Efficient synthesis of novel benzylidene barbituric and thiobarbituric acid derivatives containing ethyleneglycol spacers

Article abstract of DOI:10.1007/s13738-014-0499-2

Knoevenagel condensation reaction of ethylene glycol-based aromatic aldehyde with barbituric acid derivatives in ethanol produced novel benzylidene barbituric and thiobarbituric acid derivatives which contain good yields of ethylene glycol spacers. Structures of the products were deduced from their IR, ¹H-NMR, and ¹³C-NMR spectroscopy and mass spectra.

Full text of DOI:10.1007/s13738-014-0499-2

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0499-2
ORIgINAl PAPER
Efficient synthesis of novel benzylidene barbituric
and thiobarbituric acid derivatives containing ethyleneglycol
spacers
Malihe Faryabi · Enayatollah Sheikhhosseini
Received: 20 February 2014 / Accepted: 7 July 2014
© Iranian Chemical Society 2014
Abstract Knoevenagel condensation reaction of ethylene
glycol-based aromatic aldehyde with barbituric acid deriva-
tives in ethanol produced novel benzylidene barbituric and
thiobarbituric acid derivatives which contain good yields
of ethylene glycol spacers. Structures of the products were
[8]. Moreover, benzylidene barbituric acids are the important
building blocks in synthesizing pyrazolo[3,4-d]pyrimidines
and pyrido[2,3-d]pyrimidines [9, 10]. They also have a broad
range of biological activities. Some of these compounds have
been also investigated as nonlinear optical materials [11].
Because of their ability in coordination with transition
metals through carbonyl oxygen and one or both depro-
tonated oxygen atoms and also owing to their wide use
in medicine, the synthesis of their metal complexes has
received great interest. Most studies have concentrated on
the first-row transition metals [12, 13] and relatively few
studies have considered the barbituric acid complexes of
platinum-group metals [14] or silver and gold [15]. Fur-
thermore, it has been suggested that the presence of metal
ions in biological fluids could have a significant effect on
the therapeutic action of drugs. Many diverse applications
of metal species aim to understand the natural roles of
metal ions or exploit the unique properties of metal centers
in the study of the biology or biochemistry of nucleic acid
and nucleic acid constitutes [16, 17]. Besides, a diversity of
the complexes may be formed as a consequence of different
possibilities of ligation of the barbituric moiety.
Considering the importance of barbituric acid deriva-
tives, many classical methods have been previously reported
for their synthesis. Reaction of barbituric acid with carbonyl
compounds was considered in 1864 and its isolated prod-
ucts were monosubstituted and disubstituted ones [18]. To
obtain the formation of only one monosubstituted conden-
sation product between aromatic aldehydes and barbituric
acid, diversified acid and base catalyzed reactions [19–23]
such as dry condensation by acidic clay (Tonsil Actisil FF;
Montmorillonite KSF) catalysts have been applied [24, 25].
Jursic and Reddy performed Knoevenagel condensation
using substituted benzaldehydes and barbituric acid without
adding any external acid or base catalysts [26, 27].
1
deduced from their IR, H-NMR, and 13C-NMR spectros-
copy and mass spectra.
Keywords Barbituric acid · Thiobarbituric acid ·
Knoevenagel condensation · Arylidene barbituric acid ·
Ethylene glycol spacer
Introduction
Barbituric acid (BA) and thiobarbiturate (TBA) are not spe-
cifically appropriate to be used in human body by themselves
because of their high acidity which stops crossing the blood–
brain barrier [1]. Thus, only barbituric acid derivatives are
clinically useful. By substituting two protons in C-5 position
during barbiturate synthesis, acidity of the whole molecule
can be reduced and an unsaturated group can be added for the
later incorporation of parahydrogen into the molecule.
