One-pot and solvent-free synthesis of 3-(9-hydroxy-3-methoxy-7-aryl-6,7,9,10-tetrahydro-5H -benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-2H -chromen-2-ones and their antibacterial evaluation

Article abstract of DOI:10.3906/kim-1410-64

A series of 3-(9-hydroxy-3-methoxy-7-aryl-6,7,9,10-tetrahydro-5H -benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-2H -chromen-2-ones (5a-j) were synthesized by one-pot multicomponent reaction of 6-methoxy-1-tetralone, aryl aldehydes, and thiourea followed by cyclization with 3-(2-bromoacetyl)-2H -chromen-2-one in the presence of a Bronsted solid acid catalyst, poly(4-vinylpyridinium)hydrogen sulfate [P(4-VPH)HSO₄] (0.015 g), under solvent-free conditions at 120°C. All the synthesized compounds were characterized by spectral studies and screened for their in vitro antibacterial activity against S. aureus and B. thuringiensis (gram positive), and E. coli and K. pneumoniae (gram negative) bacterial strains. On comparing with the standard drug gentamicin, compounds derived from 4-methoxy and 3,4,5-trimethoxy benzaldehyde, i.e. 5g and 5h, showed broad spectrum antibacterial activity and the remaining compounds showed weak to moderate activity.

Full text of DOI:10.3906/kim-1410-64

Turk J Chem
Turkish Journal of Chemistry
(2015) 39: 620 – 629
¨
http://journals.tubitak.gov.tr/chem/
˙
c
⃝ TUBITAK
doi:10.3906/kim-1410-64
Research Article
One-pot and solvent-free synthesis of 3-(9-hydroxy-3-methoxy-7-aryl-6,7,9,10-
tetrahydro-5H -benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-2H -chromen-2-ones and
their antibacterial evaluation
Ravibabu VELPULA1, Janardhan BANOTHU1, Rajitha GALI1,
Yakaiah SARGAM2, Rajitha BAVANTULA1,∗
1Department of Chemistry, National Institute of Technology, Warangal, Telangana State, India
2Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, Telangana State, India
Received: 29.10.2014
•
Accepted/Published Online: 18.02.2015
•
Printed: 30.06.2015
Abstract: A series of 3-(9-hydroxy-3-methoxy-7-aryl-6,7,9,10-tetrahydro-5H -benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-
2H -chromen-2-ones (5a–j) were synthesized by one-pot multicomponent reaction of 6-methoxy-1-tetralone, aryl aldehy-
des, and thiourea followed by cyclization with 3-(2-bromoacetyl)-2H -chromen-2-one in the presence of a Brønsted solid
acid catalyst, poly(4-vinylpyridinium)hydrogen sulfate [P(4-VPH)HSO4 ] (0.015 g), under solvent-free conditions at 120
◦ C. All the synthesized compounds were characterized by spectral studies and screened for their in vitro antibacterial
activity against S. aureus and B. thuringiensis (gram positive), and E. coli and K. pneumoniae (gram negative) bacterial
strains. On comparing with the standard drug gentamicin, compounds derived from 4-methoxy and 3,4,5-trimethoxy
benzaldehyde, i.e. 5g and 5h, showed broad spectrum antibacterial activity and the remaining compounds showed weak
to moderate activity.
Key words: Quinazolinethiones, thiazoloquinazolines, poly(4-vinylpyridinium)hydrogen sulfate, one pot and solvent-
free method, antibacterial activity
1. Introduction
Quinazoline and its annulated derivatives represent an important class of heterocyclic compounds. They play
an important role in medicinal chemistry due to their wide range of biological activities such as antimicrobial,
antiviral, anticancer, anti-inflammatory, anticonvulsant, anti-HIV, pesticidal, and insecticidal properties.1−10
They were also reported as inhibitors of enzymes like poly(ADP-ribose)polymerase-1, glycogen synthase kinase-
3, and bacterial DNA polymerase III.11−13 Similarly, the thiazole nucleus is one of the most notable motifs
in medicinal chemistry, possessing several biological activities.14−20 It is an integral part of all the available
penicillins for controlling bacterial diseases.21 On the other hand, coumarin derivatives were found to possess
various pharmacological activities such as antimicrobial, anticancer, antihepatitis, antidepressant, antioxidant,
anticoagulant, and anti-HIV activities.22−28 They are also widely used as additives in foods, perfumes, and
cosmetics, in the preparation optical brighteners, and in dispersed fluorescent and laser dyes.29,30
In view of the varied biological activities shown by quinazolines, thiazoles, and coumarins, we focused
on the design of a novel structural entity that combines these three structural moieties into a single molecular
∗Correspondence: rajitabhargavi@yahoo.com
620

VELPULA et al./Turk J Chem
scaffold and to evaluate their potential additive effect on biological activity, especially antibacterial activity.
