One-Pot Multi-Component Synthesis of 1,4-Dihydropyridines Using Zn2+@KSF and Evaluating Their Antibacterial and Antioxidant Activities

Article abstract of DOI:10.1002/ardp.201400414

New 5-aryl-10-(4-(4-methoxyphenyl)thiazole-2-yl)-9,10-dihydropyrido[2,3-d:5,6-d′]dipyrimidinone-2,4,6,8-(1H,3H,5H,7H)-tetraones 6a-d were synthesized through one-pot four-component reaction of aldehydes, barbituric acid, and thiazole using Zn²⁺

Full text of DOI:10.1002/ardp.201400414

ARCH PHARM
Arch. Pharm. Chem. Life Sci. 2015, 348, 1–8
Archiv der Pharmazie
Full Paper
One-Pot Multi-Component Synthesis of 1,4-Dihydropyridines
2
þ
Using Zn @KSF and Evaluating Their Antibacterial and
Antioxidant Activities
Nosrat O. Mahmoodi, Sahar Ramzanpour, and Fateme Ghanbari Pirbasti
Department of Chemistry, Faculty of Science, University of Guilan, Rasht, Iran
0
New 5-aryl-10-(4-(4-methoxyphenyl)thiazole-2-yl)-9,10-dihydropyrido[2,3-d:5,6-d ]dipyrimidinone-2,4,6,8-
(
1H,3H,5H,7H)-tetraones 6a–d were synthesized through one-pot four-component reaction of aldehydes,
2þ
barbituric acid, and thiazole using Zn @KSF under reflux condition. The key features of this reaction are:
incorporating four heterocyclic rings, using a heterogeneous and efficient catalyst, high yield, and easy-to-
1
13
setup reaction. The structure of the products was confirmed by FT-IR, H NMR, and C NMR spectra. The
antibacterial activities of compounds 6a–d were screened against Escherichia coli, Micrococcus luteus,
Pseudomonas aeruginosa, and Staphylococcus aureus bacterial strains using the zone inhibition method.
Also, the 2,2-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities of compounds 6a–d were
evaluated.Allcompoundsshowedgoodantioxidantcapacityincomparisontoascorbicacid. TheIC50 values
of the antioxidant activity were calculated. The proposed mechanism for antioxidant activity is discussed.
2
þ
Keywords: Antibacterial / Antioxidant / Barbituric acid / 1,4-Dihydropyridines / Zn @KSF
Received: November 29, 2014; Revised: January 25, 2015; Accepted: January 30, 2015
DOI 10.1002/ardp.201400414
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
Introduction
Barbituric acid and its derivatives are found in many drugs
21–23]. These compounds are most important classes of drug
[
1
,4-Dihydropyridines (1,4-DHPs) are used commercially such as
molecules and were introduced for medical use in 1911 [24].
They have attracted much attention due to their antiviral [25],
antibiotic [26], anti-inflammatory [27], and antitumor [28]
activities. The biological activities and their ability to be
functionalized made barbituric acids a useful starting material
for synthesis of fused rings.
The scope of heterogeneous catalytic organic transforma-
tions is rapidly growing due to their well-documented
advantages over homogeneous catalytic systems. Montmoril-
lonite KSF has been used as catalysts in organic reactions and
has represented several advantages over traditional acids.
Such as the strong acidity, non-corrosive properties, mild
reaction conditions, cheapness, high yields and selectivity, and
the facility of setting and working-up. Recently, we used
KSF as an efficient catalyst for synthesis of pyridazinones
and phthalazinones [29–31], Schiff bases [32], 2-(thiazol-2-yl)-
diludine, felodipine, amlodipine, and nimodipin and also they
possess various biological activities such as cardiovascular [1],
HIV protease inhibition [2], antioxidant [3], anti-inflammato-
ry [4], calcium channel blocker [5], analgesic [6], antitumor [7],
antithrombotic [8], anticonvulsant [9], antimicrobial [10], and
anticoagulant [11].
