Ultrasound-assisted synthesis of novel 1,2,3-triazoles coupled diaryl sulfone moieties by the CuAAC reaction, and biological evaluation of them as antioxidant and antimicrobial agents

Article abstract of DOI:10.1016/j.ejmech.2014.07.042

A series of 1,2,3-triazoles coupled diaryl sulfone containing compounds were synthesized by the copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction in benign solvents under ultrasound irradiation. In situ formation of azides from α-bromoketones together with the CuAAC reaction in one pot allowed safe handling and good availability of azides for the development of a small library of compounds. The sonication reduced reaction time and increased yields compared to otherwise same conditions. All synthesized compounds were evaluated for antibacterial, antifungal and antioxidant activities. Compounds 3b, 6b and 9e-9g were found to be the most potent antifungal agents with minimal inhibitory concentration (MIC) at 25 μg/mL; moreover other compounds revealed good to moderate antimicrobial activity. Compound 8e showed an excellent antioxidant activity using a DPPH free radical scavenging assay.

Full text of DOI:10.1016/j.ejmech.2014.07.042

European Journal of Medicinal Chemistry 84 (2014) 433e443
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Ultrasound-assisted synthesis of novel 1,2,3-triazoles coupled diaryl
sulfone moieties by the CuAAC reaction, and biological evaluation of
them as antioxidant and antimicrobial agents
,
b
,
, **
Mohamed F. Mady a *, Ghada E.A. Awad c, Kåre B. Jørgensen a
a Department of Mathematics and Natural Sciences, Faculty of Science and Technology, University of Stavanger, N-4036 Stavanger, Norway
b Department of Green Chemistry, National Research Centre, Dokki, Cairo 12622, Egypt
c Chemistry of Natural and Microbial Products, National Research Center, Dokki, Cairo 12622, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 1,2,3-triazoles coupled diaryl sulfone containing compounds were synthesized by the copper-
catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction in benign solvents under ultrasound
irradiation. In situ formation of azides from a-bromoketones together with the CuAAC reaction in one pot
allowed safe handling and good availability of azides for the development of a small library of com-
pounds. The sonication reduced reaction time and increased yields compared to otherwise same con-
ditions. All synthesized compounds were evaluated for antibacterial, antifungal and antioxidant
activities. Compounds 3b, 6b and 9ee9g were found to be the most potent antifungal agents with
Received 23 April 2014
Received in revised form
11 July 2014
Accepted 12 July 2014
Available online 14 July 2014
Keywords:
One-pot reaction
Sonication
Click chemistry
Antioxidant activity
Antimicrobial activity
Diaryl sulfone
minimal inhibitory concentration (MIC) at 25
mg/mL; moreover other compounds revealed good to
moderate antimicrobial activity. Compound 8e showed an excellent antioxidant activity using a DPPH
free radical scavenging assay.
© 2014 Elsevier Masson SAS. All rights reserved.
1. Introduction
[3,4]. The antioxidants that scavenge reactive oxygen species (ROS)
may be of efficient value in preventing the onset and propagation of
Antimicrobial agents are fundamental medicines for human and
animal health and welfare, and are considered “miracle drugs” to
treat infections caused by bacteria, fungi, parasites, and viruses. The
discovery of different types of microorganisms explained the main
reasons for infection diseases [1,2]. According to the World Health
Organization (WHO) the infections caused by resistant microor-
ganisms often fail to respond to conventional treatment, resulting
in prolonged illness and greater risk of death. About 440 000 new
cases of multidrug-resistant tuberculosis (MDR-TB) emerge annu-
ally, causing at least 150 000 deaths. In addition, a high percentage
of hospital-acquired infections are caused by highly resistant bac-
teria such as methicillin-resistant Staphylococcus aureus (MRSA)
oxidative diseases such as autoimmune diseases, cardiovascular
diseases and neurovascular diseases. A balance between ROS and
antioxidants is necessary for proper physiological function [5].
These health risks encourage the development and modification of
antioxidants and antimicrobial drugs by the design and synthesis of
new chemical compounds with high efficiency, low toxicity and
broad spectrum.
The importance of sulfones in medicinal chemistry is well
recognized. In particular, organosulfone derivatives have been used
as drugs due to their high potential as antibacterial, antifungal,
anti-nociceptive and anti-inflammatory agents such as Lasix,
Aquazide h, and Sulfadimidine (Fig. 1) [6e14]. Furthermore, the
diaryl sulfone function was found a potent antimicrobial agent [15].
Some well-known medicines are available in the market, for
example Dapsone [16] and Promine [17]; as shown in Fig. 1.
Noticeably, the combination of a diaryl sulfone ring system with
various types of heterocyclic analogues has shown significant bio-
logical activities [18e22].
Abbreviations list: CuAAC, Copper-catalyzed azide-alkyne 1,3-dipolar cycload-
dition; MIC, Minimal inhibitory concentration; PEG, Poly(ethylene glycol); DPPH,
2,2-diphenyl-1-picrylhydrazyl.
* Corresponding author.
** Corresponding author. Department of Mathematics and Natural Sciences, Fac-
ulty of Science and Technology, University of Stavanger, N-4036 Stavanger, Norway.
E-mail addresses: mohamed_madii@yahoo.com (M.F. Mady), kare.b.jorgensen@
uis.no (K.B. Jørgensen).
The 1,2,3-triazole unit has received great interest and special
attention because of its wide and extensive medicinal applications,
such as antibacterial [23], antifungicidal [24], antiviral [25],
http://dx.doi.org/10.1016/j.ejmech.2014.07.042
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

434
M.F. Mady et al. / European Journal of Medicinal Chemistry 84 (2014) 433e443
Fig. 1. Examples of drugs molecules containing the diaryl sulfone moiety or sulfonyl groups.
antioxidant [26] or anti-inflammatory agents [27]. 1,4-
Disubstituted 1,2,3-triazoles are obtainable in high yields by the
copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC)
reaction often used in the click chemistry concept which play an
efficient role in drug discovery applications. This reaction proceeds
with great efficiency and selectivity in aqueous media [28,29].
The above mentioned facts encouraged us to continue our
exploration of diaryl sulfone derivatives [30e32], in the pursuit of
novel compounds with antimicrobial or antioxidant activities with
the potential of becoming new drugs. Combining the activities of
the diaryl sulfone group and the 1,2,3-triazole we have designed
and synthesized mono and bis-1,2,3-triazole derivatives of the
diaryl sulfone scaffold, as outlined in Fig. 2, by installing triple
bonds on the scaffold and clicking on new groups while forming
1,2,3-triazoles with the CuAAC reaction. Synthesis under ultra-
sound irradiation was compared to silent conditions at the same
temperature to explore the effect of sonication on the reactions. All
synthesized compounds were evaluated for their antioxidant,
antibacterial and antifungal activities, and also their minimum
inhibitory concentration (MIC).
terminal alkyne by ultrasound mediated Barbier-type prop-
argylation of the corresponding carbonyl compounds 1a,b [30].
Propargyl bromide in dry THF in the presence of Zinc, and the Lewis
acid ZnBr2 as an additive, afforded the homopropargylic alcohol
with high yields and regioselectivity above 99%. Times and yields of
the reactions under both ultrasound irradiation and silent condi-
tions are tabulated in Table 1. Ultrasound irradiation improved the
yield and decreased the reaction time compared to the silent
conditions.
Next, we investigated the scope and the generality of the CuAAC
reaction [33]. The commercially available benzyl azide was applied
on alkynes 2a,b, and later 4a,b and 5a,b, affording excellent yields
of 1,4-disubstituted 1,2,3-triazoles (3a,b and 6a,b) under both ul-
trasound irradiation and silent conditions (Scheme 1).
The synthesis of monotriazoles 3a,b involved the click reaction
between propargyl alcohol 2a,b and benzyl azide by copper sulfate
and sodium ascorbate at 25e30 ꢀC in tert-butanol:water 2:1 under
ultrasound irradiation compared to simple stirring [33] (Table 2).
Along Route A in Scheme 1 the hydroxyl group in aryl sulfones 3a,b
was propargylated with propargyl bromide in dry DMF and sodium
hydride (NaH) at ꢁ20 ꢀC under sonication or stirring, affording the
O-propargylated isomer 4a,b in high yields (Table 3) with no trace
of allene formation. The O-propargylated products were reacted
with benzyl azide using the click conditions as described in the
experimental section, to form bis-triazoles 6a,b in excellent yields
in short time. Along route B, outlined in Scheme 1, hydroxyalkynes
2a,b were first propargylated (Table 3) to bisalkynes 5a,b, before
reaction with two equivalents of azide under ultrasound irradiation
gave bis-triazoles 6a,b in better yields than by silent conditions. It is
clear from the results listed in Table 2, that the 1,3-dipolar cyclo-
addition reaction performed better under ultrasound irradiation.