Therefore, in the present communication and in continuation of our earlier studies on annulated quinazolines,
we report the synthesis of novel coumarin incorporated benzo[h]thiazolo[2,3-b]quinazolines and evaluate their
antibacterial activity.31,32
2. Results and discussion
2.1. Chemistry
Recently, our group reported the synthesis of 8-methoxy-4-aryl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-
thiones via a modified Biginelli reaction of 6-methoxy-1-tetralone, aryl aldehyde, and thiourea in the presence
of a Brønsted solid acid catalyst, poly(4-vinylpyridinium)hydrogen sulfate [P(4-VPH)HSO4 ] (0.015 g), under
solvent-free conditions at 120 ◦ C.33 This method has the advantages of good yields, shorter reaction times,
and reusability of the catalyst over five additional times without losing its activity and product yield. At the
same time, several methods are reported for the synthesis of thiazolopyrimidines or fused thiazolopyrimidines
resulting from the reaction of 3,4-dihydropyrimidin-2(1H)-thiones (Biginelli products) with chloroacetic acid,
bromoacetic acid, chloroacetyl chloride, methyl chloroacetate, ethyl bromoacetate, and 2-haloacetamides.34−43
Based upon these reports and the efficiency of acid catalyst poly(4-vinylpyridinium)hydrogen sulfate, we
developed one-pot synthesis of benzo[h]thiazolo[2,3-b]quinazoline derivatives from 6-methoxy-1-tetralone (1),
aryl aldehyde (2a–j), and thiourea (3) followed by cyclization with 3-(2-bromoacetyl)-2H -chromen-2-one (4)
in poly(4-vinylpyridinium)hydrogen sulfate [P(4-VPH)HSO4 ] (0.015 g) as an acid catalyst under solvent-free
conditions at 120 ◦ C with good yields (Table 1). The schematic representation is shown in Scheme 1. A
plausible mechanism for formation of products is shown in Scheme 2. The catalyst P(4-VPH)HSO4 was prepared
according to the literature procedure.44
Table 1. Synthesis of 3-(9-hydroxy-3-methoxy-7-aryl-6,7,9,10-tetrahydro-5H -benzo[h] thiazolo[2,3-b]quinazolin-9-yl)-
2H -chromen-2-ones (5a–j).
Entrya Compound Time (min) Yieldb (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
55
50
55
60
50
60
45
45
45
45
86
89
85
86
82
82
90
89
88
86
9
10
5j
Reaction conditions: (a) 6-Methoxy-1-tetralone (1, 1 mmol), aryl aldehyde (2a–j, 1 mmol), thiourea (3, 1 mmol), 3-(2-
Bromoacetyl)-2H -chromen-2-one (4, 1 mmol), P(4-VPH)HSO4 (0.015 g), 120 ◦ C, neat conditions. b Isolated yields.
In this work, we expected formation of the products benzo[h]thiazolo[2,3-b]quinazolines (6a–j) but, from
the IR spectra, the appearance of a broad band in the range of 3439–3447 cm−1 for the hydroxy (–OH)
group, the presence of two doublets in the range of 3.45–3.50 ppm and 4.05–4.12 ppm for thiazolidine (–CH2 –)
protons and a singlet at 8.23–8.39 ppm for hydroxy (–OH) proton from 1 H NMR, and the presence of signals
621

VELPULA et al./Turk J Chem
Scheme 1. Synthesis of 3-(9-hydroxy-3-methoxy-7-aryl-6,7,9,10-tetrahydro-5H -benzo[h] thiazolo[2,3-b]quinazolin-9-
yl)-2H -chromen-2-ones.
at 42.2–42.5 ppm and 94.7–95.5 ppm for thiazolidine (–CH2 –) and –OH attached carbons, respectively, from
13 C NMR confirmed the product as benzo[h]thiazolo[2,3-b]quinazolin-ols (5a–j) not the benzo[h]thiazolo[2,3-
b]quinazolines (6a–j). The molecular ion peak from the mass spectra and elemental analyses data further
confirmed the formation of products 5a–j.
2.2. Antibacterial activity
All the synthesized compounds (5a–j) were screened for their in vitro antibacterial activity against Staphylococ-
cus aureus and Bacillus thuringiensis (gram positive), and Escherichia coli and Klebsiella pneumoniae (gram
negative) bacterial strains with respect to the standard antibiotic drug gentamicin.
Zone of inhibition (ZOI) (in mm) values for the analogues (5a–j) at 100 µg/mL and the positive
control drug gentamicin at 30 µg/mL were determined by agar disk diffusion method.45 The bacterial strains
were grown and maintained on nutrient agar plates. All the compounds (100 µg) were dissolved in DMSO
622

VELPULA et al./Turk J Chem
Scheme 2. Plausible mechanism.
and transferred to each disk with the help of a micropipette, simultaneously maintaining the standard drug
gentamicin (30 µg/disk). After overnight incubation at 37 ◦ C, the resulting ZOIs were measured and compared
with that of the standard drug. Control measurements were carried out with DMSO. All the experiments were
performed in triplicate and the average ZOIs were recorded and are depicted in Table 2. The antibacterial
activity data revealed that the compounds having electron donating groups like methoxy and ethoxy groups on
aryl aldehyde, i.e. 5g, 5h, and 5j, showed good activity against all the tested bacterial strains. Compound
5i also showed good activity against all bacterial strains except Escherichia coli. In particular, compound 5g
against Bacillus thuringiensis and 5h against both the gram-positive bacterial strains (Staphylococcus aureus
and Bacillus thuringiensis) showed maximum ZOIs. Compounds 5b and 5e were inactive against both the
gram-positive bacterial strains, and 5c was inactive against Bacillus thuringiensis. The remaining compounds
were moderately active against all the tested bacterial strains.
