Aqua mediated synthesis of 2-amino-6-benzothiazol-2-ylsulfanyl-chromenes and its in vitro study, explanation of the structure-activity relationships (SARs) as antibacterial agent

Article abstract of DOI:10.1016/j.ejmech.2010.08.010

Multi-component reaction (MCR) involves coupling of p-bromophenol with 2-Benzothiazolethiol, malononitrile and substituted aldehydes in aqueous K ₂CO₃ as green base to synthesize 2-amino-6-benzothiazol-2- ylsulfanyl-chromenes. This multi-component reaction thus offers a higher yield and versatility in the preparation of densely functionalized oxygen heterocycles. The newly synthesized compounds were screened for their antibacterial activities against positive and gram negative pathogenic strains to bacteria. SAR analysis was performed to explore comprehensive structure-activity relationships and a statistically reliable model to explain their antibacterial activities.

Full text of DOI:10.1016/j.ejmech.2010.08.010

European Journal of Medicinal Chemistry 45 (2010) 5031e5038
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Aqua mediated synthesis of 2-amino-6-benzothiazol-2-ylsulfanyl-chromenes and
its in vitro study, explanation of the structureeactivity relationships (SARs) as
antibacterial agent
,
a
a
b
b
Mazaahir Kidwai a , Roona Poddar , Saurav Bhardwaj , Satendra Singh , Pratibha Mehta Luthra
*
a Green Research Laboratory, Department of Chemistry, University of Delhi, New Delhi 110007, India
b Medicinal and Pharmaceutical Chemistry Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, New Delhi 110007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Multi-component reaction (MCR) involves coupling of p-bromophenol with 2-Benzothiazolethiol,
malononitrile and substituted aldehydes in aqueous K2CO3 as green base to synthesize 2-amino-6-
benzothiazol-2-ylsulfanyl-chromenes. This multi-component reaction thus offers a higher yield and
versatility in the preparation of densely functionalized oxygen heterocycles. The newly synthesized
compounds were screened for their antibacterial activities against positive and gram negative patho-
genic strains to bacteria. SAR analysis was performed to explore comprehensive structureeactivity
relationships and a statistically reliable model to explain their antibacterial activities.
Received 20 September 2009
Received in revised form
4 August 2010
Accepted 6 August 2010
Available online 12 August 2010
Keywords:
2-Amino-6-benzothiazol-2-ylsulfanyl-
chromenes
Ó 2010 Elsevier Masson SAS. All rights reserved.
SAR
Aqueous medium
2-Benzothiazolethiol
Antibacterial activity
1. Introduction
moiety i.e. benzothiazol-2-ylsulfanyl-chromenes. Without any
shadow of doubt, it is proposed that the development of libraries of
Heteroaromatic compounds have awestruck significant atten-
tion in the design of biologically active molecules and advanced
organic materials [1,2]. Hence, a practical method for the prepara-
tion of such compounds is of great interest in synthetic organic
chemistry [3]. Among the family of heterocyclic compounds,
4H-chromenes are important class of oxygenated heterocyclic
compounds [4]. More recently, there has been increased interest in
the synthesis of 4H-chromenes since bioactive natural products
containing chromene ring system possess wide spectrum of activ-
ities including as antidepressant, antihypertensive, anti-tubulin,
antiviral, antioxidative, activator of potassium channels and inhi-
bition of phosphodiesterase IV or dihydrofolate reductase [5e8].
The 2-benzothiazolethiol ring system is important in medicinal
chemistry [9] and finds its application in drug development for the
treatment of allergies, hypertension, inflammation, schizophrenia
and bacterial and HIV infections [10]. Hence the fusion of 2-ben-
zothiazolethiol with chromene could provide superior biological
2-amino-6-benzothiazol-2-ylsulfanyl-chromenes might provide
additional lead molecules for new drug discovery.
One of the tools of the organic chemist to strive for the ideal
synthesis is multi-component reactions (MCRs), which could be
broadly defined, regardless of their mechanistic nature, as the
process consisting of a number (ꢀ2) of synthetic steps carried out
in the same flask without isolation of any intermediate, thus
reducing time, saving money, energy and raw materials with both
economic and environmental benefits thus leading to a product
containing the main parts of all starting materials [11]. The most
effective MCRs provide new products with optimal change in
structure and functionality from simple substrates in highly atom-
economical fashion. The MCRs, described by Strecker in 1850 [12],
after having been considered as an exotic variants of organic
reactions have become very popular in recent years for the prep-
aration of compounds following environment friendly and cheaper
strategies.
As part of our program aimed at developing efficient and envi-
ronmentally friendly methodologies for the preparation of fine
chemicals, we carried out the synthesis of 2-amino-6-benzothia-
zol-2-ylsulfanyl-chromenes via four-component reaction em-
ploying water as the reaction medium [13]. In fact, as clearly stated
* Corresponding author. Tel./fax: þ91 1127666235.
E-mail address: kidwai.chemistry@gmail.com (M. Kidwai).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.08.010

5032
M. Kidwai et al. / European Journal of Medicinal Chemistry 45 (2010) 5031e5038
by Sheldon, it is generally recognized that “the best solvent is no
solvent and if a solvent (diluent) is needed it should preferably be
water”. The use of water as the reaction medium represents
a remarkable benefit since this green solvent is highly polar and
therefore immiscible with most organic compounds; moreover the
water soluble catalyst resides and operates in the aqueous phase
thus separation of the organic materials is easy [14].
turbidity standard. The inoculum was suitably diluted so as to get
a final concentration of approximately 5 ꢁ105 cfu/ml of bacteria in
each well. Each well was inoculated with 0.01 ml of the prepared
inoculum using a multichannel micropipette and the plates were
incubated overnight at 37 ꢂC. The MICs of these compounds and
ampicillin were determined by using the standard protocol of
NCCLS Broth Microdilution MIC method (Tables 3 and 4).
The demand for novel chemotherapeutic antibacterial agents
remains attractive in the field of medicinal chemistry. So, the
judicious use of antibacterial agent is an important approach in an
attempt to control the emergence of bacterial resistance. In order to
discover more potent inhibitors, we have successfully attempted
a novel and green synthesis of benzothiazol-2-ylsulfanyl-chro-
menes through substitution of chromenes with 2-Benzothiazole-
thiol [15].