While the reactions under silent conditions needed 1e4 h for
completion with yields between 76% and 85%, ultrasound irradia-
tion gave yields between 86% and 97% after just 20e30 min.
2. Results and discussion
2.1. Chemistry
The synthesis work is outlined in Scheme 1. Route A is a stepwise
approach that allow click coupling of two different azides for more
diversity, while route B saves one step by first introducing both
alkynes and then form both triazoles simultaneously from the same
azide. The first step in the construction of our scaffold were the
preparation of the key aryl sulfone intermediates 2a,b containing a
To further expand the novel 1,2,3-triazole series a variety of
azido ketones was desired. However, it has been reported that the
1,3-dipolar cycloaddition of -azido ketones with alkynes were
difficult because -azido ketones are often unstable to heat and
light. In addition isolation and purification of the -azido ketones
a-
a
a
a
were difficult due to incomplete conversion [34]. Therefore, in situ
preparation would provide an efficient way to handle them safely.
Multicomponent reactions (MCRs) have significant advantages in
Fig. 2. The designed bioactive scaffold has three variable parts, while containing 1,2,3-
triazole and diaryl sulfone as a main backbone.

M.F. Mady et al. / European Journal of Medicinal Chemistry 84 (2014) 433e443
435
Scheme 1. Synthesis of mono and bis-1,2,3-triazoles by stepwise introduction of alkyne followed by the CuACC reaction (Route A) for increased diversity, or simultaneous bis-1,2,3-
triazole formation (Route B) for increased efficiency.
the synthesis of drug libraries by efficient introduction of molecular
complexity with good atom economy [35].
copper sulfate and sodium ascorbate at 25e30 ꢀC under ultrasound
irradiation to find optimum conditions.
As part of our program aimed to use green chemistry tools in
organic synthesis [30e32], we decided to develop a one-pot syn-
The best results were obtained when using H2O/t-BuOH (3:1) as
an efficient medium for the one-pot synthesis of 1,4-disubstituted
1,2,3-triazoles (Table 4, entry 9).
thesis of 1,4-disubstituted 1,2,3-triazoles from
a-bromoketones,
sodium azide, and alkynes. The model reaction, as shown in Table 4,
was performed in the presence of different types of solvents,
Table 2
Synthesis of 1,2,3-triazoles 3a,b; 6a,b by the CuAAC reaction (Scheme 1).
Entry
Starting
material
Product
Ultrasound irradiation
Stirring conditions
Table 1
Synthesis of homopropargyl alcohols 2a,b by the Barbier-type reaction (Scheme 1).
Time (min)
Yield (%)
Time (h)
Yield (%)
Entry
Starting
material
Product
Ultrasound
irradiation
Stirring conditions
1
2
3
4
5
6
2a
2b
4a
4b
5a
5b
3a
3b
6a
6b
6a
6b
20
20
30
30
30
30
97
91
95
93
90
86
1
1
2
2
4
4
85
76
80
81
79
78
Time (h)
Yield (%)
Time (h)
Yield (%)
1
2
1a
1b
2a
2b
1
1.5
89
80
12
12
73
70

436
M.F. Mady et al. / European Journal of Medicinal Chemistry 84 (2014) 433e443
Table 3
the product 8d took about 3 h for completion under silent condi-
tions and the yield of the product was 84%. In comparison, under
ultrasonic irradiation, the reaction time was 30 min and the yield
95%.
Synthesis of alkynes 4a,b and bis-alkynes 5a,b by propargylation of the corre-
sponding alcohols (Scheme 1).
Entry
Starting
material
Product
Ultrasound irradiation
Stirring conditions
Time (min)
Yield (%)
Time (h)
Yield (%)
2.2. Biological activities
1
2
3
4
2a
2b
3a
3b
5a
5b
4a
4b
30
30
30
30
99
90
80
78
2
2
2
2
90
85
70
66
2.2.1. Antimicrobial activity
The antimicrobial activities of all the synthesized triazole linked
diaryl sulfone derivatives were tested by the presence or absence of
inhibition zones and zone diameter against ten microbial strains:
Four Gram-positive bacteria (S. aureus ATCC 29213, Bacillus subtilis
ATCC 663, Bacillus megaterium ATCC 9885 and Sarcina lutea); three
Gram-negative bacteria (Klebsiella pneumonia ATCC 13883, Pseu-
domonas aeruginosa ATCC 2795 and Escherichia coli 25922); two
yeasts (Candida albicans NRRL Y-477 and Saccharomyces cerevisae)
and one fungi (Aspergillus niger). The results from the evaluation of
antimicrobial effects are summarized in Table 7. The compounds
were compared with the standard antibacterial drug Ciprofloxacin
and the yeast/antifungal drug Clotrimazole.
A plausible mechanism for the formation of 1,2,3-triazoles is
initial formation of the -azido ketone as an intermediate, as was
observed when reacting equimolar quantities of -halo ketone
derivative 7a with sodium azide without alkyne 2a under identical
conditions. Subsequently, 1,3-dipolar cycloaddition of -azido ke-
tone and terminal alkyne 2a afforded the desired product 8a. In
general, we found that the new solvent system, H2O/t-BuOH (3:1)
afforded keto 1,2,3-triazoles in good yield within a short time
compared to the other solvents.
a
a
a
With the optimized conditions in hand, we prepared a range of
mono and bis-keto triazoles containing aryl sulphone groups via
the one-pot click reaction as shown in Tables 5 and 6.
All compounds were purified by silica gel column chromatog-
raphy and were fully characterized by IR, 1H nuclear magnetic
resonance (NMR), 13C NMR and high-resolution mass spectral
(HRMS) analyses. Furthermore, the structures 9aec; 9eeg were
confirmed by elemental analysis (see experimental section). For
example The IR spectrum of 8d displayed a strong band at about
1701 cmꢁ1 indicating the presence of a ketone group. The 1H NMR
It was found that compounds 3a,b; 6a,b; 8ae8h; 9ae9h showed
variable antibacterial activity against Gram-positive and Gram-
negative bacteria. For example, compound 3a showed a zone in-
hibition of 19 mm against S. aureus ATCC 29213 and compounds 3a;
8be8d; 9a,9b displayed zone inhibitions in the range of 19e20 mm
against S. lutea. Other compounds showed moderate to poor inhi-
bition against both Gram-positive and Gram-negative bacteria.
The Minimum inhibitory concentration (MIC) of all compounds
was also screened as listed in Table 8. All tested compounds showed
high MICs, ranging from 50 to 200 mg/mL, against Gram-positive
spectra of 8d showed a distinct singlet signal at
triazolyl C5eH proton. 13C NMR also displayed two distinct signals
at 124.9 ppm and 192.3 ppm corresponding to the triazolyl C5
d
7.76 ppm for
and Gram-negative bacteria compared to the standard drug Cip-
rofloxacin. Unfortunately, none of the tested compound presented
any significant activity against yeast.
d
d
and the carbonyl carbon respectively. The mass spectrum of this
compound exhibits the molecular ion peak at m/z ¼ 470 [MþNa]þ,
which is in agreement with the calculated mass. As outlined in
Table 5, the one-pot three component synthesis of 1,2,3-triazoles
carried out under ultrasonic irradiation gave excellent yields and
shorter reaction times compared to the silent reaction. For example,
Antifungal activity was screened against A. niger. The com-
pounds showed good to excellent antifungal activities against the
strain, comparable to the standard drug Clotrimazole as shown in
Table 7.
Compounds 3b, 6b, 8d, 8e, 8h, 9b and 9deg showed the highest
zone inhibition against A. niger in the range 32e34 mm. The MICs of
the new compounds against this pathological strain are tabulated
in Table 8. Compounds 3b, 6b and 9eeg were found most effective
against the fungal strain with the lowest MIC of 25
Clotrimazole.
mg/mL, similar to
Table 4
Effect of solvents on the one-pot synthesis of keto 1,2,3-triazoles from in situ formed
azides.a
2.2.2. Structureeactivity relationships
The results of the antimicrobial screening revealed that the
backbone built from ketone 1b (R ¼ Me in Fig. 2), had consistently
better antifungal activity than molecules based on the aldehyde 1a
against A. niger, and some are as potent as standard drugs. The
modifications added to the hydroxyl group through the ether link at
R0 (6 compared to 3, and 9 compared to 8), with a benzyl group or
keto benzene derivatives as R00, reduced the activity of the less
active compounds but had little impact when R ¼ Me. In addition
we found that replacement of the para-hydrogen of keto benzene
9h by phenylsulfonyl, fluoro and bromo functions, as in 9eeg
respectively, increased the antimicrobial activity.
