Regioselective synthesis and antimicrobial activities of some novel aryloxyacetic acid derivatives

Article abstract of DOI:10.1016/j.ejmech.2012.01.028

Reaction of aryloxyacetic acid hydrazides 1a,b with α-haloketones such as hydrazonoyl chlorides 2a,b; phenacyl bromides 6a,b; and 2-chloro-N-(1,3-thiazol-2-yl)acetamide 10 led to the formation N-(4-halophenyl)-2-[2-(aryloxyacetyl)hydrazinylidene]propanehy

Full text of DOI:10.1016/j.ejmech.2012.01.028

European Journal of Medicinal Chemistry 50 (2012) 55e62
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Regioselective synthesis and antimicrobial activities of some novel aryloxyacetic
acid derivatives
,
b
,
c
Bakr F. Abdel-Wahab a , Rizk E. Khidre , Ghada E.A. Awad
*
*
a Applied Organic Chemistry Department, National Research Center, Dokki, Giza 12622, Egypt
b Chemical Industries Division, National Research Centre, Dokki, 12622 Giza, Egypt
c Chemistry of Natural and Microbial Products, National Research Center, Dokki, Giza 12622, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of aryloxyacetic acid hydrazides 1a,b with a-haloketones such as hydrazonoyl chlorides 2a,b;
Received 13 December 2011
Received in revised form
11 January 2012
Accepted 12 January 2012
Available online 20 January 2012
phenacyl bromides 6a,b; and 2-chloro-N-(1,3-thiazol-2-yl)acetamide 10 led to the formation N-(4-
halophenyl)-2-[2-(aryloxyacetyl)hydrazinylidene]propanehydrazonoyl chloride 3aed; (ethene-1,2-diyl)
bis-2-(naphthalen-2-yloxy)acetohydrazides 9a,b; and 2-[(2-aryloxyacetyl)hydrazinyl)]-N-(1,3-thiazol-2-
yl)acetamides 11a,b; respectively. The nucleophilic substitution reaction of 3aed with thiophenol and
sodium benzenesulfinate furnished the corresponding hydrazinylidenepropanehydrazonothioates 4aed
and sulfones 5aed, respectively. The antimicrobial activities of the synthesized compounds were eval-
uated. The obtained data indicated that the majority of the tested compounds exhibited antibacterial
activity while all those compounds showed antifungal activity. Sulfone 5d showed greater effect with all
tested organism than well known antibacterial and antifungal agents with minimal inhibitory concen-
Keywords:
Aryloxyacetohydrazides
Hydrazonoyl chlorides
Sulfones
tration (MIC) ranged between 4.125 and 16.5 mg/mL.
Antimicrobial activity
Structureeactivity relationship (SAR)
X-ray single crystal
Ó 2012 Elsevier Masson SAS. All rights reserved.
1. Introduction
their biological activity. The methodology depended on the inter-
action of aryloxyacetic acid hydrazides 1a,b with -haloketones
a
Aryloxyacetic acids and their derivatives often possess many
important biological activities. Some of these compounds are used
as herbicides and plant-growth regulators [1e5]. Hydrazides and
hydrazones have been demonstrated to possess antimicrobial [6],
anticonvulsant, analgesic, antiinflammatory, antiplatelet, antitu-
bercular, and antitumoral activities [7,8]. Hydrazones have been
reported as useful antioxidant agents [9], whereas arylhydrazones
inhibited the replication of HIV-1 [10]. In addition, sulfone deriva-
tives are known for their interesting antimicrobial bioactivities and
have attracted considerable attention in pesticide and medicinal
formulation. A large number of reports on their synthesis and
biological activities have appeared during the last years [11e18].
Encouraged by these observations and in continuation of our
previous work [19e30] we report herein the synthesis of new
hydrazone, hydrazonothioate, sulfone, and N-(1,3-thiazol-2-yl)
acetamide derivatives including aryloxyacetic acid moiety in order
to study their chemical reactivity, spectroscopic properties, and
2a,b; 6a,b; and 10. Hydrazinylidenepropanehydrazonothioates
4aed and sulfones 5aed were synthesized from nucleophilic
substitution reaction of hydrazonoyl chloride 3aed using thio-
phenol and sodium benzenesulphinate, respectively.
2. Result and discussion
2.1. Chemistry
Treatment of aryloxyacetic acid hydrazides 1a,b with hydra-
zonyl chlorides 2a,b; namely N-(4-bromophenyl)-2-oxo-pro-
panehydrazonoyl chloride (2a) and N-(4-chlorophenyl)-2-oxo-
propanehydrazonoyl chloride (2b) in refluxing ethanol afforded
N-(4-halophenyl)-2-[2-(aryloxyacetyl)hydrazinylidene]propane-
hydrazonoyl chloride 3aed in good yield. Nucleophilic substi-
tution reaction of compounds 3aed with thiophenol was
occurred in sodium ethoxide-ethanol solution to give hydrazi-
nylidenepropanehydrazonothioates 4aed. Attempts to oxidize
compound 4a to sulfone 5a with hydrogen peroxide in acetic
acid [31] was examined, but furnished a mixture of products
included 5a in about 25% yield according to TLC investigation.
The sulfone 5aed was synthesized in about 60% from
* Corresponding authors. Tel.: þ20 2 3371635; fax: þ20 2 37601877.
