Novel analogues of sydnone: Synthesis, characterization and antibacterial evaluation

Article abstract of DOI:10.1002/ardp.200300847

New sydnone derivatives bearing a substituted phenyl ring at the 3-position nave been synthesized. Two separate series of 3-(carboxyphenyl)sydnone derivatives have been prepared by cyclization of the corresponding N-nitroso-N-(carboxyphenyl)-glycine 3. The obtained 3-(carboxyphenyl)sydnones 4 were subjected to a series of different chemical reactions on the carboxylic acid group. Compound 5, the potassium salt of 4a, was reacted with α-chloroacetanilide derivatives 6 to give the corresponding esters 7. On the other hand, the acid hydrazide 9 was condensed with different aromatic aldehydes to give the corresponding arylidene derivatives 10. The synthesized compounds were tested for their antibacterial activities against both gram-positive and gram-negative organisms. Some of the test compounds exhibited high activity; among them, 10d is considered to be a lead compound possessing high broad-spectrum antibacterial activity.

Full text of DOI:10.1002/ardp.200300847

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 427−433
Novel Analogues of Sydnone 427
Mohamed A. Moustafaa,
Novel Analogues of Sydnone: Synthesis,
Characterization and Antibacterial Evaluation
Magdy M. Gineinahb,
Magda N. Nasrb,
Waleed A. H. Bayoumib
New sydnone derivatives bearing a substituted phenyl ring at the 3-position have
been synthesized. Two separate series of 3-(carboxyphenyl)sydnone derivatives
have been prepared by cyclization of the corresponding N-nitroso-N-(carboxy-
phenyl)-glycine 3. The obtained 3-(carboxyphenyl)sydnones 4 were subjected
to a series of different chemical reactions on the carboxylic acid group. Com-
pound 5, the potassium salt of 4a, was reacted with α-chloroacetanilide deriva-
tives 6 to give the corresponding esters 7. On the other hand, the acid hydrazide
9 was condensed with different aromatic aldehydes to give the corresponding
arylidene derivatives 10. The synthesized compounds were tested for their anti-
bacterial activities against both gram-positive and gram-negative organisms.
Some of the test compounds exhibited high activity; among them, 10d is con-
sidered to be a lead compound possessing high broad-spectrum antibacterial
activity.
a Department of
Pharmaceutical Chemistry,
Faculty of Pharmacy, King
Abdulazis University,
Geddah, Saudi Arabia
b Department of
Pharmaceutical Organic
Chemistry, College of
Pharmacy, University of
Mansoura,
Mansoura 35516, Egypt
Keywords: Sydnone; Arylidenebenzoylhydrazine; Antibacterial agents
Received: October 17, 2003; Accepted: February 17, 2004 [FP847]
DOI 10.1002/ardp.200300847
Introduction
of further concomitant substitutions such as acidhydra-
zide and arylidenehydrazinocarbonyl on the 3-position
Combat against bacterial infections has resulted in the
development of a wide variety of antibiotics. After
years of misuse and overuse of antibiotics, bacteria
are becoming antibiotic resistant, resulting in a poten-
tial global health crisis. There is already evidence that
antibacterial resistance is associated with an increase
in mortality. Frequently, it is recommended to use new
antibacterial agents with enhanced broad-spectrum
potency. Therefore, recent efforts have been directed
toward exploring novel antibacterial agents. The po-
tential biological activities of sydnones have received
great interest; some sydnone derivatives possess anti-
bacterial properties [1, 2]. We have recently described
high antibacterial activities of some novel phenylsyd-
none derivatives having hydrazone, acid hydrazide
and arylidenehydrazine counterparts at the 4-position
of the phenyl ring [3]. In continuation of our interest in
chemistry and biological properties of sydnone deriva-
tives, we herein report preparative methods for various
derivatives of the sydnone ring system as well as their
antibacterial properties. The antibacterial activities of
many compounds carrying amide and ester moieties
were reported [4Ϫ7]. Accordingly, conjugation of both
ester and arylamide moieties to produce carbamoyl-
methoxycabonyl derivatives was achieved. Further-
more, we deemed it interesting to study the influence
of the phenyl ring. On the basis of these consider-
ations we have planned the preparation of a new
series of 3-phenylsydnone bearing different substi-
tution at the 3- or 4-position of the phenyl ring in order
to further explore the biological properties of these
compounds.