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
DMSO
DMF
t-BuOH
12
12
12
12
12
12
12
5
None
None
None
10
8
25
33
60
90
H2O
PEGc
2.2.3. Antioxidant activity
PEG/H2O (1:1)
H2O/t-BuOH (1:1)
H2O/t-BuOH (2:1)
H2O/t-BuOH (3:1)
The antioxidant activity of all synthesized compounds were
measured against 2,2-diphenyl-1-picrylhydrazyl (DPPH) free
radical. The DPPH procedure is one of the most effective methods
for evaluating the concentration of radical scavenging materials
active by a chain-breaking mechanism [36]. DPPH radical scav-
enging activity evaluation is a rapid and convenient assay for
1
a
Reaction conditions: 7a (1.0 equiv.), NaN3 (1.2 equiv.), 2a (1.0 equiv.),
CuSO4$5H2O (0.1 equiv.) and Na ascorbate (0.3 equiv.).
b
Isolated yields.
PEG ¼ Poly(ethylene glycol), average mol wt ¼ 200.
c
screening the antioxidant activities of products. Table
9

M.F. Mady et al. / European Journal of Medicinal Chemistry 84 (2014) 433e443
437
Table 5
One-pot synthesis of triazoles 8aeh.
Entry
Starting material
X
R
Product
Ultrasound irradiation
Time (min)
Stirring conditions
Time (h)
Yield (%)
Yield (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7a
7b
7c
7d
SO2Ph
F
Br
H
SO2Ph
F
Br
H
H
H
H
H
Me
Me
Me
Me
8a
8b
8c
8d
8e
8f
60
30
30
30
60
30
30
30
90
96
94
95
89
94
91
92
4
3
3
3
4
3
3
3
80
83
85
84
79
81
80
81
8g
8h
summarizes the radical scavenging activities of all compounds,
compared to the synthetic antioxidant 4-((1-(4-Methoxyphenyl)-
1H-1,2,3-triazol-4-yl)- methoxy)aniline (BHT). It has been reported
that the aryl sulfone moiety enhance the antioxidant activity
through enhanced expression of antioxidant genes, and this new
class of powerful antioxidants might be a potent treatment for
Parkinson's disease [37,38]. Several compounds showed an excel-
lent free radical scavenging activity. Compound 8e, with R0 ¼ H and
R00 containing another diaryl sulfone moiety, was the strongest
the CuAAC-reaction in aqueous tert-butanol under ultrasound
irradiation compared to silent conditions. It was observed that ul-
trasound irradiation improved the yields and decreased the reac-
tion times. All new compounds were characterized by IR, 1H NMR,
13C NMR and HRMS analysis. All synthesized compounds were
screened for antibacterial, antifungal and antioxidant activities.
Compounds 3b; 6b and 9eeg were found to be the most effective
against fungal strains. Other compounds revealed good to moder-
ate antimicrobial activity. In addition, the antioxidant activity of all
compounds was measured using the DPPH free radical assay.
Compound 8e was more potent than the standard antioxidant BHT.
radical scavenger with an IC50 value of 20
pound 8a showed an excellent radical scavenging activity with IC50
at 74 g/mL. Compounds 9h, 9c, 9f and 9d also showed very good
scavenging activities with IC50 at 125, 150, 150 and 175 g/mL,
mg/mL. Moreover com-
m
m
4. Experimental
respectively. The other compounds also showed scavenging activ-
ity, but demanded higher concentrations of the compounds.
4.1. Chemistry
3. Conclusion
4.1.1. General
All chemicals used in this work were purchased from Fluka,
VWR or Merck and were used without purification. Melting points
were determined on a Bibby Sterilin ltd electrothermal melting
We have synthesized a series of 1,2,3-triazoles linked to an
diaryl sulfone moiety exploiting the click chemistry properties of
Table 6
One-pot synthesis of bistriazoles 9aeh.
Entry
Starting material
X
R
Product
Ultrasound irradiation
Time (min)
Stirring conditions
Time (h)
Yield (%)
Yield (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7a
7b
7c
7d
SO2Ph
F
Br
H
SO2Ph
F
Br
H
H
H
H
H
Me
Me
Me
Me
9a
9b
9c
9d
9e
9f
45
45
45
45
60
45
45
45
85
90
89
88
83
88
85
86
4
3
3
3
4
3
3
3
76
80
87
78
75
79
74
75
9g
9h

438
M.F. Mady et al. / European Journal of Medicinal Chemistry 84 (2014) 433e443
Table 7
Antimicrobial activity expressed as inhibition diameter zones in millimeters (mm) of novel triazoles against the pathological strains based on well diffusion assay.a
Entry
Gram-positive bacteria
Gram-negative bacteria
S. lutea K. pneumoniae P. aeruginosa
Yeast
fungi
S. aureus
ATCC
B. subtilis
ATCC
6633
B. megaterium
ATCC 9885
E. coli ATCC C. albicans
S. cerevisae A. niger
ATCC 13883
ATCC 27953
25922
NRRL
Y-477
29213
3a
3b
6a
6b
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
9c
9d
9e
9f
19
22
14
14
17
14
22
14
N.A.b
17
17
18
17
26
17
24
14
27
24
N.A.
17
16
15
14
20
19
14
19
N.A.
19
17
19
14
19
17
17
14
15
14
16
22
N.A.
14
17
14
17
15
17
19
N.A.
17
17
N.A.
15
N.A.
17
20
20
22
17
23
20
23
17
17
22
20
20
20
14
21
N.A.
22
19
20
22
24
25
26
24
17
20
N.A.
23
24
17
15
19
15
24
22
18
19
19
13
13
16
N.A.
15
19
26
26
23
25
N.A.
20
23
18
19
17
19
25
20
15
22
19
19
14
15
N.A.
23
19
27
26
19
24
N.A.
19
22
19
18
17
14
22
17
19
19
17
14
N.A.
14
17
20
17
25
24
21
23
N.A.
19
19
18
16
15
13
20
12
15
15
15
15
14
22
21
23
15
N.A.
15
15
N.A.
30
17
16
18
14
16
N.A.
17
N.A.
17
N.A.
14
14
N.A.
19
20
22
14
15
14
16
30
32
30
34
28
32
30
29
32
32
20
32
20
32
20
20
34
34
32
28
N.A.
33
9g
9h
17
24
N.A.
Ciprofloxacin 20
Clotrimazole
N.A.
31
N.A.
a
The experiment was carried out in triplicate and the average zone of inhibition was calculated.
N.A. (no activity).
b
point apparatus and are uncorrected. Sonochemical reactions were
dimethyl sulphoxide (DMSO-d6) using TMS as internal standard. 13
C
carried out in a Branson B1510 DTH ultrasound cleaning bath
(50 kHz, 245 W). The synthesis of O-propargylated compounds was
carried out by BRANSON Digital Sonifier 250 (230 V, 50/60 Hz)
fitted with a microtip at 40% of maximum amplitude. All reactions
were monitored by thin layer chromatography using Fluka GF254
silica gel plates with detection under UV light at 254 and 360 nm. IR
spectra were recorded from KBr tablets on a Perkin Elmer 2000
FTIR spectrometer. NMR spectra were recorded on a Varian Mer-
cury VX-300 NMR spectrometer at 300.13 and 75.47 MHz, at
ambient temperature unless otherwise stated. 1H NMR and 13C
NMR spectra were recorded in deuterated chloroform (CDCl3) or
chemical shifts were related to that of the solvent. High resolution
Mass spectra (HRMS) were recorded on an ESI-MS Thermo LTQ
Orbitrap XL (Infusion 5 mL/min, resolution: 100 000 at m/z 400, ca.
10 scans/sample averaged). The CHNS elemental analyses were
performed on a vario El analyser (microanalytical unit, Cairo Uni-
versity, Giza, Egypt). The diaryl sulfones 1a,b, and a-bromoketones
7aed were prepared according to the literature [30,39].
4.1.2. Procedure for sonicated reactions
4.1.2.1. General procedure for zinc-mediated homopropargyl alcohols
2a,b. A mixture of carbonyl compound 1a or b (1.0 mmol,1.0 equiv)
Table 8
Minimum inhibitory concentration (mg/mL) against the pathological strains based on two folds serial dilution technique.
Entry
S. aureus
ATCC
B. subtilis
ATCC
B. megaterium
ATCC 9885
S. lutea K. pneumoniae
P. aeruginosa
ATCC 27953
E. coli ATCC C. albicans
S. cerevisae A. niger
ATCC 13883
25922
NRRL
29213
6633
Y-477
3a
3b
6a
6b
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
9c
9d
9e
9f
200
200
N.A.
N.A.
200
N.A.
200
N.A.
N.A.
200
200
200
200
100
200
100
N.A.
100
100
N.A.
200
200
N.A.
N.A.
200
200
N.A.
200
N.A.
200
200
200
N.A.
200
200
200
N.A.
N.A.
N.A.
N.A.
25
N.A.
200
N.A.
200
N.A.
200
200
N.A.
200
200
N.A.
N.A.
N.A.
200
200
200
200
200
100
200
25
200
200
200
200
100
200
200
200
N.A.
200
N.A.