Benzylidene barbituric acids as potential organic oxidiz-
ers [2] are applied for preparing pyrimidine derivatives [3],
synthesizing merocyanine dyes [4], asymmetrically synthe-
sizing disulphides [5], design novel PPARγ ligands [6] and
acting as antibacterial agents [7]. Benzylidene barbiturate
derivatives including benzylidene (thio)barbiturate-β-d-
glycosides play the role of mushroom tyrosinase inhibitors
M. Faryabi · E. Sheikhhosseini (*)
Department of Chemistry, Faculty of Science, Islamic Azad
University, Kerman Branch, Kerman, Iran
e-mail: sheikhhosseiny@gmail.com
1 3

J IRAN CHEM SOC
Existence of a lipophilic group in the barbiturate structure
has been shown to improve the biological activity of these
compounds. The barbiturates and thiobarbiturates that exert
a broad range of pharmacological actions bind to the specific
regions of various receptors such as nicotinic-acetylcholine
(nAChR), γ-amino butyric acid (gABA), or BK (big potas-
sium) channel receptors that are all ligand-gated ion chan-
nels [28, 29]. Binding to gABA receptor requires C-5 atom
to be substituted in alkyl or aryl group; in other words, BA
and TBA are not biologically active by themselves. Such
substitution enhances lipid solubility and facilitates the trans-
port of BA and TBA to their enzyme targets [30].
4-tolylsulfonyl chloride in 40 ml of THF was added drop-
wise. Reaction progress was monitored by TlC. Remain-
ing tosyl chloride was removed by adding powdered NaOH
(50 mmol) and vigorously grinding it for 10 min; addition
of a few drops of t-BuOH accelerated the disappearance
of TsCl. After completion of the reaction, the product was
extracted by CH2Cl2 (3 × 30 ml), the combined organic
layer was collected by a sintered glass in vacuo, and the
resulting product was concentrated by evaporating CH2Cl2
using a rotary evaporator. The obtained crude tosylate was
sufficiently pure.
Based on the above information, in the present investiga-
tion, a series of novel benzylidene barbiturate and thiobar-
biturate derivatives containing hydrophobic ethylene glycol
spacers was designed and synthesized by the condensation
of ethylene glycol-substituted benzaldehydes with barbitu-
ric acid or thiobarbituric acid.
general procedure for the synthesis of ethylene
glycol-based dialdehyde derivatives (3a–c)
A mixture of polyethylene glycol ditosylate (10 mmol),
salicylaldehyde (25 mmol), and K2CO3 (50 mmol) in ace-
tonitrile (50 ml) was heated at reflux for 24 h. After com-
pletion of the reaction (monitored by TlC), the reaction
mixture was filtered off; then, the solvent of filtrate was dis-
tilled, diluted with toluene (50 ml), and washed with NaOH
10 % ((3 × 20 ml). The resulting product was concentrated
by the evaporation of toluene using a rotary evaporator.
Experimental part
General Commercially available materials were used with-
out further purification. Melting points were determined on
an Electrothermal 9100 apparatus and were uncorrected.
IR spectra were obtained on an ABB FT-IR FTlA 2000
general procedure for the synthesis of benzylidene
barbituric and thiobarbituric acid derivatives containing
ethylene glycol spacers (5a–i)
1
spectrometer. H-NMR and 13C-NMR spectra were run on
1
Bruker spectrometers at 300 and 400 MHz for H-NMR
and 75 and 100 MHz for 13C-NMR. CDCl3 and DMSO-d6
were applied as solvents.
A mixture of ethylene glycol-based dialdehyde deriva-
tives (3a–c) (5 mmol) and barbituric acid derivatives (4)
(10 mmol) in ethanol (10 ml) was heated at reflux for
4–5 h. Upon cooling, solid materials were precipitated from
the solution. These precipitates were filtered off, washed
with hot water, and recrystallized from EtOH to afford pure
products (5a–i) as green solids.
