Regioselective Synthesis, Antimicrobial Evaluation and QSAR Studies of Some 3-Aryl-1-heteroarylindeno[1,2-c]pyrazol-4(1H)-ones

Article abstract of DOI:10.1002/jhet.2710

A series of seventeen 3-aryl-1-heteroarylindeno[1,2-c]pyrazol-4(1H)-ones (4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k, 4l, 4m, 4n, 4o, 4p, 4q) has been synthesized and characterized by spectral (IR, ¹H NMR, and mass), X-ray crystallography and analytical results. All the indenopyrazoles (4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k, 4l, 4m, 4n, 4o, 4p, 4q) were tested for their in vitro antimicrobial activity against two Gram-positive bacteria viz. Bacillus subtilis (MTCC 441) and Staphylococcus aureus (MTCC 7443), two Gram-negative bacteria, viz. Escherichia coli (MTCC 42) and Pseudomonas aeruginosa (MTCC 741) and two fungi, viz. Candida albicans (MTCC 183) and Aspergillus niger (MTCC 282) using ceftriaxone and fluconazole as standard references against bacterial and fungal strains, respectively. Among the synthesized derivatives, 4f against B. subtilis and S. aureus, 4e against E. coli, 4g and 4j against P. aeruginosa, 4k and 4l against C. albicans, and 4k against A. niger were found to exhibit appreciable antimicrobial activities. However, 4g (minimum inhibitory concentration, 0.0036 μmol/mL) was found to be more potent than the reference, that is, fluconazole (minimum inhibitory concentration, 0.0050 μmol/mL) against A. niger. Moreover, both antibacterial and antifungal activities were found to be prolific. The radial distribution function parameters were found to be important for description of activities against the modeled strains in quantitative structure–activity relationship studies.

Full text of DOI:10.1002/jhet.2710

Month 2016 Regioselective Synthesis, Antimicrobial Evaluation and QSAR Studies of
Some 3-Aryl-1-heteroarylindeno[1,2-c]pyrazol-4(1H)-ones
Satbir Mor, Rajni Mohil, Savita Nagoria, Ashwani Kumar, Kashmiri Lal, Devinder Kumar, and Virender Singh
a
a
a
b
a
a
c
*
aDepartment of Chemistry, Guru Jambheshwar University of Science & Technology, Hisar-125001, Haryana, India
bDepartment of Pharmaceutical Sciences, Guru Jambheshwar University of Science & Technology, Hisar-125001,
Haryana, India
cDepartment of Chemistry, Dr. B. R. Ambedkar National Institute of Technology (NIT), Jalandhar-144011, Punjab, India
*
E-mail: satbir_mor@yahoo.co.in
Received March 17, 2016
DOI 10.1002/jhet.2710
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A series of seventeen 3-aryl-1-heteroarylindeno[1,2-c]pyrazol-4(1H)-ones (4a–4q) has been synthesized
1
and characterized by spectral (IR, H NMR, and mass), X-ray crystallography and analytical results. All
the indenopyrazoles (4a–4q) were tested for their in vitro antimicrobial activity against two Gram-positive
bacteria viz. Bacillus subtilis (MTCC 441) and Staphylococcus aureus (MTCC 7443), two Gram-negative
bacteria, viz. Escherichia coli (MTCC 42) and Pseudomonas aeruginosa (MTCC 741) and two fungi, viz.
Candida albicans (MTCC 183) and Aspergillus niger (MTCC 282) using ceftriaxone and fluconazole as
standard references against bacterial and fungal strains, respectively. Among the synthesized derivatives,
4f against B. subtilis and S. aureus, 4e against E. coli, 4g and 4j against P. aeruginosa, 4k and 4l against
C. albicans, and 4k against A. niger were found to exhibit appreciable antimicrobial activities. However,
4g (minimum inhibitory concentration, 0.0036 μmol/mL) was found to be more potent than the reference,
that is, fluconazole (minimum inhibitory concentration, 0.0050 μmol/mL) against A. niger. Moreover, both
antibacterial and antifungal activities were found to be prolific. The radial distribution function parameters
were found to be important for description of activities against the modeled strains in quantitative
structure–activity relationship studies.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
the fast development of resistance to the accessible antimicro-
bial drugs due to years of extensive overuse or misuse and also
due to the changing nature of the infections observed in the
elderly and other immunocompromised patients. Therefore,
searching for new antimicrobial agents with specific activity,
dissimilar from those of well-known classes, is of chief con-
cern because the majority of new molecules entering clinical
Microbial diseases have emerged as a growing threat to hu-
man health around the world. A wide variety of antimicrobials
has been developed to combat against microbial infections.
The challenge associated with fighting microbial infections
has become an increasingly complex one, partly because of
© 2016 Wiley Periodicals, Inc.

S. Mor, R. Mohil, S. Nagoria, A. Kumar, K. Lal, D. Kumar, and V. Singh
Vol 000
studies contain at least one heterocyclic moiety predominantly
N-heterocycles [1]. Among the nitrogenous heterocycles,
pyrazole derivatives have arisen a great interest in agrochem-
ical, pharmaceutical, and chemical industries [2,3]. The perva-
siveness of pyrazole cores in biologically active molecules has
stimulated the need for elegant and different ways for synthe-
sis of these heterocyclic lead. As a consequence, various
approaches have been developed for the synthesis of
pyrazoles [3,4]. Among the pyrazoles, in particular,
indenopyrazoles have gained appreciable interest in recent
years due to their widespread biological activities [5–7]. For
instance, indenopyrazoles have been recognized as potential
CNS agents [8], antidepressants [9], and tyrosine kinase in-
hibitors [10]. Indeno[1,2-c]pyrazolone acetic acids are known
to act as nonsteroidal anti-inflammatory drugs [11]. More-
over, indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide
have recently been reported as novel antitubercular agents
[12] and indeno[1,2-c]pyrazol-4-ones as potent and selective
cyclin-dependent kinase [13] and check point kinase inhibi-
tors [14,15]. The precedent for broad bioactivity profile for
indenopyrazole pharmacophores has led to the development
of various approaches for their synthesis [6,13,16]. Likewise,
benzothiazole is a privileged heterocyclic scaffold that has
attracted considerable attention because of its wide array of
interesting pharmacological activities [17]. Some reviews,
recently reported in literature, briefly describe the synthetic
strategies and biological activities of benzothiazole nucleus
[18–22]. Some of the important marketed drugs comprising
benzothiazole moiety are riluzole, sibenadet hydrochloride
(Viozan), and pramipexole [23–25].
past decades because of good success in medicinal chemis-
try research. It is a multivariate, mathematical relationship
between a set of physicochemical properties and biological
activity, which has successfully been employed for drug
design and development [26,27]. Owing to the importance
of indenoyrazoles and benzothiazoles, which qualify them
as excellent scaffolds in therapeutic and medicinal research
and in continuation of our research program on bioinspired
heterocycles [28], herein, we report regioselective synthesis,
characterization, antimicrobial evaluation, and QSAR stud-
ies of several 3-aryl-1-heteroarylindeno[1,2-c]pyrazol-4
(1H)-ones (4a–4q).
RESULTS AND DISCUSSION
Chemistry. The protocol for the synthesis of 3-aryl-1-
heteroarylindeno[1,2-c]pyrazol-4(1H)-ones (4) is depicted
in Scheme 1. The required 2-arylidene-1H-indene-1,3
(2H)-diones (2) as starting material were prepared through
Knoevenagel condensation of equimolar quantities of 1H-
indene-1,3(2H)-dione (1) with appropriate aromatic
aldehydes in ethanol in the presence of catalytic amount of
piperidine according to the procedure described in literature
[29]. The 2-hydrazinylbenzo[d]thiazole/2-hydrazinyl-6-
substituted benzo[d]thiazoles (3) were prepared from benzo
[d]thiazol-2-amine/6-substitutedbenzo[d]thiazol-2-amines
upon treatment with hydrazine hydrochloride in ethylene
glycol, which, in turn, were prepared from aniline/4-
substituted anilines using potassium thiocyanate/bromine
according to the procedures detailed in literature [30,31].