Results and discussion
Chemistry
The sydnone derivatives were prepared as shown in
Schemes 1 and 2. Baker et al. [8Ϫ10] have reported a
standard procedure for preparation of sydnones. The
conventional synthesis of 3-arylsydnone derivatives
involves reaction of equimolar amounts of 4-amino-
benzoic acid (1a) with a neutralized solution of chlo-
roacetic acid to yield the N-(4-carboxyphenyl)glycine
(2a) (Scheme 1). As candidate for cyclization, N-ni-
troso-N-(4-carboxyphenyl)glycine (3a) was used,
which in turn was prepared through nitrosation of 2a
with nitrous acid. One of the major and most con-
venient routes for sydnone ring formation is cyclodehy-
dration of 3a through refluxing with acetic anhydride
to yield 3-(4-carboxyphenyl)sydnone (4a) [11, 12]. The
high reactivity (Schemes 1 and 2) of the potassium
salts of carboxylic acids with alkyl halides was re-
flected in the reactivity of the potassium salt of 3-(4-
carboxyphenyl)sydnone (5) (Scheme 1). Thus, treat-
ment of 5 with variously substituted α-chloroacetan-
Correspondence: Magda N. Nasr, Department of Pharma-
ceutical Organic Chemistry, College of Pharmacy, University of
Mansoura, Mansoura 35516, Egypt. Phone: +20 50 224-7496,
Fax: +20 50 224-7496, e-mail: magdaahnasr@yahoo.com
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

428 Nasr et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 427−433
Scheme 1.
ilides 6 resulted in the formation of the corresponding
esters 7. Moreover, it was reported that esters of car-
boxylic acids were prepared in high yields from their
sodium salts through reaction with primary and sec-
ondary alkyl bromides and iodides at room tempera-
ture in dipolar aprotic solvents, especially hexameth-
ylphosphoric triamide (HMPT) [13]. In the current
work, potassium salt was chosen over sodium salt due
to the higher reactivity of potassium. In turn, the pot-
assium salt was prepared by a salting-out process,
using a mild basic aqueous potassium carbonate solu-
tion and acetone at room temperature. Potassium car-
bonate was used to avoid the possibility of alkaline
hydrolysis of the sydnone ring with the strong basic
potassium hydroxide. Compounds 7 were prepared by
heating a mixture of the appropriate α-chloroacetan-
ilide 6 and potassium 4-(ψ-5-oxo-1,2,3-oxadiazol-3-yl)-
phenyl carboxylate 5 in the presence of DMF as a sol-
vent (Scheme 1). By an analogous sequence of steps,
3-(3-carboxyphenyl)sydnone (4b) was prepared, start-
ing with 3-aminobenzoic acid (1b) and applying the
same general approach (Scheme 2). However, after
sydnone ring formation, the resulting carboxylic acid
4b can be converted into various functionalities. The
acid hydrazide 9 can be obtained through two different
procedures. Compound 9 could be directly synthe-
sized from the acid 4b by stirring at room temperature
with hydrazine in the presence of dicyclohexylcarbodi-
imide (DCC). The analogous reaction between the acid
4b and methanol in the presence of sulfuric acid at
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Arch. Pharm. Pharm. Med. Chem. 2004, 337, 427−433
Novel Analogues of Sydnone 429
Scheme 2.
room temperature afforded the formation of the corre-
sponding ester 3-(3-methoxycarbonylphenyl)sydnone
(8). However, the acid hydrazide 9 was advan-
tageously prepared by adoption of the ester functional
group transformation process. Thus, refluxing ester 8
with hydrazine in the presence of ethanol resulted in
the formation of 3-(3-hydrazinocarbonylphenyl)syd-
none (9). Compound 9 was used as a precursor for
the synthesis of a series of hydrazone derivatives 10
by refluxing with the appropriate aromatic aldehyde in
ethanol (Scheme 2). See Table 1 for a summary of the
physicochemical data of the newly synthesized com-
pounds.