In conclusion, we developed an efficient one-pot and solvent-free synthesis of coumarin incorporated fused
thiazolylquinazolinol derivatives (5a–j) in shorter reaction times with good yields. All the newly synthesized
compounds were screened for their in vitro antibacterial activity. Among all the compounds, those derived from
4-methoxy benzaldehyde (5g) against Bacillus thuringiensis and 3,4,5-trimethoxy benzaldehyde (5h) against
623

VELPULA et al./Turk J Chem
Table 2. Zone of inhibition values of 3-(9-hydroxy-3-methoxy-7-aryl-6,7,9,10-tetrahydro-5H -benzo[h] thiazolo[2,3-
b]quinazolin-9-yl)-2H -chromen-2-ones (5a–j) at 100 µg/mL and positive control drug gentamicin at 30 µg/mL.
Zone of inhibition (mm)
Analogue
S. aureus B. thuringiensis E. coli K. pneumoniae
5a
5b
5c
5d
5e
5f
5g
5h
5i
9
–
7
9
–
8
10
12
10
10
6
–
–
9
–
7
12
12
9
8
18
5
6
5
7
7
6
9
8
4
7
16
7
8
7
6
4
7
10
10
11
10
14
5j
Gentamicin 15
Bacterial strains:- Gram positive: S . aureus – Staphylococcus aureus, B. thuringiensis –Bacillus thuringiensis; Gram
negative: E. coli – Escherichia coli, K. pneumoniae – Klebsiella pneumoniae ‘-’ Inactive.
Staphylococcus aureus and Bacillus thuringiensis showed good activity in comparison with the standard drug
gentamicin. These compounds can be considered lead compounds for further development of potent antibacterial
agents.
3. Experimental section
3.1. General
All the reagents and solvents were purchased from Aldrich/Merck and used without further purification. Melting
points were determined in open capillaries using a Stuart SMP30 apparatus and are uncorrected. The progress
of the reactions as well as purity of compounds was monitored by thin layer chromatography with F254 silica-gel
precoated sheets using hexane/ethyl acetate 8/2 as eluent; UV light and iodine vapors were used for detection.
IR spectra were recorded on a PerkinElmer 100S spectrometer utilizing KBr pellets. 1 H NMR and 13 C NMR
spectra were obtained at 400 MHz and 100 MHz, respectively, on a Bruker spectrometer using DMSO-d6 as
solvent and TMS as internal standard. Elemental analyses were performed on a Carlo-Erba model EA1108
analytical unit and the values are ꢀ0.4% of theoretical values. Mass spectra were recorded on a Jeol JMSD-300
spectrometer.
3.2. General procedure for the synthesis of 3-(9-hydroxy-3-methoxy-7-aryl-6,7,9,10-tetrahydro-
5H -benzo[h]thiazolo[2,3-b]quinazolin-9-yl)-2H -chromen-2-ones (5a–j)
To a mixture of 6-methoxy-1-tetralone (1, 1 mmol), aryl aldehyde (2a–j, 1 mmol), and thiourea (3, 1 mmol),
P(4-VPH)HSO4 (0.015 g) was added and heated at 120 ◦ C under neat conditions for 20 min. After consuming of
all reactants (confirmed by TLC), to this mixture 3-(2-bromoacetyl)-2H -chromen-2-one (4, 1 mmol) was added
and heated at the same temperature for a further 25–40 min. After completion of the reaction as indicated by
TLC, 5 mL of ethanol was added and the mixture was stirred at room temperature for an additional 10–15 min.
The residue (catalyst) was separated by filtration and the filtrate was concentrated under reduced pressure; the
crude product was crystallized from ethanol to afford the pure product.
624

VELPULA et al./Turk J Chem
3.3. Spectral data
3.3.1. 3-(9-Hydroxy-3-methoxy-7-phenyl-6,7,9,10-tetrahydro-5H -benzo[h]thiazolo[2,3-b]quinazolin-
9-yl)-2H -chromen-2-one (5a)
Pale yellow solid; mp 244–246 ◦ C; IR (KBr, cm−1)υmax : 3443 (OH), 1717 (C=O), 1630 (C=N); 1 H NMR (400
MHz, DMSO-d6): δ 1.55–1.61 (m, 1H), 2.09 (t, 1H, J = 7.2 Hz), 2.53 (t, 1H, J = 6.8 Hz), 2.55–2.69 (m, 1H),
3.51 (d, 1H, J = 12.8 Hz), 3.77 (s, 3H), 4.10 (d, 1H, J = 12.8), 5.56 (s, 1H), 6.81–6.97 (m, 6H), 7.15 (d, 1H, J
= 8.4 Hz), 7.33–7.41 (m, 2H), 7.59–7.63 (m, 2H), 7.82–7.85 (m, 1H), 8.31 (s, 1H), 8.75 (s, 1H); 13 C NMR (100
MHz, DMSO−d6): δ 23.1, 27.0, 42.3, 55.2, 59.5, 94.8, 112.2, 114.2, 115.5, 118.0, 119.1, 122.9, 123.9, 124.8,
127.4, 127.7, 128.1, 128.4, 128.6, 129.4, 132.8, 137.2, 137.8, 142.2, 153.2, 157.5, 159.6, 165.5; MS (ESI) m/z:
509 [M+H]+ ; Anal. Calcd. for C30 H24 N2 O4 S: C, 70.85; H, 4.76; N, 5.51. Found: C, 71.08; H, 4.92; N, 5.37.
3.3.2. 3-(7-(4-Chlorophenyl)-9-hydroxy-3-methoxy-6,7,9,10-tetrahydro-5H -benzo[h]thiazolo[2,
3-b]quinazolin-9-yl)-2H -chromen-2-one (5b)
Brown solid; mp 255–257 ◦ C; IR (KBr, cm−1)υmax : 3442 (OH), 1720 (C=O), 1605 (C=N), 759 (C–Cl); 1 H
NMR (400 MHz, DMSO-d6): δ 1.57–1.61 (m, 1H), 2.09 (t, 1H, J = 7.6 Hz), 2.53–2.69 (m, 2H), 3.50 (d, 1H,
J = 12.8 Hz), 3.77 (s, 3H), 4.09 (d, 1H, J = 12.8 Hz), 5.62 (s, 1H), 6.82 (s, 1H), 6.92–7.00 (m, 3H), 7.20–7.28
(m, 1H), 7.41 (d, 2H, J = 8.0 Hz), 7.58 (d, 2H, J = 8.4 Hz), 7.66 (d, 1H, J = 7.6 Hz), 7.84 (d, 1H, J = 8.0
Hz), 8.27 (s, 1H), 8.76 (s, 1H); 13 C NMR (100 MHz, DMSO−d6): δ 23.0, 27.0, 42.50, 55.27, 58.7, 94.8, 112.4,
114.2, 115.4, 116.0, 117.9, 118.7, 119.1, 122.9, 124.8, 127.7, 128.4, 129.5, 130.5, 133.0, 133.2, 136.7, 137.3, 153.7,
157.6, 158.6, 159.6, 165.6; MS (ESI) m/z: 543 [M]+ ; Anal. Calcd. for C30 H23 ClN2 O4 S: C, 66.35; H, 4.27;
N, 5.16. Found: C, 66.52; H, 4.09; N, 5.34.
3.3.3. 3-(7-(3-Bromophenyl)-9-hydroxy-3-methoxy-6,7,9,10-tetrahydro-5H -benzo[h]thiazolo[2,3-b]
quinazolin-9-yl)-2H -chromen-2-one (5c)
Pale yellow solid; mp 238–240 ◦ C; IR (KBr, cm−1)υmax : 3447 (OH), 1719 (C=O), 1630 (C=N), 690 (C–Br);
1 H NMR (400 MHz, DMSO-d6): δ 1.55–1.64 (m, 1H), 2.07–2.13 (m, 1H), 2.54–2.69 (m, 2H), 3.48 (d, 1H, J =
12.4 Hz), 3.77 (s, 3H), 4.12 (d, 1H, J = 12.8 Hz), 5.61 (s, 1H), 6.82 (s, 1H), 6.93 (d, 1H, J = 8.8 Hz), 7.09 (s,
1H), 7.17–7.22 (m, 2H), 7.32 (s, 1H), 7.38–7.45 (m, 1H), 7.52–7.96 (m, 3H), 8.24 (s, 1H), 8.34 (s, 1H), 8.76 (s,
1H); 13 C NMR (100 MHz, DMSO−d6): δ 23.2, 27.2, 42.9, 54.3, 59.1, 94.4, 112.5, 114.8, 127.0, 127.2, 127.4,
127.8, 128.0, 128.5, 128.6, 129.2, 129.5, 131.7, 131.9, 132.7, 133.4, 136.5, 141.4, 142.4, 143.4, 149.0, 152.0, 158.9,
159.1, 164.4; MS (ESI) m/z: 587 [M]+ ; Anal. Calcd. for C30 H23 BrN2 O4 S: C, 61.33; H, 3.95; N, 4.77. Found:
C, 61.58; H, 3.78; N, 4.62.
3.3.4. 3-(7-(4-Florophenyl)-9-hydroxy-3-methoxy-6,7,9,10-tetrahydro-5H -benzo[h] thiazolo[2,3-b]
quinazolin-9-yl)-2H -chromen-2-one (5d)
Brown solid; mp 259–261 ◦ C; IR (KBr, cm−1)υmax : 3440 (OH), 1716 (C=O), 1628 (C=N), 810 (C–F); 1 H
NMR (400 MHz, DMSO-d6): δ 1.58–1.63 (m, 1H), 2.06–2.12 (m, 1H), 2.53–2.55 (m, 1H), 2.67 (t, 1H, J = 6.4
Hz), 3.50 (d, 1H, J = 12.4 Hz), 3.77 (s, 3H), 4.10 (d, 1H, J = 12.8 Hz), 5.62 (s, 1H), 6.69 (s, 1H), 6.82 (s, 1H),
6.83–6.95 (m, 1H), 7.03 (s, 1H), 7.21 (d, 2H, J = 8.4 Hz), 7.29 (d, 1H, J = 7.2 Hz), 7.42 (d, 1H, J = 7.6 Hz),
625

VELPULA et al./Turk J Chem
7.58–7.66 (m, 2H), 7.86 (t, 1H, J = 6.4 Hz), 8.31 (s, 1H), 8.75 (s, 1H); MS (ESI) m/z: 527 [M+H]+ ; Anal.
Calcd. for C30 H23 FN2 O4 S: C, 68.43; H, 4.40; N, 5.32. Found: C, 68.28; H, 4.58; N, 5.16.
3.3.5. 3-(9-Hydroxy-7-(4-hydroxyphenyl)-3-methoxy-6,7,9,10-tetrahydro-5H -benzo[h]thiazolo[2,3-
b]quinazolin-9-yl)-2H -chromen-2-one (5e)
White solid; mp 254–256 ◦ C; IR (KBr, cm−1)υmax : 3443 (OH), 1717 (C=O), 1632 (C=N); 1 H NMR (400
MHz, DMSO-d6): δ 1.59–1.66 (m, 1H), 2.06 (t, 1H, J = 7.2 Hz), 2.55 (t, 1H, J = 7.2 Hz), 2.64–2.68 (m,
1H), 3.49 (d, 1H, J = 12.8 Hz), 3.77 (s, 3H), 4.07 (d, 1H, J = 12.8 Hz), 5.43 (s, 1H), 6.22 (s, 1H), 6.70 (d,
2H, J = 8.4 Hz), 6.82 (d, 1H, J = 7.6 Hz), 6.92–6.94 (m, 1H), 7.19 (d, 1H, J = 8.4 Hz), 7.40 (t, 1H, J =
7.6 Hz), 7.58–7.83 (m, 3H), 7.84-8.30 (m, 2H), 8.69 (s, 1H), 9.38 (s, 1H); 13 C NMR (100 MHz, DMSO−d6): δ
23.2, 27.1, 42.2, 55.2, 59.2, 94.7, 111.2, 112.6, 114.2, 115.1, 115.5, 118.1, 119.2, 122.8, 123.7, 124.5, 125.1, 127.8,
129.0, 129.3, 130.0, 132.7, 137.2, 141.7, 153.3, 157.4, 159.5, 165.0; MS (ESI) m/z: 525 [M+H]+ ; Anal. Calcd.
for C30 H24 N2 O4 S: C, 68.69; H, 4.61; N, 5.34. Found: C, 68.84; H, 4.48; N, 5.50.
3.3.6. 3-(9-Hydroxy-3-methoxy-7-(3-nitrophenyl)-6,7,9,10-tetrahydro-5H -benzo[h]thiazolo[2,3-b]
quinazolin-9-yl)-2H -chromen-2-one (5f)
Yellow solid; mp 241–243 ◦ C; IR (KBr, cm−1)υmax : 3444 (OH), 1717 (C=O), 1631 (C=N), 1361 (C–NO2);
1 H NMR (400 MHz, DMSO-d6): δ 1.58–1.65 (m, 1H), 2.12–2.54 (m, 1H), 2.64–2.71 (m, 2H), 3.48 (d, 1H, J
= 12.0 Hz), 3.76 (s, 3H), 4.13 (d, 1H, J = 12.4 Hz), 5.87 (s, 1H), 6.82 (s, 1H), 6.94 (d, 1H, J = 8.0 Hz), 7.08
(d, 1H, J = 8.4 Hz), 7.36–7.48 (m, 3H), 7.53–8.25 (m, 5H), 8.39 (s, 1H), 8.82 (s, 1H); 13 C NMR (100 MHz,
DMSO−d6): δ 23.2, 27.2, 42.4, 55.2, 59.6, 94.7, 115.4, 118.0, 118.6, 118.8, 124.5, 124.7, 125.4, 126.9, 127.1,
128.0, 128.1, 128.4, 128.6, 129.4, 129.6, 132.8, 136.5, 136.7, 137.0, 142.2, 153.2, 157.7, 166.5; MS (ESI) m/z:
554 [M+H]+ ; Anal. Calcd. for C30 H23 N3 O6 S: C, 65.09; H, 4.19; N, 7.59. Found: C, 64.91; H, 4.32; N, 7.76.
