One-pot synthesis, biological evaluation and molecular docking studies of fused thiazolo[2,3-b]pyrimidinone-pyrazolylcoumarin hybrids

Article abstract of DOI:10.1007/s11030-018-9845-0

Abstract: As a part of our endeavor toward the synthesis of a new class of biologically potent heterocyclic hybrids, a series of newly fused thiazolo[2,3-b]pyrimidinones bearing a pyrazolylcoumarin moiety (6a–p) were synthesized in acceptable yields. Anti

Full text of DOI:10.1007/s11030-018-9845-0

Molecular Diversity
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ORIGINAL ARTICLE
One-pot synthesis, biological evaluation and molecular docking
studies of fused thiazolo[2,3-b]pyrimidinone-pyrazolylcoumarin
hybrids
Ramesh Gondru1 Saikiran Reddy Peddi2 Vijjulatha Manga2 Manjulatha Khanapur3 Rajitha Gali1
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Narsimha Sirassu4 Rajitha Bavantula1
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Received: 8 September 2017 / Accepted: 14 June 2018
Ó Springer International Publishing AG, part of Springer Nature 2018
Abstract
As a part of our endeavor toward the synthesis of a new class of biologically potent heterocyclic hybrids, a series of newly
fused thiazolo[2,3-b]pyrimidinones bearing a pyrazolylcoumarin moiety (6a–p) were synthesized in acceptable yields.
Anticipated structures of all titled compounds were in agreement with spectral and analytical (C, H and N) analyses. The
compounds were screened for in vitro antibacterial activity against both G? and G- bacterial strains and antiproliferative
activity against K562 (chronic myelogenous leukemia), MCF-7 (breast cancer), MDA-MB-231 (breast cancer), COLO 205
(colorectal adenocarcinoma), HepG2 (hepatocellular carcinoma) cell lines. Further, potent antibacterial compounds were
subjected to molecular docking studies in order to gain insight into their plausible binding modes and mechanism of action
against MurB. The modeling results were in agreement with the experimental data.
Graphical abstract
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Keywords Antibacterial activity Á Molecular hybrid Á Molecular docking Á MurB Á Thiazolo[2,3-b]pyrimidinones
Introduction
After cardiovascular diseases, cancer is the second most
death causing multifactorial disease [1–3] resulting from a
Electronic supplementary material The online version of this
combined influence of genetic (inherited genes, genetic
mutations and DNA damages) and environmental factors
(exposure to UV radiations, chemical agents and tobacco
consumption). Malignancy is characterized by uncontrolled
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123

Molecular Diversity
cell proliferation and differentiation [4]. The high risk of
toxicity and lack of specificity (over non-cancerous cells)
were limiting the efficacy of most of the currently using
chemotherapeutic in cancer therapy. Multi-drug resistance
(MDR) developed by the tumor cells becomes pandemic
and is making paucity of chemotherapeutic drugs. Hence,
there is an urgency to design and develop alternative
chemical entities with the multi-target mechanism of action
in disease progression pathway or which can modulate
more than one biological target with high specificity.
Also, antimicrobial drug resistance (AMDR) [5] in
microorganisms is rampant and also emerged as one of the
principal causes of mortality over the world. Intemperate
and inappropriate use of antibiotics (prolonged drug
exposure), emerging of intrinsically or acquired antibiotic
resistance traits and resistance mechanisms adopted by the
microbes (by changing the principal targets, or by acti-
vating the efflux mechanisms) leading to antibiotic resis-
tance and limiting the efficacy of the pre-existing
medication. Hence, the drug development process becomes
a formidable challenge for the development of new and
effective drug candidates with a novel mode of action [6].
Multi-component reactions (MCRs) [7, 8] are one of the
frequently used strategies in modern synthetic organic
chemistry [9] that involve more than two easily accessible
reactants join through covalent bonds to give multi-func-
tionalized complex structures in a single synthetic opera-
tion [10, 11]. MCRs can offer significant advantages [12]
such as high atom efficiency, fewer by-product production
because of the reduced number of synthetic steps, opera-
tional simplicity (workup, extraction and purification)
under mild reaction conditions, cost-effective, and also it
offers a target- and diversity-oriented synthesis. Therefore,
the development of new MCRs using green reaction con-
ditions is inevitable at present, especially in the areas of
drug discovery, organic synthesis and combinatorial
chemistry [13, 14].
chalcones and their derivatives are also significant struc-
tural motifs with a broad spectrum of biological activities
[41].
In the course of our long-standing research endeavor
toward the development of new bioactive heterocycles
[42–44], from the molecular design point of view and also
by relying on the aforementioned biological data, herein
we designed and synthesized novel heterocyclic molecular
frameworks (6a–j) embedding thiazolo[2,3-b]pyrimidinone
and pyrazolyl chromenone pharmacophores in their struc-
tural framework, hoping the synergistic influence of this
combination on antibacterial and anticancer activity. All
the synthesized compounds were assessed for their in vitro
antibacterial and anticancer activity studies. Figure 1 rep-
resents a few of the literature reported and commercially
important heterocyclic-based drugs and bioactive
molecules.
Molecular docking studies were also performed for the
synthesized molecules in order to explore the possible
binding modes and understand the mode of action of these
compounds through their interactions with E. coli MurB
enzyme, a key enzyme in peptidoglycan biosynthesis. The
peptidoglycan layer of bacterial cell wall has been an
important target in antibacterial chemotherapy for a long
time. MurB catalyzes the reduction of enolpyruvate moiety
to a lactyl ether yielding UDP-N-acetylmuramate (UDP-
MurNAc), a precursor of the cell wall [45, 46]. Subse-
quently, this UDP-MurNAc is added with three amino
acids and a dipeptide, resulting in a pentapeptide. This
pentapeptide when activated permits the cross-linking that
gives cell wall its rigidity [47]. Further, MurB along with
other Mur proteins (Mur A-F, Y, and G) catalyzes various
biosynthetic transformations, which are essential in the
formation of the peptidoglycan layer of the bacterial cell
wall [48]. Furthermore, from the literature, we came to
know that Andres et al. [49] synthesized the substituted 4-
thiazolidinone derivatives and demonstrated their ability to
inhibit MurB enzyme by acting as diphosphate mimics at
low micromolar levels. Also, they have performed docking
studies on the MurB enzyme for 4-thiazolidinones. Yang
and his co-workers [50] identified 4-chlorophenyl-3,5-
dioxopyrazolidine derivatives as novel inhibitors of MurB
of Escherichia coli, Staphylococcus aureus in the micro-
molar range. Previously, our group [44] and Bhat et al. [51]
have reported MurB as an interesting target to exhibit
antimicrobial activity for pyrazolylcoumarin-bearing aryl
thiazoles and 1,2,3-triazolyl pyrazole derivatives. Since the
compounds reported in this manuscript also possessed
similar pharmacophore sub-units, herein we selected MurB
as a potential target to authenticate ours in vitro results.
A broad spectrum of pharmacological properties of
thiazolo[2,3-b]pyrimidinones has gained much attention as
a lead molecule from the synthetic and medicinal chemists.
The biological properties include antibacterial [15],
antiviral [16], antitumor [17, 18], antioxidant [19],
antinociceptive [20], antiparkinsonian [21], antimitotic
[22, 23], anti-inflammatory [24, 25], anticonvulsant [26],
analgesic [27] and antibiofilm modulators [28]. Some of
the dihydropyrimidine-based compounds have also been
reported as calcium channel modulators [29, 30] and 5-HT2
receptor antagonists [31, 32] and also serve as inhibitors of
xanthine oxidase [33], CDC25B phosphatase enzymes and
Bcl-2 family proteins [34].
Also, pyrazoles [35, 36] and coumarin [37–39] deriva-
tives are known as bioactive pharmacophores associated
with various biological activities [40]. On the other hand,
123