Thiazoles have been found to be associated with a wide
variety of biological activities, such as antibacterial [12, 13],
antifungal [14], anti-inflammatory [15], antimalarial [16],
antioxidant [17], antitumor [18], antimicrotubule [19], and
antihypertension [20].
Correspondence: Dr. Nosrat O. Mahmoodi, Department of
Organic Chemistry, Faculty of Science, University of Guilan, PO
Box 41335-1914, Rasht, Iran.
E-mail: mahmoodi@guilan.ac.ir, nosmahmoodi@gmail.com
Fax: þ98-1313233262
4
,5-dihydropyridazin-3(2H)-one [33], and mono- and bis-
indolylimidazole [34].
Following our prior efforts in the design and synthesis of
heterocyclic compounds [35–40], and also regarding diverse
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Arch. Pharm. Chem. Life Sci. 2015, 348, 1–8
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0
9
,10-dihydropyrido[2,3-d:5,6-d ]dipyrimidinone-2,4,6,8-(1H,3H,
5H,7H)-tetraones 6a–d in reasonable yields (Scheme 2).
In order to establish the optimized reaction conditions, the
reaction of thiazole 3 (1 mmol), barbituric acid 4 (2 mmol), and
-nitrobenzaldehyde 5a (1 mmol) under different conditions
4
such as nature of solvent, type and amount of catalyst and
reaction temperature were examined (Table 1). It was found
that the reaction without any catalyst proceeded slowly with
low yield after refluxing for 24 h (entry 1, Table 1). However, by
using different catalysts under reflux condition in EtOH, the
2þ
reactionyieldsincreased;byusingZn @KSFascatalystinEtOH
78°C), the product obtained a higher yield and shorter
reaction time (entry 5, Table 1). Also, the effect of different
solvents such as ethylene glycol, EtOH, MeOH, AcOH, H O,
(
2
DMF, and acetone was examined. When the reaction was
carried out in EtOH the results showed that higher yields and
shorter reaction times were obtained (entry 5, Table 1).
Figure 1. Structure of products 6a–d and defining biological
activities of each moiety.
2þ
Moreover, the amount of catalyst Zn @KSF was investigated;
bydecreasingtheamountofcatalystto0.01 g(entry6,Table1),
the yield decreased, on the other hand by increasing the
amount of catalyst to 0.06 g (entry 7, Table 1), a slight increase
biological activities of thiazoles and barbituric acids men-
tioned above, we report one-pot semi-four-component
synthesis of novel 1,4-dihydropyridines bearing thiazole
2þ
in yield was observed. So, 0.03 g Zn @KSF per 1 mmol
substrate was efficient for the reaction. In the other efforts,
the effect of temperature on the yield of product was studied.
Low yield of product was isolated at room temperature
2þ
moiety using Zn @KSF as a green catalyst (Fig. 1).
(entry 8, Table 1), by increasing the temperature from 78 to 120°C
Results and discussion
(entries 5, 9, 10, Table 1), a decrease of yield was observed. As a
result, theoptimizedconditionforsynthesisof1,4-DHPs6a–dwas
2þ
Chemistry
obtained in the presence of Zn @KSF (0.03 g) in EtOH at 78°C.
According to proposed mechanism (Scheme 3), nucleophilic
addition of barbituric acid 4 to activated aldehyde 7 in the
presence of catalyst led to intermediate 8 which becomes
involved in the addition reaction with second molecule of 4 and
subsequent addition of 3 to adduct 9 via 10 by losing water and
finally further intramolecular cyclization led to 6a–d.
A survey in literature showed that different 1,4-DHPs have
been synthesized; however, 1,4-DHPs bearing thiazole moiety
as N source of 1,4-DHPs ring of barbituric acid have not been
reported yet.