E-mail addresses: bakrfatehy@yahoo.com (B.F. Abdel-Wahab), rizkhidre@
yahoo.com (R.E. Khidre).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.01.028

56
B.F. Abdel-Wahab et al. / European Journal of Medicinal Chemistry 50 (2012) 55e62
displacement of chlorine atom in propanehydrazonoyl chloride
3aed with sodium benzenesulphinate in refluxed ethanol
(Scheme 1).
proceeded in 2:1 molar ratio (1a:6). The mass spectrum of 9b
contains a peak at m/z 598 (Mþ ꢀ 2, 6%), which support the
structure of 9b. Also, the 1H NMR spectrum of 9b showed three
The structures suggested for all new compounds 3e5 are in
good agreement with their analytical and spectroscopic data. IR
spectra of 3aed exhibited a carbonyl absorption bands in the region
1695e1687 cmꢀ1 in addition to the absorption bands of two NH
functions in the region (3325e3315), (3189e3185) cmꢀ1. Their 1H
NMR showed two D2O exchangeable singlet signals assignable for
singlet singles at
methylene groups (2CH2) and ethylene group (CH]Ce), respec-
tively in addition to four D2O exchangeable singlet singles at : 9.85,
9.96, 10.39, and 11.13 ppm assignable to four NH groups. The
stereochemistry of compounds similar to 9a,b was elucidated
before [6,25].
d: 4.89, 4.92, and 5.29 ppm assignable for two
d
two NH groups in the regions
in addition to two singlet signals assignable for the methyl and
methylene protons in the region : 2.25e2.29 and 5.19e5.23 ppm,
d
: 10.22e10.27 and 10.91e11.13 ppm
Next, refluxing of hydrazides 1a,b with 2-chloro-N-(1,3-thiazol-
2-yl)acetamide (10) in absolute ethanol afforded 2-(2-(2-
aryloxyacetyl)hydrazinyl)-N-(1,3-thiazol-2-yl)acetamides 11a,b as
a single products (TLC) in good yields (Scheme 3).
The Structures of 11a,b were established through, spectroscopic
and elemental analysis data. The IR spectrum of 11a revealed
absorption bands at 1685 and 1662 cmꢀ1 assignable to two
carbonyl groups in addition to three broad bands of three NH
function at 3410, 3321, and 3240 cmꢀ1. Also, 1H NMR spectrum of
11a showed two D2O exchangeable singlet signals assignable to
d
respectively. The mass spectra of compounds 4aed and 5aed
confirmed the assigned structures, for example the mass spec-
trum of 4b and 5a showed peaks at 501 (Mþ ꢀ 2, 3%) and 581
(Mþ þ 2, 7%), 579 (Mþ, 10%), respectively, which support the
structure of these compounds. X-ray single crystal analysis of
sulfone 5b (Figs. 1 and 2) showed that, the stereochemical structure
of 5b is (1E, 2E) geometrical structure as postulated in Scheme 1.
Essential bond lengths and torsion angles of 5b are listed in Tables 1
and 2.
three NH groups at d: 9.44 (2H) and 10.27 (1H) ppm.
The reaction of 2-(naphthalen-2-yloxy)acetohydrazide (1a)
with phenacyl bromides namely, 2-bromoacetylbenzofuran (6a)
and 3-bromoacetyl coumarin (6b), respectively in refluxing
ethanol afforded N0,N00-[(Z)1-(2-arylethene-1,2-diyl)]bis-2-(naph-
thalen-2-yloxy)acetohydrazides] 9a,b as a single product based on
TLC. The mechanism for formation of the later compound is
assumed to proceed via a preliminary formation of the non isolated
intermediates 7 followed by its reaction with anther molecule of
hydrazides 1a with elimination of water molecule to form intimi-
dates 8 which are consequently tautomerized into compounds 9
(Scheme 2).
3. Pharmacological evaluation
3.1. Antibacterial activity
Antibacterial activity of the synthesized compounds was
tested using agar well diffusion method [32]. The activity of the
tested compounds was studied against the Staphylococcus aureus
(ATCC29213), Bacillus subtilis (ATCC6633), Bacillus megaterium
(ATCC), Sarcina lutea (Gram positive bacteria) and Klebseilla
pneumoniae (ATCC13883), Pseudomonas aeruginosa (ATCC27953),
Escherichia coli (ATCC25922), Mycobacterium phlei (Gram negative
bacteria). Standard antibiotic, Ciprofloxacin was used as standard
antibacterial agent.
Spectroscopic data (IR, 1H NMR, MS) and elemental analysis of
compounds 9aed confirmed their structure. The elemental analysis
and mass spectrum of the product proved that the reaction
O
Me
Cl
O
N
H
N
O
NH2
+
R1
R1
N
H
R2
2
1
R2 =
O
=
a
: 4-BrC6H4
a: 2-naphthyl
O
N
Me
N
b
: 4-ClC6H4
R1
N
H
b: 2,4-dichlorophenyl
PhSH/EtONa
reflux
H
N
EtOH, reflux
S
R2
Ph
O
O
4
N
Me
R1
N
H
H
N
O
O
Cl
N
R2
Me
(E)
N
S
O
PhSO2Na.2H2O
reflux
Ph
3
O
R1
(E)
HN
N
N
H
R2
5
R2
3-5
R1
a
b
c
d
4-BrC6H4
4-ClC6H4
4-BrC6H4
4-ClC6H4
2-naphthyl
2-naphthyl
2,4-dichlorophenyl
2,4-dichlorophenyl
Scheme 1. Synthetic route of compounds 3aed, 4aed, and 5aed.

B.F. Abdel-Wahab et al. / European Journal of Medicinal Chemistry 50 (2012) 55e62
57
Fig. 1. X-ray structure of 5b.
3.2. Antifungal activity
O
S
O
CH3
11
12
N
H
10
6
N
All of the synthesized compounds 3e5, 9, and 11 were tested for
their antifungal activity against Saccharomyces cerevisiae and
Candida albicans (NRRL Y-477). Ketoconazole was used as standard
antifungal agent. The result are shown in Table 3 displayed that
compounds 3aed, 4c, 5b, 5d, 9b, and 11a exhibited excellent
antifungal activity against all the two strains of fungi (zones of
inhibition range from 18 to 32 mm) compared to standard drug
except compound 4d showed high activity against only one strains
of fungi (S. cerevisiae, zones of inhibition 28 mm). Compounds 5b
Ph
N
9
8
5
O
N
H
Fig. 2. Numbering of compound 5b.