Antibacterial activity determination
The antibacterial activity of the 1, 2-bis(2-((tetrahydro-2,4,6-
trioxopyrimidin-5(6H)-ylidene)methyl)phenoxy)ethane (5a)
was carried out by disc diffusion method using 100 μl of
suspension containing 108 CFU/ml of bacteria (gram posi-
tive bacteria: Staphylococcus aureus and gram negative
bacteria: E. coli and Pseudomonas aeruginosa) spread on
Muller–Hinton agar (MHA) medium (Kim et al. [31]). Ster-
ile 6-mm diameter filter paper discs were impregnated with
5, 10 15 and 20 mg/ml of the benzylidene barbituric acid
and were placed on to MHA medium. After 24 h of incuba-
tion at 37 °C, the diameter of the clear zone around the disc
was measured and expressed in millimeters as its antibacte-
rial activity.
1, 2‑Bis(2‑((tetrahydro‑2,4,6‑trioxopyrimidin‑5(6H)‑ylidene)
methyl)phenoxy)ethane (5a) Yield 90 %. Mp = 295 °C
(dec). IR (KBr, cm−1): 3,201, 3,076, 1,755, 1,683, 1,596. 1H
NMR (400 MHz, DMSO-d6) δ: 4.49 (s, 2 CH2–O), 6.99 (t,
J = 7.8 Hz, 2 arom. H), 7.20 (d, J = 8.0 Hz, 2 arom. H), 7.51
(td, J = 8.0, 1.6 Hz, 2 arom. H), 7.96 (dd, J = 7.8, 1.2 Hz,
2 arom. H), 8.50 (s, 2 = CH), 11.11 (s, 2 NH), 11.26 (s, 2
NH). 13C NMR (100 MHz, DMSO-d6) δ: 67.8, 112.3, 118.8,
119.9, 121.9, 132.5, 133.8, 149.8, 150.1, 158.1, 161.4, 163.3.
MS (EI) m/z (%): 490 (M+, 3), 278 (4), 258 (16), 256 (1),
173 (51), 128 (100), 115 (16), 76 (59), 71 (19), 56 (10), 42
(87).
general procedure for the synthesis of ethylene glycol
ditosylate derivatives (2a–c)
A mixture of sodium hydroxide (200 mmol in 40 ml H2O)
and the corresponding ethylene glycol (70 mmol) was
stirred for 15 min at 0–5 °C; then, a mixture of 140 mmol of
1, 2‑Bis(2‑((tetrahydro‑4,6‑dioxo‑2‑thioxopyrimidin‑5(6H)
‑ylidene)methyl)phenoxy)ethane (5b) Yield 90 %.
Mp = 290–293 °C. IR (KBr, cm−1): 3,084, 1,723, 1,649,
1 3

J IRAN CHEM SOC
1
1,549. H NMR (400 MHz, DMSO-d6) δ: 4.51 (s, 2 CH2–
68.5, 69.1, 112.3, 118.6, 119.7, 121.8, 132.8, 134.7, 150.8,
158.7, 159.4, 161.7, 178.6. MS (EI) m/z (%): 566 (M+, 2),
451 (2), 398 (13), 226 (2), 198 (16), 128 (16), 115 (32), 75
(37), 172 (26), 14 (67), 59 (100), 42 (49).
O), 7.01 (t, J = 7.6 Hz, 2 arom. H), 7.21 (d, J = 8.0 Hz, 2
arom. H), 7.54 (td, J = 8.0, 1.6 Hz, 2 arom. H), 8.05 (dd,
J = 7.8, 1.2 Hz, 2 arom. H), 8.58 (s, 2 = CH), 12.22 (s,
2 NH), 12.32 (s, 2 NH). 13C NMR (100 MHz, DMSO-d6)
δ: 67.5, 112.4, 118.7, 119.9, 121.9, 132.6, 134.2, 150.9,
158.4, 159.3, 161.5, 178.5. MS (EI) m/z (%): 522 (M+,
0.4), 368 (3), 292 (8), 258 (11), 232 (48), 215 (8), 188 (11),
172 (66), 144 (100), 116 (48), 91 (87), 75 (9), 59 (48).