Molecular Diversity
Fig. 1 Representative examples of biologically active heterocyclic molecules possessing coumarin, pyrazole and thiazolo[2,3-b]pyrimidinones
moieties
compounds were achieved in good yields by one-pot three-
Results and discussion
component condensation of modified Biginelli product,
fused 3,4-dihydropyrimidin-2(1H)-thiones (4a–n), mono-
chloroacetic acid and 3-(2-oxo-2H-chromen-3-yl)-1-aryl-
Chemistry
1H-pyrazole-4-carbaldehyde (5a,b) in refluxing AcOH in
the presence of Ac2O and NaOAc. The structure
The synthetic strategy adopted to obtain the titled com-
pounds (6a–p) is outlined in Scheme 1. The target
Scheme 1 Reagents and conditions: (i) MeOH, cat. H2SO4, reflux,
4 h (yield: 80–95%); (ii) chloroacetic acid, NaOAc, AcOH/Ac2O, 5a,
b, reflux, 4–6 h (yield: 79–90%). Structures of all the synthesized
compounds were in agreement with their spectral and analytical
analyses. Isolated yields after filtration
123

Molecular Diversity
elucidation of newly synthesized compounds was well
established by FTIR, NMR and mass spectral studies as
well as elemental analyses (C, H and N).
compared with remaining derivatives. Compound 6g was
the only compound which showed bit reasonable antipro-
liferative activity against both Colo 205 and Hep G2 tumor
cell lines (Table 1). On overall comparison, compounds
derived from 4-chlorophenyl (6a) and 4-hydroxy-3-ethoxy
phenyl (6n) substitutions have exhibited moderate anti-
cancer activity against HepG2 when compared with the
others. Hence, further optimization of these two com-
pounds (6a and 6n) is required to enhance their antipro-
liferative efficacy, and they can be considered as a lead
molecule for the development of new antineoplastic drugs.
Biological activity
Antiproliferative activity
In vitro antiproliferative activity was performed against
five cancer lines (Colo205, K562, MCF-7, MDA-MB-231
and Hep G2) and normal cell line (HEK293) by MTT assay
[52] using doxorubicin as a positive control, and the results
are tabulated in Table 1.
Antibacterial Activity
The anticancer results revealed that most of the tested
samples were inactive against the tested cell lines. How-
ever, the derivatives 6a, 6h, 6k, 6m and 6n have shown
moderate antiproliferative potency against the HepG2
tumor cell line with an average percentage of inhibition
(Avg % inhibition) ranging from 39.09 to 40.35 when
The title compounds (6a–p) were assessed for their in vitro
antibacterial activity against both gram-positive (G?) and
gram-negative (G-) bacterial strains by the standard broth
microdilution technique [53, 54] by using penicillin and
123

Molecular Diversity
streptomycin as positive controls. The minimum inhibitory
concentrations (MICs) for all the synthesized compounds
were reported in lg/mL, and the results are illustrated in
Table 2.
respectively) and P. aeruginosa (MIC = 6.25 lg/mL).
Compounds 6b, 6e, 6f and 6h have shown bioactivity
against P. aeruginosa (MIC = 6.25 lg/mL), which was
better than penicillin. The compounds 6h and 6j have
shown equipotent activity than that of standards strepto-
mycin and penicillin, respectively, against B. subtilis and
P. aeruginosa (MIC = 6.25 and 12.5 lg/mL). Compounds
6m and 6n showed significant activity against S. aureus
(MIC = 3.12 lg/mL). Compound 6n showed premising
inhibition against B. subtilis, E. coli and P. aeruginosa with
MICs = 6.25 lg/mL. Finally, the compound 6l also
showed very good activity against S. aureus and B. subtilis
with MICs = 6.25 lg/mL, while the rest of the compounds
(6a, 6c, 6d, 6i, 6k, 6o and 6p) have shown modest activity
against all the tested strains with MIC values ranging from
12.5 to 50 lg/mL.
It is evident from Table 2 that the majority of the tested
compounds (6b, 6e–6h, 6j and 6l–6n) exerted significant
in vitro antibacterial activity against almost all the tested
bacterial strains with MICs ranging from 1.56 to 12.5 lg/
mL. Among the tested series, compound 6g was found to
be efficient and displayed equipotent inhibitory efficacies
and broader antibacterial spectrum than that of the refer-
ence drugs. Compound 6g exhibited excellent inhibiting
activity than the standard streptomycin (MIC = 6.25 lg/
mL) and equipotent to that of penicillin (MIC = 1.562 lg/
mL) against S. aureus and B. subtilis with MIC values
1.56 lg/mL, exerted nearly as active as positive control
drugs (MIC = 3.12 lg/mL) against gram-positive S. epi-
dermidis (MIC = 3.12 lg/mL). Also, compound 6g effec-
tively inhibited the gram-negative E. coli and K.
pneumonia (MIC = 6.25 lg/mL) and also demonstrated
inhibitory potency against P. aeruginosa (MIC = 12.5 lg/
mL) equal to that of the standard penicillin. Compounds 6f
and 6h could effectively inhibit the growth of S. aureus
with MIC values (MIC = 1.56 and 3.12 lg/mL,
Structure–activity relationship (SAR)
Interestingly, it was observed from experimental data
(Table 2) that most of the analogs displayed potent
bioactivity against gram-positive bacterial strains, i.e., B.
subtilis, S. aureus and S. epidermidis with MIC values
ranging from 1.56 to 6.25 lg/mL and also displayed
Table 1 Antiproliferative activity (Avg. % of inhibition SD) of compounds 6a–p and reference doxorubicin (DOX) against a panel of tumor
cell lines
Analogs
Cancer cell lines
Colo 205
K562
MCF-7
MDA-MB-231
Hep G2
HEK 293
6a
NA
11.76 2.65
17.73 1.32
15.78 1.50
22.22 1.65
11.17 0.97
12.63 2.47
7.12 2.13
15.19 2.66
NA
18.38 1.50
14.90 0.90
15.39 1.14
10.31 1.84
11.00 1.43
19.78 2.65
15.32 3.16
18.11 1.75
10.65 2.27
28.48 0.91
22.68 1.34
26.71 2.12
16.17 1.11
20.41 1.62
11.36 1.34
4.54 1.22
97.61 2.19
15.26 1.70
20.86 1.27
15.46 1.36
15.22 2.43
17.98 6.62
21.75 1.56
20.37 1.39
NA
40.35 1.55
21.67 3.33
15.23 2.96
14.29 2.07
13.40 1.98
22.46 2.21
36.18 1.88
39.70 3.04
19.95 2.14
36.32 2.63
39.89 1.88
21.02 2.56
39.09 2.04
40.11 2.67
10.21 1.44
35.21 1.38
92.35 1.57
- 2.60 1.50a
- 11.17 0.64
- 0.25 6.14
- 1.60 1.31
- 1.99 1.63
- 1.06 2.68
- 5.14 3.39
- 4.05 1.82
- 10.78 3.07
- 12.49 3.80
- 2.05 1.76
- 1.77 1.36
- 4.11 1.80
- 3.79 2.69
- 1.66 2.36
- 1.87 3.10
5.68 1.56
6b
6c
7.29 1.75
7.94 1.65
9.31 1.87
13.25 1.51
14.88 3.78
35.54 1.21
3.41 3.53
11.70 1.47
25.50 1.85
NA
6d
6e
6f
6g
6h
6i
NA
6j
NA
NA
6k
6l
3.33 1.28
15.22 0.89
13.49 1.39
17.62 1.07
20.12 1.77
10.67 1.55
95.57 2.22
17.62 1.07
20.11 1.98
NA
4.54 1.22
3.11 2.49
5.39 1.62
NA
6m
6n
6o
6p
DOXb
NA
15.38 5.12
NA
11.89 1.93
91.55 1.87
98.66 3.26
Values are mean SD of three replicates
NA not active
aNegative values indicate the growth of normal cell line HEK 293. Hence, the samples were not toxic to non-cancerous cells
bDOX—doxorubicin (positive control) and DMSO (negative control)
123

Molecular Diversity
Table 2 In vitro antibacterial activity data for test compounds (6a–j)
Analogs
MIC (lg/mL)
S. aureus
B. subtilis
S. epidermidis
E. coli
K. pneumonia
P. aeruginosa
6a
25 0.11
–
–
–
25 0.15
50 0.22
25 0.36
–
–
50 0.56
50 0.63
12.5 0.61
12.5 0.23
50 0.79
12.5 0.58
6.25 0.4
25 0.30
12.5 0.33
25 0.39
50 0.28
12.5 0.22
50 0.40
12.5 0.22
–
50 0.29
6.25 0.21
–
6b
–
6c
–
50 0.45
12.5 0.25
–
6d
50 0.35
25 0.62
1.56 0.22
1.56 0.35
3.12 0.28
–
–
25 0.17
6.25 0.79
6.25 0.15
12.5 0.23
6.25 0.16
–
6e
25 0.46
12.5 0.71
1.56 0.45
6.25 0.19
50 0.82
25 0.30
50 0.33
6.25 0.33
12.5 0.42
6.25 0.20
–
12.5 0.90
12.5 0.3
3.12 0.66
12.5 0.37
–
50 0.32
12.5 0.44
6.25 0.70
50 0.68
25 0.15
–
6f
6g
6h
6i
6j
12.5 0.19
–
25 0.36
–
12.5 0.66
–
6k
50 0.39
50 0.42
25 0.20
6.25 0.43
12.5 0.25
12.5 0.32
6.25 0.82
12.5 0.35
6l
6.25 0.49
3.12 0.28
3.12 0.19
–
12.5 0.38
12.5 0.31
12.5 0.45
–
12.5 0.50
12.5 0.36
6.25 0.38
25 0.55
–
6m
6n
6o
6p
12.5 0.36
6.25 0.25
1.562 0.21
–
12.5 0.27
3.125 0.45
3.125 0.22
–
Streptomycin
Penicillin
6.25 0.70
1.562 0.65
3.125 0.96
6.25 0.88
1.562 0.69
12.5 0.74
MIC (lg/mL), minimum inhibitory concentration, i.e., the lowest concentration of the test compound to inhibit the growth of bacteria completely
‘‘–’’ Indicates concentration [ 100 lg/mL
Molecular docking study
moderate-to-good inhibiting activity against gram-negative
strains, i.e., E. coli, P. aeruginosa and K. pneumonia with
MICs ranging from 6.25 to 12.5 lg/mL. On the whole from
the above in vitro results, we can conclude that the
derivatives bearing 4-chlorophenyl, 3,4-dimethoxyphenyl,
2,3,4-trimethoxyphenyl, 4-hydroxyphenyl, 4-hydroxy-3-
methoxyphenyl and 4-hydroxy-3-methoxyphenyl moieties
on the thiazolo-quinazoline scaffold were found to be
potent antibacterial agents.
Molecular docking was performed using Schrodinger suite
2010. Initially, the crystal structure of target enzyme MurB
(PDB id: 1MBB) was obtained from Protein Data Bank
(http://www.rcsb.org/pdb). It was prepared, refined and
minimized using protein preparation wizard available in
the Schrodinger suite 2010. Later receptor grid was gen-
erated around the active site of the enzyme using GLIDE
¨
5.6 ((Schrodinger LLC, 2010), Glide, version 5.6. New
Table 3 Dock scores and hydrogen bond interactions of ligands with E. coli (PDB id: 1MBB) obtained from docking studies
Compound
MIC (lg/mL)
Dock score (kcal/mol)
Residues involved in hydrogen bonding
6c
6e
6f
12.5 0.25
50 0.32
12.5 0.44
6.25 0.70
50 0.68
25 0.15
50 0.39
50 0.42
25 0.20
6.25 0.43
12.5 0.25
12.5 0.32
- 5.005
- 2.968
- 5.248
- 6.098
- 3.656
- 4.294
- 3.890
- 4.811
- 4.957
- 6.107
- 5.480
- 5.327
Lys 217, Gln 288
–
Ser 229, Tyr 254, Lys 262,
6g
6h
6i
Tyr 158, Lys 217, Lys 275
Gln 287
Gln 288
6k
6l
Gln 288
Tyr 125, Asp 270, Lys 275
6m
6n
6o
6p
Gln 287
Lys 275, Gln 287, Gln 288
–
–
123

Molecular Diversity
Fig. 2 Ligand interaction diagram of compounds 6f and 6g showing hydrogen bond interactions (pink dotted and thick lines), p–p stacking
interactions (green) and p-cationic interactions (red)
York). During grid generation, the receptor van der Waals
scaling was set to 0.9 [55]. Meanwhile, the ligands were
drawn in Maestro build panel and prepared by LigPrep
module available in the same suite. Finally, the low energy
conformers of the prepared ligands were docked into the
active site of the MurB enzyme. Docking results are tab-
ulated in Table 3; energetically most favored dock pose of
each ligand was analyzed for interactions with the target
receptor.
The docking studies clearly showed that the best active
compounds in the series (6g and 6n) could act as good
antibacterial agents which is evident from their high dock
scores (- 6.107 and - 6.098 kcal/mol, respectively).
Compound 6n showed three hydrogen bond interactions
with amino acid residues Lys 275, Gln 287, Gln 288, three
p–p stacking interactions with Tyr 190, Tyr 254 and two p-
cationic interactions with residues Lys 217 and Lys 262
(Fig. 2). On the other hand, compound 6g showed three
123