Antibacterial screening
All sydnone derivatives synthesized were tested in vi-
tro for their antibacterial activities. Three groups of 3-
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

430 Nasr et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 427−433
Table 1. Physicochemical data of the new compounds.
acid group 4 or its simple derivatives such as simple
alkyl ester 8 or acid hydrazide 9. The second group 7
possesses bulky esters of variously substituted acet-
anilide derivatives. The last group bears arylidenehyd-
razinocarbonyl functionality at the phenyl ring 10. The
test compounds were screened against four strains of
pathogenic microorganisms, two gram-positive and
two gram-negative organisms, using ciprofloxacin as
a reference standard. The minimum inhibitory concen-
trations (MICs, µg/mL) were determined using the
standard agar dilution method [14]. MIC values are
summarized in Table 2. From the compiled data, it
would be obvious that the novel sydnone derivatives
are especially potent against gram-positive organisms,
particularly against the Bacillus subtilis strain. Regard-
ing the first group of tested sydnones, it seems that all
members show almost comparable activities. How-
ever, compound 9, with acid hydrazide functionality, is
the most active, especially against gram-positive or-
ganisms.
Comp.
R
MP
(°C)
Yield Mol. Form.
(%)
7a
7b
7c
7d
7e
10a
10b
10c
10d
10e
H
197Ϫ199 80
85Ϫ87 58
255Ϫ257 68
187Ϫ189 78
193Ϫ195 75
278Ϫ280 73
C17H13N3O5
C20H17N3O7
C18H13N3O7
C19H15N3O6
C19H17N3O6
C16H12N4O3
COOC2H5
COOH
COCH3
OC2H5
C6H5
4-Cl-C6H4
4-NO2-C6H4
>300
>300
85 C16H11ClN4O3
80 C16H11N5O5
2-Cl-5-NO2-C6H3 >300
2-Furyl
75 C16H10ClN5O5
C14H10N4O4
258Ϫ260 65
phenylsydnone were selected for biological screening.
Group classification depends on the nature of the acid
derivative existing on the phenyl ring. The first group
consists of 3-phenylsydnones bearing free carboxylic
Moreover, variation of the position of the carboxylic
group from position 4 as in 4a to position 3 as in 4b
Table 2. In vitro antibacterial activities of the new compounds.
Comp.
Minimum Inhibitory Concentrations (MIC)§ (µg/mL)
Gram-positive Organismsb Gram-negative Organisms‡
B. su.
S. au.
E. co.
P. ae.
4a
4b
7a
16
16
4
32
16
4
64
64
4
32
64
8
7b
7c
7d
7e
8
9
10a
32
8
16
32
8
8
32
2
32
16
32
64
16
8
64
16
32
64
32
32
> 128
4
32
8
64
64
64
32
64
4
64
4
10b
10c
10d
10e
8
1
64
0.5
16
1
64
1
8
16
0.25
>128
0.064
0.125
64
0.032
Ciprofloxacin
§
MIC is the lowest concentration of compound needed for prevention of visible growth of microorganisms, re-
ported as the average value of duplicate determinations. MIC values were obtained by the use of an agar
dilution method, whereby organisms were deposited onto medicated agar plates by the replication device of
Steers et al. [14].