Herein, we report an efficient method for regioselective
synthesis of new 1,4-DHPs 6a–d using premade thiazole 3 as
amine part through one-pot 4 MCRs. 4-(4-Methoxyphenyl)-
thiazole-2-amine 3 was prepared from reaction of 2-bromo-1-
1
The structure of products 6a–d was characterized by FT-IR, H
13
NMR, and C NMR spectra. The FT-IR spectra of compounds 6a–
(
4-methoxyphenyl)ethanone 1 with thiourea 2 in EtOH under
d reveal the presence of two N–H stretching vibrations in 3450–
À 1
reflux condition in high yield as a white powder [41] (Scheme 1).
In this effort the reaction of 1 eq. of prepared thiazole 3, 2 eq.
barbituric acid 4, and 1 eq. aldehydes 5a–d in the presence of
catalytic amount of Zn @KSF under reflux condition led to
preparation of 5-aryl-10-(4-(4-methoxyphenyl)thiazole-2-yl)-
3250 and 3280–3120 cm , absorbance of C –– O amide appeared
À 1
1
in 1660–1700 cm . In the H NMR spectra of compounds 6a–d,
twosingletsin10.22–9.27and8.87–8.39 ppm arerelatedtoN–H
of barbituric moiety, a sharp singlet in the 5.83–5.57 is due to
C–H of 1,4-DHP and confirms the formation of 1,4-DHP ring.
2þ
Scheme 1. Preparation of 4-(4-metoxyphenyl)thiazole-2-amine 3.
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Arch. Pharm. Chem. Life Sci. 2015, 348, 1–8 2
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Synthesis of 1,4-Dihydropyridines Using Zn @KSF
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0
Scheme 2. Synthesis of 5-aryl-10-(4-(4-methoxyphenyl)thiazole-2-yl)-9,10-dihydropyrido[2,3-d:5,6-d ]dipyrimidinone-2,4,6,8-
(1H,3H,5H,7H)-tetraones 6a–d.
Sharp singlet in 5.99–5.87 ppm is related to C–H of the thiazole
moiety, and methoxy group appeared in 3.77–3.76 ppm as a
singlet. Aromatic protons appeared in the expected region
of compounds was 4000 mg/mL in DMSO as solvent. Results are
summarized in Table 2. According to the results, compound 6a
had the most antibacterial activity against E. coli whereas
it had the least antibacterial activity against S. aureus.
Moreover, compound 6c showed potent antibacterial activity
against S. aureus and M. luteus. Recently, Lobo et al. [42]
13
8.06–6.92 ppm. The C NMR spectra of compounds 6a–d reveal
signal of 1,4-DHP carbons in 38.8–35.8 ppm which confirms
the formation of 1,4-DHP ring, and methoxy group in 55.5–
55.7 ppm. Other signal appeared in 86.8–169.4 ppm.
2
reported that the presence of NO and Cl group has a positive
effect against bacterial strains. Here, in our study, compound
6a bearing nitro and compound 6c bearing two Cl groups had
good antibacterial activity. All the synthesized compounds
showed weak antibacterial activity against P. aeruginosa.
Antibacterial activity
Compounds 6a–d were evaluated for their in vitro antibacte-
rial activity against Escherichia coli (E. coli), Micrococcus
luteus (M. luteus), Pseudomonas aeruginosa (P. aeruginosa),
and Staphylococcus aureus (S. aureus) by zone inhibition
method. DMSO was used as negative control and penicillin G
and cefixim were used as standard drugs. The concentration
Antioxidant assay
DPPH or 2,2-diphenyl-2-picrylhydrazyl is a stable free radical
that can accept an electron or hydrogen radical and can be
Table 1. Optimization of the reaction conditions.