The title indenopyrazoles (4) were synthesized by stirring the
equimolar quantities of 2-arylidene-1H-indene-1,3(2H)-
Quantitative structure–activity relationship (QSAR) is
one of the most extensively used computational methodol-
ogies that have gained considerable attention during the
Scheme 1. Synthesis of 3-aryl-1-heteroarylindeno[1,2-c]pyrazol-4(1H)-ones (4).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Synthesis and Antimicrobial Evaluation of Some 3-Aryl-1-heteroarylindeno[1,2-c]
pyrazol-4(1H)-ones
diones (2) and 2-hydrazinylbenzo[d]thiazole/2-hydrazinyl-
6-substituted benzo[d]thiazoles (3) in dry pyridine/piperidine
at room temperature for 3–4days in low yields. It is
worthwhile mentioning here that all attempts made to
improve the yield of products, that is, indenopyrazoles
(4a–4q) by increasing the reaction temperature proved
abortive and heating intensified resinification.
The indenopyrazoles (4) were well characterized by satis-
factory spectroscopic (IR, 1H NMR, and mass), X-ray
crystallography and analytical data. The IR spectra of
indenopyrazoles (4a–4q) displayed strong absorption bands
in the regions 1712–1699cmꢀ1 and 1612–1602 cmꢀ1 due
to C=O stretching in conjugated five-membered cyclic
ketone [31] and C=N stretching, respectively. The main
characteristic feature of 1H NMR spectra of these
indenopyrazoles (4a–4q) is the downfield shifting of C8-H
(δ 8.64–8.52) as compared with other aromatic protons due
to anisotropic–diamagnetic effect of lone pair/s of electrons
present on nitrogen and sulphur of N1-benzothiazole moiety
[32,33]. The other aromatic and aliphatic protons were
observed in the expected regions (vide experimental). It
warrants attention here that 13C NMR spectra of the title
compounds could not be recorded due to their poor solubility.
The structures of all the indenopyrazoles (4a–4q) have been
further confirmed by their mass spectra, which showed peaks
corresponding to characteristic fragmentation patterns of
both pyrazole and benzothiazole moieties.
The structural assignment of 4 was further confirmed by
X-ray crystallography study. Crystallization of 4a from
saturated solution in chloroform at room temperature yielded
suitable yellow-colored single crystals for X-ray analysis.
The crystal structure data of 4a has been deposited at the
Cambridge Crystallographic Data Centre with deposition
number CCDC 1057798. X-ray crystal structure of
Figure 1. X-ray crystal structure of 4a. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
Table 1
Selected bond distances, bond angles, and torsion angles of 4a.
Bond
Bond distance, Å
Bond
Bond distance, Å
C7–N6
C8–N5
C15–C16
C17–C18
C7–N5
1.301 (10)
1.357 (10)
1.485 (11)
1.450 (10)
1.371 (10)
1.387 (11)
C16–C17
N1–N2
C7–S2
C15–O5
C17–N4
N4–N5
1.444 (10)
1.388 (9)
1.736 (8)
1.211 (10)
1.305 (10)
1.407 (9)
C8–C16
Bond
Bond angle, °
Bond
Bond angle, °
N6–C7–N5
123.3 (7)
107.0 (7)
106.1 (7)
109.4 (7)
111.4 (7)
123.0 (7)
115.9 (7)
124.0 (9)
131.9 (7)
108.9 (7)
110.1 (6)
117.3 (6)
141.4 (8)
107.7 (7)
121.4 (7)
119.6 (7)
N3–C42–S1
N3–C43–C48
O2–C46–C47
C41–N2–N1
C17–N4–N5
C7–N5–N4
117.8 (6)
125.4 (8)
114.5 (7)
111.7 (6)
107.4 (6)
119.0 (6)
119.4 (6)
129.2 (8)
146.2 (8)
129.2 (7)
141.7 (8)
119.1 (6)
123.7 (7)
104.4 (6)
116.4 (6)
130.9 (7)
N5–C8–C16
C8–C16–C17
N4–C17–C16
N1–C32–C33
N3–C42–N2
N3–C43–C44
O2–C46–C45
C41–N2–C42
C42–N3–C43
C8–N5–N4
N6–C7–S2
N5–C8–C9
C8–C16–C15
N4–C17–C18
N1–C32–C29
N5–C7–S2
O5–C15–C16
C17–C16–C15
C16–C17–C18
N2–C41–C40
N2–C42–S1
C43–C44–C45
C32–N1–N2
C42–N2–N1
C8–N5–C7
Bond
Torsion angle, °
Bond
Torsion angle, °
N4–C17–C18–C19
N6–C7–N5–C8
ꢀ8.1 (11)
C16–C17–C18–C23
S2–C7–N5–N4
ꢀ8.1 (12)
2.3 (12)
4.2 (9)
Standard uncertainties are given in parentheses.
Journal of Heterocyclic Chemistry
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S. Mor, R. Mohil, S. Nagoria, A. Kumar, K. Lal, D. Kumar, and V. Singh
Vol 000
Table 2
X-ray crystallographic data of 4a.
Chemical formula
C25H17N3O3S
Formula weight
439.48
Crystal system, space group
Monoclinic, P21/c
Temperature, K
293(2)
Radiation type, wavelength (Å)
Mo Kα, 0.71073
a, b, c (Å)
α, β, γ (°)
V (Å3)
Z
7.5503(8), 17.760(2), 30.472(4)
90.00, 90.701(8), 90.00
4085.8(8)
8
1.429
Density (calc) (Mg mꢀ3
)
F (000)
1824
0.193
μ (mmꢀ1
)
Crystal size (mm)
0.14 × 0.17 × 0.19
2.31, 24.67
θ
min, θmax (°)
Data collection
Reflections collected
46680
Independent reflections
12938
Observed reflections [I > 2 σ(I)]
Rint
5214
0.1406
Dataset (h, k, l)
Absorption correction
Tmin, Tmax
ꢀ10→10; ꢀ20→25; ꢀ43→44
Multiscan
0.4961, 0.7461
Refinement
R, wR, S
0.1561, 0.4194, 1.035
12938
577
No. of reflections
No. of parameters
No. of restraints
Max. and Av. shift/error
0.0
0.053, 0.010
ꢀ0.721, 0.638
Δρmin, Δρmax (e Åꢀ3
)
compound 4a is depicted in Figure 1. The summary of crys-
tal structure data is presented in Tables 1 and 2.
molecular modeling studies were performed on 2 using semi-
empirical method. The required 3D structures were prepared
and optimized with MavinSketch 5.10. The geometries of
the structures were further optimized with PM7 method
taking gradient norm value as 0.1. Different properties were
calculated using Andreas Klamt’s cosmo implicit solvation
model (pyridine) in MOPAC2012 [36,37], and results were
visualized with Jmol [38].
It is LUMO of the molecule, which will be the frontier
orbital in the reaction with nucleophiles (hydrazines in
our case). In LUMO, the values of atomic orbital
coefficients on carbon 7, 8, 9, and 11 are given in
Table 3. It can be clearly noticed that LUMO, in each case,
has the highest orbital coefficient on carbon 11; therefore,
the incoming nucleophile, that is, hydrazine will react
preferentially at this carbon. For instance, diagram
showing LUMO of the molecule 2-benzylidene-1H-
indene-1,3(2H)-dione (2, R1=H) under study is shown in
Figure 2.
In the aforementioned discussion, it has been shown that
the condensation of the terminal –NH2 of 2-hydrazinylbenzo
[d]thiazole/2-hydrazinyl-6-substitutedbenzo[d]thiazoles (3)
occurs at the exocyclic double bond of the 2-arylidene-1H-
indene-1,3(2H)-diones (2). However, in principle, the conden-
sation of either of the two nitrogen atoms of the hydrazines (3)
can occur either on the exocyclic double bond or on
1-carbonyl or 3-carbonyl group of the indanediones (2). As
a result, in all four different intermediates, that is,
dihydroindenopyrazoles (5, 6, 7, and 8) are possible as shown
in Scheme 2. These intermediates (5, 6, 7, and 8) may yield
two indenopyrazoles (4 and 9) by the base-catalyzed dehydro-
genation process [34,35]. Out of these indenopyrazoles (4 and
9), formation of 9 can easily be discarded on the ground that
such a remote placement of the benzothiazole moiety from
C8-H will not be able to deshield it in its 1H NMR spectrum,
which find support from the earlier observations reported in
the literature [32,33].
Antimicrobial activity.