QSAR methods are widely used in drug design because they
allow rapid generation of QSAR models, from which biological
Table 1
Reaction times and yields for the synthesis of 2-amino-4-aryl-6-thiazole-2-chro-
mene (6aei).
S. No.
1
Entry No.
R
Yield%a
Time (min)
2. Results
a
72
22e22.5
2.1. Chemistry
A literature survey has revealed that the reaction of phenol with
malononitrile and substituted aldehydes proceeds in ethanolic
piperidine to form chromenes derivatives. This classical procedure
employs piperidine as a hazardous organic base, refluxing for long
hours in organic solvents (ethanol, acetonitrile) and gives low yields
of products [16]. In order to study the role of the base used and to
modify the classical method to an efficient, clean and economical
protocol, aqueous K2CO3 conditions are used for the reaction. The
encouraging results obtained inspired us to synthesize some novel
pyrano-coumarin derivatives using heterocyclic aldehydes. The
structure of these chromenes derivatives was confirmed on the
basis of spectroscopic data (Scheme 1 and Table 1).
2
3
b
c
63
65
24e24.5
25e25.5
S
Cl
Encouraged by these results, we tried to extend the scope of this
process to another active thiol compound Benzoimidazole-2-thiol,
which is an important synthon for various heterocyclic compounds
(Scheme 2) (Table 2). As expected, desired products were obtained
in excellent yields in less reaction time.
4
5
d
e
55
25
23e23.5
27e27.5
H3CO
O2N
2.2. Evaluation of biological activity and QSAR of compounds
Screening of all the synthesized compounds for their antibac-
terial activity was performed by employing Broth Microdilution
MIC method [17]. Using sterile microtitre plates, 0.2 ml of Mueller
Hinton Broth was added to each of the 96 wells. Doubling dilutions
of each compound were made in the wells, thus, a plate contained
6
7
f
73
84
26e26.5
0.5e100 mg/ml dilutions of 21 different compounds and of ampi-
cillin. In each plate one well was kept as positive control (broth -
þ inoculum) and another as negative control (broth only). The
inoculum was adjusted to a turbidity equivalent to McFarland 0.5
O
O
g
25.5e26
Br
aq. K2CO3
S
S
S
OH
SH
+
μν
N
3
N
OH
1
8
h
52
64
23.5e24
CH2(CN)2
aq. K2CO3
μν
4
2
N
H
RCHO
5(a-i)
S
S
O
N
NH2
9
i
24e24.5
R
CN
6(a-i)
N
Cl
a
Scheme 1. Synthesis of 2-amino-3-cyano-6-benzothiazole-2-ylsulfanyl-chromene.
Isolated and unoptimized yields.

M. Kidwai et al. / European Journal of Medicinal Chemistry 45 (2010) 5031e5038
5033
Table 2
Br
H
N
Reaction times and yields for the synthesis of 2-amino-4-aryl-(6-benzoimidazole)-
chromene (11ael).
H
N
aq. K2CO3
R1
S
O
SH
+
μν
H
S. No. R1
R
X
Product Yieldsa Time
N
9
R1
N
(%)
(min)
OH
7/8
aq. K2CO3
μν
2
CNCH2X 10
R= H, 5-OCH3
RCHO
1
2
3
H
COOEt 11a
77
17e17.5
S
S
S
H
N
R1
S
O
N
NH2
OCH3
OCH3
COOEt 11b
65
46
15.5e16
17.5e18
11 (a-l)
R
X
Scheme 2. Synthesis of 2-amino-2-ylsulfanyl-(6-benzoimidazole)-chromene.
CN
11c
activity of newly designed molecules can be predicted. In this study,
21 compounds with available MIC on four different bacteria were
employed for the WINKS SDA 6 analysis. For QSAR analyses, all 21
compounds were selected and the chemical properties were esti-
mated with ChemDraw Ultra. The MIC values of these compounds
were used as dependent variables. The WINKS SDA 6 results are
summarized in Table 3. These statistical indexes were reasonably
high, indicating that this WINKS SDA 6 model had a strong
predictive ability. As it can be seen in Table 3, the theoretical results
of 21 compounds on four different bacteria were in good agreement
with the experimental values, suggesting that the new WINKS SDA
6 model was reliable.
The QSAR methods have been used successfully in pharmaceu-
tical applications and in this work we calculated some molecular
properties of compounds in order to correlate them with their
antibacterial activity. The calculated descriptors were selected so
that they could represent electronic and hydrophobic features of
the compounds studied, as they are supposed to be important for
their antibacterial activity (Table 4).
O
O
4
5
6
7
OCH3
OCH3
H
COOEt 11d
COOEt 11e
COOEt 11f
53
68
71
63
16e16.5
13e13.5
16.5e17
15e15.5
O2N
Cl
Cl
The calculated descriptors were:
H
CN
11g
ꢃ Electronic properties: EHOMO (the highest occupied molecular
orbital energy), ELUMO (the lowest unoccupied molecular
orbital energy)
ꢃ Hydrophobic property: log P (partition coefficient).
8
H
COOEt 11h
78
12e12.5
O2N
O2N
3. Discussion
The complete process represents an example of the one-pot and
sequential steps reaction (often referred to as tandem or cascade
reaction) where reagents and catalysts are mixed together and
experimental conditions are set up in such a way to promote the
reaction cascade. Thus the benzylidenemalononitrile 7(aei) con-
taining the electron-poor C]C double bond is quantitatively
produced by fast Knoevenagel addition of malononitrile to the
aromatic aldehyde. As we previously reported, the reaction easily
occurs in protic solvents including water without using catalyst,
although it results in net dehydration [18]. The second step that
requires the presence of K2CO3 as base presumably involves the
phenol ortho C-alkylation by reaction with the electrophilic C]C
double bond giving the intermediate 8(aei). Successively the
phenolic OH group undergoes fast nucleophilic addition to the CN
producing the final 2-amino-2-chromene 6 (Scheme 3).