Entry
Solvent
Catalyst
Amount of catalyst (g)
Temperature (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
–
–
78
78
78
78
78
78
78
rt
100
120
100
100
100
65
24
6
9
4
2
2
2
2
2
2
3
2.5
3
2
4
3
20
72
65
50
84
55
86
33
72
65
45
62
51
82
60
60
p-TSA
ZnCl
0.03
0.03
0.03
0.03
0.01
0.06
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
2
KSF
2
þ
Zn @KSF
2
þ
Zn @KSF
2
þ
Zn @KSF
2
þ
Zn @KSF
2
þ
Zn @KSF
2
þ
1
1
1
1
1
1
1
0
1
2
3
4
5
6
EtOH
Zn @KSF
2
þ
Ethylene glycol
AcOH
Zn @KSF
2
þ
Zn @KSF
2
þ
DMF
MeOH
Zn @KSF
2
þ
Zn @KSF
2
þ
H
2
O
Zn @KSF
100
50
2
þ
Acetone
Zn @KSF
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Scheme 3. Proposed mechanism for the formation of 6a–d.
Table 2. Antibacterial activity of newly synthesized compounds 6a–d as zone of inhibition (mm).
Antibacterial activity (mean Æ SD)
Compound
S. aureus
M. luteus
E. coli
P. aeruginosa
6
6
6
6
a
b
c
6.66 Æ 0.57
7.50 Æ 0.70
11.66 Æ 0.57
6.50 Æ 0.70
–
9.50 Æ 2.12
6.50 Æ 0.70
13.00 Æ 1.41
9.00 Æ 1.41
–
18.33 Æ 2.08
7.66 Æ 1.52
8.66 Æ 1.52
8.00 Æ 1.00
–
8.33 Æ 1.15
7.33 Æ 0.57
7.33 Æ 0.57
d
–
–
a)
DMSO
Penicillin G
Cefixim
b)
23
38
55
35
45
39
24
30
b)
a)
b)
Negative control.
Positive control.
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Arch. Pharm. Chem. Life Sci. 2015, 348, 1–8 2
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Synthesis of 1,4-Dihydropyridines Using Zn @KSF
Archiv der Pharmazie
converted to a stable molecule. DPPH has a strong absorption
band at 517 nm, when DPPH radical accepts an electron from
other compound, its absorption band will decrease. The
decrease in absorption band depends on the tested com-
pounds antioxidant capacity. Higher antioxidant capacity of
the tested compound led to more decrease of absorption
band. Radical scavenging activity of compounds 6a–d was
determined in concentrations 2000–62.5 mg/mL in methanol.
Also, their IC50 values were reported which is the concentra-
tion of tested compound required to scavenge 50% of the
Table 3. IC50 for DPPH assay of compounds 6a–d and
comparison to ascorbic acid.
Compound
DPPH assay IC50 (mg/mL)
6a
6b
1.11
1.28
1.12
0.33
0.38
6
6
c
d
Ascorbic acid
À 6
DPPH radical concentration (6.25 Â 10 M). The experiments
were conducted in triplicate. All compounds showed antioxi-
dant activity. According to Fig. 2 radical scavenging activity
was dose dependent and increased with concentration of the
compounds 6a–d. Compound 6d exhibited the highest DPPH
radical scavenging whereas compound 6b had the lowest
DPPH radical scavenging capacity. The IC50 values were
calculated according to line equations and are reported in
Table 3. The IC50 values were between 1.28 and 0.33 mg/mL.
Compound 6d had the lowest IC50 value (0.33 mg/mL) in
comparison to ascorbic acid (0.38 mg/mL).
(1H,3H,5H,7H)-tetraones 6a–d bearing four heterocyclic
moiety was reported. The synthesis was performed by the
reaction of barbituric acid, aldehydes, and 4-(4-methoxy-
2
þ
phenyl)thiazole-2-amine in the presence of Zn @KSF as an
efficient catalyst. Compound 6c showed good antibacterial
activity against S. aureus and M. luteus, whereas compound
6a exhibited good antibacterial activity against E. coli. All
compounds showed good and reasonable DPPH radical
scavenging activity, compound 6d exhibited very high
antioxidant capacity in comparison to ascorbic acid.
