Design, synthesis and antibacterial activity evaluation of novel 2-(4-((1-aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-oxoazetidin-1-yl)acetamide derivatives

Article abstract of DOI:10.1002/jhet.4131

In this paper, a novel series of 2-(4-((1-aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-oxoazetidin-1-yl)acetamide derivatives are synthesized in two steps. The first step involved Ugi multicomponent reaction of β-alanine, o-(propargyl)benzaldehyde and i

Full text of DOI:10.1002/jhet.4131

Design, Synthesis and Antibacterial Activity Evaluation of Novel 2-(4-((1-Aryl-
1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-oxoazetidin-1-yl)acetamide
Derivatives
Samaneh Zareie,[a] Golzar Komeili,[b] Saeed Bahadorikhalili,[c] Azadeh Yahya-Meymandi,[d]
Morteza Karami-Zarandi,[a] Bagher Larijani,[e] Mahmood Biglar,[b] Seyed Esmaeil Sadat
Ebrahimi,[b] Mohammad Mahdavi[e]*
[a]
Dr. Samaneh Zareie, Dr. Morteza Karami-Zarandi
Metabolic Diseases Research Center, Zanjan University of Medical Sciences.
[b]
Dr. Seyed Esmaeil, Sadat Ebrahimi; Miss Golzar Komeili, Dr. Mahmood, Biglar
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical
Sciences, Tehran, Iran.
[c]
Dr. Saeed Bahadorikhalili
School of Chemistry, College of Science, University of Tehran, Tehran, Iran.
[d]
Miss. Azadeh, Yahya-Meymandi
Department of Chemistry, Faculty of Science, University of Birjand, Birjand, Iran.
[e]
Prof. Bagher, Larijani; Dr. Mohammad, Mahdavi
Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical
Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran, email:
mahdavi_chem@yahoo.com.
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Abstract
In this paper, a novel series of 2-(4-((1-aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-
oxoazetidin-1-yl)acetamide derivatives are synthesized in two steps. The first step involved
Ugi multicomponent reaction of β-alanine, o-(propargyl)benzaldehyde and isocyanide
derivatives. The product of this step, underwent a click 1,3-dipolar cycloaddition reaction
with benzyl azide derivatives. The 2-(4-((1-aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-
oxoazetidin-1-yl)acetamide product was characterized and their antibacterial activities were
evaluated against various G-positive (S. aureus and B. subtilis) and G-negative (P.
aeruginosa and E. coli) bacteria, using minimal inhibition concentration (MIC). The
compounds showed very good antimicrobial activity and a number of products have been
more active than ciprofloxacin.
Keywords: Ugi multicomponent reaction; click reaction; antibiotic; β-lactam antibiotic;
triazole.
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Introduction
Infectious diseases are of high-risk menaces to human, while antibiotics are the most efficient
treatments. In spite of microbial resistance to antibiotics, this treatment is still the most used
way to treat infectious 1, 2. In general, antibiotics are small molecules, which kills the bacteria
without damaging the human cells 3. An issue in the use of antibiotics is the resistance of the
bacteria against these drugs 4-6. Therefore, it is critical to introduce novel potent antibacterial
agents for treatment of bacterial infectious to overcome the resistance against antibiotics. β-
Lactam and its derivatives are significant class of organic compounds with a vide activity in
several applications. β-Lactam are shown to be efficient for the synthesis of various
8
biologically active compounds ,7, especially antibiotic agents 9-11. Various antibiotics
14
15
including penicillins 12, cephalosporins 12, carbapenems 13, nocardicins , monobactams ,
clavulanic acid 16, sulbactams 17 and tazobactams 18, which contain β-lactam in their structure
are presented in Figure 1. Regarding the importance of β-lactam in various applications,
especially applications as antibacterial agents, several efforts have been focused on the
19
synthesis of different derivatives of this compound . It could be observed that, β-lactam is
the common core in the structure of all the mentioned compounds. 1,2,3-Triazole belongs to
an important class of organic compounds, due to their vide antibacterial, antifungal, anti-
inflammatory, antihypertensive and antiviral activities 20-24. The most common way for the
synthesis of 1,2,3-triazole derivatives is the copper catalyzed reaction of a terminal alkyne
with an azide 25-29. Acetamide derivatives and its conjugates to other scaffolds have proven to
have antibacterial effect. An efficient way for the synthesis of these structures is Ugi
multicomponent reaction, which could efficiently synthesize acetamide derivatives. In this
way, a number of methods have been developed based on Ugi multicomponent reaction for
the synthesis of acetamide group conjugates with antibacterial activities 30-32
.
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Figure 1. Chemical structure of common β-lactam containing compounds.
Multicomponent reactions are very significant in organic synthesis due to several advantages,
including the reduction the number of steps, saving of time and materials, reduction of side
products and achieving high atom economy 33-36. Among various multicomponent reactions,
which are used in organic synthesis, Ugi reaction is an interesting approach for the synthesis
of compounds with complex chemical structure in high isolated yields, short reaction time,
and mild reaction conditions. Ugi reaction is based on the reaction of a ketone or aldehyde, an
amine, an isocyanide and a carboxylic acid. This versatile reaction is applied for the synthesis
of several heteroatom containing compounds 37-39
.
Based on the significance of β-lactam containing compounds as antibacterial agents on one
hand, and regarding the role of 1,2,3-triazole derivatives as potent antibiotics, in this paper
were report the synthesis of novel 2-(4-((1-Aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-
oxoazetidin-1-yl)acetamide derivative. The desired products are synthesized in two steps. The
first step includes multicomponent Ugi reaction of 4-(prop-2-yn-1-yloxy)benzaldehyde
derivatives, β-alanine and an isocyanide derivative. In the next step, the product of step 1
reacts with an azide in the presence of copper catalyst in a mixture of H2O/t-BuOH as
solvent. The products have both β-lactam and 1,2,3-triazole in their structures (Scheme 1).
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The antibacterial activity of the synthesized compounds are evaluated and compared to
commercially available compounds.
Scheme 1. The structure of 2-(4-((1-Aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-
oxoazetidin-1-yl)acetamides
Results and Discussion
Chemistry
The synthesis of 2-(4-((1-Aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-oxoazetidin-1-
yl)acetamide derivatives is performed in two steps, as shown in Scheme 2. In the first step of
the reaction, a multicomponent Ugi reaction takes place between 4-(prop-2-yn-1-
yloxy)benzaldehyde (3), β-alanine (5) and an isocyanide derivative (4) to form N-alkyl-2-(2-
oxoazetidin-1-yl)-2-(4-(prop-2-yn-1-yloxy)phenyl)acetamide (6). For the synthesis of 4-
(prop-2-yn-1-yloxy)benzaldehyde, 4-hydroxybenzaldehyde (1) reacts with propargyl bromide
(2) in DMF in the presence of potassium carbonate. In addition, the reaction of benzyl
bromide derivatives with sodium azide gives the corresponding aryl azide (8). The second
step pf the reaction for the synthesis of the desired 2-(4-((1-Aryl-1H-1,2,3-triazol-4-
yl)methoxy)phenyl)2-(2-oxoazetidin-1-yl)acetamides involves the click reaction of an aryl
azide (8) and N-alkyl-2-(2-oxoazetidin-1-yl)-2-(4-(prop-2-yn-1-yloxy)phenyl)acetamide (6),
catalyzed by Cu(I) in H2O/t-BuOH mixture.
