
À11.75 kcal/mol) containing the chloro group and
bromo group at para position displayed better docking
score than compound 7d (À11.36 kcal/mol) which
contain bromo substitution on the ortho position. The
docking study gives an idea about interaction between
test compound and target protein. Drug likeliness study
clearly indicated that compounds 7c and 7d have
successfully passed Lipinski rule of five and thus can be
considered as ideal drug-able candidates in bacterial
therapy (Table 3).
j
interactions were quite dissimilar with target enzymatic
protein.
The results also revealed that 257HIS acted as key
amino acid and found responsible for the binding of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
1, 2, 4-Triazole Derivatives as Antimicrobial Agents
Table 3
Drug likeliness study of selected compounds.
Drug
Molecular weight
(MW, g/mol)
Log
P
No. of hydrogen bond
acceptors (NBA)
No. of hydrogen bond
donor (NHD)
No. of rotatable
hydrogen bond
likeness
(Lipinski)
S. no. Compound
1
2
2
7c
7d
7e
475.43
475.43
519.88
3.47
3.58
3.44
2
2
2
1
1
1
6
6
6
Yes
Yes
No
CONCLUSION
[10] Nizami, S. A.; Gurumurthy, M.; Chattarjee, S. J.; Panda, D.
J Adv Pharm Res 2010, 1, 26.
11] Singh, D.; Shukla, S.; Kumar, A.; Pandey, N.; Mittan, D. S.
Pharm Res 2009, 1, 127.
[12] Zoumpoulakis, P.; Camoutsis, C.; Pairas, G. Bioorg Med
Chem 2012, 20, 1569.
[
A simple novel and expedient protocol have been
developed to afford some triazole derivatives (7a–j)
synthesized and were screened for their antibacterial
activity against S. aureus, P. aeruginosa, and E. coli
using broth dilution method. Fluorescence spectral
studies were also carried out to ascertain the antibacterial
potential of compound 7c against two bacterial strains,
that is, P. aeruginosa and S. aureus. In addition,
molecular docking studies suggested that test compounds
may act through bacterial DNA gyrase inhibition. Among
all derivatives, compounds 7c and 7e exhibited
impressive antibacterial activity compared to standard
drug cefotaxime. Further, in depth investigations are
required to establish their efficacy at clinical level.
[13] Bhat, A. R.; Bhat, G. V.; Shenoy, G. G. J Pharm Pharmacol
2010, 53, 267.
[14] Al-Aabdullah, E. S.; Asiri, H. H.; Lahsasni, S.; Habib, E. E.;
Ibrahim, T. M.; El Emam, A. A. Drug Des Dev Therapy 2014, 8, 505.
15] Pattan, S.; Gadhave, P.; Tambe, V.; Dengale, S.; Thakur, D.
Indian JChem 2012, 51, 297.
16] Deng, X. Q.; Song, M.-X.; Zheng, Y.; Quan, Z.-S. Europ J
MedChem 2014, 73, 217.
[
[
[
[
17] Li, Z.; Cao, Y.; Zhan, P. MedChem 2013, 9, 968.
18] Celik, G.; Khloya, P.; Vullo, D.; Supuran, C. T.; Sharma, P. K.
Bioorg Med Chem 2014, 22, 1873.
[19] Popiołek, Ł.; Rzymowska, J.; Kosikowska, U.; Hordyjewska,
A.; Wujec, M.; Malm, A. J. Enzyme Inhib Med Chem , 29, 786.
[
20] Nagesh, H. N.; Suresh, N.; Prakash, G. V. S. B.; Gupta, S.;
Rao, J. V.; Sekhar, K. V. G. C. Med Chem Res 2015, 24, 523.
21] Ahmed, N.; Konduru, N. K.; Ahmad, S.; Owais, M. Europ J
Med Chem2014 , 82, 552.
22] Revelant, G.; Gadais, C.; Mathieu, V.; Kirsch, G.; Hesse, S.
Bioorg Med Chem Lett 2014, 24, 2724.
23] Pertino, M. W.; Lopez,
SchmedaHirschmann, G. Molecules 2013, 18, 7661.