The good antioxidant activity of compounds 6a–d can be
due to N–H groups of barbituric acid component which can
donate H radical to DPPH and then conjugate through system.
Also, C–H bond on the DHP ring can release H radical to DPPH.
The highest antioxidant capacity of compound 6d in
comparison to other derivatives can be due to methyl group
on aromatic ring which can donate H radical and can be
converted to a stable benzyl radical which can resonate in
molecule and stabilize the radical through the whole
compound. The proposed radical molecules for compound
Experimental
Chemistry
2þ
Zn @KSF was prepared according to the literature procedure
1
[43]. The H NMR spectra were obtained on a Bruker Avance
13
400 MHz spectrometer. C NMR spectra were recorded on a
Bruker100 MHzinstrument.DMSO-d wasusedassolvent. FT-IR
6
spectra were measured with a Shimadzu IR-470 spectropho-
tometer. Melting points are uncorrected and were determined
using a MettlerFp5 apparatus. DPPH radical scavenging activity
was recorded on UNICO 1200 spectrophotometer. All chemicals
were purchased from Aldrich, Merck, and Fluka.
6
d are depicted in Scheme 4.
Conclusion
In conclusion, a convenient, efficient, high yield, simple setup,
and work-up, one-pot, semi-four-component procedure for
General procedure for the synthesis of 5-aryl-10-(4-(4-
methoxyphenyl)thiazole-2-yl)-9,10-dihydropyrido[2,3-
d:5,6-d ]dipyrimidinone-2,4,6,8-(1H,3H,5H,7H)-tetraones
0
synthesis of novel 5-aryl-10-(4-(4-methoxyphenyl)thiazole-
0
2
-yl)-9,10-dihydropyrido[2,3-d:5,6-d ]dipyrimidinone-2,4,6,8-
6a–d
Thiazole 3 (1 mmol), barbituric acid 4 (2 mmol), aldehydes 5a–
2
þ
d (1 mmol), and 0.03 g Zn @KSF were dissolved in EtOH
10 mL), the mixture was refluxed for the required time (2 h).
(
The progress of the reaction was controlled by TLC (n-hexane/
EtOAc 6:3). After completion of the reaction, the hot mixture
was filtered to remove the catalyst, then cooled down, and
the solid filtered off and washed with hot water for
purification.
1
9
0-(4-(4-Methoxyphenyl)thiazole-2-yl)-5-(4-nitrophenyl)-
,10-dihydropyrido[2,3-d:5,6-d ]dipyrimidone-2,4,6,8-
0
(
1H,3H,5H,7H)-tetraone (6a)
À 1
Cream solid, yield 84%; m.p. 320–323°C; FT-IR (KBr, n cm ):
3
1
340, 3200, 2850, 1710, 1680, 1600, 1510, 1540, 1340, 1460,
250, 1010, 830, 780, 660. H NMR (400 MHz, DMSO-d , ppm):
6
1
Figure 2. DPPH radical scavenging activity of compounds 6a–d.
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10.22 (s, br. 2H, H
f
, NH), 8.87 (s, br. 2H, H
e
, NH), 8.06 (d,
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Arch. Pharm. Chem. Life Sci. 2015, 348, 1–8
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Scheme 4. DPPH radical scavenging with DHP 6d.
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Arch. Pharm. Chem. Life Sci. 2015, 348, 1–8 2
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Synthesis of 1,4-Dihydropyridines Using Zn @KSF
Archiv der Pharmazie
J ¼ 8.8 Hz, 2H, H
i
), 7.38 (d, J ¼ 8.4 Hz, 2H, H
), 5.99 (s, 1H, H
). C NMR (100 MHz, DMSO-d
6
c
), 7.29 (d, J ¼ 8.4 Hz,
), 5.57 (s, 1H,
, ppm): 169.4,
nutrient agar plates were prepared according to manufac-
tures’ instructions and incubated at 37°C. After cooling at
room temperature, a suspension of 30 mL bacteria was added
to nutrient agar plates. Cups (5 mm in diameter) were cut in
the agar using sterilized glass tube. Each well received 30 mL of
the 4 mg/mL solution of the test compounds dissolved in
DMSO. Then, plates were incubated at 37°C and after 24 h, the
inhibition zones were measured and value expressed in
millimeters. The experiments were performed in triplicate.