1‑(2‑(2‑(2‑((Tetrahydro‑1,3‑dimethyl‑2,4,6‑triox‑
opyrimidin‑5(6H)‑ylidene)methyl)phenoxy)
ethoxy)
ethoxy)‑2‑((tetrahydro‑1,3‑dimethyl‑2,4,6‑trioxopyrimi‑
din‑5(6H)ylidene)methyl) benzene (5f) Yield 90 %.
Mp = 208–210 °C. IR (KBr, cm−1): 1,732, 1,666, 1,576.
1H NMR (400 MHz, CDCl3) δ: 3.35 (s, 2 N–CH3), 3.37
(s, 2 N–CH3), 4.03 (t, J = 4.4 Hz, 2 CH2–O), 4.30 (t,
J = 4.4 Hz, 2 CH2–O), 6.97-7.03 (m, 4 arom. H), 7.47 (t,
J = 7.6 Hz, 2 arom. H), 8.08 (d, J = 7.6 Hz, 2 arom. H),
8.92 (s, 2 = CH). 13C NMR (100 MHz, CDCl3) δ: 27.9,
28.1, 68.4, 69.2, 112.4, 118.3, 119.6, 122.0, 132.4, 133.9,
149.8, 157.9, 158.2, 161.2, 163.7. MS (EI) m/z (%): 590
(M+, 3), 503 (4), 291 (2), 256 (3), 207 (4), 193 (5), 173 (4),
156 (100), 145 (26), 123 (11), 97 (87), 71 (22), 57 (86), 42
(69).
1,2‑Bis(2‑((tetrahydro‑1,3‑dimethyl‑2,4,6‑trioxopyrimi‑
din‑5(6H)‑ylidene)methyl)phenoxy) ethane (5c) Yield
90 %. Mp = 253–258 °C. IR (KBr, cm−1): 1,730, 1,672,
1,584. 1H NMR (400 MHz, DMSO-d6) δ: 3.13 (s,
2 N–CH3), 3.14 (s, 2 N–CH3), 4.46 (s, 2 CH2–O), 7.00 (t,
J = 7.6 Hz, 2 arom. H), 7.19 (d, J = 8.0 Hz, 2 arom. H),
7.51 (td, J = 7.6, 1.6 Hz, 2 arom. H), 7.88 (dd, J = 8.0,
1.2 Hz, 2 arom. H), 8.52 (s, 2 = CH). 13C NMR (100 MHz,
DMSO-d6) δ: 27.9, 28.3, 67.1, 112.2, 119.8, 122.3, 127.5,
130.2, 132.2, 133.6, 151.7, 157.8, 160.1, 162.0. MS (EI)
m/z (%): 546 (M+, 33), 459 (7), 287 (7), 258 (43), 243
(100), 199 (18), 173 (17), 159 (18), 145 (19), 131 (24), 115
(20), 103 (8), 77 (10), 65 (20).
1,2‑Bis(2‑(2‑((tetrahydro‑2,4,6‑trioxopyrimi‑
din‑5(6H)‑ylidene)methyl)phenoxy)ethoxy)ethane
(5g) Yield 90 %. Mp = 220–225 °C. IR (KBr, cm−1):
3,217, 3,074, 1,751, 1,708, 1,679, 1,561. 1H NMR
(400 MHz, DMSO-d6) δ: 3.64 (s, 2 CH2–O), 3.77 (t,
J = 4.8 Hz, 2 CH2–O), 4.21 (t, J = 4.8 Hz, 2 CH2–O), 6.97
(t, J = 7.6 Hz, 2 arom. H), 7.10 (d, J = 8.4 Hz, 2 arom. H),
7.48 (td, J = 7.8, 1.6 Hz, 2 arom. H), 7.98 (dd, J = 7.8,
1.6 Hz, 2 arom. H), 8.52 (s, 2 = CH), 11.15 (s, 2 NH),
11.33 (s, 2 NH). 13C NMR (100 MHz, DMSO-d6) δ: 68.2,
68.7, 70.1, 112.1, 118.6, 119.6, 121.8, 132.5, 133.9, 150.1,
150.2, 158.3, 161.4, 163.3. MS (EI) m/z (%): 578 (M+, 5),
364 (6), 303 (64), 215 (100), 231 (12), 173 (26), 128 (51),
116 (19), 115 (23), 78 (26), 68 (31), 43 (68).