200
200
200
200
100
100
50
200
100
200
N.A.
200
N.A.
100
200
200
200
200
N.A.
N.A.
200
N.A.
100
200
100
100
200
25
200
200
200
200
200
200
100
200
N.A.
200
200
200
N.A.
N.A.
N.A.
100
200
100
100
200
25
200
200
200
200
N.A.
N.A.
200
200
200
200
200
N.A.
N.A.
N.A.
200
200
200
100
100
200
25
200
200
200
200
N.A.
N.A.
200
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
200
200
200
N.A.
N.A.
N.A.
N.A.
N.A.
25
200
200
200
N.A.
200
N.A.
200
N.A.
200
N.A.
N.A.
N.A.
N.A.
200
200
200
N.A.
N.A.
N.A.
200
N.A.
25
50
25
50
25
50
50
50
100
50
50
200
50
100
50
200
200
25
25
25
50
N.A.
25
9g
9h
100
200
25
Ciprofloxacin 25
Clotrimazole N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.

M.F. Mady et al. / European Journal of Medicinal Chemistry 84 (2014) 433e443
439
Table 9
chromatography (SiO2; ethyl acetate/petroleum ether 4:1) to obtain
the pure product.
4.1.2.2.1. 2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-1-(4-(phenylsulfonyl)
phenyl)ethanol (3a). White solid; mp. 164e166 ꢀC; IR nmax (cmꢁ1):
3246 (OH), 1595 (C]N), 1315, 1153 (SO2); 1H NMR (DMSO-d6,
Anti-oxidant activity measured as IC50 by the DPPH
procedure.
Compounds
IC50 (mg/mL)
3a
3b
6a
6b
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
9c
9d
9e
9f
200
600
500
600
74
275
500
425
20
425
800
600
600
275
150
175
600
150
N.A.
125
50
300 MHz)
d
7.96e7.18 (m, 14H), 7.80 (s, 1H), 5.68 (d, J ¼ 4.5 Hz, 1H,
D2O-exchangeable), 5.52 (s, 2H), 4.91 (t, J ¼ 4.5 Hz, 1H), 2.95 (d,
J ¼ 6.3 Hz, 2H); 13C NMR (DMSO-d6, 75.46 MHz)
d 151.4, 143.8, 141.3,
139.5, 136.3, 133.7, 129.8, 128.7, 128.0, 127.7, 127.3, 127.2, 123.4, 71.3,
52.6, 35.3; MS (ESI) m/z 420 [MþH]þ. HRMS (ESI) calcd. for
C
23H22N3O3S [MþH]þ, 420.1379; found 420.1379.
4.1.2.2.2. 1-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2-(4-(phenyl-
sulfonyl)phenyl)propan-2-ol (3b). White solid; mp. 186e188 ꢀC; IR
nmax (cmꢁ1): 3496 (OH), 1596 (C]N), 1320, 1151 (SO2); 1H NMR
(DMSO-d6, 300 MHz)
5.43 (s, 1H, D2O-exchangeable), 3.06 (s, 2H), 1.42 (s, 3H); 13C NMR
(DMSO-d6, 75.46 MHz) 154.5, 143.0, 141.4, 138.8, 136.4, 133.6,
d 7.94e7.07 (m, 14H), 7.59 (s, 1H), 5.47 (s, 2H),
d
129.7, 128.6, 127.9, 127.2, 126.9, 126.5, 123.8, 72.8, 52.4, 39.5, 29.4;
MS (ESI) m/z 434 [MþH]þ. HRMS (ESI) calcd. for C24H24N3O3S
[MþH]þ, 434.1533; found 434.1538.
9g
9h
BHT
4.1.2.3. General procedure for synthesis of O-propargylated aryl sul-
fone derivatives 4a,b; 5a,b. A suspension of NaH (96.0 mg,
4.0 mmol, 4.0 equiv) in dry DMF (5.0 mL) in a 50 mL Erlenmeyer
flask was added a solution of a diaryl sulfone derivative (Com-
pounds 2a,b; 3a,b) (1.0 mmol, 1.0 equiv) in dry DMF (10.0 mL)
at ꢁ20 ꢀC. Then, propargyl bromide (5.0 mmol) was slowly added
dropwise to the reaction mixture under sonication. The mixture
was irradiated with the Branson digital sonifier 250 (Microtip, 40%
maximum amplitude with pulse on ¼ 15.0 s, pulse off ¼ 5.0 s)
at ꢁ20 ꢀC for a given time (monitored by TLC) as outlined in Table 3,
before the mixture was carefully quenched with H2O (20 mL) and
subsequently extracted with ethyl acetate (4 ꢂ 10 mL). The com-
bined organic layers were washed with brine and dried over
anhydrous MgSO4. The solvent was removed under reduced pres-
sure, and the crude residue obtained was purified by column
chromatography (SiO2, ethyl acetate/petroleum ether 1:3) to obtain
the propargyl ethers 4a,b; 5a,b.
in THF (10.0 mL), Zn (197.9 mg, 3.0 mmol, 3.0 equiv) and ZnBr2
(76.5 mg, 0.3 mmol, 0.3 equiv) in a 50 mL Erlenmeyer flask was
subjected to ultrasonic irradiation at 25e30 ꢀC while propargyl
bromide (356.9 mg, 3.0 mmol, 3.0 equiv) was slowly added drop-
wise. The reaction was monitored by TLC. After completion of the
reaction (Reaction times as shown in Table 1) saturated aqueous
NaHCO3 (4.0 mL) was added, and the resulting mixture was
extracted with ethyl acetate (3 ꢂ 10 mL). The combined organic
layers were washed with brine, dried over anhydrous MgSO4, and
the solvent removed under reduced pressure. The residue afforded
the corresponding homopropargyl alcohols 2a,b. The products
were purified by column chromatography (SiO2; ethyl acetate/pe-
troleum ether 1:4).
4.1.2.1.1. 1-(4-(Phenylsulfonyl)phenyl)but-3-yn-1-ol
(2a).
White solid; mp. 110e112 ꢀC; IR nmax (cmꢁ1): 3289 (OH), 3255
4.1.2.3.1. 1-Benzyl-4-(2-(4-(phenylsulfonyl)phenyl)-2-(prop-2-
(^CH), 2118 (C^C), 1316, 1155 (SO2); 1H NMR (DMSO-d6, 300 MHz)
yn-1-yloxy)ethyl)-1H-1,2,3-triazole
(4a). White
solid;
mp.
118e120 ꢀC; IR nmax (cmꢁ1): 3268 (^CH), 2128 (C^C), 1598 (C]N),
d
7.95e7.61 (m, 9H), 5.52 (t, J ¼ 4.2 Hz, 1H, D2O-exchangeable), 4.77
(t, J ¼ 5.4 Hz, 1H), 2.53e2.59 (m, 2H), 2.08 (t, J ¼ 3.9 Hz, 1H); 13C
1318, 1160 (SO2), 1210 (CeOeC); 1H NMR (CDCl3, 300 MHz)
NMR (DMSO-d6, 75.46 MHz)
d 149.8, 141.1, 139.5, 133.0, 129.2,
d
7.96e7.20 (m, 14H), 7.42 (s,1H), 5.47 (s, 2H), 4.86 (t, J ¼ 5.7 Hz,1H),
126.93, 126.8, 126.6, 80.7, 72.1, 70.0, 28.1; MS (ESI) m/z 309
4.08 (dd, J ¼ 16.5, 2.4 Hz,1H), 3.81 (dd, J ¼ 16.5, 2.4 Hz,1H), 3.19 (dd,
J ¼ 15.0, 8.1 Hz, 1H), 3.01 (dd, J ¼ 15.0, 5.4 Hz, 1H), 2.24 (t, J ¼ 1.5 Hz,
[MþNa]þ. HRMS (ESI) calcd. for C16H14O3S
þ
Na [MþNa]þ,
1H); 13C NMR (CDCl3, 75.46 MHz)
d 146.3, 143.9, 141.2, 134.8, 133.3,
309.0556; found 309.0556.
4.1.2.1.2. 2-(4-(Phenylsulfonyl)phenyl)pent-4-yn-2-ol
Pale yellow oil; IR nmax (cmꢁ1): 3503 (OH), 3296 (^CH), 2119
(C^C), 1307, 1156 (SO2); 1H NMR (DMSO-d6, 300 MHz)
7.97e7.61
(2b).
129.3, 129.0, 128.6, 127.9, 127.8, 127.7, 127.6, 122.4, 79.1, 78.9, 74.9,
56.3, 54.0, 34.4; MS (ESI) m/z 458 [MþH]þ. HRMS (ESI) calcd. for
26H24N3O3S [MþH]þ, 458.1533; found 458.1535.
d
C
(m, 9H), 5.50 (s,1H, D2O-exchangeable), 2.70 (d, J ¼ 2.7 Hz,1H), 2.49
4.1.2.3.2. 1-Benzyl-4-(2-(4-(phenylsulfonyl)phenyl)-2-(prop-2-
(d, J ¼ 2.4 Hz, 1H), 2.08 (t, J ¼ 1.35 Hz, 1H), 1.48 (s, 3H); 13C NMR
yn-1-yloxy)propyl)-1H-1,2,3-triazole
(4b). White
solid;
mp.