The results are reported as mean Æ standard deviation of zone
of inhibition in millimeter. Activity of each compound was
compared with penicillin G and cefixim as standard drugs.
DMSO was used as negative control.
2
H, H
h
), 7.01 (d, J ¼ 8.8 Hz, 2H, H
b
d
1
3
H
g
), 3.76 (s, 3H, H
a
1
1
65.1, 160.6, 154.0, 150.9, 146.79, 145.5, 130.9, 128.3, 123.3,
21.1, 114.6, 97.9, 88.8, 55.7, 38.8. Anal. calcd. for
C
H N
25 17 7
O
7
S: C, 53.66; H, 3.05; N, 17.54. Found: C, 53.68; H,
3
.07; N, 17.51%.
1
0-(4-(4-Methoxyphenyl)thiazole-2-yl)-5-(2-
0
chlorophenyl)-9,10-dihydropyrido[2,3-d:5,6-d ]-
dipyrimidone-2,4,6,8-(1H,3H,5H,7H)-tetraone (6b)
White solid, yield 82%; m.p. 322–324°C; FT-IR (KBr, n cm ):
À 1
3
250, 3150, 3050, 2950, 2820, 1700, 1660, 1600, 1570, 1510,
1
1
470, 1350, 1260, 1030, 1090. H NMR (400 MHz, DMSO-d
, NH), 8.39 (s, br. 2H, H , NH), 7.63 (d,
), 7.32 (d, J ¼ 8 Hz, 2H, H ), 7.25–7.10 (m, 3H,
), 6.92 (d, J ¼ 8.8 Hz, 2H, H ), 5.87 (s, 1H, H ), 5.67 (s,
). C NMR (100 MHz, DMSO-d , ppm):
6
,
ppm): 9.35 (s, br. 2H, H
J ¼ 7.2 Hz, 1H, H
, H , H
H, H ), 3.77 (s, 3H, H
f
e
DPPH radical-scavenging activity
k
c
DPPH radical-scavenging activity of compounds 6a–d was
evaluated according to Jin [44] method. The 2,2-diphenyl-2-
picrylhydrazyl (DPPH) solution was prepared by dissolving an
appropriate amount of DPPH in MeOH to give a concentration of
H
h
i
j
b
d
13
1
1
1
g
a
6
68.5, 163.9, 159.9, 152.1, 151.1, 150.0, 142.0, 133.0, 131.4,
30.2, 129.3, 127.3, 126.5, 123.9, 114.3, 99.8, 86.8, 55.6, 36.2.
À 5
6.25 Â 10 M. Then, 3.9 mL of this solution was added to 0.1 mL
Anal. calcd. for C25
Found: C, 54.72; H, 3.15; N, 15.31%.
H17ClN
6
O
5
S: C, 54.69; H, 3.13; N, 15.29.
of sample solution in different concentrations (2000, 1000, 500,
250, 125, 62.5 mg/mL in MeOH). The samples were shaken
vigorously and were kept in dark for 30 min, then the decrease in
theabsorbanceoftheresultingsolutionwasmeasuredat517 nm.