9
H
COOEt 11i
COOEt 11j
COOEt 11k
65
73
12.5e13
13e13.5
O2N
10
11
OCH3
OCH3
OCH3
77
74
16e16.5
12.5e13
Cl
Quick plot HOMO and LUMO surface and the three-dimensional
SCF maps of 9 compounds (4 active (6d, 6h, 6e and 6g) þ 4 inactive
(6a, 6c, 6i and 6b) and 11b) superimposed onto total electron
density accounts for the interpretation of short-range interactions
between molecules. At each point of the map in SCF, the electro-
static potential expresses the value of the electrostatic energy of
12
CN
11l
O2N
a
Isolated and unoptimized yields.

5034
M. Kidwai et al. / European Journal of Medicinal Chemistry 45 (2010) 5031e5038
Table 3
Comparison of experimental (MICExp), predicted (MICCal) and cross-validated (MICRes).
Comp
P. aeruginosa
E. coli
S. aureus
S. epidermidis
MICExp
MICCal
MICRes
MICExp
MICCal
MICRes
MICExp
MICCal
MICRes
MICExp
MICCal
MICRes
6a
6b
6c
32
32
16
2
16
8
45.5
58.5
21.9
1.8
13.5
26.5
5.9
0.2
e
16
2
32
32
4
10.0
0.4
29.7
38.8
e
6
1.6
2.3
6.8
e
4
2
4
9.3
0.4
11.5
14
5.3
1.6
7.5
6
8
64
32
16
32
32
4
32
64
125
125
250
125
64
64
16
32
64
9.6
93.9
31.5
12.8
e
1.6
29.9
0.5
6d
8
3.2
6ea
6f
e
0.5
16
8
e
e
e
10
6.7
2
1.3
e
16
1
23.6
1.8
7.6
0.2
e
4.7
17.8
e
11.3
9.8
e
11.5
0.3
20.5
3.7
6g
8
6ha
6i
16
16
125
125
125
125
32
8
16
8
32
125
64
8
e
0.5
16
125
125
125
125
64
64
16
16
32
125
64
16
e
2
e
e
11.7
133.4
131.2
123.8
176.8
e
4.3
12.4
6.2
ꢄ1.2
51.8
e
12.9
125.4
124.0
125.4
125.0
e
3.1
0.4
ꢄ1.0
0.4
0
16
125
125
250
125
64
32
16
16
64
125
32
16
8.9
125.4
124.0
125.4
125.0
e
7.1
0.4
ꢄ01.0
0.4
0
27.5
114.8
137.9
247.7
124.0
e
36.5
ꢄ10.2
ꢄ12.9
2.3
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
ꢄ1.0
e
e
e
4.3
25.8
e
3.7
9.8
e
54.8
19.2
e
9.2
3.2
e
42
9.9
e
42
6.1
e
51.3
11.3
e
12.7
4.7
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
125
64
16
e
e
67.0
e
3
53.6
e
10.4
e
46.0
e
14
e
30.9
e
33.1
e
e
r2 ¼ 0.7538, q2 ¼ 0.918
r2 ¼ 0.8997, q2 ¼ 0.980
r2 ¼ 0.9097, q2 ¼ 0.721
r2 ¼ 0.9931, q2 ¼ 0.930
a
Calculator value cannot be calculated.
interaction with a unitary positive charge which can account for the
determination of an electrostatic pattern for the compounds with
same activity and interpretation of long-range interactions with the
receptor [19]. This color-coded surface provides a measure of the
overall size of the molecule as well as the location of negative or
positive electrostatic potentials. The regions of positive electro-
static potential indicate excess positive charge, leading to repulsion
of the positively charged test probe, while regions of negative
potential indicate excess negative charge. These positive and
negative orbitals of HOMO and LUMO lobes have been determined
at values of ꢄ10 and 10 kcal molꢄ1 (structural representations can
be viewed in Fig. 1).
Fig. 1 shows HOMO and LUMO of all 9 compounds, red color
shows LUMO while blue color shows HOMO with energy
10 kcal molꢄ1. In Fig. 2, Electron density is shown in which red color
shows high electron density while light blue for zero electron
density and white color for positive density. Nitrogen in benzo-
thiazole moiety and Oxygen in chromene moiety have high electron
density while slightly less electron density in all the aromatic ring
(Figs. 1 and 2).
For 9 compounds the SCF superimposed on the electron density
shows that a negative potential is located over the oxygen atoms and
a null to positive potential is located in the remaining parts of the
structure. Through the three-dimensional MEP isosurfaces, it can be
observed that all compounds present a negative potential located
over the benzothiazole ring, with the chromene moiety showing
positive values. Peripheral points of positive potential can also
be seen around the aromatic area. In the benzothiazole and ben-
zimidazole area the electrostatic profile is similar for all compounds.
The electron potential along with HOMO and LUMO vary negligibly
on changing from benzothiazole to benzimidazole but electron
potential is higher in case 11b as compared to 6b. Similarly by
changing CN to COOEt group, there is a decrease in electron density.
Compound 6d showed maximum MIC against Pseudomonas aeru-
ginosa, while 6a showed minimum MIC for the same. Interestingly,
6d vary by 6a only due to methoxy group, both compounds have
Table 4
Calculated values of the three most important variables (log P, EHOMO, ELUMO and
DE).
Comp
P. aeruginosa
E. coli
S. aureus
S. epidermidis
log P
EHOMO
ELUMO
DE
6a
6b
6c
6d
6e
6f
6g
6h
32
32
16
2
16
8
16
2
32
32
4
4
2
4
8
64
32
16
32
32
4
32
64
125
125
250
125
64
32
16
32
64
6.05
5.72
6.64
5.96
5.78
7.28
5.91
5.97
6.54
5.28
5.19
5.43
5.38
5.25
6.2
ꢄ4.47
4.32
ꢄ4.47
5.23
0
ꢄ0.91
ꢄ0.33
ꢄ0.86
0
ꢄ0.2
ꢄ0.48
ꢄ0.01
ꢄ0.35
0
ꢄ4.12
ꢄ3.79
8
4.33
5.19
0.5
16
8
ꢄ5.06
4.35
5.55
ꢄ5.06
4.55
6.03
16
1
8
16
16
125
125
125
125
32
16
16
8
0.5
16
125
125
125
125
64
32
16
16
32
125
2
ꢄ4.14
ꢄ4.59
ꢄ5.16
ꢄ5.64
ꢄ5.00
ꢄ5.55
ꢄ5.49
ꢄ4.77
ꢄ4.85
ꢄ5.20
ꢄ5.26
ꢄ6.56
ꢄ4.13
ꢄ4.24
ꢄ5.16
ꢄ5.64
ꢄ4.72
ꢄ4.77
ꢄ5.50
ꢄ4.64
ꢄ4.86
ꢄ5.28
ꢄ5.22
ꢄ6.56
6i
16
125
125
250
125
64
32
16
16
64
125
11a
11b
11e
11f
11g
11h
11i
11j
11k
11l
0
ꢄ0.28
ꢄ0.78
0.01
ꢄ0.13
0.01
0.08
ꢄ0.04
0
5.81
5.33
5.33
5.25
32
125
125

M. Kidwai et al. / European Journal of Medicinal Chemistry 45 (2010) 5031e5038
5035
Br
ꢃ For P. aeruginosa, EHOMO and ELUMO are positive,
D
E is high
further more Log P is also high i.e. compound should be
S
S
K2CO3
H2O
hydrophobic in nature.
S
OH
SH +
ꢃ For E. coli,
hydrophobic in nature.
E is low, Log P is low i.e. compound should be
DE is low, Log P is high i.e. compound should be
N
N
3
1
OH
2
ꢃ For S. aureus,
D
hydrophilic in nature.
CN
H2O
ꢃ For S. epidermidis, EHOMO and ELUMO are positive, Log P is also
CH2(CN)2
RCHO
+
high i.e. compound should be hydrophobic in nature.
R
CN
4
5(a-i)
7(a-i)
In conclusion, 2-amino-6-benzothiazol-2-ylsulfanyl-chromenes
were synthesized via one-pot four-component coupling of p-bro-
mophenol with 2-Benzothiazolethiol, malononitrile and substituted
aldehydes in aqueous K2CO3. The method serves as a facile cons-
truction of 2-amino-6-benzothiazol-2-ylsulfanyl-chromenes start-
ing from readily and widely available simple substrates, which shall
be widely applicable for the synthesis of biologically active mole-
cules and advanced materials. All the synthesized compounds were
screened for their in vitro antibacterial activity against standard
strains of P aeruginosa, E. coli, S. aureus, and S. epidermidis. QSAR
analysis was performed to explore comprehensive structuree
activity relationships and a statistically reliable model with good
predictive power on the basis of the common substructure-based
alignment.
OH
CN
S
K2CO3
H2O
S
OH
CN
+
R
CN
7(a-i)
N
8(a-i)
R
S
CN
H
O
S
N
K2CO3
S
H2O
S
N
NH2
3
6(a-i)
R
CN
H
Scheme 3. Supposed reaction mechanism for the synthesis of 2-amino-3-cyano-2-
ylsulfanyl-(6-benzoimidazole)-chromene.
4. Experimental section
4.1. General
similar HOMO and LUMO but vary in SCF, probably because of higher
electron potential at oxygen of methoxy group. Likewise, 6h showed
maximum MIC against Escherichia coli and 6c showed less due to
presence of indole ring which has positive and negative HOMO
orbitals in indole ring. For Staphylococcus aureus, 6e has maximum
while 6i has minimum MIC, due to presence of a strong electro-
withdrawing eNO2 group which lowers electron density in chro-
mene ring. Similarly for Staphylococcus epidermidis 6g has highest
MIC while 6b has lowest MIC, in 6g there is similarity between
HOMO and LUMO orbitals at NH2 and CN positions which indicate
that the energy difference is less. It concludes that comparison of
electron densityamong various compounds could predict the extent
of interaction with the bio-receptor.
1H NMR and 13C NMR were recorded on Burker TOP SPIN
300 MHz and 75.6 MHz spectrometer with chemical shift values (d)
in ppm downfield from TMS using DMSO as solvent. IR spectra of
samples were recorded on a model PerkineElmer FTIR-1710 spec-
trometer using KBr. Elemental analysis was performed using Her-
aeus CHN-Rapid Analyzer. EI mass spectra were recorded on TOF
MS mass spectrometer. The purity of compounds was checked on
silica gel coated aluminum plates (Merck TLC: mass particle size
10e12
mm; particle distribution 5e20
mm; layer thickness 250 mm;
plate height 30
mm).
4.2. Microwave reactor
Analyzing the values of EHOMO; ELUMO; DE and log P presented in
Table 4, we can obtain important informations on the antibacterial
activity of compounds studied:
The studies were carried out in a microwave reactor (Discover,
model CEM-SP1245). The reactor was a fully baffled, cylindrical
Fig. 1. a. HOMO of three-dimensional electrostatic potential isosurfaces at ꢄ10 kcal molꢄ1 (Red color) and 10 kcal molꢄ1 (Blue color) for compounds 6d, 6h, 6c, 6g, 11b, 6a, 6c, 6i and
6b. b. LUMO of three-dimensional electrostatic potential isosurfaces at ꢄ10 kcal molꢄ1 (Red color) and 10 kcal molꢄ1 (Blue color) for compounds 6d, 6h, 6c, 6g, 11b, 6a, 6c, 6i and 6b.
(For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

5036
M. Kidwai et al. / European Journal of Medicinal Chemistry 45 (2010) 5031e5038
Fig. 2. SCFs superimposed onto total electron density at a value of 1.5936eꢄ009 au for compounds 6d, 6h, 6c, 6g, 11b, 6a, 6c, 6i and 6b.
glass vessel (capacity, 120 ml; ID, 4.5 cm) with provision for
mechanical stirring. A standard four-blade pitched turbine impeller
(diameter, 1.5 cm) was used for agitation. However, the actual
reactor volume exposed to the microwave irradiation was 45 ml
with 5.5 cm height. There was no bubble formation. Temperature in
the reactor was computer controlled.
4.2.5. 4-(5-Meoxy-benzimidazol-2-ylsulfanyl)-phenol 11b
M.pt. 238e240 ꢂC. HRMS: Mþ 259.1245. Anal. Calculated for
C14H12N2O2S C 61.75, H 4.47, N 10.29 and S 11.77%, found C 61.79, H
3.43, N 10.32 and S 11.75%. IR (y
, cmꢄ1, KBr pellet) 3405.14 (OH),
1583.98 (C]N). dH (CD3CN þ DMSO-d6, 300 MHz) 3.66 (s, 3H,
CH3O), 6.64 (m, 3H, C4eH MBI þ C2eH Phenol), 7.20 (d, 3H, C6eH
MBI), 7.22 (m, 3H, C7eH MBI þ C3eH Phenol), 9.48 (s, 1H, OH), 12.19
(s, 1H, NH). dC (DMSO-d6, 75 MHz) 55.05, 94.35, 109.47, 110.22,
117.42, 118.34, 125.90, 131.80, 133.01, 155.40, 156.92, 168.02.
4.2.1. General procedure for the synthesis of 2-Amino-4-Aryl-6-
(Benzothiazol-2-ylsulfanyl)-4H-chromene-3-carbonitrile (6aei)
A solution of p-bromophenol (0.01 mol) and 2-Benzothiazolethiol
(0.01 mol) taken in aqueous K2CO3 (5e10 ml) was microwave irra-
diated for a specific time at low power (560 W). The progress of
the reaction was monitored by TLC examination at an interval of
every30 s. Afterformationof4-(Benzothiazol-2-ylsulfanyl)-phenol 3,
aldehyde (0.01 mol) and malononitrile (0.01 mol) were added and
again irradiated. Upon completion, the reaction mixture was allowed
to cool and then filtered.
4.2.6. 2-Amino-6-(Benzothiazol-2-ylsulfanyl)-4-phenyl-2-yl-4H-
chromene-3-carbonitrile 6a
M.pt. 220e222 ꢂC. HRMS: Mþ 413.1357. Anal. Calculated for
C23H15N3OS2 C 66.80, H 3.66, N 10.16 and S 15.51%, found C 66.89, H
3.73, N 10.11 and S 15.59%. IR (y
, cmꢄ1, KBr pellet) 3437.10 (NH2),
2195.13 (C^N), 1618.38 (C]C), 1566.66 (C]N). dH (DMSO-d6,
300 MHz) 4.78 (s, 1H, C4eH), 6.48 (s, 2H, NH2), 7.23e7.31 (m, 9H,
AreH). dC (DMSO-d6, 75 MHz) 30.12, 60.78, 112.40, 116.88, 117.59,
120.36, 121.66, 122.31, 122.56, 123.14, 124.12, 125.18, 125.67, 127.06,
128.46, 129.06, 129.34, 133.58, 141.25, 156.25, 157.64, 159.87, 179.57.
4.2.2. General procedure for the synthesis of 2-Amino-4-aryl-6-
(1H-Benzoimidazol/5-methoxy-1H-Benzoimidazol-2-ylsulfanyl)-
4H-chromen-3-carbonitrile/carboxylic acid ethyl ester (11ael)
A solution of p-bromophenol (0.01 mol) and 1H-Benzoimida-
zole-2-thiol/5-Methoxy-1H-Benzoimidazole-2-thiol 7/8 (0.01 mol)
taken in aqueous K2CO3 (5e10 ml) was microwave irradiated for
a specific time at low power (560 W). The progress of the reaction
was monitored by TLC examination at an interval of every 30 s.
After formation of 4-(1H-Benzoimidazole-2-ylsulfanyl)-phenol 9,
aldehyde (0.01 mol) and malononitrile/(0.01 mol) were added and
again irradiated. Upon completion, the reaction mixture was
allowed to cool and then filtered.
4.2.7. 2-Amino-6-(Benzothiazol-2-ylsulfanyl)-4-thiophen-2-yl-4H-
chromene-3-carbonitrile 6b
M.pt. 160e163 ꢂC. HRMS: Mþ 419.0642. Anal. Calculated for
C21H13N3OS3 C 60.12, H 3.12, N 10.02 and S 22.93%, found C 60.18, H 3.19,
N 10.10 and S 22.81%. IR (y
, cmꢄ1, KBr pellet) 3444.77 (NH2), 2225.12
(C^N), 1573.83 (C]N). dH (DMSO-d6, 300 MHz) 4.65 (s, 1H, C4eH),
6.54e8.92 (m, 13H, Ar þ NH2). dC (DMSO-d6, 75 MHz) 29.46, 58.64.
4.2.8. 2-Amino-6-(Benzothiazol-2-ylsulfanyl)-4-(4-chloro-phenyl)-
2-yl-4H-chromene-3-carbonitrile 6c
4.2.3. 4-(Benzothiazol-2-ylsulfanyþl)-phenol 3
M.pt. 228e230 ꢂC. HRMS: Mþ 447.4551. Anal. Calculated for
C23H14ClN3OS2 C 61.67, H 3.15, Cl 7.91, N 9.38 and S 14.32%, found C
M.pt. 208e210 ꢂC. HRMS: M 259.1245. Anal. Calculated for
C13H9NOS2 C 60.20, H 3.50, N 5.40 and S 24.73%, found C 60.16, H
60.18, H 3.15, Cl 7.98, N 9.30 and S 14.40%. IR (y
, cmꢄ1, KBr pellet)
3.43, N 5.45 and S 24.81%. IR (
y
, cmꢄ1, KBr pellet) 3444.77 (OH),
3368.48 (NH2), 2198.82 (C^N), 1614.28 (C]C), 1577.76 (C]N). dH
(DMSO-d6, 300 MHz) 4.89 (s, 1H, C4eH), 6.54e8.92 (m, 13H,
Ar þ NH2). dC (DMSO-d6, 75 MHz) 29.64, 59.79.
1695.65 (C]N). dH (CDCl3 þ DMSO-d6, 300 MHz) 6.54 (td, 2H, C2eH
Phenol), 7.00 (t, 3H, C5eH MBT þ C2eH Phenol), 7.08 (q, 2H,
C6eH þ C7eH MBT), 7.19 (t, 1H, C4eH MBT), 8.95 (s, 1H, OH). dC
(DMSO-d6, 75 MHz) 110.60, 112.41, 117.45, 120.52, 123.66, 126.40,
129.78, 131.99, 141.04, 156.88, 190.23.