All the 17 indenopyrazoles
Molecular modeling study. In order to find out the reason
for regioselective synthesis of indenopyrazoles (4) by the
reaction of terminal amino group of hydrazine (3) with
carbon 11 of 2-arylidene-1H-indene-1,3(2H)-diones (2),
(4a–4q) were tested for their in vitro antimicrobial activity
against two Gram-positive bacteria, that is, Bacillus subtilis
(MTCC 441) and Staphylococcus aureus (MTCC 7443), two
Gram-negative bacteria, that is, Escherichia coli (MTCC 42)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis and Antimicrobial Evaluation of Some 3-Aryl-1-heteroarylindeno[1,2-c]
pyrazol-4(1H)-ones
Scheme 2. Possible route for the regioselective synthesis of indenopyrazoles (4).
Table 3
Atomic orbital coefficients of 2-arylidene-1H-indene-1,3(2H)-diones (2).
Sr. no.
Carbon
R1=H
R1=OCH3
R1=CH3
R1=Br
R1=Cl
R1=F
1
2
3
4
7
8
9
ꢀ0.2484
ꢀ0.2304
ꢀ0.3289
0.5513
ꢀ0.2173
ꢀ0.3010
ꢀ0.2935
0.5672
ꢀ0.2473
ꢀ0.2322
ꢀ0.3190
0.5560
ꢀ0.2288
ꢀ0.2160
ꢀ0.3345
0.5199
ꢀ0.2311
ꢀ0.2145
ꢀ0.3341
0.5222
ꢀ0.2382
ꢀ0.2212
ꢀ0.3289
0.5363
11
and Pseudomonas aeruginosa (MTCC 741) and two fungi,
that is, Candida albicans (MTCC 183) and Aspergillus niger
(MTCC 282). Ceftriaxone and fluconazole were used as
standard references against bacterial and fungal strains,
respectively. Serial tube dilution technique was used to
determine minimum inhibitory concentration (MIC). The
MIC values and graphical representation of antimicrobial
activities of 4a–4q against tested microorganisms are
depicted in Table 4 and Figure 3.
It is inferred from the data presented in Table 4 and
Figure 3 that the derivative 4f was found to exhibit consider-
able activity against B. subtilis, 4f exhibited convincing
inhibitory activity against S. aureus, 4e exhibited promising
inhibitory activity against E. coli, and 4g and 4j were found
moderately activate against P. aeruginosa as compared with
the reference drug, that is, ceftriaxone. The compounds 4k
and 4l were found to exhibit considerable inhibitory activity
against C. albicans, 4k was found to exhibit convincing
antifungal activity against A. niger, whereas 4g was found to
exhibit more inhibitory activity against A. niger than the
reference, that is, fluconazole. However, no general trend for
structure activity relationships (SAR) could be established.
QSAR studies.
To be aware of the structural
requirements of the indeno[1,2-c] pyrazol-4(1H)-one
analogs for antimicrobial activities in a better way, QSAR
analysis by using multiple linear regressions of the
synthesized compounds (4) has been described. The activity
data observed as MIC were converted into pMIC and used
as dependent variable. Various 2D and 3D parameters were
calculated for all the molecules and used as independent
Journal of Heterocyclic Chemistry
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S. Mor, R. Mohil, S. Nagoria, A. Kumar, K. Lal, D. Kumar, and V. Singh
Vol 000
Figure 2. LUMO of 2-benzylidene-1H-indene-1,3(2H)-dione (2, R1=H). [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Table 4
In vitro antimicrobial activity of 4a–4q.
Minimum inhibitory concentrationa
Gram-positive bacteria
Gram-negative bacteria
Fungi
Bacillus
subtilis
Staphylococcus
aureus
Escherichia
Pseudomonas
aeruginosa
Candida
albicans
Aspergillus
niger
Entry
4a
coli
0.0234
0.0292
0.0147
0.0141
0.0128
0.0037
0.0292
0.0132
0.0153
0.0317
0.0118
0.0254
0.0314
0.0151
0.0273
0.0305
0.0164
0.0028
–
0.0142
0.0146
0.0295
0.0282
0.0128
0.0037
0.0146
0.0132
0.0153
0.1271
0.0279
0.0127
0.0314
0.0151
0.0547
0.0611
0.0654
0.0028
–
0.0142
0.0585
0.0590
0.0141
0.0032
0.0304
0.0146
0.0265
0.0307
0.0317
0.0279
0.1018
0.0629
0.0302
0.0547
0.0611
0.0329
0.0028
–
0.0284
0.0292
0.0590
0.0282
0.0256
0.0304
0.0076
0.0132
0.0153
0.0082
0.0139
0.0509
0.0629
0.0302
0.0136
0.0611
0.0329
0.0028
–
0.0284
0.1170
0.0295
0.0282
0.0256
0.0608
0.0146
0.0530
0.0614
0.0635
0.0072
0.0066
0.0629
0.0302
0.0273
0.0305
0.0329
–
0.0142
0.0292
0.0590
0.0564
0.0128
0.0152
0.0036
0.0265
0.0307
0.1271
0.0072
0.0254
0.1259
0.0302
0.0547
0.0611
0.0329
–
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
Ceftriaxone
Fluconazole
0.0050
0.0050
aMinimum inhibitory concentration in μmol/mL
variables. The values of these parameters are shown in
Table 5. The preliminary requirement before developing
a statistical significant model is to examine colinearity
between the descriptors used. This is achieved by
constructing a correlation matrix [39]. The correlation
matrix displaying correlation between activity and
descriptors as well as intercorrelation among parameters
is presented in Table 6. QSAR equations were developed
by multiple linear regression analyses, and statistically
significant multiparametric QSAR models were developed.
Journal of Heterocyclic Chemistry
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Month 2016
Synthesis and Antimicrobial Evaluation of Some 3-Aryl-1-heteroarylindeno[1,2-c]
pyrazol-4(1H)-ones
Figure 3. Graphical representation of in vitro antimicrobial activity of 4a–4q. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
QSAR model for activity against Staphylococcus aureus.
RDF60s. This shows that all these parameters are in
direct correlation with the activity against E. coli.
RDF150m is the most contributing descriptor with the
highest value of standardized coefficient (0.6546) followed
by RDF60s (0.3498) and RDF105e (0.2708). These RDFs
are radial distribution function parameters. RDF150m is a
radial distribution function at 15.0Å inter-atomic distance
weighted by relative mass, while RDF60s is a radial
distribution function at 6.0 Å inter-atomic distance
weighted by relative I-state. RDF105e is a radial distribu-
tion function at 10.5Å inter-atomic distance weighted by
relative Sanderson electronegativities.
pMICsa ¼ 186:7706ð 58:9937ÞJGI2
þ0:0732ð 0:0373ÞRDF120s
ꢀ11:1051ð 3:9267Þ
(1)
ðn ¼ 15; R ¼ 0:910; R2adj ¼ 0:800; R2 ꢀ R2adj ¼ 0:026;
Se ¼ 0:164; F ¼ 29:048; p < 0:0001;
RMSE ¼ 0:147; MAE ¼ 0:125; Q2 ¼ 0:730;
RMSEcv ¼ 0:184; MAEcv ¼ 0:157; SPress ¼ 0:206;
SDEP ¼ 0:190Þ
Observation of the various statistical parameters shows that
it is a good biparametric QSAR model. The value of cross-
validation coefficient Q2 (0.730) proves that the developed
model has good predictive power. The signs of coefficients
of both the descriptors JGI2 and RDF120s are positive, which
show that these parameters are positively correlated with the
activity against S. aureus. The standardized coefficients of
JGI2 and RDF120s are 0.8342 and 0.5175, respectively,
which show that JGI2 is more contributing toward activity
as compared with RDF120s. JGI2 is a topological charge
descriptor describing mean topological charge index of order
2 [40]. RDF120s is a radial distribution function parameter
explaining radial distribution function at 12.0Å inter-atomic
distance weighted by relative I-state. Two compounds 4n
and 4q were found to be outliers in this equation.
QSAR model for activity against Candida albicans.
pMICca ¼ ꢀ0:4683 ð 0:1252ÞLipoaffinity Index
þ0:3023 ð 0:1507ÞRDF65p
(3)
þ2:1817ð 1:1452Þ
ðn ¼ 16; R ¼ 0:936; R2adj ¼ 0:858; R2 ꢀ R2adj ¼ 0:019;
Se ¼ 0:123; F ¼ 46:154; p < 0:0001;
RMSE ¼ 0:111; MAE ¼ 0:092; Q2 ¼ 0:796;
RMSEcv ¼ 0:143; MAEcv ¼ 0:116; SPress ¼ 0:159;
SDEP ¼ 0:148Þ
One compound, 4g, was found to be outlier in this
model. Lipoaffinity index and RDF65p explained the
activity against C. albicans. The lipoaffinity index
descriptor is negatively correlated with activity as shown
by negative sign of its coefficient, while positive sign of
coefficient of RDF65p indicates that it is related with
the activity in a positive manner. The value of standard-
ized coefficients of lipoaffinity index and RDF65p are –
0.7915 and 0.4245, respectively, which proves the more
contribution of lipoaffinity index toward activity.