140e142 ꢀC; IR nmax (cmꢁ1): 3287 (^CH), 2121 (C^C), 1676 (C]N),
(CDCl3, 75.46 MHz)
d 151.9, 141.5, 140.2, 133.2, 129.3, 127.7, 125.9,
79.4, 73.1, 72.4, 34.4, 29.1; MS (ESI) m/z 323 [MþNa]þ. HRMS (ESI)
1307, 1157 (SO2), 1219 (CeOeC); 1H NMR (DMSO-d6, 300 MHz)
calcd. for C17H16O3S þ Na [MþNa]þ, 323.0712; found 323.0713.
d
7.91e7.10 (m,15H), 5.44 (s, 2H), 3.91 (s, 2H), 3.07 (s, 2H), 2.45 (t, br,
1H), 1.48 (s, 3H); 13C NMR (DMSO-d6, 75.46 MHz)
d
150.2, 142.0,
4.1.2.2. General procedure for the synthesis of 1,4-disubstituted 1,2,3-
triazoles 3a,b. A mixture of terminal alkyne 2a or b (1.0 mmol,
1.0 equiv), benzyl azide (133.2 mg, 1.0 mmol, 1.0 equiv),
CuSO4$5H2O (24.9 mg, 0.1 mmol, 0.1 equiv), and sodium ascorbate
(59.4 mg, 0.3 mmol, 0.3 equiv) in H2O (1.0 mL), and tert-butanol
(2.0 mL) was sonicated at 25e30 ꢀC while monitored by TLC. After
the appropriate time (see Table 2), the mixture was extracted with
ethyl acetate (4 ꢂ 10 mL). The combined organic extracts were
washed with H2O, dried over anhydrous MgSO4, filtered and
concentrated in vacuo. The crude product was purified by column
141.1, 139.7, 136.2, 133.7, 129.8, 128.7, 127.9, 127.4, 127.3, 127.3, 123.9,
81.0, 79.5, 76.5, 52.5, 51.4, 37.6, 23.4; MS (ESI) m/z 472 [MþH]þ.
HRMS (ESI) calcd. for C27H26N3O3S [MþH]þ, 472.1689; found
472.1692.
4.1.2.3.3. 1-(Phenylsulfonyl)-4-(1-(prop-2-yn-1-yloxy)but-3-yn-
1-yl)benzene (5a). Pale yellow oil; IR nmax (cmꢁ1): 3288 (^CH),
2118 (C^C), 1307, 1155 (SO2), 1181 (CeOeC); 1H NMR (DMSO-d6,
300 MHz)
d
8.0e7.60 (m, 9H), 4.73 (t, J ¼ 6.0 Hz, 1H), 4.14 (dd,
J ¼ 15.9, 2.4 Hz, 1H), 3.98 (dd, J ¼ 16.2, 2.4 Hz, 1H), 3.47 (t, J ¼ 2.4 Hz,
1H), 2.80 (t, J ¼ 2.4 Hz, 1H), 2.64 (m, 2H); 13C NMR (DMSO-d6,

440
M.F. Mady et al. / European Journal of Medicinal Chemistry 84 (2014) 433e443
75.46 MHz)
d
146.0, 141.0, 140.6, 133.8, 129.9, 128.1, 127.4, 80.2, 79.7,
in vacuo. The crude product was purified by column chromatog-
raphy (SiO2, dichloromethane/methanol 10:1) to obtain the pure
product.
4.1.2.5.1. 2-(4-(2-Hydroxy-2-(4-(phenylsulfonyl)phenyl)ethyl)-
1H-1,2,3-triazol-1-yl)-1-(4-(phenyl sulfonyl)phenyl)ethanone (8a).
White solid; mp. 221e223 ꢀC; IR nmax (cmꢁ1): 3417 (OH), 1713 (C]
O), 1596 (C]N), 1295, 1153 (SO2); 1H NMR (DMSO-d6, 300 MHz)
77.7, 77.2, 73.4, 56.0, 26.2; MS (ESI) m/z 347 [MþNa]þ. HRMS (ESI)
calcd. for C19H16O3S þ Na [MþNa]þ, 347.0712; found 347.0714.
4.1.2.3.4. 1-(Phenylsulfonyl)-4-(2-(prop-2-yn-1-yloxy)pent-4-yn-
2-yl)benzene (5b). Yellow oil; IR nmax (cmꢁ1): 3291 (^CH), 2110
(C^C), 1307, 1156 (SO2), 1218 (CeOeC); 1H NMR (DMSO-d6,
300 MHz)
d
7.80e7.40 (m, 9H), 3.71 (d, J ¼ 6.6 Hz, 2H), 3.08 (t,
J ¼ 6.0 Hz, 1H), 3.02 (s, 2H), 2.89 (t, J ¼ 1.8 Hz, 1H), 1.40 (s, 3H); 13
C
d
8.23e7.54 (m, 18H), 7.73 (s, 1H), 6.12 (s, 2H), 5.65 (d, J ¼ 4.2 Hz, 1H,
D2O-exchangeable), 4.90 (t, J ¼ 5.7 Hz, 1H), 2.97 (d, J ¼ 6.0 Hz, 2H);
13C NMR (DMSO-d6, 75.46 MHz)
191.8, 151.4, 145.3, 143.4, 141.3,
NMR (DMSO-d6, 75.46 MHz) d 149.3, 141.0, 140.1, 133.8, 129.8, 127.4,
127.3, 80.7, 80.2, 78.7, 76.6, 73.8, 51.56, 31.45, 23.4; MS (ESI) m/z 361
d
[MþNa]þ. HRMS (ESI) calcd. for C20H18O3S
þ
Na [MþNa]þ,
140.3, 139.5, 137.9, 134.2, 133.6, 129.9, 129.7, 129.5, 127.9, 127.7,
127.3, 124.7, 71.3, 55.9, 35.2; MS (ESI) m/z 610 [MþNa]þ. HRMS (ESI)
calcd. for C30H25N3O6S2 þ Na [MþNa]þ, 610.1077; found 610.1080.
4.1.2.5.2. 1-(4-Fluorophenyl)-2-(4-(2-hydroxy-2-(4-(phenyl-
361.0869; found 361.0870.
4.1.2.4. General procedure for the synthesis of 1,4-disubstituted 1,2,3-
bistriazoles 6a,b
sulfonyl)phenyl)ethyl)-1H-1,2,3-triazol-1-yl)ethanone
(8b).
4.1.2.4.1. Route A. In an Erlenmeyer flask, a mixture of O-prop-
argylated diaryl sulfones 4a or b (1.0 mmol, 1.0 equiv), benzyl azide
(133.2 mg, 1.0 mmol, 1.0 equiv), CuSO4$5H2O (24.9 mg, 0.1 mmol,
0.1 equiv), and sodium ascorbate (59.4 mg, 0.3 mmol, 0.3 equiv) in
H2O (1.0 mL), and tert-butanol (2.0 mL) was subjected to ultrasonic
irradiation at 25e30 ꢀC for an appropriate time as outlined in
Table 2(monitored by TLC), and subsequently extracted with ethyl
acetate (4 ꢂ 10 mL). The combined organic extracts were washed
with H2O, dried over anhydrous MgSO4, filtered and concentrated in
vacuo. The crudecompoundwaspurifiedbycolumnchromatography
(SiO2, ethyl acetate/petroleum ether 4:1) to obtain the pure product.
4.1.2.4.2. Route B. A mixture of the bis-terminal alkyne 5a or b
(1.0 mmol), benzyl azide (266.4 mg, 2.0 mmol, 2.0 equiv),
CuSO4$5H2O (49.8 mg, 0.2 mmol, 0.2 equiv), and sodium ascorbate
(118.8 mg, 0.6 mmol, 0.6 equiv) in H2O (1.0 mL), and tert-butanol
(2.0 mL) was subjected to the same treatment as in Route A.