The results of preliminary antibacterial testing of compounds
3e5, 9, and 11 are, shown in Table 3, revealed that, the inhibitory
activity against Gram positive bacteria was higher than Gram
negative bacteria. Compounds 3a, 3c, 3d, 4c, 5b, 5d, 9b, and 11a
display good activity against B. subtilis, B. megaterium and
K. pneumoniae (zones of inhibition range from 18 to 32 mm).
Further compounds 4c, 4d, and 5b showed high activity against
Sarcina lutea, K. pneumoniae, and S. aureus with zones of inhibition
20, 24, and 23 mm, respectively. Compounds 3b, 5b, and 5d showed
good to excellent activity against E. coli with zones of inhibition 21,
28, and 30 mm, respectively. In addition compounds 5b and 5d
showed high activity against P. aeruginosa with zones of inhibition
26, and 28 mm, respectively. It is obvious that sulfone derivatives
(5b and 5d) exhibited excellent antibacterial activity against Gram
positive and Gram negative bacteria. Compound 5d was the most
effective against all tested microorganisms with zones of inhibition
range from 26 to 32 mm with minimum inhibitory concentrations
Table 2
Characteristic data of the synthesized compounds.
Entry Mol. formula
(M. wt)
Calcd. found
C% H%
Mp (ꢁC)
Yield % Color
N%
3a
3b
3c
C21H18BrClN4O2
(473.75)
C21H18Cl2N4O2
(429.30)
53.24 3.83 11.83 238
53.22 3.79 11.77
58.75 4.23 13.05 229
58.68 4.19 12.98
41.45 2.86 11.37 230
41.39 2.81 11.41
45.56 3.15 12.50 235
45.53 3.11 12.47
59.23 4.23 10.23 170
59.16 4.18 10.25
64.47 4.61 11.14 149
64.37 4.55 11.19
80
73
77
79
73
72
69
68
60
58
57
56
White
White
Yellow
Yellow
C17H14BrCl3N4O2
(492.58)
C17H14Cl4N4O2
(448.13)
C27H23BrN4O2S
(547.47)
C27H23ClN4O2S
(503.02)
3d
4a
4b
4c
Pale
yellow
Yellow
(MIC) range between 16.5 and 4.125 mg/mL(Table 4).
C
23H19BrCl2N4O2S 48.78 3.38
9.89 202
9.85
Orange
566.30
C23H19Cl3N4O2S
(521.85)
C27H23BrN4O4S
579.46
C27H23ClN4O4S
535.01
48.69 3.32
52.94 3.67 10.74 205
52.87 3.63 10.68
55.96 4.00
55.92 3.89
60.61 4.33 10.47 >300
4d
5a
5b
5c
Reddish
yellow
Red
Table 1
9.67 >300
Characteristic bond length [Ǻ] and torsion angles (ꢁ) of 5b.
9.71
Characteristic bond length [Ǻ]
Orange
N6eC10
N8eC12
N9eC11
N6eN8
C11eC12
N5eN9
1.356 (3)
1.291 (3)
1.317 (3)
1.360 (3)
1.449 (4)
1.330 (3)
60.55 4.28 10.44
C
23H19BrCl2N4O4S 46.17 3.20
9.36 >300
Reddish
brown
Dark
598.30
46.11 3.14
49.88 3.46 10.12 >300
49.79 3.41 10.11
71.32 4.93
71.26 4.85
69.99 4.70
69.87 4.64
57.29 4.52 15.72 165
57.21 4.46 15.75
9.38
5d
9a
9b
11a
11b
C23H19Cl3N4O4S
(553.85)
C34H28N4O5
(572.61)
brown
White
9.78 205e206 69
Torsion angles (ꢁ)
C10eN6eN8eC12
N8eN6eC10eC25
C12eN8eN6eC10
N6eN8eC12eC11
N5eN9eC11eC12
C11eN9eN5eC21
9.74
ꢀ179 (2)
179 (2)
ꢀ179 (2)
ꢀ180 (2)
ꢀ0.4 (13)
179 (2)
C35H28N4O6
9.33 201e202 67
Gray
(600.62)
C17H16N4O3S
(356.40)
C13H12Cl2N4O3S
(375.23)
9.35
73
Yellow
Yellow
41.61 3.22 14.93 210e211 70
41.56 3.13 14.89

58
B.F. Abdel-Wahab et al. / European Journal of Medicinal Chemistry 50 (2012) 55e62
O
R1
O
O
O
R2
EtOH, reflux
+ 1
Br
O
NH2
NH
R2
+
R1
N
H
N
H
O
1a
R1 = 2-naphthyl
6
7
R1
R1
O
O
R1
R1
O
O
O
O
O
O
N
N
N
H
H
H
N
H
N
H
H
N
H
N
N
H
R2
R2
9
8
R2
7,8,9
R1
a
b
2-naphthyl
2-naphthyll
2-benzofuryl
3-coumarinyl
Scheme 2. Synthetic route of compounds 9a,b.
NH
S
O
O
N
O
EtOH, reflux
NH
N
Cl
O
NH2
O
N
O
+
R1
N
R1
N
H
S
H
H
11
1
10
R1
11
a
2-naphthyl
2,4-dichlorophenyl
b
Scheme 3. Synthetic route of compounds 11a,b.
and 5d exhibit the largest activity against S. cerevisiae and Candida
albicans with zones of inhibition (30, 32 mm) and (24, 30 mm)
respectively.
The results of antimicrobial screening revealed that all
compounds displayed better antifungal activity compared with
their antibacterial activities. The antimicrobial activity of sulfones
has been confirmed by other research groups [11e18].
3.3. Structureeactivity relationship
The structureeantimicrobial activity relationship of the
synthesized compounds against the pathological strains of bacteria
and fungi revealed that, N0-[(1E,2Z)-1-[2-(4-halophenyl)hydrazi-
nylidene]-1-(phenylsulfonyl)propan-2-ylidene]-2-(naphthalen-2-
yloxy)acetohydrazides (5b and 5d) have superior antimicrobial
Table 3
Antimicrobial activity of compounds 3aed; 4c,d; 5a,b; 9b and 11a.a,b
Entry
Gram positive bacteria
Gram negative bacteria
B. megaterium Sarcina Klebseilla Pseudomonas. E. coli
Fungi
Staphylococcus B. subtilis
Mycobacterium Saccharomyces Candida
aureus
(ATCC6633) (ATCC)
lutea
pneumoniae
aeroginosa
(ATCC 25922) phlei
cerevisiae
albicans
(ATCC29213)
(ATCC13883) (ATCC27953)
(NRRL Y-477)
3a
3b
3c
3d
4c
4d
5b
5d
9b
11a
N.A.c
N.A.