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Scheme 2. The synthetic steps of 2-(4-((1-Aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-
oxoazetidin-1-yl)acetamides
Antimicrobial evaluation
The main aim of this study was to synthesize novel compounds with potent antimicrobial
activity. Therefore, the activity of the mentioned compounds was evaluated against four
bacteria, including S. aureus, P. aeruginosa, B. subtilis, and E. coli. Minimal inhibition
concentration (MIC) of the synthesized compounds were evaluated by conventional
microdilution method recommended by Clinical and Laboratory Standard Institute by testing
two G-positive (S. aureus ATCC 6538p and Bacillus subtilis ATCC 6633) and G-negative
(E. coli ATCC 8739 and P. aeruginosa ATCC 9027) bacteria. Solutions of compounds and
ciprofloxacin, as reference antibacterial agent, were prepared in dimethyl sulfoxide . Each
prepared solution of antimicrobial agents was added to Mueller-Hinton (MH) broth to reach a
final concentration ranging from 100-0.003 μg mL-1. Bacteria were cultured in MH agar
overnight and colonies were suspended in 0.85% salin to reach inocula containing (1.5 x 108
CFU/mL). To prepare bacterial suspensions for inoculation, this suspension was diluted to
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yield 5×106 CFU/mL. 96-well, round bottom microtiter plates were used. Each plate contains
positive controls (bacteria and medium), negative controls (medium only) and two-fold
dilutions of each compound. 100-μl inoculum was added to each well. Plates were incubated
in 37°C for 24h. Optical density of the wells was obtained by an ELISA reader apparatus
(BioTek, Power Wave XS2) at wavelength 600. The MIC was the lowest concentration of the
agent that no turbidity was seen in comparison to negative control. In order to ensure the
obtained MIC values, Solution inside the MIC wells were inoculated on the MH agar plates
and incubated an overnight in the 37°C.
Table 1. The structure and the antimicrobial activity of the synthesized compounds 9a-j
(Minimal inhibition concentration (MIC), μg/ml)
Compound
R
R'
R"
S. aureus P. aeruginosa B. subtilis
E. coli
0.012
0.006
0.049
0.049
0.012
0.006
0.980
0.012
0.006
0.006
0.012
Ciprofloxacin --
--
--
0.195
0.390
0.390
0.390
0.390
0.780
0.780
0.390
0.049
0.098
0.012
0.049
0.098
0.390
0.098
0.780
0.025
0.098
0.049
0.012
0.025
0.025
0.195
0.195
0.780
0.098
0.098
0.780
0.390
0.390
0.049
0.049
0.098
Cy
4-F
H
9a
9b
9c
9d
9e
9f
Cy
4-Br
2-Cl
4-NO2
2-Me
2-F
3-OMe
H
Cy
Cy
3-OMe
3-OMe
H
Cy
Cy
t-Bu
t-Bu
t-Bu
t-Bu
2-Cl
4-Cl
4-Br
4-Br
H
9g
9h
9i
H
H
3-OMe
9j
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According to the results, presented in Table 1, all the compounds have antimicrobial activity
against both G-positive and G-negative bacteria. Compounds 9h,9i and 9j have been more
active than ciprofloxacin against S. aureus. The minimal inhibition concentration of
ciprofloxacin against B. subtilis was 0.195 μg/ml. Compounds 9c, 9d, and 9h-j had inhibition
concentrations lower than that of ciprofloxacin against B. subtilis. In addition, the results
showed that the synthesized compounds have been active against G-negative bacteria,
including P. aeruginosa and E. coli. The minimal inhibition concentration of ciprofloxacin
and compounds 9h, 9i and 9j was 0.195, 0.049, 0.098 and 0.012 μg/ml, respectively against
P. aeruginosa. Ciprofloxacin had MIC of 0.049 μg/ml against P. aeruginosa, while MIC of
compounds 9h, 9i and 9j against this bacterium was 0.012, 0.025 and 0.025 μg/ml,
respectively. Compounds 9a, 9e, 9h, and 9i had MIC of 0.006 μg/ml against E. coli. MIC
activity of ciprofloxacin against this bacterium was 0.012 μg/ml. The simultaneous presence
of β-lactam and 1,2,3-triazole as two antimicrobial moieties could be the reason of the high
activity of the products.