4.1.2.4.3. 1-Benzyl-4-((2-(1-benzyl-1H-1,2,3-triazol-4-yl)-1-(4-
White solid; mp. 140e142 ꢀC; IR nmax (cmꢁ1): 3452 (OH), 1702 (C]
O), 1598 (C]N), 1305, 1153 (SO2); 1H NMR (DMSO-d6, 300 MHz)
d
8.16e7.41 (m, 13H), 7.75 (s, 1H), 6.10 (s, 2H), 5.65 (d, J ¼ 4.5 Hz, 1H,
D2O-exchangeable), 4.91 (t, J ¼ 5.7 Hz, 1H), 2.98 (d, J ¼ 6.3 Hz, 2H);
13C NMR (DMSO-d6, 75.46 MHz)
d
191.0, 165.5 (d, J ¼ 251.1 Hz),
151.4, 143.3, 141.3, 139.5, 133.6, 131.2 (d, J ¼ 9.6 Hz), 130.9 (d,
J ¼ 3.0 Hz), 129.7, 127.3, 124.8, 116.1 (d, J ¼ 21.9 Hz), 71.3, 55.6, 35.2;
MS (ESI) m/z 488 [MþNa]þ. HRMS (ESI) calcd for
C
24H20FN3O4S þ Na [MþNa]þ, 488.1051; found 488.1049.
4.1.2.5.3. 1-(4-Bromophenyl)-2-(4-(2-hydroxy-2-(4-(phenyl-
sulfonyl)phenyl)ethyl)-1H-1,2,3-triazol-1-yl)ethanone
(8c).
White solid; mp. 190e192 ꢀC; IR nmax (cmꢁ1): 3420 (OH), 1703 (C]
O), 1586 (C]N), 1306, 1154 (SO2); 1H NMR (DMSO-d6, 300 MHz)
d
7.99e7.59 (m, 13H), 7.80 (s, 1H), 6.09 (s, 2H), 5.69 (s broad, 1H,
D2O-exchangeable), 4.94 (broad, 1H), 2.99 (s broad, 2H); 13C NMR
(DMSO-d6, 75.46 MHz) 191.6, 151.4, 141.3, 139.4,137.9, 133.6, 133.2,
d
132.0, 130.1, 129.7, 128.23, 127.2, 71.23, 55.6, 35.2; MS (ESI) m/z 548
[MþNa]þ. HRMS (ESI) calcd. for C24H20BrN3O4S þ Na [MþNa]þ,
548.0250; found 548.0252.
(phenylsulfonyl)phenyl)ethoxy)-methyl)-1H-1,2,3-triazole
White solid; mp. 131e133 ꢀC; IR nmax (cmꢁ1): 1599 (C]N), 1308,
1162 (SO2), 1220 (CeOeC); 1H NMR (DMSO-d6, 300 MHz)
8.04 (s,
(6a).
d
4.1.2.5.4. 2-(4-(2-Hydroxy-2-(4-(phenylsulfonyl)phenyl)ethyl)-
1H-1,2,3-triazol-1-yl)-1-phenylethanone (8d). White solid; mp.
160e162 ꢀC; IR nmax (cmꢁ1): 3307 (OH), 1701 (C]O), 1596 (C]N),
1H), 7.97e7.11 (m,19H), 7.73 (s,1H), 5.53 (s, 2H), 5.48 (s, 2H), 4.83 (t,
J ¼ 6.6 Hz, 1H), 4.36 (s, 2H), 3.06 (dd, J ¼ 14.7, 8.1 Hz, 1H), 2.95 (dd,
J ¼ 14.4, 6.0 Hz, 1H); 13C NMR (DMSO-d6, 75.46 MHz)
d
147.4, 143.8,
1309, 1154 (SO2); 1H NMR (DMSO-d6, 300 MHz)
d 8.06e7.56 (m,
143.0, 141.1, 140.2, 136.3, 136.0, 133.8, 129.8, 128.8, 128.7, 128.1,
128.0, 127.9, 127.8, 127.5, 127.4, 124.1, 123.4, 79.1, 61.8, 52.7, 52.5,
33.4; MS (ESI) m/z 591 [MþH]þ. HRMS (ESI) calcd. for C33H31N6O3S
[MþH]þ, 591.2173; found 591.2179.
14H), 7.76 (s, 1H), 6.10 (s, 2H), 5.67 (d, J ¼ 4.5 Hz, 1H, D2O-
exchangeable), 4.92 (t, J ¼ 6.3 Hz, 1H), 2.99 (d, J ¼ 6.0 Hz, 2H); 13C
NMR (DMSO-d6, 75.46 MHz) d 192.3, 151.4, 143.3, 141.3, 139.5, 134.2,
133.6, 129.8, 129.0, 128.2, 127.3, 124.9, 71.4, 55.7, 35.2; MS (ESI) m/z
470 [MþNa]þ. HRMS (ESI) calcd. for C24H21N3O4S þ Na [MþNa]þ,
470.1142; found 470.1142.
4.1.2.4.4. 1-Benzyl-4-(((1-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(4-
(phenylsulfonyl)phenyl)Propan-2-yl)oxy)methyl)-1H-1,2,3-triazole
(6b). White solid; mp. 150e152 ꢀC; IR nmax (cmꢁ1): 1595 (C]N),
1307, 1156 (SO2), 1219 (CeOeC); 1H NMR (DMSO-d6, 300 MHz)
4.1.2.5.5. 2-(4-(2-Hydroxy-2-(4-(phenylsulfonyl)phenyl)propyl)-
1H-1,2,3-triazol-1-yl)-1-(4-(phenylsulfonyl)phenyl)ethanone
(8e).
d
7.94e7.10 (m, 21H), 5.48 (s, 2H), 5.43 (s, 2H), 3.06 (s, 2H), 2.07 (s,
White solid; mp. 205e207 ꢀC; IR nmax (cmꢁ1): 3431 (OH), 1710 (C]
2H), 1.42 (s, 3H); 13C NMR (CDCl3, 75.46 MHz)
d
150.1, 145.5, 143.1,
O), 1595 (C]N), 1307, 1156 (SO2); 1H NMR (DMSO-d6, 300 MHz)
141.4, 140.5, 134.8, 134.5, 133.2, 129.3, 129.1, 129.0, 128.8, 128.6,
128.0,127.7, 127.6, 127.1, 122.8,122.1, 79.3, 57.2, 54.1, 53.8, 39.4, 23.1;
MS (ESI) m/z 605 [MþH]þ. HRMS (ESI) calcd. for C34H33N6O3S
[MþH]þ, 605.2329; found 605.2338.
d
8.19e7.58 (m, 19H), 6.08 (s, 2H), 5.45 (s broad, 1H), 3.10 (s, 2H),
1.41 (s, 3H); 13C NMR (DMSO-d6, 75.46 MHz)
d
191.8, 154.7, 145.2,
141.4, 140.2, 138.8, 137.9, 134.2, 133.6, 129.9, 129.7, 129.4, 127.9,
127.6, 127.2, 126.9, 126.5, 72.7, 55.9, 39.2, 29.2; MS (ESI) m/z 624
[MþNa]þ. HRMS (ESI) calcd. for C31H27N3O6S2 þ Na [MþNa]þ,
624.1233; found 624.1236.
4.1.2.5. General procedure for the one-pot synthesis of 1,4-
disubstituted 1,2,3-monotriazoles 8aeh. To a solution of a
a
-bro-
4.1.2.5.6. 1-(4-Fluorophenyl)-2-(4-(2-hydroxy-2-(4-(phenyl-
moketone (7aed) (1.0 mmol, 1.0 equiv), NaN3 (78.01 mg, 1.2 mmol,
1.2 equiv), and terminal alkyne 2a or b (1.0 mmol, 1.0 equiv) in H2O
(3.0 mL), and tert-butanol (1.0 mL) was added CuSO4$5H2O
(24.9 mg, 0.10 mmol, 0.10 equiv) and sodium ascorbate (59.4 mg,
0.30 mmol, 0.30 equiv). The reaction mixture was sonicated in the
water bath of an ultrasonic cleaner at 25e30 ꢀC until the reaction
was complete, as indicated by TLC (Reaction times are given in
Table 5). Then the organic phase was extracted with dichloro-
methane (4 ꢂ 10 mL). The combined organic extracts were washed
with H2O, dried over anhydrous MgSO4, filtered and concentrated
sulfonyl)phenyl)propyl)-1H-1,2,3-triazol-1-yl)ethanone
(8f).
White solid; mp. 183e185 ꢀC; IR nmax (cmꢁ1): 3404 (OH), 1702 (C]
O), 1598 (C]N), 1307, 1156 (SO2); 1H NMR (DMSO-d6, 300 MHz)
d
8.13e7.40 (m, 14H), 6.05 (s, 2H), 5.48 (s broad, 1H, D2O-
exchangeable), 3.10 (s, 2H), 1.43 (s, 3H); 13C NMR (CDCl3,
75.46 MHz)
d
188.6, 166.4 (d, J ¼ 256.0 Hz), 153.3, 141.4, 139.4, 133.1,
130.8 (d, J ¼ 9.6 Hz),130.2 (d, J ¼ 3.0 Hz),129.2,127.5, 126.0,116.3 (d,
J ¼ 21.9 Hz), 74.1, 55.3, 39.2, 29.8; MS (ESI) m/z 502 [MþNa]þ. HRMS
(ESI) calcd. for C25H22FN3O4S þ Na [MþNa]þ, 502.1207; found
502.1206.