1 ‑ ( 2 ‑ ( 2 ‑ ( 2 ‑ ( ( Te t ra h y d ro ‑ 2 , 4 , 6 ‑ t r i o x o p y r i m i ‑
d i n ‑ 5 ( 6 H ) ‑ y l i d e n e ) m e t h y l ) p h e n o x y ) e t h o x y )
e t h o x y ) ‑ 2 ‑ ( ( t e t r a h y d ro ‑ 2 , 4 , 6 ‑ t r i o x o p y r i m i ‑
din‑5(6H)‑ylidene)methyl)benzene (5d) Yield 90 %.
Mp = 240–243 °C. IR (KBr, cm−1): 3,195, 3,098, 1,753,
1
1,683, 1,592. H NMR (300 MHz, DMSO-d6) δ: 3.87 (s,
2 CH2–O), 4.25 (s, 2 CH2–O), 7.00 (t, J = 7.4 Hz, 2 arom.
H), 7.10 (d, J = 8.3 Hz, 2 arom. H), 7.48 (d, J = 7.2 Hz, 2
arom. H), 7.97 (t, J = 7.8 Hz, 2 arom. H), 8.53 (s, 2 = CH),
11.15 (s, 2 NH), 11.32 (s, 2 NH). 13C NMR (75 MHz,
DMSO-d6) δ: 68.4, 69.1, 112.0, 118.6, 119.7, 122.0, 132.6,
134.1, 150.1, 158.1, 158.3, 161.5, 163.4. MS (EI) m/z (%):
534 (M+, 0.3), 276 (2), 231 (4), 215 (73), 188 (7), 172 (46),
159 (14), 143 (100), 128 (14), 115 (59), 102 (14), 89 (95),
76 (37), 63 (96), 50 (35).
1,2‑Bis(2‑(2‑((tetrahydro‑4,6‑dioxo‑2‑thioxopyrimi‑
din‑5(6H)‑ylidene)methyl)phenoxy)ethoxy)
ethane
(5h) Yield 90 %. Mp = 270–275 °C. IR (KBr, cm−1):
3,070, 1,706, 1,659, 1,547. 1H NMR (400 MHz, DMSO-d6)
δ: 3.65 (s, 2 CH2–O), 3.78 (t, J = 4.8 Hz, 2 CH2–O), 4.21
(t, J = 4.8 Hz, 2 CH2–O), 6.98 (t, J = 7.6 Hz, 2 arom. H),
7.11 (d, J = 8.0 Hz, 2 arom. H), 7.51 (td, J = 7.8, 1.6 Hz,
2 arom. H), 8.07 (dd, J = 7.8, 1.2 Hz, 2 arom. H), 8.56
(s, 2 = CH), 12.26 (s, 2 NH), 12.40 (s, 2 NH). 13C NMR
(100 MHz, DMSO-d6) δ: 68.3, 68.7, 70.1, 112.3, 118.6,
119.6, 121.8, 132.7, 134.6, 150.8, 158.6, 159.4, 161.6,
178.6. MS (EI) m/z (%): 610 (M+, 2), 495 (2), 340 (3), 247
(5), 173 (15), 161 (6), 144 (14), 131 (19), 115 (55), 102
(21), 89 (70), 75 (38), 59 (100).
1‑(2‑(2‑(2‑((Tetrahydro‑4,6‑dioxo‑2‑thioxopy‑
rimidin‑5(6H)ylidene)methyl)phenoxy)ethoxy)
ethoxy)‑2‑((tetrahydro‑4,6‑dioxo‑2‑thioxopyrimi‑
din‑5(6H)‑ylidene)methyl)benzene (5e) Yield 90 %.