Organisms selected: B. su., Bacillus subtilis ATCC 6633; S. au., Staphylococcus aureus ATCC 29213; E. co.,
Escherichia coli ATCC 25922; P. ae., Pseduomonas aeruginosa ATCIC 9027.
‡
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 427−433
Novel Analogues of Sydnone 431
revealed that this change has no significant effect on
the antibacterial activity. We have briefly investigated
the structure-activity relationship of the arylhydrazone
group in compounds 10. The presence and lipophilicity
of substituents at the arylidene phenyl ring were con-
sidered to be a key factor in determining biological ac-
tivity. In particular, it was found that the coupled pres-
ence of a chloro group at the 2-position and a nitro
group at the 5-position in compound 10d is highly ef-
fective for enhancing the antibacterial activity, particu-
larly against gram-negative bacteria. However, com-
pound 10b exhibited better activity than compound
10c against all types of organisms. This could be
reasonably attributed to the presence of the chloro
group, which is more lipophilic than the nitro group of
10c. At this point, it is necessary to mention the im-
portance of the substituents at the phenyl ring with re-
spect to biological activity. In order to define more
clearly the role of the substituents for the activity pro-
file, we have prepared the unsubstituted phenyl de-
rivative 10a in addition to the unsubstituted furyl ana-
logue 10e. When directly compared to the substituted
analogues in this study, compounds 10a and 10e
exhibited decreased antibacterial activity against all
organisms. However, these results run contrary to the
activity profile of the esters 7, in which case the ethyl
ester-containing compound at the terminal phenyl ring,
exemplified by compound 7b, was found to be less
potent than the free carboxylic acid-containing com-
pound, such as 7c. Moreover, the lipophilic methylcar-
bonyl group in compound 7d revealed lower biological
activity than the parent carboxylic acid 7c. However,
compound 7a with an unsubstituted phenyl ring pos-
sesses the highest activity among the members of this
series of compounds.
Experimental
Chemistry
Melting points (°C, uncorrected) were determined on a
Fischer-Johns apparatus. IR spectra (KBr) were recorded on
a Pye-Unicam SP1000 Spectrometer (ν in cmϪ1). 1H- and
13C-NMR spectra were recorded on a FT-NMR spectrometer
(400 MHz) JNM-LA, using TMS as internal standard (chemi-
cal shifts in ppm, δ units). Mass spectral data were recorded
on a JEOL JMS-600H spectrometer. The results of elemental
analyses (C, H, N) were within 0.4% of the theoretical val-
ues. Thin layer chromatography was performed on silica gel
GLF plates, 250 microns. The compound 3-(4-carboxy-phen-
yl)sydnone (4a) was prepared according to published pro-
cedure [15]. The intermediates 6a؊f were prepared applying
reported methods [16Ϫ20].
N-(3-Carboxyphenyl)glycine (2b)
A solution of chloroacetic acid (9.45 g, 0.1 mol) in water (100
mL) was neutralized with a 10% sodium hydroxide solution
while cooling. 3-Aminobenzoic acid (1b) (13.8 g, 0.1 mol) was
added to the product, and the reaction mixture was refluxed
for 10 h. After cooling to room temperature, the separated
solid was collected by filtration, dried and recrystallized from
ethanol to give 16.8 g (85%) of 2b, m.p. 260Ϫ262°C. 1H-
NMR (DMSO-d6): 4.73 (s, 2H, CH2), 5.93 (br s, 1H, NH; D2O
exchangeable), 7.41Ϫ8.23 (m, 4H, Ar-H), 12.11 (br s, 2H,
2COOH; D2O exchangeable).
N-Nitroso-N-(3-carboxyphenyl)glycine (3b)
To a well-stirred mixture of the glycine derivative 2b (1.95 g,
10 mmol) in 10% hydrochloric acid (10 mL) at 0Ϫ5°C, a solu-
tion of sodium nitrite (0.69 g, 10 mmol) in water (10 mL) was
added dropwise over a period of 30 min. Stirring was con-
tinued for a further 1 h. The product was collected by filtration,
washed thoroughly with cold water, dried and recrystallized
from methanol to yield 1.64 g (73%) of 3b, m.p. 158Ϫ160°C.