Lipoaffinity index is an electrotopological state atom-type
descriptor explaining lipoaffinity of molecules [41].
RDF65p is a radial distribution function at 6.5 Å
inter-atomic distance weighted by relative polarizabilities.
QSAR model for activity against Escherichia coli.
pMICec ¼ 0:1052 ð 0:0387Þ RDF150m
þ0:0974 ð 0:0878ÞRDF105e
þ0:2809 ð 0:2048ÞRDF60s
ꢀ3:6472 ð 2:6542Þ
(2)
ðn ¼ 17; R ¼ 0:924 ; R2adj ¼ 0:819; R2 ꢀ R2adj
¼ 0:034;
Se ¼ 0:150 ; F ¼ 25:142 ; p < 0:0001;
RMSE ¼ 0:131; MAE ¼ 0:105; Q2 ¼ 0:781;
RMSEcv ¼ 0:160; MAEcv ¼ 0:135; SPress ¼ 0:183 ;
SDEP ¼ 0:165Þ
It is a triparametric model with positive signs of coeffi-
cients of all three descriptors RDF150m, RDF105e, and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Mor, R. Mohil, S. Nagoria, A. Kumar, K. Lal, D. Kumar, and V. Singh
Vol 000
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis and Antimicrobial Evaluation of Some 3-Aryl-1-heteroarylindeno[1,2-c]
pyrazol-4(1H)-ones
QSAR model for activity against Aspergillus niger.
(coefficient of determination) and R2adj is very less
confirming that R2adj is very close to coefficient of determi-
nation. Moreover, the value of the standard error of estimate
is very small for all the models, and all models are significant
with a value of p<0.0001. All these statistical parameters
prove that the developed models have good fitting ability.
High values of leave one out cross-validation coefficient
(Q2 > 0.7) verify the good predictive ability and robustness
of the models [44]. Root mean squared error (RMSE) and
root mean squared error of cross-validation (RMSEcv) are
very close to each other for all models, confirming that the
illustrated models have adequate generalizability [45]. No
statistically significant models were found for activity against
B.subtilis and P. aeruginosa. The observed (Obs) and
predicted (Pre) activities along with residuals (Res) are
depicted in Table 7. Further, evidence of the predictive
pMICan ¼ þ 0:0309ð 0:0205ÞVR2_Dze
ꢀ1:8720ð 0:6241ÞRDF20v
þ 0:7457ð 0:2317ÞRDF150v
þ4:6439ð 1:2103Þ
(4)
ðn ¼ 16; R ¼ 0:930; R2adj ¼ 0:831; R2 ꢀ R2adj ¼ 0:034;
Se ¼ 0:159; F ¼ 25:532; p < 0:0001;
RMSE ¼ 0:138; MAE ¼ 0:109; Q2 ¼ 0:777;
RMSEcv ¼ 0:177; MAEcv ¼ 0:144; SPress ¼ 0:204;
SDEP ¼ 0:183Þ
For this triparametric model, compound 4m was found to
be outlier. Positive sign of coefficient of VR2_Dze and
RDF150v shows that they are in direct correlation with the
activity, whereas negative sign of coefficient of RDF20v
indicates the inverse correlation with the activity. It means
increase in the values of VR2_Dze and RDF150v while
decrease in the value of RDF20v simultaneously is favorable
for activity. The standardized coefficients of VR2_Dze,
RDF20v, and RDF150v are 0.3616, –0.7623, and 0.8025, re-
spectively. This specifies that contribution of RDF150v and
RDF20v (almost equal and opposite) is more than VR2_Dze.
RDF150v and RDF20v are radial distribution functions at
15.0 and 2.0 Å inter-atomic distances weighted by relative
van der Waals volumes, respectively [42]. VR2_Dze is a nor-
malized Randic-like eigenvector-based index from Barysz
matrix/weighted by Sanderson electronegativities [43].
All the previously discussed models are statistically sound
as the requirements for a good QSAR model for a small
dataset are met by these equations. The value of correlation
coefficient R for all the models is more than 0.9, while the
value of R2adj is ≥0.8. Also, the difference between R2
Figure 4. Plot between observed pMICsa and predicted pMICsa for
QSAR model of Staphylococcus aureus. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
Table 7
Observed (Obs) and predicted activities (Pre) along with residuals (Res) of the developed QSAR models.
pMICsa
Pre
pMICec
Pre
pMICca
Pre
pMICan
Pre
Obs
Res
Obs
Res
Obs
Res
Obs
Res
Entry
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
1.8477
1.8356
1.5302
1.5498
1.8928
2.4318
1.8356
1.8794
1.8153
0.8959
1.5544
1.8962
1.5031
–
1.683
1.8637
1.6353
1.6338
1.6545
2.2013
1.9964
2.018
2.0214
0.9412
1.6357
1.6526
1.4429
–
ꢀ0.1647
0.0281
0.1051
0.084
1.8477
1.2328
1.2291
1.8508
2.4949
1.5171
1.8356
1.5768
1.5129
1.4989
1.5544
0.9923
1.2013
1.52
1.7213
1.5632
1.4242
1.7137
2.465
1.3769
1.7737
1.6891
1.5196
1.5797
1.6123
1.019
1.1715
1.3301
1.208
1.2958
1.3602
ꢀ0.1264
0.3303
0.1951
ꢀ0.1371
ꢀ0.0298
ꢀ0.1402
ꢀ0.062
0.1123
0.0068
0.0808
0.0579
0.0267
1.5467
0.9318
1.5302
1.5498
1.5918
1.2161
–
1.2757
1.2118
1.1972
2.1427
2.1805
1.2013
1.52
1.6636
1.1196
1.5217
1.5622
1.5527
0.9855
–
1.4107
1.3481
1.2579
2.0857
2.0799
1.0885
1.5181
1.5083
1.6031
1.3522
0.1169
0.1878
ꢀ0.0085
0.0125
ꢀ0.0391
ꢀ0.2306
–
1.8477
1.5346
1.2291
1.2487
1.8928
1.8182
2.4437
1.5768
1.5129
0.8959
2.1427
1.5952
–
1.8394
1.4745
1.2634
1.4606
1.7255
1.6975
2.5246
1.7007
1.4671
1.1932
2.0921
1.5123
–
ꢀ0.0083
ꢀ0.0601
0.0342
0.2118
ꢀ0.2383
ꢀ0.2305
0.1607
0.1386
0.2061
0.0454
0.0813
ꢀ0.2436
ꢀ0.0602
–
ꢀ0.1673
ꢀ0.1207
0.0809
0.135
0.1239
0.1363
0.0607
ꢀ0.057
ꢀ0.1005
ꢀ0.1129
ꢀ0.0019
ꢀ0.0555
0.0874
ꢀ0.1306
ꢀ0.0458
0.2973
ꢀ0.0506
ꢀ0.0829
–
ꢀ0.0298
ꢀ0.1898
ꢀ0.054
0.0818
1.52
1.262
1.214
1.4828
1.5842
1.2026
1.2765
1.2029
0.0642
1.262
1.214
–
1.2673
1.2967
–
0.0053
0.0827
–
1.262
1.214
1.4828
1.5638
1.5157
1.4828
ꢀ0.0594
0.0625
ꢀ0.1226
ꢀ0.2799
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Mor, R. Mohil, S. Nagoria, A. Kumar, K. Lal, D. Kumar, and V. Singh
assessment of the selected models is provided by contrasting
Vol 000
the experimental and predicted values of the activities and the
spreading plot of residuals (i.e., residuals as function of ob-
served activities). These plots are exhibited in Figures 4–11.
These plots indicate that experimental and predicted activities
are very close to each other confirming the good predictive
ability of the developed models.
Figure 8. Plot between observed pMICca and predicted pMICca for
QSAR model of Candida albicans. [Color figure can be viewed in the on-
line issue, which is available at wileyonlinelibrary.com.]
Figure 5. Plot between observed pMICsa and residuals for QSAR model
of Staphylococcus aureus. [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
Figure 9. Plot between observed pMICca and residuals for QSAR model
of Candida albicans. [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
Figure 6. Plot between observed pMICec and predicted pMICec for
QSAR model of Escherichia coli. [Color figure can be viewed in the on-
line issue, which is available at wileyonlinelibrary.com.]
Figure 10. Plot between observed pMICan and predicted pMICan for
QSAR model of Aspergillus niger. [Color figure can be viewed in the on-
line issue, which is available at wileyonlinelibrary.com.]
The developed QSAR models show that radial distribu-
tion functions (RDF) descriptors are most significant in
describing the antimicrobial activity of the compounds,
which is in accordance with the results reported by Zhang
et al. [46]. The RDF of a molecule with n atoms can be
understood as the probability distribution to find an atom in
a spherical volume of radius R. These descriptors tell about
inter-atomic distances in the whole molecule, bond
distances, ring types, planar and non-planar systems, atom
types and other important structural patterns. These are not
Figure 7. Plot between observed pMICec and residuals for QSAR model
of Escherichia coli. [Color figure can be viewed in the online issue, which
is available at wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis and Antimicrobial Evaluation of Some 3-Aryl-1-heteroarylindeno[1,2-c]
pyrazol-4(1H)-ones
spectra were recorded on Waters Micromass Q-Tof Micro
(electrospray ionization) spectrometer. The value given in
the parentheses represents relative intensities corresponding
to the base peak taken as 100. Elemental analysis was
carried out using Vario Micro Cube Elementar CHNS
analyzer. Analytical results for C, H, and N were within
0.4% of the theoretical values. The purity of the
compounds was checked by thin-layer chromatography
using ready-made silica gel (SIL G/UV254, ALUGRAM)
plates. The spots were visualized under ultraviolet lamp.
Solvents were dried using standard literature procedures.
Ceftriaxone (Hi-Media) and fluconazole (Aurobindo
Pharmaceuticals Pvt. Ltd, Mandal, A. P., India) were used
as reference antimicrobial agents against the tested
microorganisms. 1H-Indene-1,3(2H)-dione (1) needed for the
purpose was prepared by the reaction of diethylphthalate and
dry ethylacetate in the presence of sodium wire and absolute
ethanol as per literature procedure [48].
Figure 11. Plot between observed pMICan and residuals for QSAR
model of Aspergillus niger. [Color figure can be viewed in the online is-
sue, which is available at wileyonlinelibrary.com.]
dependent on number of atoms and are invariant to transla-
tion and rotation of the complete molecule. These descriptors
can be interpreted easily and, therefore, offer an option for
reversal of the code back into the consequent 3D
structure [47].
General procedure for the synthesis of 2-arylidene-1H-
indene-1,3(2H)-diones (2).
A solution of equimolar
quantities of 1H-indene-1,3(2H)-dione (1) (0.010mol),
appropriate benzaldehyde/4-substituted benzaldehyde
(0.010mol), and 8–10 drops of piperidine in ethanol
(50mL) was heated at reflux on water bath for 8–10h. The
solid separated out on cooling from the reaction mixture
was filtered and recrystallized from chloroform to give
pure compounds (2) in high yields [29].
CONCLUSION
In conclusion, the present study reports the regioselective
synthesis of a series of 17 indenopyrazole derivatives (4)
using easily obtainable starting compounds under environ-
mentally benign conditions. The title compounds (4) were
screened for in vitro antimicrobial activities against two
Gram-positive and two Gram-negative bacteria, and two
fungi. Most of the compounds exhibited convincing results,
however, with a degree of variation. Moreover, both antibac-
terial and antifungal activities were found to be prolific. The
RDF descriptors were found to be important for describing
the activities against the modeled strains in QSAR studies.
The importance of this investigation lies in the possibility that
the new compounds might be more efficacious leads against
bacteria and fungi, and working on these foundations, their
biological effects could be utilized for designing more potent
antibacterial and antifungal agents of therapeutic use.
General procedure for the synthesis of 2-hydrazinylbenzo[d]
thiazole/2-hydrazinyl-6-substitutedbenzo[d]thiazoles (3).
2-
Hydrazinylbenzo[d]thiazole/2-hydrazinyl-6-substitutedbenzo
[d]thiazoles (3) were prepared from the appropriate benzo[d]
thiazol-2-amine/6-substitutedbenzo[d]thiazol-2-amines upon
treatment with hydrazine hydrochloride in ethylene glycol,
which, in turn, were prepared from the corresponding aniline/
4-substituted anilines using potassium thiocyanate/bromine
according to the procedures detailed in literature [30,31].
General procedure for the synthesis of 3-aryl-1-heteroarylindeno
[1,2-c]pyrazol-4(1H)-ones (4).
A solution of equimolar
quantities of 2-(benzylidene/4-substitutedbenzylidene)-1H-
indene-1,3(2H)-diones (2) (0.005 mol) and an appropriate
2-hydrazinylbenzo[d]thiazole/2-hydrazinyl-6-substitutedbenzo
[d]thiazoles (3) (0.005mol) in dry pyridine (30mL) containing
5% piperidine was stirred with the aid of magnetic stirrer for
3–4 days at room temperature. Thereafter, the reaction
mixture was neutralized with ice-cold dil. HCl, and mixture
was extracted with chloroform. The organic layer thus
obtained was dried over anhydrous sodium sulphate.
Evaporation of the solvent afforded the crude product, which
was purified on a silica gel column (2.5×45cm), prepacked
in hexane. Elution of the column with hexane:ethylacetate
(95:5, v/v) gave a homogeneous residue, which was
crystallized from chloroform to furnish the corresponding
indenopyrazoles (4) in varying yields. The spectral and
analytical data of 4a–4q are given as follows.
EXPERIMENTAL
Chemistry.
Melting points (ºC) were determined in
open capillaries and are uncorrected. The IR absorption
spectra were scanned on Perkin Elmer Spectrum, BX II
FTIR using potassium bromide (KBr) pellets, and the
wavenumbers (υ) are given in cmꢀ1. The 1H NMR
spectrometer spectra were recorded on Bruker Avance II
400 spectrometer at 400MHz in dimethyl sulfoxide-d6.
The chemical shifts (δ) are reported in parts per million
(ppm) using tetramethylsilane as an internal standard.
Coupling constants (J) are valued in hertz (Hz). Mass
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Mor, R. Mohil, S. Nagoria, A. Kumar, K. Lal, D. Kumar, and V. Singh
Vol 000
1-(6-Methoxybenzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)indeno
[1,2-c]pyrazol-4(1H)-one (4a). The compound was obtained
as yellow needles (chloroform), yield 31%, mp 259–260ºC
(Lit. [31a] mp 260–262ºC); IR (KBr): 1701 (s, conjugated
C=O, stretch), 1607 (s, C=N, stretch), 1544, 1496, 1465,
1294, 1255, 1186, 1029, 954, 883, 819, 746cmꢀ1; 1H NMR
(400MHz, DMSO-d6): δ 3.89 (s, 3H, OCH3-4″), 3.92 (s,
3H, OCH3-6′), 7.03 (d, 2H, J=8.00Hz, H-3″ & H-5″), 7.12
(m, 1H, H-5′), 7.34–7.67 (m, 5H, H-4, H-5, H-6, H-7, H-7′),
7.92 (d, 1H, J=8.80Hz, H-4′), 8.35 (d, 2H, J=8.00Hz,
H-2″ & H-6″), 8.57 (dd, 1H, J= 6.00 and 2.40 Hz, H-8); ms
(TOF MS ES+): m/z 440.1 (M++1, 100), 439.4 (M+, 16),
411.1 (31), 409.4 (11), 407.1 (10), 395.6 (4), 333.3 (28),
332.6 (13), 306.6 (26), 165.2 (17), 138.2 (8), 135.1 (12);
Anal. Calcd. for C25H17N3O3S (439.10): C, 68.32; H, 3.90;
N, 9.56. Found: C, 68.60; H, 4.32; N, 9.93.