N.A.
N.A.
N.A.
N.A.
23
27
N.A.
N.A.
18
N.A.
18
18
18
N.A.
20
29
18
18
21
N.A.
22
20
20
N.A.
23
32
20
22
N.A.
N.A.
N.A.
N.A.
20
N.A.
N.A.
26
21
24
20
21
18
24
24
28
21
23
25
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
26
N.A.
21
N.A.
16
N.A.
15
N.A.
13
N.A.
30
24
26
27
24
23
28
30
32
21
22
N.A.
23
21
20
21
18
20
N.A.
24
30
20
20
N.A.
N.A.
N.A.
N.A.
28
28
30
N.A.
N.A.
20
N.A.
N.A.
24
N.A.
N.A.
23
N.A.
N.A.
22
Ciprofloxacin 20
Ketoconazole N.A.
22
N.A.
24
N.A.
N.A.
22
N.A.
N.A.
N.A.
N.A.
a
Antimicrobial activity expressed as inhibition diameter zones in millimeters (mm) of chemical compounds against the pathological strains based on well diffusion assay.
The experiment was carried out in triplicate and the average zone of inhibition was calculated.
N.A. No activity.
b
c

B.F. Abdel-Wahab et al. / European Journal of Medicinal Chemistry 50 (2012) 55e62
59
Table 4
Minimum inhibitory concentration (
m
g/mL) against the pathological strains based on two folds serial dilution technique.
Entry
Staphylococcus B. subtilis
B. megaterium Sarcina Klebseilla
Pseudomonas E. coli
aeroginosa (ATCC 25922) phlei
(ATCC13883) (ATCC27953)
Mycobacterium Saccharomyces Candida
aureus
(ATCC6633) (ATCC 9885)
lutea
pneumoniae
cerevisiae
albicans
(ATCC 29213)
3a
3b
3c
3d
4c
4d
5b
5d
9b
11a
e
66
e
16.5
e
e
33
16.5
33
33
66
16.5
16.5
16.5
33
33
16.5
e
e
e
e
16.5
16.5
8.25
16.5
33
4.125
8.25
4.125
16.5
16.5
e
33
33
33
66
66
e
e
e
e
16.5
e
e
e
66
66
66
e
16.5
16.5
16.5
e
e
e
e
e
e
e
e
e
e
16.5
e
e
e
e
e
e
e
_
e
16.5
8.25
e
33
8.25
66
66
8.25
e
16.5
8.25
16.5
8.25
8.25
e
e
16.5
16.5
e
8.25
4.125
e
8.25
4.125
66
66
e
8.25
e
4.125
e
e
e
e
e
e
Ciprofloxacin 8.25
Ketoconazole
16.5
e
16.5
e
16.5
e
16.5
e
e
4.125
8.25
properties (i.e. biologically more active) than either their corre-
sponding phenyl-N-(4-halophenyl)-2-{2-[(2-aryloxy)acetyl]hydra-
zinylidene}-propanehydrazonothioates (4c and 4d) or N-(4-
halophenyl)-2-{2-[(2-aryloxy)acetyl]hydrazinylidene}propanehyd-
razonoyl chlorides 3aed. The replacement of chloro function in
position 1 of hydrazone 3 by phenylsulfonyl function to produce
compound 5 increased the antimicrobial activity. It is obvious from
our antimicrobial data that sulfone 5d showed higher antimicrobial
activity compared to 5b which can be correlated to the presence
a large number of chloro substituent.
5.1.2. General procedure for synthesis of N-(4-halophenyl)-2-{2-
[(2-aryloxy)acetyl]hydrazinylidene}propanehydrazonoyl chlorides
3aed
A mixture of aryloxyacetic acid hydrazides 1a or 1b (10 mmol)
and 2-oxo-N-arylpropanehydrazonoyl chloride 2a or 2b (10 mmol)
in absolute ethanol (50 mL) was refluxed till the solid was formed,
filtered off while hot, washed with ethanol, and recrystallized from
EtOH/DMF to afford the corresponding N-(4-halophenyl)-2-(2-(2-
(aryloxy)acetyl)hydrazono)propanehydrazonoyl chloride 3aed,
respectively.
4. Conclusion
5.1.2.1. (1E,2Z)-N-(4-Bromophenyl)-2-{2-[(naphthalen-2-yloxy)acet-
yl]hydrazinylidene}propanehydrazonoyl chloride (3a). Reaction time
ꢀ1
~
In conclusion, we have described the synthesis of a number of
novel aryloxyacetic acid hydrazide derivatives such as N-(4-
halophenyl)-2-[2-(aryloxyacetyl)hydrazinylidene]propanehydrazon-
oyl chloride 3aed, (2-[(2-aryloxyacetyl)hydrazinyl)]-N-(1,3-thiazol-
2-yl)acetamides hydrazonothioates 4aed, sulfones 5aed, (ethene-
1,2-diyl)bis-2-(naphthalen-2-yloxy)acetohydrazides 9a,b; and (2-
[(2-aryloxyacetyl)hydrazinyl)]-N-(1,3-thiazol-2-yl) acetamides 11a,b
in good yield. The antibacterial and antifungal activities of the
synthesized compounds were evaluated showing moderate to
excellent activities. Sulfone 5d exhibited the highest antibacterial and
antifungal activities comparable to standard antibiotics.
5 h, IR (KBr):
n
¼ 3315, 3189 (2NH), 1695 (C]O), 1630 (C]N) cm
;
1H NMR (DMSO-d6):
d
¼ 2.29 (s, 3H, CH3), 5.19 (s, 2H, CH2),
7.11e7.35 (m, 8H, AreH), 7.65e7.79 (m, 3H, AreH), 10.22 (s, D2O
exch., 1H, ]NNHe), 10.91(s, D2O exch., 1H, eCONHe) ppm; MS m/z
(%) ¼ 477 (Mþ þ 3, 5), 407 (6), 393 (11), 266 (15),175 (60),143 (100),
114 (98), 77 (25), 65 (36).
5.1.2.2. (1E,2Z)-N-(4-Chlorophenyl)-2-{2-[(naphthalen-2-yloxy)acet-
yl]hydrazinylidene}propanehydrazonoyl chloride (3b). Reaction time
~
n
4.5 h, IR (KBr):
¼ 3319, 3185 (2NH), 1688 (C]O), 1617 (C]N)
cmꢀ1
;
1H NMR (DMSO-d6):
d
¼ 2.25 (s, 3H, CH3), 5.21 (s, 2H, CH2),
7.18e7.41 (m, 8H, AreH), 7.74e7.82 (m, 3H, AreH), 10.24 (s, D2O
exch., 1H, ]NNHe), 11.11(s, D2O exch., 1H, eCONHe) ppm; MS m/z
(%) ¼ 432 (Mþ þ 3,1.5), 429 (Mþ, 7), 393 (13), 266 (21),143 (100), 77
(15), 65 (43).
5. Experimental
5.1. Chemistry
5.1.1. General
5.1.2.3. (1E,2Z)-N-(4-Bromophenyl)-2-{2-[(2,4-dichlorophenoxy)acet-
All melting points were taken on Electrothermal IA 9000 series
digital melting point apparatus. Elemental analytical data (in accord
with the calculated values) were obtained from the microanalytical
unit, National Research Centre, Dokki, Giza, Egypt. The IR spectra
(KBr) were recorded on a Shimadzu CVT-04 spectrophotometer. The
1H NMR spectra were measured with a JEOL E.C.A-500 MHz spec-
trometer using tetramethylsilane (TMS) as internal standard in
yl]hydrazinylidene}propanehydrazonoyl chloride (3c). Reaction time
~
6 h, IR (KBr):
n
¼ 3317, 3188 (2NH), 1693 (C]O), 1612 (C]N)
cmꢀ1; 1H NMR (DMSO-d6):
d
¼ 2.27 (s, 3H, CH3), 5.21 (s, 2H, CH2),
6.97 (d, 2H, J ¼ 9.15 Hz, 4-BrAreH), 7.28e7.54 (m, 4H, AreH), 7.57
(d, 1H, J ¼ 1.5 Hz, H3-2,4-Cl2AreH), 10.22 (s, D2O exch., 1H, ]
NNHe),11.13 (s, D2O exch., 1H, eCONHe) ppm; MS m/z
(%) ¼ 494 (Mþ þ 2, 6), 492 (Mþ, 9), 310 (18), 286 (31) 142 (100),
126 (73), 77 (21), 65 (38).
CDCl3 or DMSO-d6. Chemical shift (d) values are given in parts per
million. The mass spectra were determined using a Varian MAT CH-
5 spectrometer (70 eV). The appropriate precautions in handling
moisture-sensitive compounds were considered. Solvents were
dried by standard techniques. TLC: Merck 0.2 mm silica gel 60 F154
anal aluminum plates. 2-(Naphthalen-2-yloxy)acetohydrazide 1a
[33,34]; 2-(2,4-dichlorophenoxy)acetohydrazide 1b [35]; hydrazo-
noyl chlorides 2a,b [36,37]; 2-bromoacetylbenzofuran 6a [38]; 3-
bromoacetyl coumarin 6b [39]; and 2-chloro-N-(1,3-thiazol-2-yl)
acetamide 10 [40] were prepared according to the reported
procedures.
5.1.2.4. (1E,2Z)-N-(4-Chlorophenyl)-2-{2-[(2,4-dichlorophenoxy)acet-
yl]hydrazinylidene}propanehydrazonoyl chloride (3d). Reaction time
ꢀ1
~
n
6 h, IR (KBr):
¼ 3325, 3186 (2NH), 1687 (C]O), 1621 (C]N) cm
;
1H NMR (DMSO-d6):
2H, J ¼ 9.20 Hz, 4-ClAreH), 7.28e7.52 (m, 4H, AreH), 7.58 (d,1H,
Hz, H3-2,4-Cl2AreH), 10.27 (s, D2O exch., 1H, ]
d
¼ 2.28 (s, 3H, CH3), 5.23 (s, 2H, CH2), 6.98 (d,
J
¼
2
NNHe),11.10(s, D2O exch., 1H, eCONHe) ppm; MS m/z (%) ¼ 450
(Mþ þ 2, 5), 448 (Mþ, 8), 310 (27), 286 (31), 142 (100), 126 (73), 77
(13), 65 (39).

60
B.F. Abdel-Wahab et al. / European Journal of Medicinal Chemistry 50 (2012) 55e62
5.1.3. General procedure for synthesis of phenyl-N-(4-halophenyl)-
2-{2-[(2-aryloxy)acetyl]hydrazinylidene}-propanehydrazonothioates
4aed
BrAreH), 7.21e7.42 (m, 10H, AreH), 7.62e7.73 (m, 3H, AreH),
10.56 (s, D2O exch., 1H, ]NNHe), 10.95(s, D2O exch., 1H,
eCONHe) ppm; MS m/z (%) ¼ 581 (Mþ þ 2, 7), 579 (Mþ, 10), 500
(32), 393 (11), 268 (15), 144 (100), 77 (25).
To a solution of 3aed (3 mmol) in 15 mL absolute ethanol was
taken in around bottomed flask fitted with a reflux condenser and
guarded with calcium chloride tube, was added solution of sodium
benzenethiolate prepared from 69.2 mg of sodium, absolute
ethanol (10 mL), and 0.33 g (3 mmol) of thiophenol. The mixture
was refluxed for 5e7 h, then cooled, and filtered the solid product,
washed with ethanol, dried and finally recrystallized from EtOH to
afford 4aed.
5.1.4.2. N0-[(1E,2Z)-1-[2-(4-Chlorophenyl)hydrazinylidene]-1-(phenyls-
ulfonyl)propan-2-ylidene]-2-(naphthalen-2-yloxy)acetohydrazide (5b).
~
Reaction time 8 h, IR (KBr):
n
¼ 3350, 3284 (2NH), 1685 (C]O), 1618
(C]N) cmꢀ1; 1H NMR (DMSO-d6):
d
¼ 2.46 (s, 3H, CH3), 4.56 (s, 2H,
CH2), 6.77 (s, 1H, H1-naphthyl), 7.05 (d, 2H, J ¼ 9.20 Hz, 4-ClAreH),
7.19e7.41 (m, 10H, AreH), 7.62e7.76 (m, 3H, AreH), 10.63 (s, D2O
exch., 1H, ]NNHe), 10.91 (s, D2O exch., 1H, eCONHe) ppm; MS m/z
(%) ¼ 537 (Mþ þ 2, 3), 535 (Mþ, 9), 499 (35), 393 (17), 268 (38),145
(100), 77 (19).
5.1.3.1. (1E,2Z)-Phenyl-N-(4-bromophenyl)-2-{2-[(naphthalen-2-yloxy)
acetyl]hydrazinylidene}-propanehydrazonothioate (4a). Reaction time
ꢀ1
~
7 h, IR (KBr):
n
¼ 3248, 3184 (2NH), 1695 (C]O), 1607 (C]N) cm
;
1H NMR (DMSO-d6):
d
¼ 2.30 (s, 3H, CH3), 4.69 (s, 2H, CH2), 6.81 (s,1H,
5.1.4.3. X-ray crystallography of 5b. A single crystal of compound
5b was obtained by slow evaporation at room temperature, from
a mixture of DMF/H2O (v/v ¼ 5:1). The crystal structure was solved
and refined using maxus (nonius, Deflt and MacScience, Japan) [41].
Diffraction measurement device, Kappa CCD; computing data
H1-naphthyl), 7.05 (d, 2H, J ¼ 9.20 Hz, 4-BrAreH), 7.18e7.40 (m, 10H,
AreH), 7.62e7.73 (m, 3H, AreH), 10.52 (s, D2O exch., 1H, ]NNHe),
10.91(s, D2O exch., 1H, eCONHe) ppm; MS m/z (%) ¼ 549 (Mþ þ 2,
6), 547 (Mþ, 8), 393 (23), 268 (17), 145 (100), 110 (60), 77 (28).
collection, Kappa CCD; Mo Ka radiation (
l
¼ 0.27 mmꢀ1) and
5.1.3.2. (1E,2Z)-Phenyl-N-(4-chlorophenyl)-2-{2-[(naphthalen-2-yloxy)
acetyl]hydrazinylidene}-propanehydrazonothioate (4b). Reaction time
a graphite monochromator were used for data collection. The
chemical formula and ring labeling system is shown in Fig.1. Crystal
data for compound 5b: C27H23ClN4O4S, Mr, 535.022; system,
monoclinic; crystal colour, orange, space group, C2/c; unit cell
dimensions, a, 18.9779 (13) Å; b,10.8647 (9) Å; c, 25.302 (2) Å; cell
~
6 h, IR (KBr):
n
¼ 3246, 3183 (2NH),1697 (C]O),1630 (C]N) cmꢀ1; 1H
NMR (DMSO-d6):
d
¼ 2.27 (s, 3H, CH3), 4.64 (s, 2H, CH2), 6.78 (s, 1H,
H1-naphthyl), 7.05 (d, 2H, J ¼ 9.20 Hz, 4-ClAreH), 7.22e7.43 (m, 10H,
AreH), 7.66e7.78 (m, 3H, AreH), 10.53 (s, D2O exch., 1H, ]NNHe),
10.87 (s, D2O exch., 1H, eCONHe) ppm; MS m/z (%) ¼ 501 (Mþ ꢀ 2,
3), 500 (7), 393 (30), 268 (35), 204 (65), 145 (100), 110 (60), 77 (15).
angle,
a
, 90.00ꢁ;
b
, 97.428 (2)ꢁ;
g
, 90.00ꢁ; V, 5173.2 (7) Å3; Z, 8; Dx,
1.374 mg mꢀ3
; q m (Mo-Ka),
range for data collection, 2.910e27.103ꢁ;
0.27 mmꢀ1; cell parameters, 2785; T ¼ 298 K; independent
reflections, 6015; measured reflections, 6908; observed reflections,
830; Rint, 0.052; R(all), 0.383; R(gt), 0.046; wR(ref), 0.080; wR(all),
5.1.3.3. (1E,2Z)-Phenyl-N-(4-bromophenyl)-2-{2-[(2,4-dichlorophe-
noxy)acetyl]hydrazinylidene}propanehydrazonothioate
(4c).
0.229; wR(gt), 0.082; S(ref), 3.706; S(all), 4.276; S(gt), 3.817; D/smax,
Reaction time 8 h, IR (KBr):
n
¼ 3253, 3186 (2NH), 1693 (C]O),
0.045, Drmax, 1.56 e Å3; Drmin, ꢀ1.48 e Å3. Range for collecting data,
h, ꢀ23 / 24; k, ꢀ13 / 13; l, ꢀ32 / 31; h, 0 / 24; k, 0 / 13;
l, ꢀ32 / 31. Full crystallographic data for the structures 5b have
been deposited at the Cambridge Crystallographic Data Center
(CCDC) as supplementary publication number 794328. Copies of
the data can be obtained, free of charge, on application to CCDC 12
Union Road, Cambridge CB2 1EZ, UK [Fax: þ44 1223 336033; e-
mail: deposit@ccdc.cam.ac.uk or at www.ccdc.cam.ac.uk].