IR: 3240 (OH), 1712 (C=O), 1569 (N=O).
In conclusion, the results of the present study indicate
that 3-arylsydnones possess antibacterial properties,
and substitutions at the 3-phenyl ring might be detri-
mental with regard to activity. Substituent combination
at the terminal phenyl ring of arylidene derivatives of
acid hdrazide might produce powerful antibacterial ag-
ents. Therefore, derivative 10d with its potent broad-
ened spectrum of antibacterial activity is an interesting
lead compound for further development.
3-(3-Carboxyphenyl)sydnone (4b)
A mixture of N-nitrosoglycine derivative 3b (2.9 g, 13 mmol)
and acetic anhydride (15 mL) was heated in a water bath for
3 h. Excess solvent was removed under reduced pressure,
and the residue was triturated with cold water and recrys-
tallized from methanol to give 1.99 g (80%) of 4b, m.p.
245Ϫ247°C. IR: 3138 (CH, sydnone), 1736 (C=O, sydnone),
1702 (C=O). 1H-NMR (DMSO-d6): 7.63Ϫ8.55 (m, 5H, Ar-H
and CH sydnone), 11.30 (s, 1H, COOH; D2O exchangeable).
Potassium 4-(ψ-5-oxo-1,2,3-oxadiazol-3-yl)phenyl carboxylate
(5)
3-(4-Carboxy-phenyl)sydnone (4a) (2 g, 10 mmol) was dis-
solved in a 20% potassium carbonate solution (8 mL) at room
temperature. The aqueous solution thus obtained was fil-
tered, and the filtrate was slowly added to ice-cold acetone.
The pale orange crystals obtained were collected by filtration,
washed with anhydrous acetone and then air dried to give
the potassium salt (2.32 g, 95%) of 5, m.p. >300°C. 1H-NMR
(DMSO-d6): 7.31Ϫ8.42 (m, 5H, Ar-H and CH sydnone).
Acknowledgments
The authors are thankful to Dr. Samy M. Kheira,
Department of Microbiology, College of Pharmacy,
Mansoura University, Egypt, for carrying out the anti-
bacterial screening.
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432 Nasr et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 427−433
3-[4-(Arylcarbamoylmethoxycarbonyl)phenyl]sydnones (7aϪe)
then cooled to room temperature. The separated solid was
collected by filtration, dried and recrystallized from DMF to
give pure product. IR, 10a: 3300 (NH), 3136 (CH, sydnone),
1733 (C=O, sydnone), 1674 (C=O, amide), 1595 (C=N-). 10b:
3286 (NH), 3179 (CH, sydnone), 1757 (C=O, sydnone), 1666
(C=O, amide), 1587 (C=N-). 10c: 3279 (NH), 3117 (CH, syd-
none), 1735 (C=O, sydnone), 1670 (C=O, amide), 1584 (C=
N-). 10d: 3255 (NH), 3115 (CH, sydnone), 1732 (C=O, syd-
none), 1672 (C=O, amide), 1600 (C=N-). 10e: 3262 (NH),
3130 (CH, sydnone), 1750 (C=O, sydnone), 1660 (C=O, am-
ide), 1622 (C=N-). 1H-NMR (DMSO-d6), 10a: 7.52Ϫ8.47 (m,
10H, Ar-H, N=C-H, and C-H sydnone), 12.16 (s, 1H, NH; D2O
exchangeable). 10d: 7.86Ϫ8.90 (m, 9H, Ar-H, N=C-H, and
C-H sydnone), 12.52 (s, 1H, NH; D2O exchangeable). MS
(m/z), 10c: 323 C16H11N4O4 (M-30, 12.7), 295 C15H11N4O3
(M-58, 100), 221 C14H9N2O (6.7), 132 C7H4N2O (8.7).