Mp = 246–248 °C. IR (KBr, cm−1): 3,068, 1,714, 1,665,
1
1,552. H NMR (300 MHz, DMSO-d6) δ: 3.87 (s, 2 CH2–
O), 4.26 (s, 2 CH2–O), 6.96 (t, J = 7.5 Hz, 2 arom. H), 7.11
(d, J = 8.4 Hz, 2 arom. H), 7.50 (t, J = 8.0 Hz, 2 arom. H),
8.06 (d, J = 7.8 Hz, 2 arom. H), 8.57 (s, 2 = CH), 12.27 (s,
2 NH), 12.33 (s, 2 NH). 13C NMR (75 MHz, DMSO-d6) δ:
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J IRAN CHEM SOC
X
Scheme 1 Synthesis of
benzylidenebarbituric and
thiobarbituric acid derivatives
containing ethylene glycol
spacers
O
O
RN
NR
STO
OTS
O
O
OH
n = 0, 1, 2
O
O
O
O
O
K2CO3/DMF
X = O, S
R = H, Me
n = 0, 1, 2
2
1
3
4
X
X
RN
NR
RN
NR
O
O
O
O
O
O
O
n = 0, 1, 2
5
1,2‑Bis(2‑(2‑((tetrahydro‑1,3‑dimethyl‑2,4,6‑tri‑
oxopyrimidin‑5(6H)‑ylidene)methyl)phenoxy) ethoxy)
for investigating this strategy for the synthesis of a chemi-
cal library of these products. To this purpose, reactions of
thiobarbituric acid and N,N-dimethylbarbituric acid with
ethylene glycol-based dialdehyde were performed (Table 1,
entry 2 and 3). Solids separated out in all the reactions were
collected by filtration and washed with hot methanol or
ethanol to afford the analytically pure products in good to
high yields.
Afterward, to expand the structural diversity accessi-
ble via the developed approach, reactions with alternative
diethylene and triethylene ether-based aromatic dialde-
hydes were investigated. The aromatic aldehydes were
selected based on the addition of molecule lipophilicity.
It was found that these conditions were compatible with a
range of ethylene ether substituents. The conditions were
also sufficiently mild to be tolerated by the number of
ether groups including ethylene, diethylene, and triethylene
ether. Reaction of 3a with barbituric acid led to maximum
yield (90 % yield, Table 1, entry 1).
ethane (5i) Yield 90 %. Mp = 147–150 °C. IR (KBr,
cm−1): 1,713, 1,666, 1,580. 1H NMR (400 MHz, CDCl3) δ:
3.36 (s, 2 N–CH3), 3.41 (s, 2 N–CH3), 3.78 (s, 2 CH2–O),
3.91 (t, J = 4.8 Hz, 2 CH2–O), 4.24 (t, J = 4.8 Hz, 2 CH2–
O), 6.95 (d, J = 8.0 Hz, 2 arom. H), 7.02 (t, J = 7.6 Hz, 2
arom. H), 7.47 (td, J = 8.0, 1.6 Hz, 2 arom. H), 8.05 (dd,
J = 7.8, 1.6 Hz, 2 arom. H), 8.92 (s, 2 = CH). 13C NMR
(100 MHz, CDCl3) δ: 28.3, 28.9, 68.4, 69.5, 71.1, 111.7,
117.3, 120.0, 122.4, 132.7, 134.5, 151.4, 155.1, 158.9,
160.4, 162.4. MS (EI) m/z (%): 634 (M+, 5), 606 (9), 578
(7), 522 (5), 339 (11), 313 (9), 264 (18), 243 (100), 202
(10), 180 (33), 173 (40), 156 (42), 133 (50), 115 (31), 107
(44), 91 (62), 69 (87), 56 (87).