24] Pertino, M. W.; Verdugo, V.; Theoduloz, C.;
SchmedaHirschmann, G. Molecules 2523, 2014, 19.
25] Kumar, B. N. P.; Mohana, K. N.; Mallesha, L. J Fluorine
Chem 2013, 156, 15.
26] Abdel-Aziz, M.; Abuo-Rahma, G. E.-D. A. A.; Beshr, E. A.
[
[
CONFLICT OF INTEREST
[
C.;
Theoduloz,
C.;
Authors declare that there is no conflict of interest.
[
[
Acknowledgments. The authors are highly thankful to the Vice
Chancellor, Banasthali Vidyapith, Banasthali, India, for providing
necessary facilities to carry out present research work. The
authors are also thankful to Punjab University Chandigarh and
Central Drug Research Institute (CDRI) Lucknow, India, for
carrying out Mass and NMR spectral analysis of samples.
[
M.; Ali, T. F. S. Bioorg Med Chem 2013, 21, 3839.
[27] Ayad Raauf, M. R. Al-Mustansiriyah J Pharm Sci 2013, 13, 75.
[28] Singh, D. P.; Dwivedi, S. K.; Hashim, S. R.; Singhal, R. G.
Pharmaceutical 2010, 8, 2416.
[
29] Epand, R. M.; Epand, R. F. Biochim Biophys Acta, Biomembr
009, 1788, 289.
30] Nguyen, L. T.; Haney, E. F.; Vogel, H. J. Trends Biotechnol
011, 29, 464.
31] www.arguslab.com (last accessed on 04/07/2017 at Banasthali
Viyapith, Banasthali, India)
32] www.pymol.com ((last accessed on 04/07/2017 at Banasthali
Viyapith, Banasthali, India)
2
2
[
REFERENCES AND NOTES
[
[
1] Upmanyu, N.; Kumar, S.; Kharya, M. D.; Shah, K.; Mishra, P.
Acta Pol Pharm 2011, 68, 221.
[
[
[
2] Agrawal, R.; Pancholi, S. S. Der Pharm Chem 2011, 6, 32.
3] Sahin, D.; Bayrak, H.; Demirbas, A.; Demirbas, N.; Karaogl,
S. A. Turk J Chem 2012, 36, 411.
4] Vatmurge, N. S.; Hazra, B. G.; Pore, V. S.; Shirazi, F.;
Chavan, P. S.; Deshpande, M. V. Bioorg Med Chem Lett 2043, 2008, 18.
[33] Daina, A.; Michielin, O.; Zoete, V. Sci Rep 2017, 7, 42717.
[34] Jain, S.; Sharma, A.; Agrawal, M.; Sharma, S.; Dwivedi, J.;
[
Kishore, D. J Chem 2012, 20, 1.
35] Dwivedi, J.; Yumna, A.; Jain, S.; Sharma, S. J Saudi ChemSoc
016, 20, 16.
36] Arya, N.; Dwivedi, J.; Khedkar, V. M.; Coutinho, E. C.; Jain,
K. S. Arch Pharm Chem Life Sci 2013 346.
37] Wang, J. C. Untangling the Double Helix: DNA Entanglement
[
[
[
5] Zhou, C. H.; Wang, Y. Curr Med Chem 2014, 19, 239.
6] Godhani, D. R.; Jogel, A. A.; Sanghani, A. M.; Mehta, J.
2
[
Indian J Chem 2015, 54, 556.
7] Ledeti, I.; Bercean, V.; Alexa, A.; Soica, C.; Suta, L. M.;
Dehelean, C.; et al. J Chem 2015, 2015, 1.
8] Rao, D. V. N.; Prasad, A. R. G.; Spoorthy, Y. N.; Rao, D. R.;
Ravindranath, L. K. J Taibah Uni Med Sci 2014, 9, 293.
9] Chanda, S.; Baravalia, Y.; Baluja, S. J ArchAppl Sci Res 2010,
, 117.
[
[
and the Action of the DNA Topoisomerases; Cold Spring
HarborLaboratory Press: Cold Spring Harbor NY, 2009.
[
[38] Maxwell, A.; Lawson, D. M. Curr Top Med Chem 2003, 3,
[
283.
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet