L-Proline catalyzed one-pot multi-component synthesis of 2-(1,3-diphenyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one derivatives and their biological studies

Article abstract of DOI:10.1016/j.cclet.2014.03.015

A new series of quinazolin-4(3H)-one derivatives containing a (1,3-diphenyl-1H-pyrazol-4-yl) core with substituents at the 2-position and aromatic or heteroaromatic substituents at the 3-position were synthesized using an l-proline catalyzed one-pot multi-component reaction approach. All the synthesized compounds were characterized and screened for their antimicrobial, antifungal and anti-tubercular activities.

Full text of DOI:10.1016/j.cclet.2014.03.015

G Model
CCLET 2899 1–4
Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
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Original article
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L
-Proline catalyzed one-pot multi-component synthesis of
2-(1,3-diphenyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one derivatives
and their biological studies
Q1 Hemal B. Mehta a, Bharat C. Dixit b, Ritu B. Dixit a,
*
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a Ashok and Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences, New Vallabh Vidyanagar 388121, India
b Chemistry Departments, V. P. and R. P. T. P Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar 388120, India
A R T I C L E I N F O
A B S T R A C T
Article history:
A new series of quinazolin-4(3H)-one derivatives containing a (1,3-diphenyl-1H-pyrazol-4-yl) core with
Received 11 September 2013
Received in revised form 20 January 2014
Accepted 18 February 2014
Available online xxx
substituents at the 2-position and aromatic or heteroaromatic substituents at the 3-position were
synthesized using an
L-proline catalyzed one-pot multi-component reaction approach. All the
synthesized compounds were characterized and screened for their antimicrobial, antifungal and
anti-tubercular activities.
ß 2014 Ritu B. Dixit. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords:
Quinazolin-4(3H)-one
Pyrazole
L
-Proline
Antimicrobial
Antifungal
Anti-tubercular activity
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1. Introduction
one of the amino acids that have very significant roles in catalysis 30
[14–19].
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The discovery of new biologically active molecules with high
potency represents a high priority for medicinal chemists because
the common pathogenic species have developed drug resistance
against available anti-infectious medicines [1]. To address this
emerging challenge, we have attempted to synthesize different
types of biologically active compounds, particularly biologically
active quinazolin-4(3H)-one derivatives in recent years [2–4]. The
quinazolin-4(3H)-one moiety is associated with promising activi-
ties such as hypnotic, sedative, analgesic, anti-convulsant, anti-
tussive, anti-bacterial, anti-diabetic, anti-inflammatory effects and
many more [5–7]. In addition to that, researchers have been
interested in designing compounds bearing pyrazole heterocycles
in the backbone, due to their diverse biological utilities such as
antimicrobial [8], anti-inflammatory [9], antioxidant [10], antitu-
mor [11], anti-TB [12], analgesic and ulcerogenic activities [13].
From the perusal of above literature survey, we undertook the 32
synthesis of structurally hybrid molecules containing both 33
quinazolin-4(3H)-one and pyrazole scaffolds in a single molecular 34
framework using L-proline as a catalyst, which may improve the 35
pharmacological activity of the synthesized compounds. Structural 36
characterization of prepared compounds has been carried out 37
using FT-IR, mass, 1H NMR and 13C NMR spectroscopy. In vitro 38
antimicrobial study for all the synthesized compounds was carried 39
out against six bacterial and two fungal species using the broth 40
dilution MIC (minimum inhibitory concentration) method [20]. 41
Antituberculosis activity was carried out utilizing the in vitro 42
mycobacterial susceptibility tests [21].
43
2. Experimental
44
a-Amino acids are amphoteric in nature and are found as
All the chemicals used for syntheses and biological assays were 45
obtained from local vendors (make-Merck India, Pvt. Ltd.) and used 46
without further purification. The progress of the reaction was 47
monitored by TLC analysis on aluminum sheets coated with silica 48
get 60 F254 (Merck) using hexane:EtOAc:MeOH = 8:2:0.5 solvent 49
system as the mobile phase by UV visualization. Melting point 50
(uncorrected) for all the synthesized compounds was assessed 51
using a digital melting point apparatus. Elemental analysis for each 52
zwitter ions, are useful in various organic transformations like
coupling reactions, Mannich type addition reactions, aldol
condensations and many asymmetric syntheses.
L-Proline is
*
Corresponding author.
E-mail address: ritsdixit@yahoo.co.in (R.B. Dixit).
http://dx.doi.org/10.1016/j.cclet.2014.03.015
1001-8417/ß 2014 Ritu B. Dixit. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: H.B. Mehta, et al., L-Proline catalyzed one-pot multi-component synthesis of 2-(1,3-diphenyl-1H-
pyrazol-4-yl)quinazolin-4(3H)-one derivatives and their biological studies, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.03.015

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CCLET 2899 1–4
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compound was carried out using a CARLO ERBA-1108 elemental
analyzer. Mass spectral analysis was carried out using a Thermo
fisher Scientific, MS-LCQ Fleet instrument. The FT-IR spectral
analysis was performed using a SHIMADZU 8400s spectroscopic
grade KBr pellets in a frequency range of 400–4000 cmÀ1. The 1H
NMR and 13C NMR spectra were recorded on a Bruker 400 MHz
instrument using DMSO as a solvent as well as an internal
reference standard.
General procedure for the synthesis of compounds 5a–h and
6a–h: Synthesis of the titled compounds 5a–h was carried out
using 1-phenyl-3-aryl-1H-pyrazole-4-carbaldehyde 1 (0.002 mol),
isatioc anhydride 2 (0.002 mol), aromatic amines 3a–h (0.002 mol)
the titled compounds, 1-phenyl-3-aryl-1H-pyrazole-4-carbalde-
hyde 1, was prepared using a literature method [22]. It was made
by the Vilsmeier–Haack formylation of hydrazone prepared from
acetophenone and phenyl hydrazine. Compounds 5a–h were
prepared using a one-pot multi-component reaction between
1-phenyl-3-aryl-1H-pyrazole-4-carbaldehyde 1, isatioc anhydride
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88
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90
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2 and aromatic amines 3a–h using
L
-proline as a catalyst in
methanol, which was further oxidized using 5% neutral KMnO4 in
acetone to produce final products 6a–h. The prepared compounds
were obtained in comparatively good yields (68–91%). A possible
mechanism for the reaction is shown in Scheme 2. The first step of
the reaction is the formation of an enamine, which provides a
highly electrophilic carbon center for the nucleophilic nitrogen of
amine to form the intermediate (X). Intermediate (X) undergoes
subsequent steps such as decarboxylation, attack of aldehyde,
formation of aldimine, cyclization and finally elimination to give
final products 5a–h, which were further oxidized to produce 6a–h.
Different concentrations of catalyst were studied and the optimum
loading appeared to be 5 mol% as shown in Table 1. Time required
and yields obtained for all the titled compounds 5a–h are shown in
Table 2.
and
L-proline 4 (5 mol%) in 10 mL of MeOH in a 25 mL round
bottom flask attached with a reflux condenser. Reaction mixture
was refluxed for 1–2.5 h and the precipitates were filtered and
recrystallized from MeOH. Compounds 5a–h were oxidized using
5% KMnO4 in acetone for 8 h at room temperature and the product
was extracted with chloroform. Excess of chloroform was removed
in vacuo and the crystals of product 6a–h were separated.
Physical data, spectroscopic characterizations and experimen-
tal protocols for antimicrobial and antituberculosis for compounds
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96
97
98
99
74 Q2 5a–h and 6a–h are given in Supporting information.
Titledcompounds5a–hand6a–hwerecharacterizedusingFT-IR,
mass, 1H NMR and 13C NMR spectroscopic methods. FT-IR spectra of
compounds showed characteristic bands for functionalities such as
–NH, C55O, C–N–C linkage of quinazolinone, F, NO2, Cl and Br around
3220, 1700, 1591/1540, 1225, 1530/1350, 750 and 620 cmÀ1
respectively. In addition, band due to –NH stretching in compounds
5a–h around 3220 cmÀ1 disappeared in compounds 6a–h upon
oxidation. In 1H NMR spectra of the titled compounds, aliphatic
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102
103
104
105
106
107
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3. Results and discussion
3.1. Chemistry
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The synthesis route of the titled compounds (5a–h and 6a–h) is
shown in Scheme 1. The first intermediate required for synthesis of
Scheme 1. Synthetic route for entitled compounds 5a–h and 6a–h.
Scheme 2. Plausible reaction mechanism for the role of L-proline as a catalyst.
Please cite this article in press as: H.B. Mehta, et al., L-Proline catalyzed one-pot multi-component synthesis of 2-(1,3-diphenyl-1H-
pyrazol-4-yl)quinazolin-4(3H)-one derivatives and their biological studies, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.03.015

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H.B. Mehta et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
3
Table 1
3.2. Biology
124
Comparison of the time required and yield obtained under different catalytic
condition for the synthesis of 5a.
In case of antimicrobial screening (Table 3) for gram positive 125
bacteria, compound 6c (62.5 g/mL) showed superior whereas 5b, 126
5c, 6a and 6b (100 g/mL) showed equivalent activity against 127
Bacillus subtilis as compared to Ampicillin. Against Clostridium 128
tetani, compound 5d (62.5 g/mL) exhibited significant inhibition 129
while 6g showed comparable inhibition (100 g/mL) to Ciproflox- 130
acin. Amongst all tested compounds 5g and 6d showed good 131
activity (62.5 g/mL) while 5d showed similar activity (100 g/ 132
mL) against Streptococcus pnumonia when compared with Ampi- 133
cillin. In case of gram negative bacteria, compound 5d (62.5 g/ 134
mL) found to possess excellent inhibition while compound 5a 135
(100 g/mL) demonstrated similar activity against Escherichia coli 136
compared to Ampicillin. Compounds 5e and 6g (62.5 g/mL) 137
showed significant potency whereas 5d, 5h, 6h and 5g, 6d (100 g/ 138
mL) showed similar activity against Salmonella typhi, Vibrio 139
cholerae as compared to Ampicilin. 140
The anti fungal (Table 3) activity results revealed that amongst 141
all the tested compounds 5a, 6a and 5g (200 g/mL) showed 142
Entry
Catalyst mol (%)
Time required (min)
Yield
m
m
1
2
3
4
5
Free
1
210
165
140
95
56
62
77
80
70
2
m
5
m
10
130
m
m
Table 2
m
Time required and yield obtained for entitled compounds 5a–h.
m
Entry
Product
Substitution (R)
Time (min)
Yield (%)
m
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
Ph
95
105
130
140
150
130
125
135
80
83
82
79
78
81
68
70
m
Ph-4-Me
Ph-4-OMe
Ph-4-Cl
Ph-4-Br
Ph-4-F
Ph-4-NO2
4-pyr
m
5g
5h
superior activity against Candida albicans compared to the 143
standard drug Greseofulvin but none of the compounds displayed 144
higher potency against Aspergillus fumigates. Rest of the com- 145
pounds exhibited good to moderate activity against tested 146
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
protons of –CH3, OCH3 and CHNH appeared at
and 6.40–6.51 in compounds 5b/6b, 5c/6c and 5a–h respectively.
All the aromatic protons present in quinazolinone and phenyl rings
appeared around 7.05–8.10. Furthermore, protons of –NH in the
quinazolinone ring and CH of pyrazole ring appeared at around
8.15 and 8.70 as a doublet and a singlet respectively. In 13C NMR
aliphatic carbons appeared at around 24, 53 and 66 due to the
d2.17–2.19, 3.89–3.90
d
organisms but not as effective as the standard drugs.
147
Structural activity relationship (SAR) study revealed that 148
change of substitutions or replacement of one of the carbon atom 149
with nitrogen in phenyl ring present at the 3-position of 150
quinazolinone ring may enhance or diminish the potency. 151
Introduction of electron donating groups (–CH3 and –OCH3) in 152
parent structure improved the strength against gram positive 153
bacteria B. subtilis but retained or lost potency in case of other 154
bacterial species. On the other hand, electron withdrawing groups 155
(–Cl, –Br and –NO2) may improve the activity up to 3–4-fold 156
against bacterial species. In case of antifungal activity, alteration of 157
substitution at the phenyl ring decreased the activity of the titled 158
d
d
d
presence of –CH3, OCH3 and CHNH in compounds 5b/6b, 5c/6c and
5a–h respectively. Aromatic carbons present in the structure, gave
peaks in the range of
C55O appeared at
d
114–157. Moreover, carbons of C–OCH3 and
d
156 and 163/161 in 5c/6c and 5a–h/6a–h
respectively. Results of elemental analysis of all the synthesized
compounds are in good agreement with the calculated data. In
addition, mass spectra of all the compounds showed molecular ion
M+ (two peaks in case of chloro and bromo derivatives) correspond-
ing to their exact mass.
compounds.
159
Antituberculosis (Table 3) activity results revealed that only 160
compounds 5d, 5g, 6d and 6g showed >90% of inhibition using 161
Table 3
In vitro antibacterial, antifungal and antimycobacterial activity (MIC,
mg/mL) of compounds 5a–h and 6a–h.
Entry
Substitution (Ar)
Gram positive-bacteria
Gram negative-bacteria
Fungi
CA
MTB-H37RV
% inhibition
BS
CT
SP
EC
ST
VC
AF
1000
MIC
5a
Ph
125
100
100
250
500
200
250
500
100
100
200
200
200
200
200
250
100
250
125
100
200
500
200
200
200
100
500
200
200
125
125
250
100
200
250
500
200
100
200
250
200
67
36
48
98
86
71
93
82
74
45
41
96
80
73
95
77
–
–
–
5b
Ph-4-Me
Ph-4-OMe
Ph-4-Cl
Ph-4-Br
Ph-4-F
Ph-4-NO2
4-pyr
500
250
500
500
1000
200
>1000
200
>1000
500
1000
500
500
1000
>1000
–
>1000
>1000
500
5c
–
5d
62.5
62.5
12.5
–
5e
200
200
500
200
250
250
200
200
250
250
100
200
250
50
125
250
500
200
250
250
500
250
250
200
250
250
100
50
62.5
>1000
500
5f
250
200
100
250
250
200
200
250
125
250
100
100
50
–
5g
62.5
500
62.5
–
5h
6a
250
200
200
200
1000
>1000
>1000
>1000
500
Ph
–
6b
Ph-4-Me
Ph-4-OMe
Ph-4-Cl
Ph-4-Br
Ph-4-F
Ph-4-NO2
4-pyr
–
6c
62.5
–
6d
200
250
250
500
200
250
50
50
–
62.5
50
–
6e
125
250
500
500
100
50
50
–
500
6f
>1000
500
–
6g
62.5
25
–
6h
Ampicillin
200
100
50
25
–
500
–
–
Chloramphenicol
Ciprofloxacin
Nystatin
–
–
–
–
100
–
25
25
–
–
–
–
–
–
100
500
–
100
–
–
Greseofulvin
Rifampicin
–
–
–
–
–
–
100
–
–
–
–
–
–
–
–
–
98
99
40
Isoniazid
–
–
–
–
–
–
–
–
0.20
Bold numbers indicates more or equally potent compounds compare to standard drugs.
BS, Bacillus subtilis, CT, Clostridium tetani, SP, Streptococcus pnumonia, EC, Escherichia coli, ST, Salmonella typhi, VC, Vibrio cholerae, CA, Candida albicans, AF, Aspergillus fumigates.
Please cite this article in press as: H.B. Mehta, et al., L-Proline catalyzed one-pot multi-component synthesis of 2-(1,3-diphenyl-1H-
pyrazol-4-yl)quinazolin-4(3H)-one derivatives and their biological studies, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.03.015

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Rifampicin and Isoniazid as positive controls against
Mycobacterium tuberculosis H37RV bacteria. SAR analysis demon-
strated that compounds with –Cl and –NO2 groups showed
significant improvement in % inhibition in comparison with the
unsubstituted compound. Compounds 5d and 6g showed consid-
erably higher MIC values than Rifampicin.
168
4. Conclusion
169
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The synthetic strategy disclosed here permits the assembly of
two biologically active motifs into one heterocyclic framework, i.e.
pyrazolyl quinazolin-4(3H)-one derivatives. From SAR study, we
conclude that substituents at the phenyl ring adjacent to the
pyrazole ring have significant effects on the potency.
174
Acknowledgments
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The authors are thankful to Director, Ashok and Rita Patel
Institute of Integrated Study and Research in Biotechnology and
Allied Sciences, Chairman, Charutar Vidya Mandal & Director,
SICART for providing all necessary research facilities.
179
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Please cite this article in press as: H.B. Mehta, et al., L-Proline catalyzed one-pot multi-component synthesis of 2-(1,3-diphenyl-1H-
pyrazol-4-yl)quinazolin-4(3H)-one derivatives and their biological studies, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.03.015