A mixture of the potassium salt of 3-(4-carboxyphenyl)syd-
none (5) (2.93 g, 12 mmol) and the appropriate substituted
chloroacetanilide 6a؊e (10 mmol) in DMF (20 mL) was
heated in a water bath for 5 h, allowed to cool to room tem-
perature and then poured over ice-water. The separated solid
was collected by filtration, dried and recrystallized from DMF/
water to give pure products. IR: 7a: 3268 (NH), 3195 (CH,
sydnone), 1739 (C=O, sydnone), 1720 (C=O, ester), 1692
(C=O, amide). 7b: 3275 (NH), 3178 (CH, sydnone), 1741 (C=
O, sydnone), 1722, 1707 (two C=O, ester), 1698 (C=O, am-
ide). 7c: 3400 (OH), 3268 (NH), 3195 (CH, sydnone), 1739
(C=O, sydnone), 1720 (C=O, ester), 1692 (C=O, amide). 7d:
3250 (NH), 3132 (CH, sydnone), 1770 (C=O, sydnone), 1745
(C=O, ester), 1732 (C=O, COCH3), 1662 (C=O, amide). 7e:
3286 (NH), 3120 (CH, sydnone), 1760 (C=O, sydnone), 1730
(C=O, ester), 1684 (C=O, amide). 1H-NMR (DMSO-d6), 7b:
1.31 (t, 3H, CH3), 4.28 (q, 2H, CH2), 5.04 (s, 2H, CH2),
7.70Ϫ8.33 (m, 9H, Ar-H and C-H sydnone), 10.67 (s, 1H, NH;
D2O exchangeable). 7e: 1.32 (t, 3H, CH3), 3.99 (q, 2H, CH2),
4.98 (s, 2H, CH2), 6.88Ϫ8.35 (m, 8H, Ar-H), 7.94 (s, 1H, C-
H sydnone), 10.13 (s, 1H, NH; D2O exchangeable). MS
(m/z), 7a: 281 C16H13N2O3 (M-58, 100), 162 C9H8NO2 (15.1),
148 C8H6NO2 (14.5), 104 C7H6N (42.3).
Antibacterial activity
The synthesized compounds were evaluated for their in vitro
antibacterial activity against representative gram-positive and
gram-negative organisms applying the standard agar dilution
method using Mueller-Hinton medium. MIC were determined
after 18 h of incubation at 35°C. The concentrations of the
bacterial suspensions were verified by determining standard
colony counts on antibiotic-free agar plates. MIC was con-
sidered to be the lowest concentration that completely in-
hibited growth on agar plates, disregarding a single colony or
a faint haze caused by the inoculum. Ciprofloxacin was used
as a reference compound.
3-(3-Methoxycarbonylphenyl)sydnone (8)
A mixture of 3-(3-carboxyphenyl)-sydnone (4b) (2.1 g, 10
mmol), absolute methanol (50 mL) and concentrated sulfuric
acid (1 mL) was stirred at room temperature for 24 h. Then
a solution of sodium bicarbonate (5%) was added portion-
wise until effervescence ceased. The solid obtained was col-
lected by filtration, suspended in sodium bicarbonate solution
(5%, 20 mL) and stirred for 10 min to dissolve unreacted acid.
The precipitate was collected by filtration, washed with water,
dried and recrystallized from ethanol to give 1.76 g (80%) of
8, m.p. 178Ϫ180°C. IR: 3114 (CH, sydnone), 1768 (C=O,
sydnone), 1725 (C=O). 1H-NMR (DMSO-d6): 3.82 (s, 3H,
CH3), 7.38-8.47 (m, 5H, Ar-H and CH sydnone).
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Arch. Pharm. Pharm. Med. Chem. 2004, 337, 427−433
Novel Analogues of Sydnone 433
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