M.F. Mady et al. / European Journal of Medicinal Chemistry 84 (2014) 433e443
441
4.1.2.5.7. 1-(4-Bromophenyl)-2-(4-(2-hydroxy-2-(4-(phenyl-
z 802 [MþNa]þ. HRMS (ESI) calcd. for C35H28Br2N6O5S þ Na
[MþNa]þ, 825.0101; found 825.0109; Anal. calcd. for
sulfonyl)phenyl)propyl)-1H-1,2,3-triazol-1-yl)ethanone
(8g).
White solid; mp. 179e181 ꢀC; IR nmax (cmꢁ1): 3418 (OH), 1702 (C]
C35H28Br2N6O5S: C, 52.25; H, 3.51; N, 10.45; S, 3.99%. Found: C,
O), 1586 (C]N), 1307, 1155 (SO2); 1H NMR (DMSO-d6, 300 MHz)
52.20; H, 3.49; N, 10.50; S, 4.05%.
d
7.96e7.59 (m, 14H), 6.04 (s, 2H), 5.45 (s, 1H, D2O-exchangeable),
4.1.2.6.4. 2-(4-((2-(1-(2-Oxo-2-phenylethyl)-1H-1,2,3-triazol-4-
yl)-1-(4-(phenylsulfonyl) phenyl)ethoxy)methyl)-1H-1,2,3-triazol-1-
yl)-1-phenylethanone (9d). White solid; mp. 180e182 ꢀC; IR nmax
(cmꢁ1): 1701 (C]O), 1596 (C]N), 1307, 1154 (SO2), 1227 (CeOeC);
3.10 (s, 2H), 1.42 (s, 3H); 13C NMR (DMSO-d6, 75.46 MHz)
d
191.5,
154.7, 141.3, 138.7, 133.5, 133.2, 131.9, 130.1, 129.7, 127.2, 126.9, 126.5,
72.6, 55.4, 39.2, 29.3; MS (ESI) m/z 562 [MþNa]þ. HRMS (ESI) calcd.
for C25H22BrN3O4S þ Na [MþNa]þ, 562.0407; found 562.0409.
4.1.2.5.8. 2-(4-(2-Hydroxy-2-(4-(phenylsulfonyl)phenyl)propyl)-
1H-1,2,3-triazol-1-yl)-1-phenylethanone (8h). White solid; mp.
140e142 ꢀC; IR nmax (cmꢁ1): 3396 (OH), 1703 (C]O), 1596 (C]N),
1H NMR (DMSO-d6, 300 MHz, 50 ꢀC)
d 8.02e7.50 (m, 21H), 6.14 (s,
2H), 6.09 (s, 2H), 4.88 (t, J ¼ 6.6 Hz, 1H), 4.49 (d, J ¼ 12.0 Hz, 1H),
4.40 (d, J ¼ 12.0 Hz, 1H), 3.13 (dd, J ¼ 15.0, 7.5 Hz, 1H), 3.04 (dd,
J ¼ 15.0, 5.7 Hz, 1H); 13C NMR (DMSO-d6, 75.46 MHz, 50 ꢀC)
d 191.8,
1307, 1155 (SO2); 1H NMR (DMSO-d6, 300 MHz)
15H), 6.07 (s, 2H), 5.49 (s broad, 1H, D2O-exchangeable), 3.12 (s,
2H), 1.44 (s, 3H); 13C NMR (DMSO-d6, 75.46 MHz)
192.2, 154.8,
d
8.05e7.58 (m,
191.6, 146.9, 143.2, 142.3, 140.6, 139.8, 133.8, 133.7, 133.6, 133.5,
133.3, 129.3, 128.5, 128.4, 127.6, 127.5, 127.1, 126.9, 125.2, 124.2, 78.5,
61.4, 55.3, 55.2, 33.1; MS (ESI) m/z 669 [MþNa]þ. HRMS (ESI) calcd.
for C35H30N6O5S þ Na [MþNa]þ, 669.1891; found 669.1892.
4.1.2.6.5. 2-(4-(((1-(1-(2-Oxo-2-(4-(phenylsulfonyl)phenyl)
ethyl)-1H-1,2,3-triazol-4-yl)-2-(4-(phenylsulfonyl)phenyl)propan-2-
yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-1-(4-(phenylsulfonyl)phenyl)
ethanone (9e). White solid; mp. 220e222 ꢀC; IR nmax (cmꢁ1): 1709
(C]O), 1595 (C]N), 1307, 1156 (SO2), 1222 (CeOeC); 1H NMR
d
141.4, 138.8, 134.2, 133.6, 129.7, 128.9, 128.1, 127.3, 126.9, 126.6, 72.8,
55.7, 39.5, 29.3; MS (ESI) m/z 484 [MþNa]þ. HRMS (ESI) calcd for
C
25H23N3O4S þ Na [MþNa]þ, 484.1301; found 484.1300.
4.1.2.6. General procedure for the one-pot synthesis of 1,4-
disubstituted 1,2,3-bistriazoles 9aeh. To a solution of a -bromo-
a
ketone (7aed) (2.0 mmol, 2.0 equiv), NaN3 (156.02 mg, 2.4 mmol,
2.4 equiv), and bis-terminal alkyne 5a or b (1.0 mmol, 1.0 equiv) in
H2O (3.0 mL), and tert-butanol (1.0 mL) was added CuSO4$5H2O
(49.8 mg, 0.20 mmol, 0.20 equiv) and sodium ascorbate (118.8 mg,
0.60 mmol, 0.60 equiv). The reaction mixture was sonicated in the
water bath of an ultrasonic cleaner at 25e30 ꢀC until the reaction
was complete, as indicated by TLC (Reaction times are given in
Table 6). Then the organic phase was extracted with dichloro-
methane (4 ꢂ 10 mL). The combined organic extracts were washed
with H2O, dried over anhydrous MgSO4, filtered and concentrated in
vacuo. The crude product was purified by column chromatography
(SiO2, dichloromethane/methanol 10:1) to obtain the pure product.
4.1.2.6.1. 2-(4-((2-(1-(2-Oxo-2-(4-(phenylsulfonyl)phenyl)ethyl)-
1H-1,2,3-triazol-4-yl)-1-(4-(phenylsulfonyl)phenyl)ethoxy)methyl)-
(DMSO-d6, 300 MHz, 50 ꢀC)
d 8.21e7.62 (m broad, 29H), 6.12 (s
broad, 2H), 6.01 (s broad, 2H), 4.43 (s broad, 2H), 3.09 (s broad, 2H),
1.61 (s broad, 3H); MS (ESI) m/z 941 [MþH]þ. HRMS (ESI) calcd. for
C
C
48H41N6O9S3 [MþH]þ, 941.2092; found 941.2082; Anal. calcd. for
48H40N6O9S3: C, 61.26; H, 4.28; N, 8.93; S, 10.22%. Found: C, 61.19;
H, 4.21; N, 9.01; S, 10.25%.
4.1.2.6.6. 1-(4-Fluorophenyl)-2-(4-(((1-(1-(2-(4-fluorophenyl)-2-
oxoethyl)-1H-1,2,3-triazol-4-yl)-2-(4-(phenylsulfonyl)phenyl)
propan-2-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethanone
(9f).
White solid; mp. 210e212 ꢀC; IR nmax (cmꢁ1): 1702 (C]O), 1598
(C]N), 1307, 1157 (SO2), 1231 (CeOeC); 1H NMR (DMSO-d6,
300 MHz, 50 ꢀC)
d 8.09e7.30 (m broad, 19H), 6.18 (s broad, 2H), 6.07
(s broad, 2H), 4.44 (s broad, 2H), 3.34 (s broad, 2H), 1.62 (s broad,
3H); MS (ESI) m/z 719 [MþNa]þ. HRMS (ESI) calcd. for
1H-1,2,3-triazol-1-yl)-1-(4-(phenylsulfonyl)phenyl)ethanone
(9a).
C
36H30F2N6O5S þ Na [MþNa]þ, 719.1859; found 719.1862; Anal.
White solid; mp. 145e147 ꢀC; IR nmax (cmꢁ1): 1709 (C]O), 1596
calcd. for C36H30F2N6O5S: C, 62.06; H, 4.34; N, 12.06; S, 4.60%.
Found: C, 62.15; H, 4.31; N, 12.03; S, 4.56%.
(C]N), 1307, 1156 (SO2), 1222 (CeOeC); 1H NMR (DMSO-d6,
300 MHz, 50 ꢀC)
d
8.21e7.56 (m broad, 29H), 6.16 (s broad, 2H), 6.11
4.1.2.6.7. 1-(4-Bromophenyl)-2-(4-(((1-(1-(2-(4-bromophenyl)-
2-oxoethyl)-1H-1,2,3-triazol-4-yl)-2-(4-(phenylsulfonyl)phenyl)
(s broad, 2H), 4.88 (t broad, 1H), 4.43 (s broad, 2H), 3.06 (d broad,
2H). MS (ESI) m/z 927 [MþH]þ. HRMS (ESI) calcd. for C47H39N6O9S3
[MþH]þ, 927.1935; found 927.1925. Anal. calcd. for C47H38N6O9S3:
C, 60.89; H, 4.13; N, 9.07; S, 10.38%. Found: C, 60.96; H, 4.10; N, 9.10;
S, 10.35%.
propan-2-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethanone
(9g).