3-(4-Fluorophenyl)-1-(6-methoxybenzo[d]thiazol-2-yl)indeno
[1,2-c]pyrazol-4(1H)-one (4b). The compound was obtained
as yellow needles (chloroform), yield 30%; mp 240–242ºC;
IR (KBr): 1701 (s, conjugated C=O, stretch), 1604 (s, C=N,
stretch), 1541, 1483, 1357, 1267, 1232, 1157, 1103, 1043,
956, 887, 840, 738cmꢀ1; 1H NMR (400MHz, DMSO-d6):
δ 3.87 (s, 3H, OCH3-6′), 7.18 (dd, 1H, J=11.60 and
2.64Hz, H-5′), 7.30–7.68 (m, 6H, H-5, H-6, H-7, H-7′, H-
3″, H-5″), 8.02 (d, 1H, J= 9.00Hz, H-4′), 8.37 (d, 2H,
J=8.00Hz, H-2″ & H-6″), 8.63 (dd, 1H, J= 7.32 and
2.41Hz, H-8); ms (TOF MS ES+): m/z 429.1 (M++2, 8),
428.1 (M++1, 25), 410.1 (8), 361.3 (9), 360.3 (38), 338.3
(100), 332.1 (31), 321.3 (39), 306.1 (23), 303.3 (37),
282.3 (4), 256.9 (12), 165.2 (11), 163.1 (8), 149.0 (16),
135.1 (11); Anal. Calcd. for C24H14FN3O2S (427.08): C,
67.44; H, 3.30; N, 9.83. Found: C, 67.71; H, 3.19; N, 11.90.
1-(6-Methoxybenzo[d]thiazol-2-yl)-3-p-tolylindeno[1,2-c]pyrazol-4
H-5′), 7.49–7.68 (m, 6H, H-5, H-6, H-7, H-7′, H-3″, H-5″),
8.03 (d, 1H, J=8.90Hz, H-4′), 8.33 (d, 2H, J=8.20Hz, H-
2″ & H-6″), 8.64 (dd, 1H, J=7.72 and 2.41Hz, H-8); ms
(TOF MS ES+): m/z 466.3 (M++Na, 9), 444.1 (M++1, 100),
443.2 (M+, 23), 415.3 (26), 394.9 (37), 337.2 (16), 305.9
(51), 254.2 (17), 165.1 (18),135.4 (9); Anal. Calcd. for
C24H14ClN3O2S (443.05): C, 64.94; H, 3.18; N, 9.47.
Found: C, 64.73; H, 3.56; N, 9.13.
3-(4-Bromophenyl)-1-(6-methoxybenzo[d]thiazol-2-yl)indeno
[1,2-c]pyrazol-4(1H)-one (4e).
The compound was
obtained as yellow needles (chloroform), yield 33%; mp
260–262ºC; IR (KBr): 1699 (s, conjugated C=O, stretch),
1605 (s, C=N, stretch), 1543, 1506, 1490, 1466, 1379,
1
1265, 1234, 1157, 1056, 887, 802, 729 cmꢀ1; H NMR
(400 MHz, DMSO-d6): δ 3.91 (s, 3H, OCH3-6′), 7.05 (m,
1H, H-5′), 7.33 (d, 1H, J= 2.40Hz, H-7′), 7.37–7.68 (m,
5H, H-5, H-6, H-7, H-3″, H-5″), 7.91 (d, 1H, J = 9.20 Hz,
H-4′), 8.38 (d, 2H, J = 8.00Hz, H-2″ & H-6″), 8.57 (dd,
1H, J = 7.40 and 2.41Hz, H-8); ms (TOF MS ES+): m/z
510.1 (M++Na, 12), 490.3 (M++3, 31), 488.1 (M++1, 9),
459.2 (22), 408.1 (16), 333.1 (8), 332.6 (100), 306.1
(27), 265.4 (38), 165.1 (14), 138.2 (8), 102.3 (13); Anal.
Calcd. for C24H14BrN3O2S (487.00): C, 59.03; H, 2.89;
N, 8.60. Found: C, 59.34; H, 3.18; N, 8.21.
3-(4-Fluorophenyl)-1-(6-methylbenzo[d]thiazol-2-yl)indeno[1,2-
c]pyrazol-4(1H)-one (4f). The compound was obtained as
yellow needles (chloroform), yield 28%; mp 268–270ºC;
IR (KBr): 1701 (s, conjugated C=O, stretch), 1607 (s,
C=N, stretch), 1539, 1498, 1463, 1336, 1300, 1236, 1159,
1101, 956, 853, 810, 740 cmꢀ1 1H NMR (400MHz,
;
DMSO-d6): δ 2.52 (s, 3H, CH3-6′), 7.15–7.67 (m, 7H,
H-5, H-6, H-7, H-5′, H-7′, H-3″, H-5″), 7.91 (d, 1H,
J=8.40Hz, H-4′), 8.39 (d, 2H, J=8.00 Hz, H-2″ & H-6″),
8.60 (dd, 1H, J=7.60 and 2.40Hz, H-8); ms (TOF MS
ES+): m/z 434.1 (M++Na, 23), 412.2 (M++1, 100), 411.2
(M+, 23), 384.2 (76), 394.9 (37), 321.3 (12), 290.1 (21),
254.2 (16), 236.2 (18), 149.2 (29), 135.4 (11), 122.2 (4);
Anal. Calcd. for C24H14FN3OS (411.08): C, 70.06; H,
3.43; N, 10.21. Found: C, 70.45; H, 3.12; N, 10.45.
(1H)-one (4c).
The compound was obtained as yellow
needles (chloroform), yield 38%; mp 288–290ºC (Lit. [31a]
mp 290–292ºC); IR (KBr): 1707 (s, conjugated C=O,
stretch), 1606 (s, C=N, stretch), 1496, 1465, 1363, 1263,
1232, 1155, 1028, 954, 885, 821, 734cmꢀ1 1H NMR
;
(400MHz, DMSO-d6): δ 2.47 (s, 3H, CH3-4″), 3.88 (s, 3H,
OCH3-6′), 7.05 (m, 1H, H-5′), 7.35–7.71 (m, 6H, H-5,
H-6, H-7, H-7′, H-3″, H-5″), 7.91 (1H, d, J=8.21Hz,
H-4′), 8.37 (d, 2H, J=8.20 Hz, H-2″& H-6″), 8.59 (dd,
1H, J=7.37 and 2.40Hz, H-8); ms (TOF MS ES+): m/z
424.1 (M++1, 27), 423.2 (36), 409.2 (19), 395.1 (100),
317.3 (39), 306.6 (28), 252.2 (41) 138.1 (12); Anal. Calcd.
for C25H17N3O2S (423.10): C, 70.90; H, 4.05; N, 9.92.
Found: C, 70.59; H, 3.67; N, 10.28.
3-(4-Chlorophenyl)-1-(6-methylbenzo[d]thiazol-2-yl)indeno
[1,2-c]pyrazol-4(1H)-one (4g).
The compound was
obtained as yellow needles (chloroform), yield 29%, mp
188–190ºC; IR (KBr): 1704 (s, conjugated C=O,
stretch), 1606 (s, C=N, stretch), 1557, 1486, 1434,
1
1246, 1154, 1127, 926, 883, 807, 735 cmꢀ1; H NMR
(400 MHz, DMSO-d6): δ 2.37 (s, 3H, CH3-6′) 7.23–8.39
(m, 11H, H-5, H-6, H-7, H-4′, H-5′, H-7′, H-2″, H-3″,
H-4″, H-5″, H-6″), 8.54 (dd, 1H, J = 7.42 and 2.33 Hz,
H-8); ms (TOF MS ES+): m/z 428.4 (M++1, 100), 427.1
(M+, 24) 392.1 (37), 387.9 (15), 337.1 (41), 329.0 (5),
308.1 (81), 301.9 (8), 289.9 (12), 279.2 (6), 177.2 (13),
149.2 (18), 136.1 (12); Anal. Calcd. for C24H14ClN3OS
(427.05): C, 67.36; H, 3.30; N, 9.82. Found: C, 67.12;
H, 3.12; N, 10.13.
3-(4-Chlorophenyl)-1-(6-methoxybenzo[d]thiazol-2-yl)indeno
[1,2-c]pyrazol-4(1H)-one (4d). The compound was obtained
as yellow needles (chloroform), yield 34%; mp 248–250ºC;
IR (KBr): 1699 (s, conjugated C=O, stretch), 1604 (s, C=N,
stretch), 1548, 1475, 1456, 1269, 1246, 1155, 1039, 956,
1
887, 810, 732 cmꢀ1; H NMR (400MHz, DMSO-d6): δ
3.91 (s, 3H, OCH3-6′), 7.19 (dd, 1H, J=8.90 and 2.40 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis and Antimicrobial Evaluation of Some 3-Aryl-1-heteroarylindeno[1,2-c]
pyrazol-4(1H)-ones
3-(4-Bromophenyl)-1-(6-methylbenzo[d]thiazol-2-yl)indeno
[1,2-c]pyrazol-4(1H)-one (4h).