Experimental
General remarks
All the chemicals were purchased from Merck, Aldrich and Acros and used in the reactions
as received without any further purification. For observing the performance of the reactions,
thin layer chromatography (TLC) plates pre-coated with fluorescent indicator with
1
visualization by UV light (Merck, Germany) were used. H NMR (400 MHz), 13C NMR
19
(100.5 MHz) and F NMR (376.2 MHz) were recorded on 400 MHz instruments (Brucker-
400 series). The chemical shifts in parts per million (ppm, δ) are reported downfield from
1
TMS (0 ppm) in DMSO-d6 or CDCl3 solvents. Multiplicities of H NMR spin couplings are
reported as s for singlet, b for broad peaks, d for the doublet, t for the triplet, q for the quartet,
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dd for a doublet of the doublet, or m for multiplet and overlapping spin systems. Values for
apparent coupling constants (J) are reported in Hz. IR spectra were recorded on a Brucker-
TENSOR 27 instrument. A Thermo Finnigan-FlashEA 1112 series instrument was used for
CHNS elemental analysis. Agilent Technologies-5975C was used for recording the mass
spectra of the samples.
Synthesis of 4-(prop-2-yn-1-yloxy)benzaldehyde
4-hydroxybenzaldehyde derivative (15 mmol) was dissolved in DMF (20 mL) and potassium
carbonate (2.484 g, 18 mmol) was added. The reaction mixture was stirred at 80 °C for 1h
and then propargyl bromide (1.785 g, 15 mmol) was added dropwise to the above mixture
during 30 min. the reaction mixture was stirred for more 3h. After the completion of the
reaction, the mixture was cooled to room temperature and added to ice water mixture and the
compound (3) was obtained as a white precipitate in the isolated yield of 96%.
Synthesis of N-alkyl-2-(2-oxoazetidin-1-yl)-2-(4-(prop-2-yn-1-yloxy)phenyl)acetamides
4-(prop-2-yn-1-yloxy)benzaldehyde (10 mmol), β-alanine (0.89 g, 10 mmol) and isocyanide
derivative (10 mmol) were added into a flask containing methanol (20 mL) and stirred at 50
°C for 24h. The reaction performance was monitored by TLC and after the reaction was
completed, ice water (50 mL) was added to the reaction mixture and stirred for more 1h. The
product was formed as a white precipitate, which was separated by filtration and dried in a
vacuum oven overnight.
Synthesis
of
2-(4-((1-Aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-oxoazetidin-1-
yl)acetamide derivatives
A derivative of N-alkyl-2-(2-oxoazetidin-1-yl)-2-(4-(prop-2-yn-1-yloxy)phenyl)acetamide (5
mmol) benzyl azide (5 mmol) were added to a flask containing a 50:50 (v/v) mixture of
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H2O/t-BuOH (10 mL) and coper sulfate (5 mol%) and ascorbic acid (5 mol%) were added to
the mixture. The reaction was stirred at room temperature for 24h until the formation of a
white precipitate. The product was separated by filtration and purified by recrystallization
from ethanol to give the desired product.
Spectral data of the products
N-Cyclohexyl-2-{4-[3-(4-fluoro-benzyl)-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-2-(2-
oxo-azetidin-1-yl)-acetamide (9a)
White solid; isolated yield: 72%, mp = 225.8-227.7 °C. IR (KBr): 3340, 1728, 1680 cm-1; 1H
NMR (DMSO-d6) δ 8.28 (s, 1H), 8.18 – 8.10 (m, 1H), 7.39 (dd, J = 8.5, 5.6 Hz, 2H), 7.24 –
7.18 (m, 4H), 7.06 – 7.00 (m, 2H), 5.60 (s, 2H), 5.34 (s, 1H), 5.12 (s, 2H), 3.54 (d, J = 7.3
Hz, 1H), 3.45 (d, J = 2.9 Hz, 1H), 3.03 (s, 1H), 2.89 – 2.82 (m, 1H), 2.81 – 2.73 (m, 1H),
1.82 – 1.73 (m, 1H), 1.63 (d, J = 35.1 Hz, 3H), 1.53 (d, J = 14.2 Hz, 1H), 1.26 – 1.04 (m,
13
5H); C NMR (DMSO) δ 167.83, 167.01, 162.35 (d, J = 234 Hz), 158.08, 143.41, 132.68,
130.78, 130.71 (d, J = 26 Hz), 129.2, 128.7, 125.0, 116.1, 115.9, 115.2, 61.5, 57.2, 52.5,
48.07 38.8, 36.1, 32.6, 32.6, 25.5, 24.9, 24.8; 19F NMR (DMSO) δ -116.03; Anal for
C27H30FN5O3, Calcd: C, 65.97; H, 6.15; N, 14.25; found: C, 65.94; H, 6.17; N, 14.29; MS (70
eV): m/z = 491 (M+).