~
1612 (C]N) cmꢀ1; 1H NMR (DMSO-d6):
d
¼ 2.26 (s, 3H, CH3), 4.66
(s, 2H, CH2), 6.42 (d, 2H, J ¼ 9.20 Hz, 4-BrAreH), 7.10e7.31 (m, 9H,
AreH), 7.47 (d, 1H, J ¼ 3 Hz, H3-2,4-Cl2AreH), 10.57 (s, D2O exch.,
1H, ]NNHe), 10.95 (s, D2O exch., 1H, eCONHe) ppm; MS m/z
(%) ¼ 568 (Mþ þ 2, 3), 566 (Mþ, 5), 415 (17), 310 (27), 286 (39), 166
(100), 126 (73), 77 (35).
5.1.3.4. (1E,2Z)-Phenyl-N-(4-bromophenyl)-2-{2-[(2,4-dichlorophe-
noxy)acetyl]hydrazinylidene}propanehydrazonothioate
(4d).
5.1.4.4. N0-[(1E,2Z)-1-[2-(4-Bromophenyl)hydrazinylidene]-1-(phe-
~
Reaction time 7.5 h, IR (KBr):
n
¼ 3249, 3182 (2NH), 1689 (C]O),
nylsulfonyl)propan-2-ylidene]-2-(2,4-dichlorophenoxy)acetohydra-
1620 (C]N) cmꢀ1; 1H NMR (DMSO-d6):
d
¼ 2.24 (s, 3H, CH3), 4.62
zide (5c). Reaction time 8 h, IR (KBr):
n
¼ 3347, 3282 (2NH), 1695
~
(s, 2H, CH2), 6.45 (d, 2H, J ¼ 9.20 Hz, 4-ClAreH), 7.18e7.33 (m, 9H,
AreH), 7.52 (d, 1H, J ¼ 3 Hz, H3-2,4-Cl2AreH), 10.51 (s, D2O exch.,
1H, ]NNHe),10.93 (s, D2O exch., 1H, eCONHe) ppm; MS m/z
(%) ¼ 523 (Mþ þ 2, 4), 521 (Mþ, 7), 415 (13), 310 (25), 286 (31), 166
(100), 93(13), 77 (23), 63 (30).
(C]O), 1622 (C]N) cmꢀ1
;
1H NMR (DMSO-d6):
d
¼ 2.43 (s, 3H,
CH3), 4.55 (s, 2H, CH2), 6.66 (d, 2H, J ¼ 9.20 Hz, 4-BrAreH), 7.08 (d,
2H, J ¼ 8.40 Hz, 4-BrAreH), 7.47 (d, 1H, 2.5 Hz, H3-2,4-Cl2AreH),
7.65e7.92 (m, 7H, AreH), 10.28 (s, D2O exch., 1H, ]NNHe), 11.14 (s,
D2O exch., 1H, eCONHe) ppm; MS m/z (%) ¼ 600 (Mþ þ 2, 7), 598
(Mþ, 10), 454 (17), 310 (27), 286 (39), 142 (100), 77 (28).
5.1.4. General procedure for synthesis of N0-[(1E,2Z)-1-[2-(4-halop-
henyl)hydrazinylidene]-1-(phenylsulfonyl)propan-2-ylidene]-2-(nap-
hthalen-2-yloxy)acetohydrazides 5aed
5.1.4.5. N0-[(1E,2Z)-1-[2-(4-Chlorophenyl)hydrazinylidene]-1-(phe-
nylsulfonyl)propan-2-ylidene]-2-(2,4-dichlorophenoxy)acetohydra-
~
To a solution of 3aed (1 mmol) in absolute ethanol (50 mL),
sodium benzenesulfinate dihdyrate (0.4 g, 2 mmol) was added. The
mixture was refluxed for 10 h, then left to cool. The reaction
mixture was poured into cold water and the solid product filtered
off, washed with water, dried and finally recrystallized from EtOH/
DMF to afford sulfone 5aed.
zide (5d). Reaction time 8 h, IR (KBr):
n
¼ 3347, 3280 (2NH), 1704
(C]O),1612 (C]N) cmꢀ1; 1H NMR (DMSO-d6):
d
¼ 2.46 (s, 3H, CH3),
4.57 (s, 2H, CH2), 6.65 (d, 2H, J ¼ 9.20 Hz, 4-ClAreH), 7.07(d, 2H,
J ¼ 8.50 Hz, 4-ClAreH), 7.44 (d, 1H, J ¼ 2.30 Hz, H3-2,4-Cl2AreH),
7.60e7.93(m, 7H, AreH), 10.24 (s, D2O exch., 1H, ¼NNHe), 11.11(s,
D2O exch.,1H, eCONHe) ppm; MS m/z (%) ¼ 553 (Mþ, 3), 551 (3), 454
(40), 427 (20), 286 (20), 175 (55), 142 (100), 126 (75), 63 (18).
5.1.4.1. N0-[(1E,2Z)-1-[2-(4-Bromophenyl)hydrazinylidene]-1-(pheny-
lsulfonyl)propan-2-ylidene]-2-(naphthalen-2-yloxy)acetohydrazide
5.1.5. General procedure for the synthesis of N0,N00-[(Z)-1-(2-aryle-
thene-1,2-diyl)]bis[2-(naphthalen-2-yloxy)acetohydrazides] 9a,b
To a solution of 2-(naphthalen-2-yloxy)acetohydrazide 1a (1.9 g,
10 mmol) in ethanol (50 mL), 2-bromoacetylbenzofuran 6a or 3-
~
(5a). Reaction time 7 h, IR (KBr):
n
¼ 3345, 3279 (2NH),1698 (C]O),
¼ 2.28 (s, 3H, CH3), 4.54 (s,
2H, CH2), 6.79 (s, 1H, H1-naphthyl), 7.05 (d, 2H, J ¼ 9.15 Hz, 4-
1606 (C]N) cmꢀ1; 1H NMR (DMSO-d6):
d

B.F. Abdel-Wahab et al. / European Journal of Medicinal Chemistry 50 (2012) 55e62
61
bromoacetyl coumarin 6b (5 mmol) was added. The reaction
mixture was refluxed for 7 h, then to cool to room temperature. The
formed solid was filtered off, washed with ethanol and recrystal-
lized from EtOH/DMF to afford compounds 9a and 9b, respectively.
prepared using DMSO employed for dissolving the tested
compound. Ciprofloxacin (50 g/mL) and Ketoconazole (50 g/mL)
m
m
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
microorganisms and compared with that of the standard. The
observed zone of inhibition is presented in Table 3,4. Antimicrobial
activities were expressed as inhibition diameter zones in millime-
ters (mm). The experiment was carried out in triplicate and the
average zone of inhibition was calculated.