329.0 (46), 310.3 (26), 177.2 (13), 136.1 (12); Anal. Calcd.
for C23H11Cl2N3OS (447.00): C, 61.62; H, 2.47; N, 9.37.
Found: C, 61.37; H, 2.42; N, 9.05.
The compound was
obtained as yellow needles (chloroform), yield 31%; mp
238–240ºC; IR (KBr): 1705 (s, conjugated C=O, stretch),
1607 (s, C=N, stretch), 1583, 1498, 1451, 1244, 1135,
3-(4-Bromophenyl)-1-(6-chlorobenzo[d]thiazol-2-yl)indeno
[1,2-c]pyrazol-4(1H)-one (4l).
The compound was
1107, 966, 893, 824, 716 cmꢀ1 1H NMR (400MHz,
;
obtained as yellow needles (chloroform), yield 41%; mp
270–271ºC; IR (KBr): 1703 (s, conjugated C=O,
stretch), 1607 (s, C=N, stretch), 1547, 1486, 1464,
DMSO-d6): δ 2.37 (s, 3H, CH3-6′), 7.01–8.38 (m, 10H,
H-5, H-6, H-7, H-4′, H-5′, H-7′, H-2″, H-3″, H-5″,
H-6″), 8.58 (dd, 1H, J = 7.42 and 2.39Hz, H-8); ms
(TOF MS ES+): m/z 472.3 (M++1, 100), 470.9 (M+, 9),
453.2 (23), 416.2 (22), 392.2 (39), 360.3 (76), 338.3
(87), 339.0 (16), 315.9 (24), 279.1 (8), 264.2 (4), 223.0
(7), 177.2 (4), 149.1 (28), 114.2 (6); Anal. Calcd. for
C24H14BrN3OS (471.00): C, 61.03; H, 2.99; N, 8.90.
Found: C, 61.27; H, 3.14; N, 8.79.
1
1219, 1147, 1113, 946, 873, 803, 735 cmꢀ1; H NMR
(400 MHz, DMSO-d6): δ 7.10–8.36 (m, 10H, H-5, H-6,
H-7, H-4′, H-5′, H-7′, H-2″, H-3″, H-5″, H-6″), 8.56
(dd, 1H, J = 7.20 and 2.29 Hz, H-8); ms (TOF MS ES+):
m/z 491.8 (M++1, 100), 463.4 (32), 441.3 (9), 419.1
(19), 391.2 (82), 381.2 (28), 338.3 (24), 330.8 (18),
279.1 (68), 264 (35), 187.2 (6), 136.1 (7); Anal. Calcd.
for C23H11BrClN3OS (490.95): C, 56.06; H, 2.25; N,
8.53. Found: C, 56.35; H, 1.96; N, 8.23.
1-(6-Methylbenzo[d]thiazol-2-yl)-3-p-tolylindeno[1,2-c]pyrazol-4
(1H)-one (4i).
The compound was obtained as yellow
needles (chloroform), yield 27%; mp 302–324ºC (Lit. [31a]
mp 305–307ºC); IR (KBr): 1707 (s, conjugated C=O,
stretch), 1604 (s, C=N, stretch), 1543, 1496, 1454, 1249,
1155, 1103, 956, 883, 813, 736cmꢀ1; 1H NMR (400MHz,
DMSO-d6): δ 2.38 (s, 3H, CH3-6′), 2.49 (s, 3H, CH3-4″),
7.11–8.01 (m, 8H, H-5, H-6, H-7, H-4′, H-5′, H-7′, H-3″,
H-5″), 8.36 (d, 2H, J=8.20 Hz, H-2″ & H-6″), 8.58 (dd,
1H, J=7.42 and 2.39Hz, H-8); ms (TOF MS ES+): m/z
408.1 (M++1, 100), 407.2 (M+, 12), 379.4 (36), 365.1 (28),
315.8 (41), 303.2 (19), 274.4 (43), 254.2 (17), 149.2 (12),
134.5 (11); Anal. Calcd. for C25H17N3OS (407.11): C,
73.69; H, 4.21; N, 10.31. Found: C, 73.86; H, 4.49; N, 10.60.
1-(6-Methylbenzo[d]thiazol-2-yl)-3-phenylindeno[1,2-c]pyrazol-4
(1H)-one (4j). The compound was obtained as yellow needles
(chloroform), yield 29%; mp 234–236ºC (Lit. [31a] mp
235_236ºC); IR (KBr): 1703 (s, conjugated C=O, stretch),
1607 (s, C=N, stretch), 1541, 1496, 1463, 1249, 1155, 1099,
956, 883, 802, 729cmꢀ1; 1H NMR (400MHz, DMSO-d6): δ
2.53 (s, 3H, CH3-6’), 7.35–7.70 (m, 8H, H-5, H-6, H-7,
H-5′, H-7′, H-3″, H-4″, H-5″), 7.94 (d, 1H, J=8.40 Hz,
H-4′), 8.41 (d, 2H, J=8.00Hz, H-2″ & H-6″), 8.59 (dd, 1H,
J=8.00 and 2.50Hz, H-8); ms (TOF MS ES+): m/z 416.1
(M++Na, 21%), 444.1 (M++1, 100), 443.2 (M+, 23), 410.1
(48), 394.9 (37), 373.1 (29), 365.1 (16), 315.8 (18), 303.2
(27), 254.2 (17), 149.2 (9), 111.1 (18); Anal. Calcd. for
C24H15N3OS (393.09): C, 73.26; H, 3.84; N, 10.68. Found:
C, 73.55; H, 3.53; N, 10.35.
1-(Benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)indeno[1,2-c]pyrazol-4
(1H)-one (4m).
The compound was obtained as yellow
needles (chloroform), yield 25%; mp 204–206ºC; IR
(KBr): 1708 (s, conjugated C=O, stretch), 1604 (s, C=N,
stretch), 1541, 1496, 1458, 1359, 1303, 1236, 1163, 1099,
1
954, 840, 748cmꢀ1; H NMR (400MHz, DMSO-d6): δ
7.37–7.91 (m, 8H, H-5, H-6, H-7, H-5′, H-6′, H-7′, H-3″,
H-5″), 8.01 (m, 1H, H-4′), 8.35 (d, 2H, J=8.00Hz, H-2″
& H-6″), 8.62 (dd, 1H, J=7.38 and 2.41Hz, H-8); ms
(TOF MS ES+): m/z 398.3 (M++1, 18), 397.2 (28), 376.7
(18), 370.1 (100), 338.4 (43), 320.7 (31), 302.2 (39), 276.4
(19), 245.2 (16), 227.1 (42), 135.1 (19); Anal. Calcd. for
C23H12FN3OS (397.07): C, 69.51; H, 3.04; N, 10.57.
Found: C, 69.88; H, 2.73; N, 10.76.
1-(Benzo[d]thiazol-2-yl)-3-(4-chlorophenyl)indeno[1,2-c]
pyrazol-4(1H)-one (4n). The compound was obtained as
yellow needles (chloroform), yield 29%; mp 238–240ºC;
IR (KBr): 1712 (s, conjugated C=O, stretch), 1602 (s,
C=N, stretch), 1547, 1496, 1473, 1456, 1247, 1157, 1105,
952, 883, 759, 731cmꢀ1; 1H NMR (400MHz, DMSO-d6):
δ 7.37–7.89 (m, 8H, H-5, H-6, H-7, H-5′, H-6′, H-7′, H-3″,
H-5″), 8.03 (m, 1H, H-4′), 8.36 (d, 2H, J=8.20Hz, H-2″
& H-6″), 8.61 (dd, 1H, J=7.40 and 2.41Hz, H-8); ms
(TOF MS ES+): m/z 414.1 (M++1, 11), 385.5 (100), 379.1
(16), 337.2 (17), 302.6 (21), 294.2 (65), 276.1 (36), 265.1
(23), 134.2 (14), 111.2 (6); Anal. Calcd. for
C23H12ClN3OS (413.04): C, 66.75; H, 2.92; N, 10.15.
Found: C, 66.94; H, 2.58; N, 10.53.
1-(6-Chlorobenzo[d]thiazol-2-yl)-3-(4-chlorophenyl)indeno
[1,2-c]pyrazol-4(1H)-one (4k).