2-{4-[3-(4-Bromo-benzyl)-3H-[1,2,3]triazol-4-ylmethoxy]-3-methoxy-phenyl}-N-
cyclohexyl-2-(2-oxo-azetidin-1-yl)-acetamide (9b)
1
White solid; isolated yield: 68%, mp = 205.8-209 °C. IR (KBr): 3343, 1735, 1679 cm-1; H
NMR (DMSO-d6) δ 8.29 (s, 1H), 8.18 – 8.06 (m, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.29 (d, J =
7.9 Hz, 2H), 7.12 (d, J = 8.1 Hz, 1H), 6.87 (s, 1H), 6.82 (d, J = 7.5 Hz, 1H), 5.61 (s, 2H),
5.33 (s, 1H), 5.11 (s, 2H), 3.71 (s, 3H), 3.59 – 3.53 (m, 1H), 3.48 (s, 1H), 3.07 (s, 1H), 2.86
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(d, J = 14.3 Hz, 1H), 2.79 (d, J = 9.4 Hz, 1H), 1.76 (d, J = 11.0 Hz, 1H), 1.71 – 1.60 (m, 3H),
13
1.52 (s, 1H), 1.28 – 1.18 (m, 3H), 1.13 – 1.04 (m, 2H); C NMR (DMSO) δ 167.8, 167.0,
149.3, 147.5, 143.4, 135.8, 132.1, 130.6, 129.2, 125.3, 121.9, 120.2, 114.0, 111.8, 62.1, 57.4,
55.8, 52.5, 48.1, 38.9, 36.1, 32.6, 32.5, 25.6, 24.9, 24.8; Anal for C28H32BrN5O4, Calcd: C,
57.74; H, 5.54; N, 12.02; found: C, 57.79; H, 5.55; N, 11.98; MS (70 eV): m/z = 581 (M+).
2-{4-[3-(2-Chloro-benzyl)-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-N-cyclohexyl-2-(2-
oxo-azetidin-1-yl)-acetamide (9c)
White solid; isolated yield: 79%, mp = 228.8-231.8 °C. IR (KBr): 3330, 1725, 1670 cm-1; 1H
NMR (DMSO-d6) δ 8.27 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.44 –
7.32 (m, 2H), 7.23 (d, J = 8.3 Hz, 3H), 7.04 (d, J = 8.5 Hz, 2H), 5.73 (s, 2H), 5.36 (s, 1H),
5.15 (s, 2H), 3.59 – 3.50 (m, 1H), 3.47 (s, 1H), 3.05 (s, 1H), 2.87 (d, J = 14.3 Hz, 1H), 2.79
(d, J = 11.7 Hz, 1H), 1.77 (d, J = 10.6 Hz, 1H), 1.71 – 1.59 (m, 3H), 1.53 (d, J = 12.2 Hz,
13
1H), 1.32 – 1.16 (m, 3H), 1.14 – 1.04 (m, 2H); C NMR (DMSO) δ 167.8, 167.0, 158.0,
143.2, 133.6, 133.0, 130.9, 130.7, 130.0, 129.2, 128.7, 128.1, 125.5, 115.2, 61.4, 57.1, 51.0,
48.0, 38.8, 36.1, 32.6, 25.5, 24.8; Anal for C27H30ClN5O3, Calcd: C, 63.84; H, 5.95; N, 13.79;
found: C, 63.88; H, 5.93; N, 13.84; MS (70 eV): m/z = 507 (M+).