Results and discussion
Structures of compounds (5a–i) were deduced from
1
Oligo ethylene glycol ditosylate (2) was obtained from the
reaction of oligo ethylene glycol with para-tolyl solfunyl
chloride stirring in dichloromethane [24]. Optimization
study for determining the reaction conditions for Knoev-
enagel condensation reaction was initiated with barbituric
acid. Dialdehyde (3) obtained from the reaction of salicy-
laldehyde with ethylene glycol ditosylate in the presence of
K2CO3 was commercially treated with the available barbi-
turic acid in ethanol at reflux (Scheme 1). It was satisfying
to observe that the reaction was complete in 4 h and was
typically characterized by the separation of a solid product
in the reaction mixture.
their spectroscopic and also mass spectral data. The H-
NMR spectra of the products showed a distinguished peak
in region δ: 8.06–8.92 ppm for the -CH olefin protons and
singlet and triplet signals (δ: 3.64–4.46 ppm) for the meth-
ylene protons and also a broad singlet signal at δ: 11.11–
12.40 ppm for the –NH moiety. Partial assignments of
these resonances are given in the “Experimental” section.
Antibacterial activity of the (5a)
The results regarding the antibacterial activity of the 5a is
indicated in Table 2. 1,2-Bis(2-((tetrahydro-2,4,6-triox-
opyrimidin-5(6H)-ylidene)methyl)phenoxy)ethane showed
good activity against Staphylococcus aureus and did not
display any antibacterial activity against Escherichia coli
Isolation and spectroscopic characterization of the sepa-
rated solid indicated the desired ethylene glycol-based ben-
zylidene barbituric acid (5a). This result was a motivation
1 3

J IRAN CHEM SOC
Table 1 Synthesis of
benzylidenebarbituric and
thiobarbituric acid derivatives
containing ethylene glycol
spacers
Entry
Dialdehyde 3
Barbiturate 4
Product 5
Yield (%)
O
O
NH
HN
HN
O
O
NH
O
O
O
O
O
HN
NH
O
O
O
O
O
O
4a
5a
3a
1
90
S
S
NH
O
HN
HN
O
NH
O
O
O
O
S
O
HN
NH
O
O
O
O
O
4b
5b
3a
2
3
85
80
O
O
N
N
N
O
N
O
O
O
O
O
O
O
N
N
O
O
O
O
O
3a
4c
5c
O
O
HN
NH
O
NH
HN
O
O
O
O
O
O
O
O
HN
NH
O
O
O
O
O
O
3b
4a
5d
4
83
S
S
HN
O
HN
NH
O
NH
O
O
S
O
O
HN
NH
O
O
O
O
O
O
O
O
3b
5e
4b
5
6
85
86
O
N
O
O
N
N
O
O
O
N
O
O
O
O
O
N
N
O
O
O
O
O
O
3b
4c
5f
O
O
HN
NH
NH
O
O
HN
O
O
O
O
O
HN
NH
O
O
O
O
O
O
O
O
O
O
4a
5g
3c
7
8
75
79
S
S
HN
NH
NH
O
O
HN
O
S
O
O
O
HN
NH
O
O
O
O
O
O
O
O
O
O
4b
3c
5h
O
O
N
N
N
N
O
O
O
O
O
O
O
O
O
N
N
O
O
O
O
O
O
O
O
5i
3c
4c
9
82
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J IRAN CHEM SOC
Table 2 Antibacterial activity of 5a
Microorganism Inhibition zone in mm
5a
6. S. Sundrival, B. Viswanad, P. Ramarao, A.K. Chakraborti, P.V.
Bharatam, Bioorg Med Chem lett 18, 4959 (2008)
7. T. Tihomir, Z. Nace, M.P. Manica, K. Danijel, P.M. lucija, Eur J
Med Chem 45, 1667 (2010)
8. Y. Qin, C. Rihui, Y. Wei, C. Zhiyong, W. Huan, M. lin, S. Hua-
5 mg/ml
10 mg/ml
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In conclusion, a very simple and highly efficient synthe-
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dialdehyde derivatives with active methylene compounds
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