White solid; mp. 217e219 ꢀC; IR nmax (cmꢁ1): 1702 (C]O), 1586
(C]N), 1306, 1156 (SO2), 1224 (CeOeC); 1H NMR (DMSO-d6,
300 MHz, 50 ꢀC)
d 7.91e7.61 (m broad, 19H), 6.07 (s broad, 2H), 5.98
4.1.2.6.2. 1-(4-Fluorophenyl)-2-(4-((2-(1-(2-(4-fluorophenyl)-2-
oxoethyl)-1H-1,2,3-triazol-4-yl)-1-(4-(phenylsulfonyl)phenyl)ethoxy)
methyl)-1H-1,2,3-triazol-1-yl)ethanone (9b). White solid; mp.
202e204 ꢀC; IR nmax (cmꢁ1): 1700 (C]O), 1598 (C]N), 1307, 1156
(SO2), 1232 (CeOeC); 1H NMR (DMSO-d6, 300 MHz, 50 ꢀC)
(s broad, 2H), 4.48 (s broad, 2H), 3.10 (s broad, 2H), 1.65 (s broad,
3H); MS (ESI) m/z 817 [MþH]þ. HRMS (ESI) calcd. for
C
C
36H31Br2N6O5S [MþH]þ, 817.0438; found 817.0432; Anal. calcd. for
36H30Br2N6O5S: C, 52.82; H, 3.69; N, 10.27; S, 3.92%. Found: C,
52.91; H, 3.64; N, 10.22; S, 3.97%.
d
8.09e7.33 (m broad, 19H), 6.09 (s, 2H), 6.04 (s, 2H), 4.96 (t broad,
1H), 4.51 (s broad, 2H), 3.12 (s broad, 2H); 13C NMR (DMSO-d6,
75.46 MHz, 50 ꢀC)
4.1.2.6.8. 2-(4-(((1-(1-(2-Oxo-2-phenylethyl)-1H-1,2,3-triazol-4-
yl)-2-(4-(phenylsulfonyl)phenyl)propan-2-yl)oxy)methyl)-1H-1,2,3-
triazol-1-yl)-1-phenylethanone (9h). White solid; mp. 207e209 ꢀC;
IR nmax (cmꢁ1): 1702 (C]O), 1596 (C]N), 1307, 1156 (SO2), 1227
d
189.9, 189.8, 164.9 (d, J ¼ 251.9 Hz), 164.8 (d,
J ¼ 252.0 Hz), 146.7, 140.7, 139.8,132.8, 130.5 (d, J ¼ 9.5 Hz), 130.4 (d,
J ¼ 9.4 Hz), 128.9, 127.2, 126.8, 126.6, 115.3 (d, J ¼ 22.0 Hz), 115.2 (d,
J ¼ 21.9 Hz), 78.5, 61.7, 55.1, 55.0, 32.9; MS (ESI) m/z 705 [MþNa]þ.
HRMS (ESI) calcd. for C35H28F2N6O5S þ Na [MþNa]þ, 705.1702;
found 705.1703; Anal. calcd. for C35H28F2N6O5S: C, 61.58; H, 4.13; N,
12.31; S, 4.70%. Found: C, 61.66; H, 4.11; N, 12.29; S, 4.67%.
4.1.2.6.3. 1-(4-Bromophenyl)-2-(4-((2-(1-(2-(4-bromophenyl)-2-
oxoethyl)-1H-1,2,3-triazol-4-yl)-1-(4 (phenylsulfonyl)phenyl)ethoxy)
methyl)-1H-1,2,3-triazol-1-yl)ethanone (9c). White solid; mp.
200e202 ꢀC; IR nmax (cmꢁ1): 1702 (C]O), 1586 (C]N), 1306, 1154
(SO2), 1225 (CeOeC); 1H NMR (DMSO-d6, 300 MHz, 50 ꢀC)
(CeOeC); 1H NMR (DMSO-d6, 300 MHz, 50 ꢀC)
d 8.03e7.51 (m,
21H), 6.09 (s, 2H), 5.99 (s, 2H), 4.52 (d, J ¼ 12.0 Hz, 1H), 4.43 (d,
J ¼ 12.0 Hz, 1H), 3.27 (s, 2H), 1.64 (s, 3H); 13C NMR (DMSO-d6,
75.46 MHz, 50 ꢀC)
d 191.9, 191.8, 150.6, 144.3, 141.6, 141.1, 139.5,
134.1, 134.0, 133.8, 133.8, 133.3, 129.4, 128.7, 128.6, 127.8, 127.2,
127.0, 126.9, 125.1, 124.9, 78.7, 56.8, 55.5, 55.3, 37.6, 23.6; MS (ESI)
m/z 683 [MþNa]þ. HRMS (ESI) calcd. for C36H32N6O5S þ Na
[MþNa]þ, 683.2047; found 683.2051.
4.1.3. Procedure for silent reactions
d
7.93e7.60 (m broad, 19H), 6.10 (s broad, 2H), 6.01 (s broad, 2H),
All previous reactions were performed with the same reactants
at same temperature and same scale as shown above, but without
4.94 (t broad, 1H), 4.50 (s broad, 2H), 3.11 (d broad, 2H). MS (ESI) m/

442
M.F. Mady et al. / European Journal of Medicinal Chemistry 84 (2014) 433e443
ultrasound irradiation. The reactions were run under stirring for
the appropriate time as indicated by TLC (see Tables 1e6). The
products were obtained and purified as described for the reactions
under ultrasound.
was made against concentration and IC50 was determined. All re-
sults of antioxidant activity are summarized in Table 9.
Acknowledgments
4.2. Biological testing
This work was supported by an Yggdrasil research grant from
the Research Council of Norway (202902/V11) and by the Egyptian
Ministry of Higher Education and State for Scientific Research with
a ParOwn Research Fellowship. They are gratefully acknowledged
for the financial support.
4.2.1. Antimicrobial activity
The compounds were individually tested against a panel of gram
positive and gram negative bacterial pathogens, yeast and fungi.
Antimicrobial tests were carried out by the agar well diffusion
method [40] using 100
m
L of suspension containing 1 ꢂ108 CFU/mL
Appendix A. Supplementary data
of pathological tested bacteria and 1 ꢂ 106 CFU/mL of yeast and
fungi spread on nutrient agar (NA) and Sabouraud dextrose agar
(SDA) respectively. After the media had cooled and solidified, wells
(10 mm in diameter) were made in the solidified agar and loaded
1H and 13C NMR spectra of all new compounds in this article can
be found in the online version at http://dx.doi.org/10.1016/j.
ejmech.2014.07.042.
with 100
mL of test compound solution; prepared by dissolving
200 mg of the chemical compound in 1 mL of dimethyl sulfoxide
(DMSO). The inculcated plates were then incubated for 24 h at 37 ꢀC
for bacteria (48 h at 28 ꢀC for fungi). Negative controls were pre-
pared using DMSO employed for dissolving the tested compound.
Ciprofloxacin (50 mg/mL) and Clotrimazole (50 mg/mL) were used
as standard for antibacterial and antifungal activity respectively.
After incubation time, antimicrobial activity was evaluated by
measuring the zone of inhibition against the test organisms and
compared with that of the standard. The observed zone of inhibi-
tion is presented in Table 7. Antimicrobial activities were expressed
as inhibition diameter zones in millimeters (mm). The experiments
were carried out in triplicate and the average zone of inhibition was
calculated.
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4.2.3.1. DPPH free radical scavenging activity. The hydrogen atom or
electron donation ability of the corresponding compounds was
measured from the bleaching of the purple colored methanolic
solution of DPPH. This spectrophotometric assay uses stable radical
diphenylpicrylhydrazyl (DPPH) as a reagent. One hundred micro-
liters of various sample concentrations were added to 5 mL of
0.004% methanolic solution of diphenylpicrylhydrazyl (DPPH). Af-
ter 60 min of incubation in dark, the absorbance was read against a
blank at 517 nm. Inhibition free radical DPPH in percent (I%) was
calculated as in Eq (1) :
I% ¼ (Ablank ꢁ Asample)/(Ablank) ꢂ 100
(1)
where Ablank is the absorbance of the control reaction (containing
all reagents except the test compound), and Asample is the absor-
bance of the test sample [42,43].
For determination of IC50 (The concentration that make 50%
inhibition of the DPPH color), different concentrations of the
chemical compounds were dissolved in methanol to obtain final
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