N-Cyclohexyl-2-{3-methoxy-4-[3-(4-nitro-benzyl)-3H-[1,2,3]triazol-4-ylmethoxy]-
phenyl}-2-(2-oxo-azetidin-1-yl)-acetamide (9d)
1
White solid; isolated yield: 75%, mp = 210-213.8 °C. IR (KBr): 3335, 1732, 1680 cm-1; H
NMR (DMSO-d6) δ 8.36 (s, 1H), 8.25 (d, J = 8.4 Hz, 2H), 8.15 (d, J = 7.7 Hz, 1H), 7.55 (d, J
= 8.4 Hz, 2H), 7.13 (d, J = 8.3 Hz, 1H), 6.88 (s, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.81 (s, 2H),
5.33 (s, 1H), 5.13 (s, 2H), 3.71 (s, 3H), 3.55 (d, J = 7.5 Hz, 1H), 3.48 (s, 1H), 3.07 (s, 1H),
2.86 (d, J = 16.8 Hz, 1H), 2.79 (d, J = 14.6 Hz, 1H), 1.76 (d, J = 10.9 Hz, 1H), 1.65 (dd, J =
13
26.6, 12.9 Hz, 3H), 1.55 – 1.50 (m, 1H), 1.24 (t, J = 18.5 Hz, 5H); C NMR (DMSO) δ
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167.8, 167.1, 149.3, 147.7, 147.5, 143.8, 143.5, 129.5, 125.6, 124.3, 120.2, 114.0, 111.9,
62.1, 57.5, 55.8, 52.3, 48.0, 38.9, 36.1, 32.6, 32.5, 25.5, 24.8; Anal for C28H32N6O6, Calcd: C,
61.30; H, 5.88; N, 15.32; found: C, 61.27; H, 5.90; N, 15.36; MS (70 eV): m/z = 548 (M+).
N-Cyclohexyl-2-{3-methoxy-4-[3-(2-methyl-benzyl)-3H-[1,2,3]triazol-4-ylmethoxy]-
phenyl}2-2-(2-oxo-azetidin-1-yl)-acetamide (9e)
1
White solid; isolated yield: 60%, mp = 231-233.6 °C. IR (KBr): 3335, 1732, 1680 cm-1; H
NMR (DMSO-d6) δ 8.32 (s, 1H), 8.08 (s, 1H), 7.88 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 7.8 Hz,
1H), 7.43 – 7.35 (m, 2H), 7.24 (d, J = 8.6 Hz, 3H), 5.74 (s, 2H), 5.53 (s, 1H), 5.30 (s, 2H),
3.48 (s, 1H), 3.01 (s, 1H), 2.91 – 2.69 (m, 2H), 1.25 (s, 9H); 13C NMR (DMSO) δ 167.8,
167.1, 149.4, 147.7, 147.5, 143.8, 143.6, 129.5, 129.3, 126.6, 125.7, 124.4, 120.3, 114.0,
111.9, 62.1, 57.5, 55.9, 52.4, 48.1, 39.0, 32.6, 32.5, 25.6, 24.9, 24.8; Anal for C29H35N5O4,
Calcd: C, 67.29; H, 6.82; N, 13.53; found: C, 67.33; H, 6.80; N, 13.49; MS (70 eV): m/z =
517 (M+).