5.1.5.1. N0,N00-[(Z)-1-(Benzofuran-2-yl)ethene-1,2-diyl]bis[2-(naph-
thalen-2-yloxy)acetohydrazide] (9a). Reaction time 8 h IR, (KBr):
ꢀ1
~
n
¼ 3422e3039 (4NH), 1688, 1658 (2C]O), 1602 (C]N) cm
;
1H
NMR (DMSO-d6):
d
¼ 4.90 (s, 2H, CH2), 4.94 (s, 2H, CH2), 5.31 (s, 1H,
C]CHe), 7.35e7.74 (m, 10H, AreH), 7.79e7.84 (m, 9H, AreH), 9.90
(s, 1H, D2O exch., NH), 10.21 (s, 1H, D2O exch., NH), 11.79 (s, 1H, D2O
exch., NH), 12.83 (s, 1H, D2O exch., NH) ppm; MS m/z (%): 555
[Mþ ꢀ 17(OH), 3], 378 (11), 492 (5), 352 (20), 209 (30), 144 (70), 115
(75), 78 (100), 63 (80).
5.2.2. Minimal inhibitory concentration (MIC) measurement
The bacteriostatic activity of the active compounds (having
inhibition zones (IZ) ꢃ 16 mm) was then evaluated using the two
fold serial dilution technique [42]. Two fold serial dilutions of the
tested compounds solutions were prepared using the proper
nutrient broth. The final concentration of the solutions was 66; 33;
5.1.5.2. N0,N00-[(Z)-1-(2-Oxo-2H-chromen-3-yl)ethene-1,2-diyl]bis[2-
(naphthalen-2-yloxy)acetohydrazide] (9b). Reaction time 7 h, IR
~
(KBr):
n
¼ 3455e3142 (4NH), 1686, 1655 (2C]O), 1605 (C]N)
16.5; 8.25; and 4.125 mg/mL. The tubes were then inoculated with
cmꢀ1; 1H NMR (DMSO-d6):
d
¼ 4.89 (s, 2H, CH2), 4.92 (s, 2H, CH2),
the test organisms, grown in their suitable broth at 37 ꢁC for 24 h
for bacteria (about 1 ꢂ 108 CFU/mL), each 5 mL received 0.1 mL of
the above inoculum and incubated at 37 ꢁC for 24 h. The lowest
concentration showing no growth was taken as the minimum
inhibitory concentration (MIC).
5.29 (s, 1H, C]CHe), 7.30e7.47 (m, 11H, AreH), 7.72e7.85 (m, 8H,
AreH), 9.85 (s, 1H, D2O exch., NH), 9.96 (s, 1H, D2O exch., NH), 10.39
(s, 1H, D2O exch., NH), 11.13 (s, 1H, D2O exch., NH) ppm; MS m/z (%):
598 (Mþ ꢀ 2, 5), 530 (5), 327 (7), 256 (6), 201 (10), 137 (15), 78
(100), 63 (40).
References
5.1.6. General procedure for the synthesis of (2-[(2-aryloxyacetyl)
hydrazinyl)]-N-(1,3-thiazol-2-yl)acetamides 11a,b
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lute ethanol (50 mL) was refluxed till the solid was formed, filtered
off while hot, washed with ethanol, and recrystallized from EtOH to
afford the corresponding 2-{2-[(aryl-2-yloxy)acetyl]hydrazinyl}-N-
(1,3-thiazol-2-yl)acetamides 11a,b respectively.
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5.1.6.1. 2-{2-[(Naphthalen-2-yloxy)acetyl]hydrazinyl}-N-(1,3-thiazol-
~
2-yl)acetamide (11a). Reaction time 6 h, IR (KBr):
n
¼ 3410, 3321,
3240 (3NH),1685,1662 (2C]O),1607 (C]N) cmꢀ1; 1H NMR (DMSO-
d6):
d
¼ 4.59 (s, 2H, CH2), 4.71 (s, 2H, CH2), 7.22e7.42 (m, 4H, AreH),
7.74e7.81 (m, 5H, AreH), 9.44 (s, 2H, D2O exch., 2NH), 10.27 (s, 1H,
D2O exch., NH) ppm; MS m/z (%): 356 (Mþ, 8), 216 (21), 158 (22), 144
(100), 77 (28).
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43 (2008) 917e924.
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Z. Li, F. Liu, W. Xue, P. Lu, Zhuo Chen, Bioorg. Med. Chem. 15 (2007)
3981e3989.
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1 (2011) 78e86.
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123e136.
5.1.6.2. 2-{2-[(2,4-Dichlorophenoxy)acetyl]hydrazinyl}-N-(1,3-thiazol-
~
2-yl)acetamide (11b). Reaction time 7 h, IR (KBr):
n
¼ 3395, 3323,
33 216 (3NH), 1688, 1654 (2C]O), 1602 (C]N) cmꢀ1
(DMSO-d6):
;
1H NMR
d
¼ 4.55 (s, 2H, CH2), 4.71 (s, 2H, CH2), 6.96e7.08 (m, 2H,
AreH), 7.18e7.32 (m,1H, AreH), 7.41e7.56 (m, 2H, AreH), 9.22 (s,1H,
D2O exch., NH), 10.23 (s, 2H, D2O exch., 2NH) ppm; MS m/z (%): 374
(Mþ ꢀ 1, 8.5), 345 (10), 238 (44),177 (70),164 (80),109 (48), 45 (100).
5.2. Biology experiments
5.2.1. Materials and methods
Chemical compounds were individually tested against a panel of
gram positive and gram negative bacterial pathogens, and fungi.
Antimicrobial tests were carried out by the agar well diffusion
method (Perez et al., 1990) using 100 mL of suspension containing
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