3.3.7. 3-(9-Hydroxy-3-methoxy-7-(4-methoxyphenyl)-6,7,9,10-tetrahydro-5H -benzo[h]thiazolo[2,
3-b]quinazolin-9-yl)-2H -chromen-2-one (5g)
White solid; mp 237–239 ◦ C; IR (KBr, cm−1)υmax : 3440 (OH), 1720 (C=O), 1628 (C=N), 1155 (C–O–C); 1 H
NMR (400 MHz, DMSO-d6): δ 1.63–2.10 (m, 2H), 2.55 (t, 1H, J = 6.8 Hz), 2.64–2.68 (m, 1H), 3.44 (s, 3H),
3.50 (d, 1H, J = 12.8 Hz), 3.74 (s, 3H), 4.05 (d, 1H, J = 12.8 Hz), 5.54 (s, 1H), 6.37 (s, 1H), 6.82–6.95 (m,
4H), 7.15–7.20 (m, 2H), 7.40 (t, 1H, J = 7.6 Hz), 7.56–7.67 (m, 2H), 7.82–7.84 (m, 1H), 8.23 (s, 1H), 8.72 (s,
1H); MS (ESI) m/z: 539 [M+H]+ ; Anal. Calcd. for C31 H26 N2 O5 S: C, 65.13; H, 4.87; N, 5.26. Found: C,
65.38; H, 4.67; N, 5.08.
3.3.8. 3-(9-Hydroxy-3-methoxy-7-(3,4,5-trimethoxyphenyl)-6,7,9,10-tetrahydro-5H -benzo[h]thia-
zolo[2,3-b]quinazolin-9-yl)-2H -chromen-2-one (5h)
White solid; mp 226–228 ◦ C; IR (KBr, cm−1)υmax : 3439 (OH), 1720 (C=O), 1627 (C=N), 1142 (C–O–C);
1 H NMR (400 MHz, DMSO-d6): δ 1.62–1.78 (m, 1H), 2.05–2.15 (m, 1H), 2.55-2.84 (m, 2H), 3.48 (d, 1H, J =
12.4 Hz), 3.63 (s, 3H), 3.72 (s, 3H), 3.74 (s, 3H), 3.76 (s, 3H), 4.16 (d, 1H, J = 12.4 Hz), 5.83 (s, 1H), 6.22 (d,
1H, J = 8.4 Hz), 6.63 (d, 1H, J = 8.8 Hz), 6.79–6.83 (m, 1H), 6.91–6.94 (m, 1H), 7.15–7.87 (m, 4H), 8.27 (s,
626

VELPULA et al./Turk J Chem
1H), 8.35 (s, 1H), 8.64 (s, 1H); MS (ESI) m/z: 599 [M+H]+ ; Anal. Calcd. for C33 H30 N2 O7 S: C, 66.21; H,
5.05; N, 4.68. Found: C, 66.40; H, 4.84; N, 4.46.
3.3.9. 3-(9-Hydroxy-7-(4-hydroxy-3-methoxyphenyl)-3-methoxy-6,7,9,10-tetrahydro-5H -benzo[h]
thiazolo[2,3-b]quinazolin-9-yl)-2H -chromen-2-one (5i)
White solid; mp 230–232 ◦ C; IR (KBr, cm−1)υmax : 3440 (OH), 1721 (C=O), 1629 (C=N); 1 H NMR (400
MHz, DMSO-d6): δ 1.62–1.66 (m, 1H), 2.07 (t, 1H, J = 7.6 Hz), 2.55 (t, 1H, J = 6.8 Hz), 2.64–2.68 (m, 1H),
3.44 (s, 3H), 3.49 (d, 1H, J = 12.4 Hz), 3.76 (s, 3H), 4.10 (d, 1H, J = 12.4 Hz), 5.42 (s, 1H), 6.38 (s, 1H),
6.82–6.94 (m, 1H), 7.18 (d, 1H, J = 8.4 Hz), 7.38 (t, 1H, J = 8.0 Hz), 7.54–7.65 (m, 4H), 7.83 (d, 2H, J = 8.0
Hz), 8.30 (s, 1H), 8.68 (s, 1H), 8.91 (s, 1H); MS (ESI) m/z: 555 [M+H]+ ; Anal. Calcd. for C31 H26 N2 O6 S:
C, 67.13; H, 4.73; N, 5.05. Found: C, 67.30; H, 4.58; N, 5.22.