Molecular Diversity
hydrogen bond interactions with Tyr158, Lys 217, Lys 275
(Fig. 2) and a p–p stacking interaction with Arg 159
(Fig. 2). Compounds 6o, 6p, 6f, and 6c which possessed
good activity values next to compounds 6n and 6g in the
series showed dock scores of - 5.480, - 5.327, - 5.248
and - 5.005 kcal/mol, respectively (Table 3). Compound
6f showed three hydrogen bonds with Ser 229, Tyr 254,
Lys 262 and a p-cationic interaction with Lys 217, whereas
compound 6c showed two hydrogen bonds with Lys 217
and Gln 288. Surprisingly, compounds 6o and 6p showed
only p–p stacking and p-cationic interactions. Compound
6o showed p–p stacking interactions with Tyr 254 and p-
cationic interactions with Lys 262, whereas compound 6p
showed p–p stacking interactions with Tyr 125 and p-ca-
tionic interactions with Lys 217 and Lys 262. Another
noteworthy thing is that compounds which exhibited poor
biological activities (6k, 6h and 6e) showed poor dock
scores of - 3.890, - 3.656 and - 2.968 kcal/mol,
respectively. Compound 6k showed hydrogen bond inter-
action with Gln 288, p–p stacking interactions with Tyr254
and p-cationic interactions with Lys 262, whereas com-
pound 6h showed only one hydrogen bond interaction with
Gln 287 and hydrogen bond interactions were utterly
absent in the case of compound 6e. Interestingly, com-
pounds 6m, 6l and 6i which exhibited relatively better
activity compared to 6k, 6h and 6e showed dock scores of
- 4.957, - 4.811 and - 4.294 kcal/mol. Compound 6l
showed three hydrogen bond interactions with Tyr 125,
Asp 270, Lys 275, two p-cationic interactions with Lys
217, Lys 262 and a p–p stacking interaction with Tyr 254.
Both compounds 6m and 6i showed p-cationic interactions
with Lys 262 apart from hydrogen bond interactions with
Gln 287 and Gln 288, respectively. Furthermore, com-
pound 6m also showed p–p stacking interactions with Tyr
254. On the whole, it was observed that the docking results
well corroborated with in vitro antibacterial studies, indi-
cating that these compounds can be further optimized and
developed as lead compounds.
derivatives 6a and 6n had better antiproliferative activity
against Hep G2 cell line when compared with other com-
pounds. Regarding antibacterial studies, compounds 6b,
6e–6h, 6j and 6l–6n showed broad and excellent antibac-
terial efficacy against both G? and G- strains comparable
to that of the standards. These in vitro antibacterial studies
were further supported by molecular docking. Overall,
from the in vitro anticancer and antibacterial studies, we
can conclude that the presence of positive mesomeric
groups on phenyl ring has been suggested to be responsible
for the promising in vitro antibacterial activities of the title
compounds. Based on the above results, the synthesized
series of compounds could be potential candidates for
further development of novel antimicrobial agents.
Experimental
General
All chemical reagents and solvents were purchased from
commercial sources and used without further purification.
Melting points were determined in open capillaries using
electrothermal digital apparatus model Stuart SMP30 and
were uncorrected. Reactions were monitored by TLC on
silica gel-coated aluminum sheets, and the developed
chromatogram was visualized under UV light and iodine
vapors. IR spectra were recorded on PerkinElmer 100S
spectrophotometer using KBr disks. NMR spectra (1H and
13C) were recorded on a Bruker 400 MHz spectrometer
using chloroform-D and DMSO-d6 as solvents and TMS as
an internal standard. Chemical shift values were reported in
ppm (d), and coupling constants (J) in Hertz (Hz). Standard
abbreviations indicating a splitting pattern (multiplicity)
were designated as follows: singlet (s), doublet (d), triplet
(t) and multiplet (m). 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.
Conclusion
Biological protocols
In summary, a series of novel heterocyclic hybrids (6a–p)
were designed and synthesized by the one-pot three-com-
ponent approach with the hope of discovering new bioac-
tive molecular frameworks with an enhanced broad
spectrum of pharmacological activities. All the newly
synthesized compounds were well characterized by spec-
tral and elemental analyses. The compounds were investi-
gated for their in vitro antiproliferative and antibacterial
activities by MTT and broth microdilution technique,
respectively. From the experimental studies, it was
revealed that among the synthesized compounds (6a–p),
Tested cancer cell lines and antiproliferative activity
In vitro cytotoxic activity was carried out against human
colorectal adenocarcinoma (Colo 205), chronic myeloge-
nous leukemia (K562), breast adenocarcinoma (MCF-7),
breast adenocarcinoma (MDA-MB-231), hepatocellular
carcinoma chronic myelogenous (Hep G2), and human
embryonic kidney 293 cells (HEK293). One of the most
effective anticancer agents, doxorubicin (DOX), was used
as a positive control (reference), and the results are sum-
marized in Table 1. The cell lines were obtained from the
123

Molecular Diversity
General procedure for the synthesis of 4-aryl-3,4,5,6-
tetrahydrobenzo[h]quinazoline-2(1H)-thiones (4a–n)
National Centre for Cell Sciences, Pune, India, and were
cultured at a seeding density of 0.2 9 106 in DMEM/
RPMI medium supplemented with 10% FBS, 100 Um/L
penicillin, and 100 lgm/L streptomycin, respectively, and
maintained in a humidified atmosphere with of 5% CO2 at
37 1 °C. The samples were dissolved in dimethylsul-
foxide (DMSO, not exceeding the final concentration of
0.01%) and further diluted in cell culture medium. The
antiproliferative response of the extract was assessed by the
quantitative colorimetric 3-(4,5-dimethythiazol-2-yl)-2,5-
diphenyl tetrazolium bromide (MTT) assay. Cells
(* 10,000) were plated in 200 lL growth medium in the
presence or absence of test sample (10 lM concentration)
in 96-well culture plates for 24 h. Then, the culture plates
(inserted in the swing bucket rotors of the A-2-DWP) were
centrifuged at 2000 rpm for 10 min at room temperature
using Eppendorf 5810R centrifuge. 100 lL of the super-
natant discarded, and 20 lL of MTT (5 mg/mL in PBS)
was added to each well and incubated for 4 h at 37 1 °C.
The viability of the cells was determined using a spec-
trophotometer at 570 nm. HEK 293 cells were screened to
evaluate the toxicity of the samples. The response param-
eter was expressed in the average percentage of inhibition
of samples at 10 lM concentrations. The experiment was
performed in triplicate, and the results were taken as a
mean SD and are given in Table 1.
Equimolar concentrations of tetralones 1 (1 mmol), aro-
matic aldehydes 2 (1 mmol) and thiourea 3 (1 mmol) were
refluxed (without stirring) in a clean round-bottomed flask
containing absolute ethanol at refluxing temperature for 4 h
in the presence of catalytic amount of concentrated sulfuric
acid. After the completion of reaction (monitored by TLC),
the separated crystalline solid was filtered under suction,
washed with water, dried to afford pure product.
General procedure for the synthesis of 3-(2-oxo-2H-chromen-
3-yl)-1-aryl-1H-pyrazole-4-carbaldehyde (5a and 5b) Start-
ing materials carbaldehydes (5a and 5b) were synthesized
according to the literature method [56].
General procedure for the synthesis of 10-((3-(2-oxo-2H-
chromen-3-yl)-1-aryl-1H-pyrazol-4-yl)methylene)-7-aryl-7,10-
dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-ones
(6a–p) A mixture of compound 4a–n (1 mmol), mono-
chloroacetic acid (1.5 mmol), anhydrous sodium acetate
(2 mmol), glacial acetic acid (2 mL), acetic anhydride
(1.5 mL) and carbaldehydes (5a,b) (1 mmol) was refluxed
with stirring at 60 °C for 4–6 h. The progress of the
reaction was monitored by TLC. Upon completion of the
reaction, the reaction mixture was cooled to room tem-
perature and poured on to crushed ice under vigorous
stirring. The precipitate was filtered under suction, washed
with cold water and recrystallized from glacial acetic acid
to afford analytically pure products (6a–p) in excellent
yields.
Tested microbial strains and antibacterial activity
The title compounds (6a–p) were assessed for their in vitro
antibacterial activity against both gram-positive (Staphy-
lococcus aureus (MTCC 121), Bacillus subtilis (MTCC 96)
and Staphylococcus epidermidis (MTCC 2639)) and gram-
negative bacterial strains (Escherichia coli (MTCC 40),
Klebsiella pneumonia (MTCC 109) and Pseudomonas
aeruginosa (MTCC 2453)). Standard pathogenic microbial
cultures were procured from the Microbial Type Culture
Collection and Gene Bank (MTCC), Chandigarh, India,
which was recognized by the World Intellectual Property
Organization (WIPO). The experiments were carried out in
triplicate, and the results were taken as a mean SD. The
minimum inhibitory concentrations (MICs) of all the syn-
thesized compounds are reported in lg/mL after 24 h at
37 1, and the results are tabulated in Table 2. Antibac-
terial activity was assessed by the standard broth
microdilution technique. The antibiotics, penicillin and
streptomycin were used as positive controls (standards),
and DMSO was used as a negative control (solvent con-
trol), and they were also screened under identical condi-
tions for the comparison of activity results.
Characterization data of the products
7-(4-chlorophenyl)-10-((3-(2-oxo-2H-chromen-3-yl)-1-phenyl-
1H-pyrazol-4-yl)methylene)-7,10-dihydro-5H-benzo[h]thia-
zolo[2,3-b]quinazolin-9(6H)-one (6a) Yellow solid; M.P.:
273–275 °C; IR (KBr, cm-1) tmax: 1720 cm-1 (coumarin
C=O), 1709 cm-1 (thiazole C=O), 1631 cm-1 (pyrimidine
C=N), 1596 cm-1 (pyrazole C=N), 1532 cm-1 (C=C of a,
1
b-unsaturated carbonyl); H NMR (400 MHz, DMSO-d6):
d 1.90–2.33 (m, 2H), 2.63–2.78 (m, 2H), 5.86 (s, 1H), 7.14
(d, 1H, J = 6.8 Hz), 7.19–7.27 (m, 2H), 7.42–7.50 (m, 7H),
7.54–7.61 (m, 3H), 7.69 (d, 1H, J = 6.8 Hz), 7.80 (d, 2H,
J = 7.2 Hz), 7.85 (d, 2H, J = 8.0 Hz), 8.05 (d, 1H,
J = 8.0 Hz), 8.78 (s, 1H); 13C NMR (100 MHz, CDCl3) d
165.02, 159.81, 154.21, 150.22, 148.79, 144.02, 139.15,
137.51, 135.28, 134.78, 134.64, 132.52, 132.43, 129.75,
129.04, 128.48, 128.01, 127.89, 127.37, 127.22, 126.75,
124.77, 123.32, 121.64, 120.25, 119.72, 119.63, 118.91,
118.41, 116.78, 115.64, 59.35, 27.43, 24.99;MS (ESI) m/z:
665 [M]?;Anal. calcd. for C39H25ClN4O3S: C, 70.42; H,
3.79; N, 8.42. Found: C, 70.71; H, 3.93; N, 8.72.
123

Molecular Diversity
7-(4-chlorophenyl)-10-((1-(3,4-dinitrophenyl)-3-(2-oxo-2H-
chromen-3-yl)-1H-pyrazol-4-yl)methylene)-7,10-dihydro-5H-
benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one (6b) Orange
solid; M.P.: 236–238 °C; IR (KBr, cm-1) tmax: 1719 cm-1
(coumarin C=O), 1706 cm-1 (thiazole C=O), 1633 cm-1
(pyrimidine C=N), 1597 cm-1 (pyrazole C=N), 1538 cm-1
(pyrimidine C=N), 1598 cm-1 (pyrazole C=N), 1535 cm-1
1
(C=C of a, b-unsaturated carbonyl); H NMR (400 MHz,
DMSO-d6): d 1.85–1.94 (m, 1H), 2.22–2.29 (m, 1H), 2.56–
2.67 (m, 1H), 2.70–2.76 (m, 1H), 3.71 (s, 3H), 3.75 (s, 3H),
5.72 (s, 1H), 6.70 (s, 1H), 6.81–6.91 (m, 3H), 7.27 (d, 2H,
J = 8.4 Hz), 7.39-7.60 (m, 6H), 7.70 (t, 2H, J = 8.4 Hz),
7.84 (d, 1H, J = 7.6 Hz), 8.04 (d, 2H, J = 8.0 Hz), 8.40 (s,
1H), 8.75 (s, 1H); MS (ESI) m/z: 490 [M ? H]?; Anal.
calcd. for C41H30N4O5S: C, 71.29; H, 4.38; N, 8.11. Found:
C, 71.48; H, 4.69; N, 7.85.
1
(C=C of a, b-unsaturated carbonyl); H NMR (400 MHz,
DMSO-d6): d 1.88–2.34 (m, 2H), 2.61–2.79 (m, 2H), 5.88
(s, 1H), 7.13–7.50 (m, 10H), 7.68–7.72 (m, 1H), 7.79–7.85
(m, 2H), 8.21 (s, 1H), 8.39 (d, 1H, J = 9.2 Hz), 8.72–8.74
(m, 1H); 8.93–8.95 (m, 2H); MS (ESI) m/z: 755 [M]?-
;Anal. calcd. for C39H23ClN6O7S: C, 62.03; H, 3.07; N,
11.13. Found: C, 61.86; H, 3.22; N, 10.82.
7-(3,4-dimethoxyphenyl)-3-methoxy-10-((3-(2-oxo-2H-chro-
men-3-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)-7,10-dihydro-
5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one (6f) Yel-
3-methoxy-10-((3-(2-oxo-2H-chromen-3-yl)-1-phenyl-1H-
pyrazol-4-yl)methylene)-7-phenyl-7,10-dihydro-5H-
low solid; M.P.: 262–264 °C; IR (KBr, cm-1) tmax
:
1728 cm-1 (coumarin C=O), 1705 cm-1 (thiazole C=O),
1634 cm-1 (pyrimidine C=N), 1599 cm-1 (pyrazole C=N),
benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one (6c) Yellow
solid; M.P.: 268–270 °C; IR (KBr, cm-1) tmax: 1717 cm-1
(coumarin C=O), 1711 cm-1 (thiazole C=O), 1635 cm-1
(pyrimidine C=N), 1606 cm-1 (pyrazole C=N), 1537 cm-1
1
1533 cm-1 (C=C of a, b-unsaturated carbonyl); H NMR
(400 MHz, DMSO-d6): d 1.94–2.32 (m, 2H), 2.60–2.74 (m,
2H), 3.70 (s, 3H), 3.75 (s, 3H), 3.79 (s, 3H), 5.73 (s, 1H),
6.75–6.97 (m, 5H), 7.42–7.59 (m, 6H), 7.71 (d, 2H,
J = 7.6 Hz), 7.85 (d, 1H, J = 6.0 Hz), 8.05 (d, 2H,
J = 7.2 Hz), 8.41 (s, 1H), 8.77 (s, 1H); MS (ESI) m/z: 721
[M]?; Anal. calcd. for C42H32N4O6S: C, 69.99; H, 4.47; N,
7.77. Found: C, 70.23; H, 4.22; N, 7.58.
1
(C=C of a, b-unsaturated carbonyl); H NMR (400 MHz,
DMSO-d6): d 1.86–1.93 (m, 1H), 2.27–2.32 (m, 1H), 2.56–
2.67 (m, 1H), 2.71–2.77 (m, 1H), 3.75 (s, 3H), 5.80 (s, 1H),
6.74–6.84 (m, 2H), 7.29–7.36 (m, 5H), 7.41–7.72 (m, 8H),
7.84 (d, 1H, J = 6.8 Hz), 8.05 (d, 2H, J = 8.4 Hz), 8.41 (s,
1H), 8.78 (s, 1H); 13C NMR (100 MHz, CDCl3) d 165.05,
159.42, 154.20, 148.73, 144.00, 139.24, 137.17, 134.09,
132.48, 129.74, 128.76, 128.46, 128.27, 127.84, 127.16,
125.70, 124.74, 124.60, 121.10, 120.29, 120.00, 119.72,
118.91, 118.51, 116.77, 113.79, 113.58, 111.23, 60.03,
55.32, 27.90, 24.99; MS (ESI) m/z: 662 [M ? H]?; Anal.
calcd. for C40H28N4O4S: C, 72.71; H, 4.27; N, 8.48. Found:
C, 72.50; H, 4.55; N, 8.71.
3-methoxy-10-((3-(2-oxo-2H-chromen-3-yl)-1-phenyl-1H-
pyrazol-4-yl)methylene)-7-(2,3,4-trimethoxyphenyl)-7,10-di-
hydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one
(6g) Yellow solid; M.P.: 266–268 °C; IR (KBr, cm-1
)
t
max: 1728 cm-1 (coumarin C=O), 1703 cm-1 (thiazole
C=O), 1633 cm-1 (pyrimidine C=N), 1597 cm-1 (pyrazole
1
C=N), 1532 cm-1 (C=C of a, b-unsaturated carbonyl); H
NMR (400 MHz, DMSO-d6): d 1.86–2.25 (m, 2H), 2.55–
2.74 (m, 2H), 3.71 (s, 3H), 3.74 (s, 3H), 3.75 (s, 6H), 5.85
(s, 1H), 6.72–6.81 (m, 3H), 6.97 (d, 1H, J = 8.0 Hz), 7.41–
7.49 (m, 4H), 7.59 (t, 2H, J = 8.0 Hz), 7.69 (t, 2H,
J = 8.0 Hz), 7.84 (d, 1H, J = 7.6 Hz), 8.05 (d, 2H,
J = 7.6 Hz), 8.40 (s, 1H), 8.76 (s, 1H); 13C NMR
(101 MHz, CDCl3) d 165.09, 159.85, 159.49, 154.20,
150.08, 148.77, 144.05, 139.16, 137.15, 134.33, 132.54,
130.26, 130.18, 129.76, 128.47, 127.88, 127.20, 125.55,
124.78, 124.66, 121.37, 120.25, 119.78, 119.72, 118.90,
118.44, 116.78, 115.83, 115.61, 113.61, 113.37, 111.27,
60.07, 59.21, 55.32, 55.09, 52.46, 27.88, 24.98; MS (ESI)
m/z: 751 [M]?; Anal. calcd. for C43H34N4O7S: C, 68.79; H,
4.56; N, 7.46. Found: C, 68.48; H, 4.32; N, 7.22.
10-((1-(3,4-dinitrophenyl)-3-(2-oxo-2H-chromen-3-yl)-1H-
pyrazol-4-yl)methylene)-3-methoxy-7-phenyl-7,10-dihydro-
5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one
(6d)
Orange solid; M.P.: 233–235 °C; IR (KBr, cm-1) tmax
:
1720 cm-1 (coumarin C=O), 1709 cm-1 (thiazole C=O),
1634 cm-1 (pyrimidine C=N), 1605 cm-1 (pyrazole C=N),
1
1539 cm-1 (C=C of a, b-unsaturated carbonyl); H NMR
(400 MHz, DMSO-d6): d 1.90–1.93 (m, 1H), 2.27–2.31 (m,
1H), 2.57–2.61 (m, 1H), 2.71–2.76 (m, 1H), 3.74 (s, 3H),
5.79 (s, 1H), 6.73–6.83 (m, 2H), 7.29–7.40 (m, 6H), 7.49 (t,
2H, J = 8.4 Hz), 7.67–7.84 (m, 3H), 8.21 (s, 1H), 8.38 (d,
1H, J = 8.8 Hz), 8.71–8.95 (m, 3H); MS (ESI) m/z: 785
[M ? H]?; Anal. calcd. for C40H26N6O8S: C, 63.99; H,
3.49; N, 11.19. Found: C, 64.29; H, 3.78; N, 11.32.
7-(3-hydroxy-4-methoxyphenyl)-3-methoxy-10-((3-(2-oxo-2H-
chromen-3-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)-7,10-di-
hydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one
3-methoxy-7-(4-methoxyphenyl)-10-((3-(2-oxo-2H-chromen-
3-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)-7,10-dihydro-5H-
benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one (6e) Yellow
solid; M.P.: 254–256 °C; IR (KBr, cm-1) tmax: 1729 cm-1
(coumarin C=O), 1704 cm-1 (thiazole C=O), 1634 cm-1
(6h) Yellow solid; M.P.: 244–246 °C; IR (KBr, cm-1
t
)
max: 3516 cm-1 (OH), 1729 cm-1 (coumarin C=O),
1702 cm-1 (thiazole C=O), 1634 cm-1 (pyrimidine C=N),
123

Molecular Diversity
1596 cm-1 (pyrazole C=N), 1535 cm-1 (C=C of a, b-un-
saturated carbonyl); 1H NMR (400 MHz, DMSO-d6): d
1.90–1.99 (m, 1H), 2.23–2.31 (m, 1H), 2.58–2.66 (m, 1H),
2.70–2.79 (m, 1H), 3.71 (s, 3H), 3.75 (s, 3H), 5.66 (s, 1H),
6.73–6.83 (m, 4H), 6.93 (s, 1H), 7.39–7.71 (m, 8H), 7.84
(d, 1H, J = 7.6 Hz), 8.04 (d, 2H, J = 8.4 Hz), 8.40 (s, 1H),
8.75 (s, 1H), 9.09 (s, 1H); 13C NMR (100 MHz, CDCl3) d
165.15, 159.82, 159.40, 154.20, 150.05, 148.71, 146.57,
146.05, 144.02, 139.18, 137.21, 134.10, 132.49, 131.22,
129.74, 128.47, 127.84, 127.17, 125.73, 124.75, 124.56,
121.61, 121.07, 120.30, 120.11, 119.70, 118.92, 118.53,
116.76, 114.49, 113.98, 113.59, 111.24, 110.98, 59.80,
56.06, 55.32, 28.01, 24.98; MS (ESI) m/z: 707 [M]?; Anal.
calcd. for C41H30N4O6S: C, 69.68; H, 4.28; N, 7.93. Found:
C, 69.48; H, 3.99; N, 8.27.
for C40H27ClN4O4S: C, 69.11; H, 3.91; N, 8.06. Found: C,
69.41; H, 4.19; N, 8.31.
7-(4-bromophenyl)-3-methoxy-10-((3-(2-oxo-2H-chromen-3-
yl)-1-phenyl-1H-pyrazol-4-yl)methylene)-7,10-dihydro-5H-
benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one (6k) Yellow
solid; Yield: 80%; M.P.: 268–270 °C; IR (KBr, cm-1
)
t
max: 1722 cm-1 (coumarin C=O), 1709 cm-1 (thiazole
C=O), 1633 cm-1 (pyrimidine C=N), 1596 cm-1 (pyrazole
1
C=N), 1538 cm-1 (C=C of a, b-unsaturated carbonyl); H
NMR (400 MHz, CDCl3): d 2.02–2.10 (m, 1H), 2.19–2.27
(m, 1H), 2.69–2.74 (m, 1H), 2.78–2.84 (m, 1H), 3.84 (s,
3H), 5.66 (s, 1H), 6.70 (s, 1H), 6.84 (d, 1H, J = 8.8 Hz),
7.34 (t, 3H, J = 8.0 Hz), 7.40–7.47 (m, 4H), 7.53–7.59 (m,
3H), 7.62 (d, 2H, J = 6.8 Hz), 7.88 (d, 2H, J = 8.0 Hz),
7.89 (d, 1H, J = 8.8 Hz), 8.05 (s, 1H), 8.23 (s, 1H); MS
(ESI) m/z: 740 [M]?; Anal. calcd. for C40H27BrN4O4S: C,
64.95; H, 3.68; N, 7.57. Found: C, 64.72; H, 91; N, 7.27.
7-(4-fluorophenyl)-3-methoxy-10-((3-(2-oxo-2H-chromen-3-
yl)-1-phenyl-1H-pyrazol-4-yl)methylene)-7,10-dihydro-5H-
benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one (6i) Yellow
solid; M.P.: 254–256 °C; IR (KBr, cm-1) tmax: 1718 cm-1
(coumarin C=O), 1706 cm-1 (thiazole C=O), 1633 cm-1
(pyrimidine C=N), 1601 cm-1 (pyrazole C=N), 1539 cm-1
7-(4-hydroxyphenyl)-3-methoxy-10-((3-(2-oxo-2H-chromen-
3-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)-7,10-dihydro-5H-
benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one (6l) Yellow
solid; M.P.: 242–244 °C; IR (KBr, cm-1) tmax: 3511 cm-1
(OH), 1720 cm-1 (coumarin C=O), 1708 cm-1 (thiazole
C=O), 1632 cm-1 (pyrimidine C=N), 1596 cm-1 (pyrazole
1
(C=C of a, b-unsaturated carbonyl); H NMR (400 MHz,
DMSO-d6): d 1.86–1.92 (m, 1H), 2.26–2.32 (m, 1H), 2.59–
2.75 (m, 2H), 3.75 (s, 3H), 5.83 (s, 1H), 6.75 (s, 1H), 6.82
(d, 1H, J = 8.4 Hz), 7.18 (t, 2H, J = 8.8 Hz), 7.40–7.61
(m, 8H), 7.70 (t, 2H, J = 8.8 Hz), 7.85 (d, 1H, J = 7.6 Hz),
8.05 (d, 2H, J = 8.4 Hz), 8.41 (s, 1H), 8.77 (s, 1H); 13C
NMR (100 MHz, CDCl3) d 164.97, 159.86, 159.20,
154.18, 153.90, 151.83, 150.36, 148.69, 144.02, 139.22,
137.09, 133.14, 132.48, 129.76, 128.46, 127.82, 127.18,
126.01, 124.75, 124.34, 120.48, 120.34, 120.25, 119.71,
118.91, 118.62, 116.76, 113.50, 111.15, 107.34, 55.91,
55.29, 27.90, 24.51; MS (ESI) m/z: 679 [M]?; Anal. calcd.
for C40H27FN4O4S: C, 70.78; H, 4.01; N, 8.25. Found: C,
71.06; H, 3.87; N, 8.58.
1
C=N), 1535 cm-1 (C=C of a, b-unsaturated carbonyl); H
NMR (400 MHz, CDCl3 ? DMSO-d6): d 1.96–2.04 (m,
1H), 2.09–2.17 (m, 1H), 2.57–2.75 (m, 2H), 3.73 (s, 3H),
5.50 (s, 1H), 6.59 (s, 1H), 6.66–6.72 (m, 3H), 7.14 (d, 2H,
J = 8.0 Hz), 7.28–7.34 (m, 2H), 7.46 (t, 4H, J = 8.8 Hz),
7.54 (t, 2H, J = 7.2 Hz), 7.73 (d, 3H, J = 7.6 Hz), 8.04 (s,
1H), 8.21 (s, 1H), 8.98 (s, 1H); MS (ESI) m/z: 677 [M]?;
Anal. calcd. for C40H28N4O5S: C, 70.99; H, 4.17; N, 8.28.
Found: C, 71.32; H, 4.39; N, 8.07.
7-(4-hydroxy-3-methoxyphenyl)-3-methoxy-10-((3-(2-oxo-2H-
chromen-3-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)-7,10-di-
hydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one
7-(4-chlorophenyl)-3-methoxy-10-((3-(2-oxo-2H-chromen-3-
yl)-1-phenyl-1H-pyrazol-4-yl)methylene)-7,10-dihydro-5H-
benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one (6j) Yellow
solid; M.P.: 251–253 °C; IR (KBr, cm-1) tmax: 1720 cm-1
(coumarin C=O), 1709 cm-1 (thiazole C=O), 1631 cm-1
(pyrimidine C=N), 1596 cm-1 (pyrazole C=N), 1532 cm-1
(6m) Yellow solid; Yield: 80%; M.P.: 245–247 °C; IR
(KBr, cm-1) tmax: 3518 cm-1 (OH), 1726 cm-1 (coumarin
C=O), 1700 cm-1 (thiazole C=O), 1638 cm-1 (pyrimidine
C=N), 1601 cm-1 (pyrazole C=N), 1540 cm-1 (C=C of a,
1
b-unsaturated carbonyl); H NMR (400 MHz, DMSO-d6):
d 2.04–2.12 (m, 1H), 2.18–27 (m, 1H), 2.64–2.82 (m, 2H),
3.13 (s, 6H), 5.56 (s, 1H), 6.67 (t, 1H, J = 8.0 Hz), 6.75–
6.84 (m, 3H), 6.88 (d, 1H, J = 9.2 Hz), 7.35–7.42 (m, 3H),
7.53 (t, 2H, J = 7.6 Hz), 7.64 (t, 2H, J = 7.6 Hz), 7.70 (s,
1H), 7.79 (t, 1H, J = 8.0 Hz), 7.85 (t, 2H, J = 7.2 Hz), 8.26
(d, 2H, J = 8.0 Hz), 8.82 (s, 1H); MS (ESI) m/z: 707 [M]?;
Anal. calcd. for C41H30N4O6S: C, 69.68; H, 4.28; N, 7.93.
Found: C, 69.40; H, 4.03; N, 7.70.
1
(C=C of a, b-unsaturated carbonyl); H NMR (400 MHz,
DMSO-d6): d 1.90–2.33 (m, 2H), 2.61–2.78 (m, 2H), 3.75
(s, 3H), 5.86 (s, 1H), 7.15–7.27 (m, 3H), 7.42–7.59 (m,
9H), 7.69 (s, 1H), 7.79–7.86 (m, 2H), 8.05 (d, 2H,
J = 7.2 Hz), 8.41 (s, 1H), 8.78 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 165.04, 159.84, 154.20, 150.22,
148.79, 144.05, 139.15, 137.48, 135.28, 134.79, 134.63,
132.54, 132.42, 129.77, 129.04, 128.48, 128.01, 127.91,
127.37, 127.23, 126.76, 124.79, 123.31, 121.63, 120.23,
119.74, 119.62, 118.90, 118.40, 116.79, 115.65, 59.35,
59.10, 27.43, 24.99; MS (ESI) m/z: 695 [M]?; Anal. calcd.
7-(3-ethoxy-4-hydroxyphenyl)-3-methoxy-10-((3-(2-oxo-2H-
chromen-3-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)-7,10-di-
hydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one
123

Molecular Diversity
(6n) Yellow solid; M.P.: 264–266 °C; IR (KBr, cm-1
max: 3520 cm-1 (OH), 1726 cm-1 (coumarin C=O),
)
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t
1701 cm-1 (thiazole C=O), 1633 cm-1 (pyrimidine C=N),
1592 cm-1 (pyrazole C=N), 1539 cm-1 (C=C of a, b-un-
saturated carbonyl) 1H NMR (400 MHz, CDCl3): d 1.41 (t,
3H, J = 6.8 Hz), 2.10–2.25 (m, 2H), 2.68–2.84 (m, 2H),
3.84 (s, 3H), 4.09 (q, 2H, J = 6.8 Hz), 5.61 (s, 1H), 5.70 (s,
1H), 6.71 (s, 1H), 6.80–6.88 (m, 2H), 6.95 (d, 2H,
J = 8.0 Hz), 7.34 (t, 1H, J = 7.2 Hz), 7.41–7.45 (m, 2H),
7.53–7.63 (m, 5H), 7.78 (d, 2H, J = 8.0 Hz), 7.88 (d, 1H,
J = 8.0 Hz), 8.05 (s, 1H), 8.23 (s, 1H); MS (ESI) m/z: 721
[M]?; Anal. calcd. for C42H32N4O6S: C, 69.99; H, 4.47; N,
7.77. Found: C, 70.21; H, 4.23; N, 7.98.
´
´
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´
ˇ
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3-methoxy-7-(naphthalen-1-yl)-10-((3-(2-oxo-2H-chromen-3-
yl)-1-phenyl-1H-pyrazol-4-yl)methylene)-7,10-dihydro-5H-
benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one (6o) Yellow
solid; M.P.: 242–244 °C; IR (KBr, cm-1) tmax: 1718 cm-1
(coumarin C=O), 1710 cm-1 (thiazole C=O), 1639 cm-1
(pyrimidine C=N), 1600 cm-1 (pyrazole C=N), 1539 cm-1
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(C=C of a, b-unsaturated carbonyl); H NMR (400 MHz,
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CDCl3): d 1.88–2.01 (m, 1H), 2.28–2.33 (m, 1H), 2.59–2.90
(m, 2H), 3.83 (s, 3H), 5.58 (s, 1H), 6.70–6.76 (m, 3H), 7.36–
7.45 (m, 6H), 7.52–7.77 (m, 8H), 7.81 (d, 1H, J = 7.2 Hz),
8.01 (d, 2H, J = 8.0 Hz), 8.39 (s, 1H), 8.77 (s, 1H); MS (ESI)
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7-(2-chlorophenyl)-3-methoxy-10-((3-(2-oxo-2H-chromen-3-
yl)-1-phenyl-1H-pyrazol-4-yl)methylene)-7,10-dihydro-5H-
benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one (6p) Yellow
solid; M.P.: 255–257 °C; IR (KBr, cm-1) tmax: 1722 cm-1
(coumarin C=O), 1707 cm-1 (thiazole C=O), 1639 cm-1
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CDCl3): d 1.90–1.95 (m, 1H), 2.28–2.36 (m, 1H), 2.61–
2.81 (m, 2H), 3.73 (s, 3H), 5.88 (s, 1H), 7.13–7.25 (m, 3H),
7.49–7.52 (m, 9H), 7.66 (s, 1H), 7.77–7.90 (m, 2H), 8.01
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Acknowledgements We greatly acknowledge Tripos Inc., USA, and
¨
Schrodinger LLC, New York, for providing the software. The authors
thank the Director, National Institute of Technology, Warangal, for pro-
viding research facilities and one of the authors RG gratefully acknowl-
edges MHRD for financial assistance. The author Saikiran Reddy Peddi
(IF150172) would like to thank DST for a research fellowship.
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Affiliations
Ramesh Gondru1 Saikiran Reddy Peddi2 Vijjulatha Manga2 Manjulatha Khanapur3 Rajitha Gali1
•
•
•
•
•
Narsimha Sirassu4 Rajitha Bavantula1
•
3
& Rajitha Bavantula
rajitabhargavi@yahoo.com
Department of Biochemistry, School of Life Sciences,
University of Hyderabad, Hyderabad,
Telangana State 500046, India
4
1
Department of Chemistry, Kakatiya University, Warangal,
Telangana State 506 009, India
Department of Chemistry, National Institute of Technology,
Warangal, Telangana State 506004, India
2
Department of Chemistry, Osmania University, Hyderabad,
Telangana State 500007, India
123