N-cyclohexyl-2-(4-((1-(2-fluorobenzyl)-1H-1,2,3-triazol-5-yl)methoxy)phenyl)-2-(2-
oxoazetidin-1-yl)acetamide (9f)
1
White solid; isolated yield: 71%, mp = 215-218 °C. IR (KBr): 3335, 1732, 1680 cm-1; H
NMR (DMSO-d6) δ 8.30 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.9 Hz, 2H), 7.32 –
7.17 (m, 4H), 7.04 (d, J = 8.1 Hz, 2H), 5.61 (s, 2H), 5.36 (s, 1H), 5.14 (s, 2H), 3.55 (s, 1H),
3.46 (s, 1H), 3.36 (s, 1H), 2.86 (d, J = 13.9 Hz, 1H), 2.79 (d, J = 11.8 Hz, 1H), 1.77 (d, J =
11.6 Hz, 1H), 1.71 – 1.59 (m, 3H), 1.53 (d, J = 12.1 Hz, 1H), 1.27 – 1.07 (m, 5H); 13C NMR
(DMSO) δ 167.8, 167.01, 158.07 (d, J = 241 Hz), 149.4, 147.6, 143.3, 136.7, 134.6, 130.6 (d,
J = 22 Hz),129.3, 129.1, 128.8, 126.7, 125.3, 120.3, 114.1, 111.9, 62.1, 57.5, 55.9, 51.4, 48.1,
38.9, 36.1, 32.6, 25.6, 24.8, 19.1; 19F NMR (DMSO) δ -116.57; Anal for C25H28FN5O3,
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Calcd: C, 64.50; H, 6.06; N, 15.04; found: C, 64.46; H, 6.09; N, 14.99; MS (70 eV): m/z =
465 (M+).
N-tert-Butyl-2-{4-[3-(2-chloro-benzyl)-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-2-(2-oxo-
azetidin-1-yl)-acetamide (9g)
White solid; isolated yield: 66%, mp = 212.5-215.8 °C. IR (KBr): 3335, 1732, 1680 cm-1; 1H
NMR (DMSO-d6) δ 8.35 (s, 1H), 8.10 (s, 1H), 7.88 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.1 Hz,
2H), 7.36 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 5.64 (s, 2H), 5.43 (s, 1H), 5.29 (s,
13
2H), 3.48 (s, 1H), 3.01 (s, 1H), 2.90 – 2.82 (m, 1H), 2.81 – 2.72 (m, 1H), 1.25 (s, 9H); C
NMR (DMSO) δ 168.4, 163.3, 142.8, 135.3, 133.6, 133.1, 132.2, 131.0, 130.3, 130.3, 129.2,
125.4, 115.6, 115.1, 61.9, 57.2, 52.4, 50.8, 44.9, 34.4, 28.7; Anal for C25H28ClN5O3, Calcd:
C, 62.30; H, 5.86; N, 14.53; found: C, 62.33; H, 5.89; N, 14.48; MS (70 eV): m/z = 481 (M+).
N-tert-Butyl-2-{4-[3-(4-chloro-benzyl)-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-2-(2-oxo-
azetidin-1-yl)-acetamide (9h)
White solid; isolated yield: 85%, mp = 219.2-222.5 °C. IR (KBr): 3335, 1732, 1680 cm-1; 1H
NMR (DMSO-d6) δ 8.34 (s, 1H), 8.12 (s, 1H), 7.88 (d, J = 6.9 Hz, 2H), 7.63 – 7.52 (m, 2H),
7.29 (d, J = 5.6 Hz, 2H), 7.25 – 7.20 (m, 2H), 5.62 (s, 2H), 5.48(s, 1H), 5.28 (s, 2H), 3.48 (s,
1H), 3.01 (s, 1H), 2.86 (d, J = 10.2 Hz, 1H), 2.77 (d, J = 9.9 Hz, 1H), 1.25 (s, 9H); 13C NMR
(DMSO) δ 171.4, 168.4, 156.4, 142.8, 135.7, 132.2, 132.1, 130.6, 129.2, 125.4, 121.9, 115.6,
61.8, 60.0, 52.5, 50.8, 44.4, 34.7, 28.7; Anal for C25H28ClN5O3, Calcd: C, 62.30; H, 5.86; N,
14.53; found: C, 62.27; H, 5.85; N, 14.59; MS (70 eV): m/z = 481 (M+).