4.2.9. 2-Amino-6-(Benzothiazol-2-ylsulfanyl)-4-(4-methoxy-phe)-
2-yl-4H-chromene-3-carbonitrile 6d
M.pt. 240e242 ꢂC (Decompose). HRMS: Mþ 443.7618. Anal.
Calculated for C24H17N3O2S2 C 64.99, H 3.86, N 9.47 and S 14.46%,
4.2.4. 4-(Benzimidazol-2-ylsulfanyl)-phenol 11a
M.pt. 223e225 ꢂC. HRMS: Mþ 242.1723. Anal. Calculated for
C13H9N2OS C 64.44, H 4.16, N 11.56 and S 13.23.73%, found C 64.41, H
found C 64.88, H 3.81, N 9.39 and S 14.41%. IR (y
, cmꢄ1, KBr pellet)
3384.55 (NH2), 2197.02 (C^N), 1619.97 (C]C), 1589.52 (C]N). dH
(DMSO-d6, 300 MHz) 3.56 (s, 3H, OCH3), 4.12 (s, 1H, C4eH),
6.54e8.92 (m, 13H, Ar þ NH2). dC (DMSO-d6, 75 MHz) 35.69, 62.68.
4.205, N 11.51 and S 13.29%. IR (y
, cmꢄ1, KBr pellet) 3461.26 (OH),
1592.76 (C]N). dH (CD3CN þ DMSO-d6, 300 MHz) 6.72(d, 2H, C2eH
Phenol), 7.13 (m, 4H, C4eH þ C5eH þ C6eH þ C7eH MMBI), 7.26 (d,
2H, C3eH Phenol), 7.08 (q, 2H, C6eH þ C7eH MBT), 7.19 (t, 1H, C4eH
MBT), 9.08 (s, 1H, OH), 11.88 (s, 1H, NH). dC (DMSO-d6, 75 MHz)
109.25, 109.42, 110.45, 110.95, 117.52, 122.10, 122.69, 131.37, 132.23,
132.51, 156.90, 157.25, 168.97.
4.2.10. 2-Amino-6-(Benzothiazol-2-ylsulfanyl)-4-(3-nitro-phenyl)-
2-yl-4H-chromene-3-carbonitrile 6e
M.pt. 140e142 ꢂC. HRMS: Mþ 458.4521. Anal. Calculated for
C23H14N4O3S2 C 60.25, H 3.08, N 12.22 and S 13.99%, found C 60.32,

M. Kidwai et al. / European Journal of Medicinal Chemistry 45 (2010) 5031e5038
5037
H 3.11, N 12.29 and S 14.06%. IR (
y
, cmꢄ1, KBr pellet) 3433.63 (NH2),
2H, CH2eO), 5.64 (s, 1H, C4eH), 6.67 (s, 2H, NH2), 6.74e77 (m, 5H,
Ar), 7.13e16 (m, 5H, Ar), 12.39 (s, 1H, NH).
2193.65 (C^N), 1602.71 (C]C), 1515.35 (C]N). dH (DMSO-d6,
300 MHz) 4.65 (s, 1H, C4eH), 6.54e8.92 (m, 13H, Ar þ NH2). dC
(DMSO-d6, 75 MHz) 32.64, 64.69.
4.2.17. 2-Amino-(4-benzo[1,3]dioxol-5-yl)-6-(5-methoxy-1H-
benzoimidazol-2-ylsulfanyl)-4H-chromene-3-carboxylic acid ethyl
ester 11d
4.2.11. 2-Amino-6-(Benzothiazol-2-ylsulfanyl)-4-naphthalen-2yl-
4H-chromene-3-carbonitrile 6f
M.pt. 122e124 ꢂC. HRMS: Mþ 498.4515. Anal. Calculated for
C27H23N3O6SC62.66,H4.48,N8.12,andS6.20%,foundC62.71, H4.53,
M.pt. 168e170 ꢂC. HRMS: Mþ 463.3558. Anal. Calculated for
C27H17N3OS2 C 69.95, H 3.70, N 9.06 and S 13.83%, found C 69.89, H
N 8.23 and S 6.34%. IR (y
, cmꢄ1, KBr pellet) 3128.98 (NH2), 3060.82
3.79, N 9.06 and S 13.91%. IR (
y
, cmꢄ1, KBr pellet) 3433.59 (NH2),
(NH), 1721.61 (C]O), 1643.97 (C]C), 1621.91 (C]C), 1591.81 (C]N),
1218.12 (AreCeO), 1201.91 (AreCeO), 1151.71 (AliphaticeCeO). dH
(DMSO-d6, 300 MHz) 2.31 (t, 3H, CH3), 3.65 (s, 3H, CH3O), 3.81 (q, 2H,
CH2eO), 5.34 (s, 2H, OeCH2eO), 5.62 (s, 1H, C4eH), 6.61 (NH2),
7.18e21 (m, 5H, Ar), 7.26e7.29 (m, 9H, Ar), 12.05 (s, 1H, NH).
2225.61 (C^N), 1653.53 (C]C), 1687.82 (C]N). dH (DMSO-d6,
300 MHz) 4.23 (s, 1H, C4eH), 6.54e8.92 (m, 16H, Ar þ NH2). dC
(DMSO-d6, 75 MHz) 30.54, 63.87.