MeOH was used as blank and a sample of 3.9 mL DPPH containing
0.1 mL of MeOH instead of sample was used as control. Inhibition
of free radical DPPH in percentage was calculated as follows:
1
0-(4-(4-Methoxyphenyl)thiazole-2-yl)-5-(2,4-
0
dichlorophenyl)-9,10-dihydropyrido[2,3-d:5,6-d ]-
dipyrimidone-2,4,6,8-(1H,3H,5H,7H)-tetraone (6c)
White solid, yield 80%; m.p. 321–323°C; FT-IR (KBr, n cm ):
À 1
ꢀ
ꢁ
3
1
450, 3280, 3120, 2950, 2820, 1700, 1660, 1600, 1580, 1510,
Ablank À A
sample
1
460, 1370, 1250, 1030, 1100. H NMR (400 MHz, DMSO-d
6
,
Radical scavenging activity ¼
 100
A
blank
ppm): 9.48 (s, br. 2H, H
J ¼ 8.8 Hz, 1H, H ), 7.37 (s, 1H, H
d, J ¼ 8.8 Hz, 1H, H
.83 (s, 1H, H ), 3.76 (s, 3H, H
ppm): 168.7, 163.9, 160.9, 152.1, 151.1, 142.1, 141.0, 133.7,
f
, NH), 8.53 (s, br. 2H, H
e
, NH), 7.62 (d,
i
j
), 7.28 (d, J ¼ 8 Hz, 2H, H
c
), 7.15
b d
), 5.87 (s, 1H, H ),
where Ablank is the absorbance of negative control (containing
all reagents except test compounds) and Asample is the
absorbance of the test compounds and all the reagents. IC50
of the samples was calculated by plotting the radical scavenging
percentage against sample concentration.
(
5
h
), 6.94 (d, J ¼ 8 Hz, 2H, H
13
g
a 6
). C NMR (100 MHz, DMSO-d ,
1
9
32.8, 131.9, 131.4, 130.3, 130.2, 127.3, 126.6, 126.1, 114.3,
9.9, 86.8, 55.5, 35.8. Anal. calcd. for C25 S: C, 51.48;
H
2 6 5
16Cl N O
H, 2.76; N, 14.39. Found: C, 51.50; H, 2.74; N, 14.41%.
The authors greatly acknowledge the helpful assistance of
Dr. Zohreh Ramezanpour (International Sturgeon Research
Institute, Rasht, Iran) and Miss Somaie Rasooli for running
antibacterial assay. The chemical experiments of this research
were supported by the Research Committee of University of
Guilan.
1
0-(4-(4-Methoxyphenyl)thiazole-2-yl)-5-(paratolyl)-9,10-
0
dihydropyrido[2,3-d:5,6-d ]dipyrimidone-2,4,6,8-
(
1H,3H,5H,7H)-tetraone (6d)
À 1
Cream solid, yield 84%; m.p. 327–329°C; FT-IR (KBr, n cm ):
3
400, 3120, 2920, 2820, 1680, 1650, 1570, 1510, 1460, 1250,
1
1
020, 840, 780, 620. H NMR (400 MHz, DMSO-d
, NH), 8.51 (s, br. 2H, H
, NH), 7.53 (d, J ¼ 6.8 Hz, 2H,
), 7.08–6.88 (m, 6H, H , H , H ), 5.88 (s, 1H, H ), 5.59 (s, 1H,
), 3.76 (s, 3H, H ), 2.50 (s, 3H, H ). C NMR (100 MHz, DMSO-
, ppm): 169.3, 168.5, 164.2, 155.4, 152.2, 151.1, 134.4, 130.8,
29.3, 128.6, 127.1, 114.3, 99.8, 86.8, 55.6, 37.0, 20.9. Anal.
calcd. for C26 S: C, 59.08; H, 3.82; N, 15.89. Found: C,
9.06; H, 3.84; N, 15.91%.
6
, ppm): 9.27
The authors have declared no conflict of interest.
(
s, br. 2H, H
f
e
H
H
d
c
b
h
i
d
13
g
a
j
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Antibacterial assay
The antibacterial activity of compounds was evaluated
biologically using the Agar well-diffusion method. First,
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