2-{4-[3-(4-Bromo-benzyl)-3H-[1,2,3]triazol-4-ylmethoxy]-phenyl}-N-tert-butyl-2-(2-oxo-
azetidin-1-yl)-acetamide (9i)
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1
White solid; isolated yield: 72%, mp = 210.5-213 °C. IR (KBr): 3335, 1732, 1680 cm-1; H
NMR (DMSO-d6) δ 8.17 (s, 1H), 7.24 – 7.05 (m, 5H), 6.82 (s, 3H), 5.62 (s, 2H), 5.32 (s, 1H),
5.11 (s, 2H), 3.75 – 3.51 (m, 5H), 3.06 (s, 1H), 2.91 – 2.72 (m, 2H), 2.31 (s, 3H), 1.75 – 1.53
(m, 5H), 1.25 – 1.05 (m, 5H); 13C NMR (DMSO) δ 167.7, 167.0, 149.3, 147.5, 143.2, 136.7,
134.5, 130.8, 129.2, 129.1, 128.7, 126.6, 125.2, 120.2, 114.14 111.9, 62.1, 57.5, 55.8, 51.3,
48.0, 38.9, 36.1, 32.5, 25.5, 24.8, 19.0; Anal for C25H28BrN5O3, Calcd: C, 57.04; H, 5.36; N,
13.30; found: C, 57.01; H, 5.40; N, 13.27; MS (70 eV): m/z = 525 (M+).
2-{4-[3-(4-Bromo-benzyl)-3H-[1,2,3]triazol-4-ylmethoxy]-3-methoxy-phenyl}-N-tert-
butyl-2-(2-oxo-azetidin-1-yl)-acetamide (9j)
1
White solid; isolated yield: 77%, mp = 214.7-217 °C. IR (KBr): 3335, 1732, 1680 cm-1; H
NMR (DMSO-d6) δ 8.34 (s, 1H), 7.88 (s, 1H), 7.70 – 7.50 (m, 3H), 7.42 – 7.24 (m, 4H), 5.62
(s, 2H), 5.46 (s, 1H), 5.26 (s, 2H), 3.80 (s, 3H), 3.49 (s, 1H), 3.03 (s, 1H), 2.91 – 2.70 (m,
2H), 1.26 (s, 9H); 13C NMR (DMSO) δ 174.1, 170.2, 153.2, 149.7, 142.7, 135.7, 132.1,
130.7, 130.3, 126.2, 125.6, 121.9, 113.0, 110.1, 64.9, 62.1, 55.9, 53.6, 52.56 44.6, 34.1, 28.7;
Anal for C26H30BrN5O4, Calcd: C, 56.12; H, 5.43; N, 12.59; found: C, 56.08; H, 5.48; N,
12.62; MS (70 eV): m/z = 555 (M+).
Conclusion
In conclusion, a twostep approach was utilized for the synthesis of novel series of 2-(4-((1-
aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)2-(2-oxoazetidin-1-yl)acetamide derivatives. The
first step involved Ugi multicomponent reaction of β-alanine, o-(propargyl)benzaldehyde and
isocyanide derivatives. A reaction between the product of the first step with benzyl azides via
click 1,3-dipolar cycloaddition reaction gave the desired 2-(4-((1-aryl-1H-1,2,3-triazol-4-
yl)methoxy)phenyl)2-(2-oxoazetidin-1-yl)acetamide products.
The products
were
characterized be melting point, FT-IR, 1H NMR, 13C NMR, Mass and elemental analysis. The
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antibacterial activities of the products were evaluated against various G-positive (S. aureus
and B. subtilis) and G-negative (P. aeruginosa and E. coli) bacteria, using minimal inhibition
concentration (MIC). The compounds showed very good antimicrobial activity and a number
of products have been more active than ciprofloxacin. For instance, compounds 9h-j showed
MIC amounts at least two fold lower than ciprofloxacin against tested bacterial species.
Accordingly, some of introduced components in this study could effectively kill gram
positive and negative bacteria in lower doses in compare to ciprofloxacin.
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