4.2.12. 2-Amino-6-(Benzothiazol-2-ylsulfanyl)-4-(benzo[1,3]
dioxol-phenyl)-2-yl-4H-chromene-3-carbonitrile 6g
4.2.18. 2-Amino-6-(5-methoxy-1H-benzoimidazol-2-ylsulfanyl)-4-
(4-nitro-phenyl)-4H-chromene-3-carboxylic acid ethyl ester 11e
M.pt. 148e150 ꢂC. HRMS: Mþ 518.5498. Anal. Calculated for
C26H22N4O6S C 60.22, H 4.28, N 10.80 and S 6.18%, found C 60.28, H
M.pt. 188e190 ꢂC. HRMS: Mþ 457.4564. Anal. Calculated for
C24H15N3O3S2 C 63.00, H 3.30, N 9.18 and S 14.02%, found C 63.08, H
3.38, N 9.16 and S 13.95%. IR (y
, cmꢄ1, KBr pellet) 3433.63 (NH2),
2193.65 (C^N), 1602.71 (C]C), 1515.35 (C]N). dH (DMSO-d6,
300 MHz) 4.98 (s, 1H, C4eH), 5.42 (s, 2H, CH2), 6.34e8.15 (m, 12H,
Ar þ NH2). dC (DMSO-d6, 75 MHz) 29.45, 65.97.
4.23, N 10.91 and S 6.24%. IR (y
, cmꢄ1, KBr pellet) 3123.16 (NH2),
3065.86 (NH), 1720.42 (C]O), 1617.89 (C]C), 1592.67 (C]N),
1202.50 (AreCeO), 1183.22 (AliphaticeCeO). dH (DMSO-d6,
300 MHz) 1.49 (t, 3H, CH3), 3.78 (s, 3H, CH3O), 4.51 (q, 2H, CH2), 5.21
(s, 1H, C4eH), 6.73 (t, 3H, Ar þ NH2), 7.06(d, 1H, Ar), 7.44 (t, 2H, Ar),
8.15 (d, 2H, Ar), 8.38 (d, 3H, Ar), 11.91 (s, 1H, NH).
4.2.13. 2-Amino-6-(Benzothiazol-2-ylsulfanyl)-4-(2H-indol-3-yl)-
2-yl-4H-chromene-3-carbonitrile 6h
M.pt. 215e217 ꢂC. HRMS: Mþ 452.4853. Anal. Calculated for
C25H16N4OS2 C 66.35, H 3.56, N 12.38 and S 14.17%, found C 66.41, H
4.2.19. 2-Amino-(1H-benzoimidazol-2-ylsulfanyl)-4-(4-chloro-
phenyl)-64H-chromene-3-carboxþylic acid ethyl ester 11f
3.49, N 12.45 and S 14.15%. IR (y
, cmꢄ1, KBr pellet) 3281.49 (NH2),
2222.31 (C^N), 1625.78 (C]C), 1589.67 (C]C), 1569.25 (C]N). dH
(DMSO-d6, 300 MHz) 5.56 (s, 1H, C4eH), 6.22e9.45 (m, 15H,
Ar þ NH2 þ NH). dC (DMSO-d6, 75 MHz) 28.19, 65.26, 109.44, 111.00,
113.07, 115.92, 115.97, 118.96, 120.36,121.96, 122.50, 123.21, 123.87,
124.14, 124.65, 125.12, 126.35, 125.63, 126.72, 133.44, 136.33, 152.33,
154.39, 163.47, 182.46.
M.pt. 80e82 ꢂC. HRMS: M 477.9815. Anal. Calculated for
C25H20ClN3O3S C 62.82, H 4.22, N 8.79, and S 6.71%, found C 62.77, H
4.29, N 8.83 and S 6.88%. IR (y
, cmꢄ1, KBr pellet) 3037.48 (NH2),
2990.58 (NH), 1724.31 (C]O), 1646.45 (C]C), 1622.65 (C]C),
1590.44 (C]N), 1200.59 (AreCeO), 1155.08 (AliphaticeCeO). dH
(DMSO-d6, 300 MHz) 1.41 (t, 3H, J ¼ 8.4, CH3), 4.41 (q, 2H, J ¼ 4.1,
CH2), 5.02 (s, 1H, C4eH), 7.51 (s, 2H, NH2), 7.53 (d, 2H, Ar), 7.97 (m,
3H, Ar), 8.27 (m, 6H, Ar), 12.01 (s, 1H, NH).
4.2.14. 2-Amino-6-(Benzothiazol-2-ylsulfanyl)-4-(2-
chloroquinolin-3-yl)-2-yl-4H-chroþmene-3-carbonitrile 6i
M.pt. 170e172 ꢂC. HRMS: M 498.4515. Anal. Calculated for
C26H15ClN4OS2 C 62.58, H 3.03, Cl 7.10, N 11.23 and S 12.85%, found C
4.2.20. 2-Amino-6-(1H-benzoimidazol-2-ylsulfanyl)-4-(4-chloro-
phenyl)-4H-chromene-3-carbonitrþile 11g
62.64, H 3.11, Cl 7.16, N 11.29 and S 12.96%. IR (
y
, cmꢄ1, KBr pellet)
M.pt. 156e158 ꢂC. HRMS: M 430.9841. Anal. Calculated for
C23H15ClN4OS C 64.11, H 3.51, N 13.00, and S 7.44%, found C 64.15, H
3281.49 (NH2), 2222.31 (C^N), 1625.78 (C]C), 1589.67 (C]C),
1569.25 (C]N). dH (DMSO-d6, 300 MHz)5.42(s,1H, C4eH), 7.22e8.31
(m, 13H, Ar þ NH2). dC (DMSO-d6, 75 MHz) 29.45, 68.97, 109.44,
111.00, 113.07, 115.92, 115.97, 120.36,121.96, 122.50, 123.21, 123.87,
124.14, 124.65, 125.12, 133.44, 136.33, 154.39, 163.47, 164.52, 183.45.
3.53, N 13.09 and S 7.49%. IR (y
, cmꢄ1, KBr pellet) 3152.99 (NH2),
3034.71 (NH), 2227.48 (CN),1654.44 (C]C),1621.91 (C]C), 1583.97
(C]N), 1215.75 (AreO). dH (DMSO-d6, 300 MHz) 5.13 (s, 1H, C4eH),
7.12 (s, 1H, Ar), 7.13 (s, 2H, NH2), 7.55 (m, 6H, Ar), 7.94 (d, 4H, Ar),
12.26 (s, 1H, NH).
4.2.15. 2-Amino-6-(1H-Benzoimidazol-2-ylsulfanyl)-4-thiophen-2-
yl-4H-chromen-3-carboxylic acid þethyl ester 11a
4.2.21. 2-Amino-6-(1H-benzoimidazol-2-ylsulfanyl)-4-(4-nitro-
phenyl)-4H-chromene-3-carboxyliþc acid ethyl ester 11h
M.pt. 182e184 ꢂC. HRMS: M 449.3241. Anal. Calculated for
C23H19N3O3S2 C 61.45, H 4.26, N 9.35 and S 14.27%, found C 61.76, H
M.pt. 181e182 ꢂC. HRMS: M 488.5315. Anal. Calculated for
C25H20N4O5S C 61.47, H 4.13, N 11.47, and S 6.56%, found C 61.51, H
4.41, N 9.61 and S 14.41%. IR (y
, cmꢄ1, KBr pellet) 3152.50 (NH2),
3089.76 (NH),1717.82 (C]O),1632.81 (C]C),1615.91 (C]C),1597.87
(C]N), 1251.04(C-O). dH (DMSO-d6, 300 MHz) 2.30 (t, 3H, CH3), 3.73
(q, 2H, CH2-O), 5.42 (s, 1H, C4eH), 6.67 (NH2), 6.70e6.72 (m, 5H, Ar),
7.02e7.04 (m, 5H, Ar),12.35 (s, 1H, NH). dC (DMSO-d6, 75 MHz) 13.21,
28.56, 55.67, 94.51, 109.80, 126.42, 133.12, 155.81, 164.52, 167.76.
4.18, N 11.54 and S 6.61%. IR (y
, cmꢄ1, KBr pellet) 3152.00 (NH2),
2991.86 (NH), 1721.05 (C]O), 1617.38 (C]C), 1594.12 (C]N),
1202.34 (AreCeO), 1179.83 (AliphaticeCeO). dH (DMSO-d6,
300 MHz) 1.44 (t, 3H, CH3), 4.42 (q, 2H, CH2eO), 5.07 (s, 1H, C4eH),
7.11 (s, 2H, NH2), 7.18 (m, 3H, Ar), 7.54 (d, 2h, Ar), 8.19 (d, 2H, Ar),
8.38 (d, 3H, Ar), 12.20 (s, 1H, NH).
4.2.16. 2-Amino-6-(5-methoxy-1H-benzoimidazol-2-ylsulfanyl)-4-
thiophen-2-yl-4H-chromene-3-carþboxylic acid ethyl ester 11b
M.pt. 203e205 ꢂC. HRMS: M 479.7309. Anal. Calculated for
C24H21N3O4S2 C 60.11, H 4.41, N 8.76 and S 13.37%, found C 60.23, H
4.2.22. 2-Amino-6-(5-methoxy-1H-benzoimidazol-2-ylsulfanyl)-4-
(3-nitro-phenyl)-4H-chromene-3-carboxylic acid ethyl ester 11j
M.pt. 106e108 ꢂC. HRMS: Mþ 518.6725. Anal. Calculated for
C26H22N4O6S C 60.22, H 4.28, N 10.80, and S 6.18%, found C 60.27, H
4.53, N 8.64 and S 13.51%. IR (y
, cmꢄ1, KBr pellet) 3126.31 (NH2),
3087.21 (NH), 1717.72 (C]O), 1638.43 (C]C), 1618.91 (C]C),
1597.87 (C]N), 1214.20 (AreCeO), 1155.94 (AliphaticeCeO). dH
(DMSO-d6, 300 MHz) 2.32 (t, 3H, CH3), 3.70 (s, 3H, CH3O), 3.77 (q,
4.35, N 10.83 and S 6.23%. IR (y
, cmꢄ1, KBr pellet) 3152.00 (NH2),
3114.55 (NH), 1721.05 (C]O), 1617.38 (C]C), 1591.12 (C]N),
1202.34 (AreCeO). dH (DMSO-d6, 300 MHz) 1.34 (t, 3H, CH3), 3.65

5038
M. Kidwai et al. / European Journal of Medicinal Chemistry 45 (2010) 5031e5038
(s, 3H, CH3O), 4.35 (q, 2H, CH2eO), 5.18 (s, 1H, C4eH), 6.62 (s, 2H,
NH2), 7.16 (s, 2H, Ar), 7.63 (d, 3H, Ar), 8.21 (d, 4H, Ar), 8.63 (s,1H, Ar),
10.02 (s, 1H, Ar), 11.53 (s, 1H, NH).
Appendix. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ejmech.2010.08.010.
4.2.23. 2-Amino-4-(4-chloro-phenyl)-6-(5-methoxy-1H-
benzoimidazol-2-ylsulfanyl)-4H-chromene-3-carboxylic acid ethyl
ester 11k
References
M.pt. 202e204 ꢂC. HRMS: Mþ 507.8010. Anal. Calculated for
C26H22ClN3O4S C 61.47, H 4.37, N 8.27, and S 6.31%, found C 61.54, H
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4.42, N 8.23 and S 6.34%. IR (y
, cmꢄ1, KBr pellet) 3037.02 (NH2),
2989.92 (NH), 1724.10 (C]O), 1612.45 (C]C), 1589.64 (C]N),
1200.13 (AreCeO), 1158.12 (AliphaticeCeO).
4.3. Computational methods
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In QSAR, all the properties (e.g. Critical Temp, Critical Pressure,
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AMI (NDDO) Hamiltonian. First of all, optimized geometries were
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calculation of the three-dimensional electrostatic potential iso-
surfaces (3D-EPI) and molecular electrostatic potential super-
imposed onto total electron density (MEP-STED) was done with
help of Arugslab (Figs. 1 and 2) [22]. The run type was set at SCF
type (RHF) with maximum of 200 cycles. The basic set Minimal
Valence Basis is STO 6G. Statistical Data Analysis was done with
the help of WINKS SDA [23].
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Acknowledgements
[20] ChemDraw 7 from CambridgeSoft Corporation.
[21] ACDLABS 12.0 from Advanced Chemistry Development.
[22] Arugslab from ArgusLab Molecular Modeling and Drug Docking Software.
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The authors (R. Poddar and S. Bhardwaj) are thankful to CSIR New
Delhi for their seniorand junior research fellowship and M. Kidwai is
grateful to the University of Delhi for providing finance assistance.