3.3.10. 3-(7-(3-Ethoxy-4-hydroxyphenyl)-9-hydroxy-3-methoxy-6,7,9,10-tetrahydro-5H -benzo[h]
thiazolo[2,3-b]quinazolin-9-yl)-2H -chromen-2-one (5j)
White solid; mp 233–235 ◦ C; IR (KBr, cm−1)υmax : 3440 (OH), 1723 (C=O), 1630 (C=N), 1139 (C–O–C); 1 H
NMR (400 MHz, DMSO-d6): δ 1.05 (t, 3H, J = 7.2 Hz), 1.61–1.66 (m, 1H), 2.07 (t, 1H, J = 8.0 Hz), 2.54
(t, 1H, J = 7.6 Hz), 2.63–2.69 (m, 1H), 3.41–3.46 (m, 2H), 3.49 (d, 1H, J = 12.4 Hz), 3.76 (s, 3H), 4.10 (d,
1H, J = 12.4 Hz), 5.39 (s, 1H), 6.71 (s, 1H), 6.83 (d, 1H, J = 6.0 Hz), 6.91–6.94 (m, 1H), 7.18 (d, 1H, J =
8.4 Hz), 7.39 (t, 1H, J = 7.6 Hz), 7.54–7.85 (m, 5H), 8.31 (s, 1H), 8.68 (s, 1H), 8.85 (s, 1H); MS (ESI) m/z:
569 [M+H]+ ; Anal. Calcd. for C32 H28 N2 O6 S: C, 67.59; H, 4.96; N, 4.93. Found: C, 67.73; H, 4.80; N, 5.12.
Acknowledgments
We would like to thank the Director, National Institute of Technology, Warangal, for providing research facilities.
The authors RV and RG thank CSIR-UGC New Delhi, India, for research fellowships.
References
1. Ram, V. J.; Tripathi, B. K.; Srivastava, A. K. Bioorg. Med. Chem. 2003, 11, 2439–2444.
2. Xia, Y.; Yang, Z. Y.; Hour, M. J.; Kuo, S. C.; Xia, P.; Bastow, K. F.; Nakanishi, Y.; Nampoothiri, P.; Hackl, T.;
Hamel, E.; et al. Bioorg. Med. Chem. Lett. 2001, 11, 1193–1196.
3. El-Sharief, A.; Ammar, Y. A.; Zahran, M. A.; Ali, A. H.; El-Gaby, M. Molecules 2001, 6, 267–278.
4. Kumar, K. S.; Ganguly, S.; Veerasamy, R.; Clercq, E. D. Eur. J. Med. Chem. 2010, 45, 5474–5479.
5. Malleshappa, N. N; Harun, M. Arabian J. Chem. 2013, 6, 35–48.
6. Ashok, K.; Chatrasal, S. Eur. J. Med. Chem. 2009, 44, 83–90.
7. El-Azab, A. S.; Eltahir, K. E. Bioorg. Med. Chem. Lett. 2012, 22, 327–333.
8. Pandeya, S. N.; Sriram, D.; Nath, G.; De Clercq, E. Pharm. Acta. Helv. 1999, 74, 11–17.
9. Sen Gupta, A. K.; Pandey, A. K. Pestic. Sci. 1989, 26, 41–49.
10. Wu, J.; Bai, S.; Yue, M.; Luo, L. J.; Shi, Q. C.; Ma, J.; Du, X. L.; Kang, S. H.; Hu, D.; Yang, S. Chem. Pap. 2014,
68, 969–975.
11. Shridhar, S. K.; Satyakam, S.; Janki, R. S.; Woon-Kai, L.; Tanaji, T. T. Eur. J. Med. Chem. 2012, 50, 264–273.
12. Testard, A.; Loge, C.; Leger, B.; Robert, J. M.; Lozach, O.; Blairvacq, M.; Meijer, L.; Thiery, V.; Besson, T. Bioorg.
Med. Chem. Lett. 2006, 16, 3419–3423.
627

VELPULA et al./Turk J Chem
13. Guiles, J.; Sun, X.; Critchley, I. A.; Ochsner, U.; Tregay, M.; Stone, K.; Bertino, J.; Green, L.; Sabin, R.; Dean,
F.; et al. Bioorg. Med. Chem. Lett. 2009, 19, 800.
14. Omar, K.; Geronikoki, A.; Zoumpoulakis, P.; Camoutsis, C.; Sokovic, M.; Ciric, A.; Glamoclija, J. Bioorg. Med.
Chem. 2010, 18, 426–432.
15. Shiradkar, M. R.; Murahari, K. K.; Gangadasu, H. R.; Suresh, T.; Kalyan, C. A.; Panchal, D.; Kaur, R.; Burange,
P.; Ghogare, J.; Mokale, V.; et al. Bioorg. Med. Chem. 2007, 15, 3997–4008.
16. Hassan, G. S.; El-Messery, S. M.; Al-Omary, F. A.; El-Subbagh, H. I. Bioorg. Med. Chem. Lett. 2012, 22,
6318–6323.
17. Bell, F. W.; Cantrell, A. S.; Hogberg, M.; Jaskunas, S. R.; Johansson, N. G.; Jordan, C. L.; Kinnick, M. D.; Lind,
P.; Morin, J. M.; Noreen, R.; et al. J. Med. Chem. 1995, 38, 4929–4936.
18. Siddiqui, N.; Ahsan, W. Med. Chem. Res. 2011, 20, 261–268.
19. Shih, M. H.; Ke, F. Y. Bioorg. Med. Chem. 2004, 12, 4633–4643.
20. Andreani, A.; Rambaldi, M.; Leoni, A.; Locatelli, A.; Pifferi, G. J. Pharm. Belg. 1994, 49, 308–314.
¨
21. Oncu¨, M.; Punar, M.; Eraksoy, H. Chemotherapy 2004, 50, 98–100.
22. Arshad, A.; Osman, H.; Bagley, M. C.; Lam, C. K.; Mohamad, S.; Zahariluddin, A. S. M. Eur. J. Med. Chem.
2011, 46, 3788–3794.
23. Sashidhara, K. V.; Kumar, A.; Kumar, M.; Sarkar, J.; Sinha, S. Bioorg. Med. Chem. Lett. 2010, 20, 7205–7211.
24. Neyts, J.; De Clercq, E.; Singha, R.; Chang, Y. H.; Das, A. R.; Chakraborty, S. K.; Hong, S. C.; Tsay, S. C.; Hsu,
M. H.; Hwu, J. R. J. Med. Chem. 2009, 52, 1486–1490.
25. Sashidhara, K. V.; Kumar, A.; Chatterjee, M.; Rao, K. B.; Singh, S.; Verma, A. K.; Palit, G. Bioorg. Med. Chem.
Lett. 2011, 21, 1937–1941.
26. Tyagi, A. K.; Raj, H. G.; Vohra, P.; Gupta, G.; Kumari, R.; Kumar, P.; Gupta, R. K. Eur. J. Med. Chem. 2003,
40, 413–420.
27. Huang, L.; Yuon, X.; Yu, D.; Lee, K. H.; Chin, H. C. Virology 2005, 332, 623–628.
28. Ruszat, R.; Wyler, S.; Forster, T.; Reich, O.; Christian, G. S.; Thomas, C. G.; Sulser, T.; Bachmann, A. Eur.
Assoc. Urol. 2006, 50, 675–683.
29. Zahradnik, M. The Production and Application of Fluorescent Brightening Agents; Wiley: New York, NY, USA,
1992.
30. Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural Coumarins: Occurrence, Chemistry and Biochemistry;
Wiley: New York, NY, USA, 1982.
31. Janardhan, B.; Manjulatha, K.; Srinivas, B.; Rajitha, B.; Muralikrishna, N.; Sadanandam, A. R. Soc. Chem. Adv.
2014, 4, 22866–22874.
32. Janardhan, B.; Srinivas, B.; Rajitha, Crooks, P. A. Tetrahedron Lett. 2014, 55, 224–226.
33. Janardhan, B.; Rajitha, B.; Crooks, P. A. J. Saudi Chem. Soc. 2012, http://dx.doi.org/10.1016/j.jscs.2012.10.007.
34. Tozkoparan, B.; Ertan, M.; Kelicen, P.; Demirdamar, R. Il Farmaco 1999, 54, 588–593.
35. Mohamed, S. F.; Flefel, E. M.; Amra, A. E.; Abd El-Shafy, D. N. Eur. J. Med. Chem. 2010, 45, 1494–1501.
36. Rashad, A. E.; Sayed, H. H.; Shamroukh, A. H. Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 2767–2777.
37. El-Baih, F. E. M.; Al-Rasheed, H. H.; Al-Hazimi, H. M. J. Saudi Chem. Soc. 2005, 9, 575–596.
38. Flefel, E. E.; Salama, M. A.; El-Shahat, M. Phosphorus, Sulfur Silicon Relat. Elem. 2007, 182, 1739–1756.
39. Abd El-Galil, E. A.; Maigali, S. S.; Abdulla, M. M. Monatsh. Chem. 2008, 139, 1409–1415.
40. Kolb, S.; Mondesert, O.; Goddard, M.-L.; Jullien, D.; Villoutreix, B. O.; Ducommun, B.; Garbay, C.; Braud, E.
Chem. Med. Chem. 2009, 4, 633–648.
628

VELPULA et al./Turk J Chem
41. Kulakov, I. V.; Nurkenov, O. A.; Turdybekov, D. M.; Issabaeva, G. M.; Mahmutova, A. S.; Turdybekov, K. M.
Chem. Heterocycl. Compd. 2009, 45, 856–859.
42. Abu-Hashem, A. A.; Youssef, M. M.; Hussein, H. A. R. J. Chin. Chem. Soc. 2011, 58, 41–48.
43. Kulakov, I. V. Chem. Heterocycl. Compd. 2009, 45, 1019–1021.
44. Khaligh, N. G. Ultrason. Sonochem. 2012, 19, 736–739.
45. Bauer, A. W.; Kirby, M. M.; Sherris, J. C.; Truck, M. Am. J. Clin. Pathol. 1966, 45, 493–496.
629

Copyright of Turkish Journal of Chemistry is the property of Scientific and Technical
Research Council of Turkey and its content may not be copied or emailed to multiple sites or
posted to a listserv without the copyright holder's express written permission. However, users
may print, download, or email articles for individual use.