The compound was
1-(Benzo[d]thiazol-2-yl)-3-(4-bromophenyl)indeno[1,2-c]
pyrazol-4(1H)-one (4o). The compound was obtained as
yellow needles (chloroform), yield 27%; mp 218–220ºC;
IR (KBr): 1707 (s, conjugated C=O, stretch), 1604 (s,
C=N, stretch), 1513, 1474, 1436, 1242, 1140, 1107, 916,
obtained as yellow needles (chloroform), yield 26%; mp
190–192ºC; IR (KBr): 1709 (s, conjugated C=O, stretch),
1612 (s, C=N, stretch), 1544, 1476, 1457, 1235, 1121,
1093, 952, 873, 822, 735cmꢀ1 1H NMR (400MHz,
;
1
878, 803, 733cmꢀ1; H NMR (400MHz, DMSO-d6): δ
DMSO-d6): δ 7.21–8.38 (m, 10H, H-5, H-6, H-7, H-4′, H-
5′, H-7′, H-2″, H-3″, H-5″, H-6″), 8.52 (dd, 1H, J=7.40
and 2.25Hz, H-8); ms (TOF MS ES+): m/z 448.4 (M++1,
100), 447.2 (M+, 9) 412.2 (19), 391.2 (29), 338.3 (22),
7.02–8.38 (m, 11H, H-5, H-6, H-7, H-4′, H-5′, H-7′, H-2″,
H-3″, H-4″, H-5″, H-6″), 8.58 (dd, 1H, J=7.12 and
2.38Hz, H-8); ms (TOF MS ES+): m/z 458.3 (M++1, 100),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Mor, R. Mohil, S. Nagoria, A. Kumar, K. Lal, D. Kumar, and V. Singh
Vol 000
457.2 (M+, 37) 441.3 (26), 429.1 (27), 413.1 (51), 391.2
(48), 381.1 (17), 338.3 (79), 329.0 (21), 310.2 (17), 279.1
(81), 276.3 (28), 264.3 (67), 177.2 (13), 136.1 (12); Anal.
Calcd. for C23H12BrN3OS (456.99): C, 60.27; H, 2.64; N,
9.17. Found: C, 60.36; H, 2.51; N, 8.92.
100μL of suspension of the respective microorganism in
sterile saline. The inoculated test tubes were incubated at 37
1ºC for 24h in the case of B. subtilis, S. Aureus, E. coli, and
P. aeruginosa, at 37 1ºC for 48h in the case of C. albicans
and at 37 1ºC for 120h in the case of A. niger and their
MIC were determined. The reference compounds
(ceftriaxone and fluconazole) were also tested under similar
conditions to compare the results of synthesized compounds.
The data obtained from antibacterial and antifungal studies
are listed in Table 4 and expressed in Figure 3.
1-(Benzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)indeno[1,2-c]
pyrazol-4(1H)-one (4p). The compound was obtained as
yellow needles (chloroform), yield 28%; mp 262–264ºC
(Lit. [31a] mp 264_266ºC); IR (KBr): 1710 (s, conjugated
C=O, stretch), 1612 (s, C=N, stretch), 1541, 1469, 1456,
;
1315, 1255, 1033, 954, 883, 748cmꢀ1 1H NMR
QSAR studies. The antimicrobial evaluation data of 17
synthesized compounds was used to develop QSAR models.
The structures of all the molecules were sketched and
optimized with Marvin Sketch 5.10 [50]. The conformation
of all the molecules were prepared as that of fundamental
motif 1-(benzo[d]thiazol-2-yl/6-substitutedbenzo[d]thiazol-
2-yl)-3-(phenyl/4-substitutedphenyl)indeno [1,2-c]pyrazol-4
(1H)-ones. A total of 1875 descriptors (one-dimensional,
two-dimensional, and three-dimensional parameters)
were calculated using PaDEL Descriptor 2.21 program
[51]. In order to lessen duplication and errors, the
invariable or near-invariable descriptors and parameters
having a value of zero for even one molecule were
removed. If the pairwise correlation of two parameters
was more than 0.75, then the one with higher pair
correlation with other descriptors was left out from the
original matrix of variables to lessen redundancy in
information. Stepwise multiple linear regression variable
subset selection was applied for variable selection and
model development using SPSS software package [SPSS,
1996]. Different parameters used to analyze the models
were correlation coefficient R, adjusted coefficient of
determination Ra2dj, R2 ꢀRa2dj, root mean squared error,
mean average error (MAE), standard error of estimate
(SE), Fischer’s value (F), root mean squared error of
cross-validation (RMSE), mean average error of
(400MHz, DMSO-d6): δ 3.91 (s, 3H, OCH3-4″), 6.99–8.03
(m, 9H, H-5, H-6, H-7, H-4′, H-5′, H-6′, H-7′, H-3″, H-
5″), 8.48 (d, 2H, J=8.20Hz, H-2″, H-6″), 8.64 (dd, 1H,
J=7.32 and 2.50Hz, H-8); ms: (TOF MS ES+) m/z 432.1
(M++Na, 100), 410.3 (26), 381.1 (33), 378.1 (26), 338.1
(52), 333.2 (16), 276.2 (29), 245.0 (11), 217.8 (28), 148.2
(7), 104.2 (8); Anal. Calcd. for C24H15N3O2S (409.09): C,
70.40; H, 3.69; N, 10.26. Found: C, 69.01; H, 3.38; N, 10.57.
1-(Benzo[d]thiazol-2-yl)-3-phenylindeno[1,2-c]pyrazol-4(1H)-
one (4q). The compound was obtained as yellow needles
(chloroform), yield 25%; mp 244–246ºC (Lit. [31a] mp
246_247ºC); IR (KBr): 1699 (s, conjugated C=O, stretch),
1604 (s, C=N, stretch), 1595, 1535, 1504, 1489, 1458,
1440, 1373, 1242, 1103, 952, 879, 756, 732cmꢀ1 1H
;
NMR (400MHz, DMSO-d6): δ 7.05–8.11 (m, 10H, H-5,
H-6, H-7, H-4′, H-5′, H-6′, H-7′, H-3′′, H-4′′, H-5′′), 8.40
(d, 2H, J=8.22Hz, H-2′′& H-6″), 8.59 (dd, 1H, J= 7.50
and 2.40Hz, H-8); ms (TOF MS ES+): m/z 380.1 (M++1,
100), 338.1 (19), 351.2 (34), 302.3 (27), 294.3 (11), 276.4
(24), 274.3 (26), 168.5 (13), 134.1 (8); Anal. Calcd. for
C23H13N3OS (379.08): C, 72.80; H, 3.45; N, 11.07.
Found: C, 72.41; H, 3.32; N, 11.39.
Antimicrobial activity.
The indenopyrazoles (4a–4q)
were screened for their in vitro antimicrobial activity against
six microorganisms, that is, two Gram-positive bacteria, viz.
B. subtilis (MTCC 441) and S. aureus (MTCC 7443), two
Gram-negative bacteria, viz. E. coli (MTCC 42) and P.
aeruginosa (MTCC 741), and two fungi, viz. C. albicans
(MTCC 183) and A. niger (MTCC 282) by serial tube
dilution technique [49]. Double-strength nutrient broth and
Sabouraud dextrose broth were used for bacterial and fungal
growth, respectively. The stock solutions (100 μg/mL) of all
the test compounds were prepared by dissolving 1.0mg of
the test compound in 10 mL of dimethylsulphoxide (DMSO).
Ceftriaxone and fluconazole were used as standard references
against bacterial and fungal strains, respectively. The fresh
cultures were obtained by inoculation of the respective
microorganism in suitable medium (double-strength nutrient
broth in case of bacteria and Sabouraud dextrose broth in the
case of fungi) followed by incubation at 37 1ºC. The stock
solutions of the test compounds were serially diluted in test
tubes containing 1mL of sterile medium to obtain the
concentration of 50–1.56μg/mL and then inoculated with
cross-validation
(RMSEcv),
and
cross-validation
coefficient QL2OO (leave-one-out). QL2OO method is the
only technique that uses the entire information on hand
and is very pertinent primarily in small datasets as in the
present study [45].
Acknowledgments. We gratefully acknowledge the financial
support [file no. 09/752(0011)/2007-EMR-1] from CSIR, New
Delhi. Thanks to SAIF, Panjab University, Chandigarh, for
providing NMR and mass spectra of the compounds. We are
highly thankful to Prof. Geeta Hundal, Dept. of Chemistry, Guru
Nanak Dev University, Amritsar, Punjab, India, for providing
X-ray data.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis and Antimicrobial Evaluation of Some 3-Aryl-1-heteroarylindeno[1,2-c]
pyrazol-4(1H)-ones
[23] Pittenger, C.; Coric, V.; Banasr, M.; Bloch, M.; Krystal, J. H.;
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet