Synthesis, antibacterial evaluation and QSAR studies of 7-[4-(5-aryl-1,3,4-oxadiazole-2-yl)piperazinyl] quinolone derivatives

Article abstract of DOI:10.1016/j.ejmech.2011.04.035

A series of 7-[4-(5-aryl-1,3,4-oxadiazole-2-yl)piperazinyl] quinolones (I-XXI) were synthesized using an appropriate synthetic route and characterized by elemental and spectral analysis. The antibacterial activities of all the synthesized compounds were e

Full text of DOI:10.1016/j.ejmech.2011.04.035

European Journal of Medicinal Chemistry 46 (2011) 3543e3550
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, antibacterial evaluation and QSAR studies of 7-[4-(5-aryl-1,3,
4-oxadiazole-2-yl)piperazinyl] quinolone derivatives
,
,
Rajnish Kumar a b, Ashwani Kumar b, Sandip Jain b, Darpan Kaushik a
*
a Rajendra Institute of Technology and Sciences, 4th Milestone Hisar Road, Sirsa-125055, India
b Department of Pharmaceutical Sciences, G J US T, Hisar 125001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 7-[4-(5-aryl-1,3,4-oxadiazole-2-yl)piperazinyl] quinolones (I-XXI) were synthesized using an
appropriate synthetic route and characterized by elemental and spectral analysis. The antibacterial
activities of all the synthesized compounds were evaluated against identifiable bacterial strains.
Compounds III, IV, VII, VIII, IX, X, XI, XV, & XVIII showed better activity than parent compound against
all the selected strains. QSAR study on the synthesized molecules tested for their antibacterial activity
was performed using multiple linear regression method. Generated models revealed a decrease in HOMO
energy as favorable descriptor for determining and predicting the antibacterial activity of the synthesized
compounds. Further, the developed models were cross validated using LOO method for their predictive
nature.
Received 27 January 2011
Received in revised form
4 April 2011
Accepted 12 April 2011
Available online 29 April 2011
Keywords:
Fluoroquinolone derivatives
Synthesis
Antibacterial activity
QSAR
Ó 2011 Published by Elsevier Masson SAS.
1. Introduction
enzyme and therefore it is essential. The antibacterial activity is
greatly influenced by the steric bulk of N-1 substituents and
Fluoroquinolones are the most widely used antibacterial agents
in modern therapy due to their broad spectrum and excellent oral
bioavailability [1]. Most of the compounds introduced in last
decade possess improved activity against Gram positive pathogens
as compared to ciprofloxacin whereas some have potent activity
against anaerobes and pathogens that are resistant to many other
groups of antimicrobials [2].
The fluoroquinolones targets two related enzymes, DNA gyrase
and DNA topoisomerase IV [3]. Gyrase is responsible for intro-
ducing negative supercoils in DNA and for relieving torsional stress
expected to accumulate ahead of transcription and replication
complexes. Topoisomerase IV provides a potent decatenating
activity. Both gyrase and topoisomerase IV are essential enzymes,
and therefore the agents that inhibit them are expected to block
bacterial growth.
optimal groups are found to be cyclopropyl, ethyl, fluorophenyl and
t-butyl, while C-8 substituents should be small in size to show
optimum activity [5,7]. Groups at C-5 and C-6 have also been
optimized in which an amino and fluoro substituents respectively
at C-5 and C-6 appears to be the best. The structure activity rela-
tionship analysis of the fluoroquinolone antibiotics shows one of
the most significant structural changes for the activity was
increasing bulk at C-7 position of the main 6-fluoroquinolone
scaffold. The steric bulk at C-7 position leads to reduced side effects,
improved potency and in vivo efficacy against Gram positive
species [8].
A number of QSAR studies have been reported for the fluo-
roquinolone nucleus. The recent study on three sets of structurally
similar fluoroquinolones was performed [8] using comprehensive
set of molecular descriptors with the help of Artificial Neural
Network (ANN) technique. The report suggested role of topological &
electrostatic descriptors to have high coding capabilities for the
antibacterial activity of the compounds. Further study of relationship
between antibacterial activity of fluoroquinolone derivatives against
Pseudomonas aeruginosa and descriptors like steric, electronic and
hydrophobic using quantum chemical and chemometric methods
revealed importance of ELUMO (energy of lowest unoccupied
molecular orbital), ΔEHL (energy difference between the highest
occupied and lowest unoccupied molecular orbitals), Q5 (charge at
The SAR of fluoroquinolones has been subjected to extensive
review [4e6].
b-keto carboxylic acid moiety is required for
hydrogen bonding interaction with DNA bases in the single
stranded region of double helix of DNA created by the action of the
* Corresponding author. Tel.: þ91 1666 250838; fax: þ91 1666 250840.
E-mail address: darpkaush@yahoomail.com (D. Kaushik).
0223-5234/$ e see front matter Ó 2011 Published by Elsevier Masson SAS.
doi:10.1016/j.ejmech.2011.04.035

3544
R. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 3543e3550
R5 position of fluoroquinolone nucleus), Q6 (charge at R6 position of
fluoroquinolone nucleus), MR (molar refractivity) and MP (molec-
ular polarizability [9]. Keeping in view of all these studies with the
aim to increase bulk at C-7 position in fluoroquinolone nucleus
various derivatives were synthesized having substituted oxadiazole
at C-7 position. The synthesized compounds were evaluated for their
antibacterial activity. Further the synthesized compounds were
subjected to QSAR investigations using MLR technique in order to
determine the contribution of molecular descriptors in antibacterial
potential using descriptors like (i) topological descriptors like first
Zagreb index M1 (ZM1) [10], total structure connectivity index (xt)
[11] Wiener index (W) [12], Balban distance connectivity index (J)
[13] eccentric connectivity index (CSI) [14] (ii) connectivity indices
acids (1aeg) and semicarbazide undergoes cyclodehydration in the
presence of phosphorous oxychloride, which acts as a dehydrating
agent to form 2-amino-5-aryl-1,3,4-oxadiazoles [21]. Diazotization
of 2-amino-5-aryl-1,3,4-oxadiazoles in presence of nitrous acid,
leads to formation of diazonium chloride salt, to which, further
addition of finely divided copper powder having catalytic action at
room temperature, leads to formation of 2-chloro-5-aryl-1,3,4-
oxadiazoles along with evolution of nitrogen gas. Reaction of the
latter with piperazinyl group of quinolones in DMF in the presence
of a base (sodium bicarbonate) resulted in the synthesis of the final
compounds (Scheme 1). The physicochemical characteristics of the
synthesized compounds are presented in Table 1.
[15] like connectivity index chi-0 (
c
0), Randic connectivity index chi-
3); (iii)
2.2. Antibacterial evaluation
1( c
c
1), connectivity index chi-2 ( 2) connectivity index chi-3 (
c
quantum chemical descriptors like HOMO energy [16] LUMO energy
[17] and Total energy [18] and (iv) physical properties like molar
refractivity (MR) [19] and partition coefficient (clogP) [20] of newly
synthesized titled derivatives.
All the final synthesized compounds were evaluated for their
in vitro antibacterial activities against human pathogens. The
in vitro antibacterial activity were performed against aerobic Gram
positive bacterial strains including Staphylococcus aureus subsp.
aureus (MTCC 1430 equivalent to ATCC 12600), Bacillus subtilis
(MTCC 2423 equivalent to ATCC 21332) and Gram negative bacte-
rium Escherichia coli (MTCC 739 equivalent to ATCC 10536) using
serial dilution method [22,23]. As all are derivatives of marketed
drugs, that is why initial preliminary screening were not performed
and directly, the synthesized compounds were evaluated for the
MIC (minimun inhibitory concentration), where DMSO was used as
2. Results & discussion
2.1. Chemistry
The synthesis of compounds (I-XXI) was achieved with
a synthetic route depicted in Scheme 1. Different arylcarboxylic
Ar
COOH
Arylacid (1a-g)
c: Ar=
a: Ar=
d: Ar=
b: Ar=
NH2NHCONH2
POCl3
NO2
NO2
e: Ar=
NO2
f: Ar=
N
N
Ar
NH2
OCH3
OCH3
O
OCH3
NO2
2-amino-5-aryl-1,3,4-oxadiazoles (2a-g)
g: Ar=
HCl, Cu
Cl
NaNO2
N
N
Ar
Cl
O
2-chloro-5-aryl-1,3,4-oxadiazoles (3a-g)
O
F
COOH
DMF, NaHCO3
R1
4a: R1=H, R2= CH2CH3, R3=H
N
N
R2
4b: R1=H, R2= Cyclopropyl, ,R3=H
4c: R1=CH3, R2= Cyclopropyl, R3=OCH3
HN
R3
4a-c
O
F
COOH
R1
N
N
N
R3
R2
O
Ar
N
N
N- substituted piperazinyl quinolones (I-XXI)
Scheme 1. Scheme for the syntheses 7-[4-(5-aryl-1,3,4-oxadiazole-2-yl)piperazinyl] quinolone derivatives.

R. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 3543e3550
3545
Table 1
Physicochemical characteristics of 7-[4-(5-aryl-1,3,4-oxadiazole-2-yl) piperazinyl] quinolone derivatives.
Compound
Ar
R1
R2
R3
Mol. formula (MW)
Mpa
(ꢁC)
Yield
(%)
Rfb
I
II
III
IV
V
VI
VII
VIII
IX
Phenyl
3-nitrophenyl
4-nitrophenyl
3,4-dinitrophenyl
4-methoxyphenyl
3,4-dimethoxyphenyl
2-chlorophenyl
Phenyl
H
H
CH3
H
H
CH3
H
H
CH3
H
H
CH3
H
H
CH3
H
H
CH3
H
H
Ethyl
H
H
OCH3
H
H
OCH3
H
H
OCH3
H
H
OCH3
H
H
OCH3
H
H
OCH3
H
H
C24H22FN5O4 (463.47)
C25H21FN6O6 (520.48)
C27H25FN6O7 (564.53)
C24H20FN7O8 (553.47)
C26H24FN5O5 (505.51)
C29H30FN5O7 (579.59)
258e260
279e281
175e179
263e265
289e291
171e173
269e272
271e274
161e163
256e258
283e285
187e189
263e264
298e301
168e171
245e246
286e287
191e195
253e256
287e288
164e167
61
68
56
65
43
48
50
59
57
71
58
69
52
63
67
48
52
53
62
57
39
0.45
0.34
0.46
0.48
0.59
0.28
0.46
0.52
0.45
0.68
0.57
0.64
0.39
0.31
0.63
0.50
0.35
0.36
0.31
0.37
0.36
Cyclopropyl
Cyclopropyl
Ethyl
Cyclopropyl
Cyclopropyl
Ethyl
Cyclopropyl
Cyclopropyl
Ethyl
Cyclopropyl
Cyclopropyl
Ethyl
Cyclopropyl
Cyclopropyl
Ethyl
Cyclopropyl
Cyclopropyl
Ethyl
C24H21ClFN5O4 (497.92)
C25H22FN5O4 (475.48)
C27H25FN6O7 (564.53)
C24H21FN6O6 (508.47)
C25H20FN7O8 (565.48)
C28H28FN5O6 (549.56)
C26H26FN5O6 (523.53)
3-nitrophenyl
4-nitrophenyl
X
XI
3,4-dinitrophenyl
4-methoxyphenyl
3,4-dimethoxyphenyl
2-chlorophenyl
Phenyl
3-nitrophenyl
4-nitrophenyl
3,4-dinitrophenyl
4-methoxyphenyl
3,4-dimethoxyphenyl
2-chlorophenyl
XII
XIII
XIV
XV
XVI
XVII
XVIII
XIX
XX
XXI
C25H21ClFN5O4 (509.93)
C27H26FN5O5 (519.54)
C24H21FN6O6 (508.47)
C25H21FN6O6 (520.48)
C27H24FN7O9 (609.53)
C25H24FN5O5 (493.50)
C27H26FN5O6 (535.54)
C27H25ClFN5O5 (553.98)
Cyclopropyl
Cyclopropyl
CH3
OCH3
a
Melting point of compounds at their decomposition.
TLC mobile phase e Methanol:25% aqueous ammonia:ethyl acetate:acetonitrile:: 1:1:2:1.
b
negative control while ciprofloxacin was used as a positive control
showing inhibition of growth of microbes. According to the values
of control, the results were evaluated. The results of antibacterial
activity are presented in Table 2.
The compounds III, X and XV were found to be the most
effective compounds against S. aureus with pMIC value of 3.61, 3.63,
and 3.62 respectively. For activity against B. subtilis the compounds
IV, VIII, IX, X and XV yielded better activity in comparison to other
Table 2
Observed and calculated antimicrobial activity of 7-[4-(5-aryl-1,3,4-oxadiazole-2-yl)piperazinyl] quinolone derivatives using the best QSAR models.
Compounds
pMIC sa (eq. (1))
pMIC bs (eq. (2))
pMIC bs (eq. (3))
pMIC ec (eq. (4))
pMIC ec (eq. (5))
Obs.
Calc.
Res.
Obs.
Calc.
Res.
Obs.
Calc.
Res.
Obs.
Calc.
Res.
Obs.
Calc.
Res.
I
II
III
IV
V
VI
VII
VIII
IX
X
XI
XII
XIII
XIV
XV
XVI
2.58
2.24
3.61
3.24
3.12
3.36
3.21
3.26
3.25
3.63
2.95
3.17
2.43
2.43
3.62
2.84
2.63
2.64
3.20
2.91
3.24
3.16
2.818
2.664
3.466
3.179
2.944
3.204
3.344
3.142
3.369
3.526
3.229
2.975
2.862
2.709
3.509
2.691
2.628
3.073
2.748
2.580
2.898
e
ꢀ0.238
ꢀ0.424
0.144
0.061
0.176
0.156
ꢀ0.134
0.118
ꢀ0.119
0.104
ꢀ0.279
0.195
ꢀ0.432
ꢀ0.279
0.111
0.149
0.002
ꢀ0.433
0.452
0.330
0.342
e
2.58
2.28
3.11
3.87
3.09
3.27
3.21
3.87
3.55
3.63
3.25
3.09
2.43
2.38
3.54
2.84
2.32
2.96
3.20
2.67
3.24
3.16
2.784
2.592
2.967
3.733
2.941
3.263
3.437
3.687
3.469
3.664
3.295
3.101
2.838
2.648
3.620
2.625
2.547
3.101
2.697
2.487
2.882
e
ꢀ0.204
ꢀ0.312
0.143
0.137
0.149
2.58
2.28
3.11
3.87
3.09
3.27
3.21
3.87
3.55
3.63
3.25
3.09
2.43
2.38
3.54
2.84
2.32
2.96
e
2.742
2.537
2.938
3.722
2.909
3.254
3.440
3.673
3.474
3.683
3.288
3.115
2.800
2.597
3.595
2.572
2.489
3.081
e
ꢀ0.162
ꢀ0.257
0.172
0.148
0.181
0.016
ꢀ0.230
0.197
0.076
ꢀ0.053
ꢀ0.038
ꢀ0.025
ꢀ0.370
ꢀ0.217
ꢀ0.055
0.268
ꢀ0.169
ꢀ0.121
e
2.65
2.17
3.24
3.63
3.20
3.27
3.60
3.22
3.55
3.24
3.65
3.07
2.68
2.43
2.94
2.69
2.32
3.66
3.50
2.67
3.17
3.52
2.821
2.642
2.993
3.241
2.968
3.269
3.432
3.198
3.462
3.644
3.999
2.985
2.872
2.695
3.042
2.673
2.600
3.818
2.740
2.544
2.913
e
ꢀ0.171
ꢀ0.472
0.247
0.389
0.232
0.001
0.168
0.022
0.088
ꢀ0.404
ꢀ0.349
0.085
ꢀ0.192
ꢀ0.265
ꢀ0.102
0.017
ꢀ0.280
ꢀ0.158
0.760
0.126
0.257
e
2.65
2.17
3.24
3.63
3.20
3.27
3.60
3.22
3.55
3.24
3.65
3.07
2.68
2.43
2.94
2.69
2.32
3.66
e
2.758
2.559
2.948
3.224
2.921
3.256
3.436
3.176
3.469
3.671
3.988
3.006
2.814
2.617
3.003
2.593
2.513
3.787
e
ꢀ0.108
ꢀ0.389
0.292
0.406
0.279
0.014
0.164
0.044
0.081
ꢀ0.431
ꢀ0.338
0.064
ꢀ0.134
ꢀ0.187
ꢀ0.063
0.097
ꢀ0.193
ꢀ0.127
e
0.007
ꢀ0.227
0.183
0.081
ꢀ0.034
ꢀ0.045
ꢀ0.011
ꢀ0.408
ꢀ0.268
ꢀ0.08
0.215
ꢀ0.227
ꢀ0.141
0.503
XVII
XVIII
XIX
XX
0.183
0.358
2.67
3.24
3.16
2.425
2.847
e
0.245
0.393
e
2.67
3.17
3.52
2.450
2.860
e
0.220
0.310
e
XXI
Ciprofloxacina
e
a
Not included in dataset for QSAR analysis.

3546
R. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 3543e3550
Table 3
Values of selected molecular descriptors used in the regression analysis.
Compound
HOMO energy
LUMO Energy
Total Energy
MR
ClogP
CSI
W
J
X0
X1
X2
X3
Xt
ZM1
I
II
III
IV
V
VI
VII
VIII
IX
ꢀ8.6262
ꢀ8.5843
ꢀ8.6662
ꢀ8.7241
ꢀ8.6604
ꢀ8.7308
ꢀ8.7687
ꢀ8.7141
ꢀ8.7757
ꢀ8.8182
ꢀ8.7377
ꢀ8.8044
ꢀ8.6382
ꢀ8.5966
ꢀ8.6778
ꢀ8.5916
ꢀ8.5746
ꢀ8.6954
ꢀ8.6072
ꢀ8.5615
ꢀ8.6477
ꢀ0.8885
ꢀ0.8626
ꢀ0.8811
ꢀ1.5047
ꢀ1.5474
ꢀ1.5021
ꢀ1.6811
ꢀ1.7212
ꢀ1.6771
ꢀ2.4895
ꢀ2.5277
ꢀ2.4834
ꢀ0.8986
ꢀ0.8740
ꢀ0.8917
ꢀ0.8829
ꢀ0.8537
ꢀ8.9584
ꢀ0.8773
ꢀ0.8419
ꢀ0.8647
128.22
183.15
2958.48
118.78
173.79
2949.12
118.77
173.78
2949.06
160.93
222.57
2991.21
141.19
196.13
2971.42
3062.78
3118.90
2988.51
130.92
185.72
2960.49
12.538
12.667
13.614
13.141
13.278
14.222
13.141
13.278
14.222
13.753
13.879
14.833
13.146
13.284
14.227
13.763
13.901
14.844
13.021
13.158
14.102
2.91225
3.61625
3.37516
2.68331
3.38731
3.14267
2.68331
3.38731
3.14266
2.43179
3.13579
2.89114
2.97425
3.67825
3.43355
2.69393
3.39793
3.50328
3.38835
4.09235
3.84775
1100
1037
1173
1257
1190
1334
1311
1240
1392
1366
1299
1443
1272
1201
1353
1344
1273
1425
1133
1070
1206
4060
3799
4750
5202
4891
6006
5289
4975
6102
6392
6031
7310
4866
4570
5637
5630
5301
6476
4387
4111
5110
1.048
1.149
1.131
1.027
1.131
1.105
1.012
1.115
1.097
1.036
1.141
1.103
1.022
1.124
1.101
1.022
1.126
1.096
1.047
1.156
1.129
24.104
23.819
26.551
26.551
26.267
28.999
26.551
26.267
28.999
28.999
28.714
31.747
25.681
25.397
28.129
27.258
26.974
29.706
24.974
24.649
27.422
16.991
16.457
18.367
18.296
17.761
19.672
18.296
17.761
19.672
19.655
19.066
20.976
17.923
17.389
19.299
18.872
18.337
20.248
17.402
16.867
18.778
15.850
15.017
17.053
17.383
16.575
18.586
17.371
16.538
18.574
18.928
18.095
20.133
16.641
15.808
17.843
17.362
16.529
18.565
16.378
15.545
17.581
13.628
13.345
14.696
14.676
14.348
15.745
14.738
14.409
15.806
15.684
15.392
16.749
14.747
14.119
15.515
15.207
14.879
16.272
14.095
13.767
15.163
0.192
0.199
0.187
0.187
0.193
0.182
0.187
0.193
0.182
0.182
0.188
0.178
0.188
0.194
0.183
0.185
0.199
0.186
0.198
0.197
0.185
198
186
214
214
202
230
214
202
230
230
218
246
208
196
224
218
206
234
204
192
220
X
XI
XII
XIII
XIV
XV
XVI
XVII
XVIII
XIX
XX
XXI
synthesized compounds. The antimicrobial spectrum of quinolones
derivatives against E. coli demonstrated that compounds IV, VII, IX,
XI & XVIII were the most active ones.
(MLR) method as employed in the BuildQsar software [27]. The
developed models (eq. (1)e(5)) were cross validated using Leave
one out (LOO) method.
Preliminary analysis was carried out in terms of a correlation
analysis between pMIC and various molecular descriptors and the
results are presented in Table 4. This was done to remove the
chances of intercorrelation among the molecular descriptors that
may lead to false predicting models.
The data depicted in Table 4, indicated that antibacterial activity
against all three microbes were showing good correlation with
HOMO energy (r ¼ 0.734 for pMIC sa, 0.882 for pMIC bs, 0.840 for
pMIC ec). The correlation with HOMO energy as an independent
variable with pMIC sa, pMIC bs and pMIC ec were significant as
shown in the equations below.
2.3. QSAR analysis
An attempt was made to establish the relationship between
structure and antibacterial activity. The MIC values obtained from
the experiment were expressed in terms of mg/ml concentration.
For the purpose of correlation, the MIC values were converted to
their molar units and subsequently to free energy related negative
logarithmic state, which is log (1/MIC) and further used as
dependent variable in developing the QSAR models. The structures
of the molecules were drawn using HYPERCHEM 8.0.5 [24] and
later subjected to minimization of energy using the MMþ method.
The energy minimized molecules were subjected to molecular
descriptor calculation. Topological descriptors and connectivity
indices were calculated using Dragon 3.0 web version [25],
quantum chemical descriptors and physical properties were
calculated with the help of CS Chemoffice [26]. The values of the
selected descriptors used in the regression analysis are presented in
Table 3. The models were built using the multiple linear regression
2.3.1. QSAR model for antibacterial activity against S. aureus
pMIC sa ¼ ꢀ3:6847ðꢂ1:6354Þ HOMO energy
ꢀ 28:9669ðꢂ14:1897Þ
(1)
(n ¼ 21; r ¼ 0.734; R2 ¼ 0.538; s ¼ 0.272; F ¼ 22.238; p < 0.0002;
Q2 ¼ 0.444; SPress ¼ 0.299; SDEP ¼ 0.291).
Table 4
Correlation matrix for pMIC with molecular descriptors.
pMIC sa pMIC bs pMIC ec HOMO energy LUMO energy Total energy MR
1.000
ClogP CSI
W
J
X0
X1
X2
X3
Xt
ZM1
pMIC sa
pMIC bs
pMIC ec
0.926
0.859
HOMO energy 0.734
LUMO energy 0.007
1.000
0.907
0.839
0.215
0.148
0.440
0.408
0.525
0.631
0.188
0.644
0.625
0.747
0.594
0.624
0.684
1.000
0.750
0.145
0.089
0.302
0.404
0.436
0.484
0.326
0.494
0.503
0.629
0.475
0.571
0.592
1.000
0.341
0.085
0.462
0.595
0.694
0.753
0.261
0.729
0.710
0.818
0.683
0.683
0.745
1.000
0.205
0.540
0.032
0.504
0.526
0.000
0.511
0.521
0.455
0.524
0.447
0.477
Total energy
0.198
0.418
0.355
0.458
0.575
0.155
0.599
0.575
0.694
0.544
0.579
0.635
1.000
0.794
0.092
0.533
0.530
0.193
0.611
0.663
0.531
0.657
0.648
0.631
MR
ClogP
CSI
W
1.000
0.010 1.000
0.815 0.501 1.000
0.871 0.448 0.946 1.000
0.192 0.791 0.298 0.136 1.000
0.925 0.322 0.904 0.984 0.000 1.000
0.924 0.372 0.927 0.974 0.109 0.985 1.000
0.837 0.471 0.891 0.964 0.186 0.968 0.975 1.000
0.932 0.345 0.938 0.973 0.106 0.982 0.995 0.963 1.000
0.823 0.474 0.888 0.888 0.334 0.889 0.950 0.942 0.941 1.000
0.870 0.432 0.897 0.943 0.211 0.954 0.985 0.985 0.974 0.981 1.000
J
X0
X1
X2
X3
Xt
ZM1

R. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 3543e3550
3547
Fig. 3. Histogram of residual pMIC ec value of the compounds calculated using eq. (5).
Fig. 1. Histogram of residual pMIC sa value of the compounds calculated using eq. (1).
(n ¼ 20; r ¼ 0.840; R2 ¼ 0.705; s ¼ 0.247; F ¼ 43.217; p < 0.0001;
Q2 ¼ 0.624; SPress ¼ 0.279; SDEP ¼ 0.272) [Compound XIX outlier].
The quality of the model is indicated by following parameters. r,
correlation coefficient; R2, squared multiple correlation coefficient;
F, Fischer’s significance statistics; s, standard error of estimate; Q2,
cross validated r2; SPress, predicted residual sum of square; SDEP,
standard deviation of prediction of errors; n, number of data points.
The treatment of data for developing QSAR models in the case of
pMIC bs (eq. (2)) and pMIC ec (eq. (4)) has shown compound XIX as
an outlier because of higher leverage value of 0.503 & 0.760
respectively as shown in Table 2. When outliers are present,
regression analysis may produce results that strongly reflect a small
number of atypical cases rather than the general relationship
observed in the rest of data. The outliers often have dramatic effect
on the fitted least square regression function, therefore it is impor-
tant to study the outlying case carefully and decide whether they
should be retained or eliminated [28]. Therefore, the analysis was
done using method of deleted residuals [29]. The compound XIX was
deleted from the dataset and the regression equation was calculated
using other n ꢀ 1 ¼20 cases. The results of the analysis are presented
in eq. (3) (for pMIC bs) & in eq. (5) (for pMIC ec). Using these new
regression equations with compound XIX deleted from the dataset,
we calculated the predicted value for compound XIX. Further, the
deleted residual was calculated using the difference between
the actual observed value and the estimated expected value from the
developed model. The value of deleted residual for the compound
XIX for eq. (3) was found to be 0.56 and for eq. (5) was found to be
0.84. The greater magnitude of the deleted residual than of the
ordinary residual further put forward the compound XIX as an
2.3.2. QSAR model for antibacterial activity against B. subtilis
pMIC bs ¼ ꢀ4:5854ðꢂ1:4281Þ HOMO energy
ꢀ 36:7704ðꢂ12:3913Þ
(n ¼ 21; r ¼ 0.839; R2 ¼ 0.703; s ¼ 0.238; F ¼ 45.159; p < 0.0001;
Q2 ¼ 0.645; SPress ¼ 0.260; SDEP ¼ 0.254).
(2)
pMIC bs ¼ ꢀ4:8993ðꢂ1:2952Þ HOMO energy
ꢀ 39:5206ðꢂ11:2421Þ
(n ¼ 20; r ¼ 0.882; R2 ¼ 0.777; s ¼ 0.210; F ¼ 63.165; p < 0.0001;
Q2 ¼ 0.730; SPress ¼ 0.232; SDEP ¼ 0.226) [Compound XIX outlier].
(3)
2.3.3. QSAR model for antibacterial activity against E. coli
pMIC ec ¼ ꢀ4:2824ðꢂ1:8127Þ HOMO energy
ꢀ 34:1193ðꢂ15:7283Þ
(n ¼ 21; r ¼ 0.750; R2 ¼ 0.562; s ¼ 0.302; F ¼ 24.448; p < 0.0001;
Q2 ¼ 0.457; SPress ¼ 0.336; SDEP ¼ 0.328).
(4)
pMIC ec ¼ ꢀ4:7565ðꢂ1:5202Þ HOMO energy
ꢀ 38:2724ðꢂ13:1950Þ
(5)
Fig. 4. Plot of calculated pMIC sa activity values against the observed pMIC sa values
Fig. 2. Histogram of residual pMIC bs value of the compounds calculated using eq. (3).
for the linear regression developed model by eq. (1).

3548
R. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 3543e3550
3. Conclusion
Summarizingly, a series of substituted fluoroquinolone deriva-
tives have been synthesized successfully in appreciable yields and
screened for their in vitro antibacterial activity against aerobic
bacterial strains of E. coli, S. aureus, and B. subtilis. QSAR analysis
carried out to investigate the role of molecular descriptors in
attributing the antibacterial activity of the synthesized derivatives
indicated the importance of the HOMO energy in predicting the
antibacterial activity. Further, the QSAR models are statistically,
chemically and significantly sound and explain more than 99% of
confidence level; finally it can be concluded from the developed
models, that this work shows substantial promise in the prediction
of the antibacterial activity of other novel fluoroquinolone deriva-
tives prior to their synthesis.
Fig. 5. Plot of calculated pMIC bs activity values against the observed pMIC bs values
for the linear regression developed model by eq. (3).
4. Experimental
outlier. Therefore, an improvement in statistical parameters was
carried out by treating it as an outlier from the dataset.
Melting points were determined in an open end capillary tube
on Elico melting point apparatus and are uncorrected. Reaction
progress was monitored by ascending thin layer chromatography
on silica gel sheets (Merck silica gel-G), visualized by iodine vapors
and the purity of the compounds was ascertained by single spot on
TLC plates. Proton nuclear magnetic resonance (1H NMR) spectra
were recorded in Bruker Avance II 400 NMR spectrometer using
The QSAR equations derived showed a very good r (correlation
coefficient) value of 0.734, 0.882 and 0.840 for three different
models respectively. All three are associated with low value of
standard error of estimate and found to be highly statistically
significant with high F test value of 22.238, 63.165 and 43.217
respectively. All three models also showed high confidence level of
more than 99.98%. All the developed models were cross validated
with LOO method for their predicting power every time an equa-
tion is developed by eliminating one compound from the series and
the activity of the eliminated compound is determined using the
developed equation. The histogram plot of residual values of QSAR
model of equations (1), (3) and (5) are depicted in Figs. 1e3 are
showing distribution toward both positive and negative axis indi-
cating good predictive power of the developed models. The
observed antibacterial activity is plotted against predicted activity
using the developed models. The fit line is shown in the Figs. 4e6.
Perusal of above equation indicated that HOMO energy is having
detrimental effect on the development of molecules, so during
pharmacophore development, we have to avoid the nucleophilic
group substitutions on phenyl ring of the oxadiazole.
deuterated DMSO and are reported in parts per million (d) relative
to tetramethylsilane (TMS) as an internal standard. Infrared (IR)
spectra were recorded on Thermo FTIR spectrometer (KBr disks).
The MS-ESI spectra were recorded on Waters Micromass Q-TOF
micro. Elemental analysis (CHN) was performed on Vario ELIII
CHNS analyzer using sulphanilic acid as a standard and all the
values were within ꢂ0.4% of the theoretical composition.
4.1. General procedure for the synthesis of 2-amino-5-aryl-1,3,4-
oxadiazoles (2aeg)
A mixture of substituted aromatic acid (1aeg) (0.1 mmol) with
semicarbazide (0.01 mmol) in phosphorous oxychloride (15 ml)
was refluxed over a steam bath for 5e6 h. The progress of reaction
was monitored by TLC using ethyl acetate: acetone (9:1) as eluent.
The reaction mixture was cooled and poured on to crushed ice
(200 g) with continuous stirring. The solid mass separated was
neutralized with sodium bicarbonate solution (10% W/V). The
resulted solid thus obtained was collected by filtration, washed
well with cold water, dried in vacuum and recrystallized from
ethanol. The compounds are already reported previously [30,31].
HOMO is the outer most orbital containing the electrons. The
generated QSAR models indicated the higher value of HOMO energy
contributing negatively to the antibacterial activity. An electron
donating substituent such as hydroxyl or methyl or methoxy group
on the ring increases the HOMO energy, similarly electron with-
drawing groups such as halogens, lowers the HOMO energy. Thus,
the design of molecules with electron withdrawing substituents
would have been suggested to have better antibacterial activity.
4.2. General procedure for the synthesis of 2-chloro-5-aryl-1,3,4-
oxadiazoles (3aeg)
Compound 2aeg (10 mmol) were ground with an excess of
NaNO2 (1.59 g, 30 mmol) and the mixture was introduced in small
portions and with stirring into a ice cooled solution of conc. HCl
(30 ml) and water (13 ml), containing Cu powder (0.45 g). The
reaction mixture was allowed to reach room temperature and
heated to 55 ꢁC for 20 min. The reaction mixture was cooled and
extracted with 30 ml CHCl3 (three times). The combined extracts
were washed with NaHCO3 solution, dried over Na2SO4 and evap-
orated to give crude. The product was crystallized from ethanol.
The compounds were characterized by IR (cmꢀ1, KBr) 1624e1590
(C]N stretch), 1274e1229 (aryleCeOeCeassym. stretch),
1065e1025 (aryleCeOeCesym. stretch), 690e671 (CeCl). Mass
spectra of compound 3a exhibited molecular ion peak at m/z 180
(Mþ), other important fragment were observed at 182 (Mþ þ 2).
Compound 3a is already reported previously [32].
Fig. 6. Plot of calculated pMIC ec activity values against the observed pMIC ec values
for the linear regression developed model by eq. (5).

R. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 3543e3550
3549
4.3. General procedure for synthesis of N-substituted piperazinyl
quinolones (I-XXI)
4.3.6. 1-Ethyl-6-fluoro-7-(4-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-
yl)piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (X)
IR (cmꢀ1, KBr): 3047 (aromatic CeH stretch), 1720 (carboxylic
C]O str), 1629 (pyridinone C]O str), 1588 (pyridinone ring C]C
A
mixture of equimolar quantity of compound 3aeg
(0.05 mmol), piperazinyl quinolone (0.05 mmol) and NaHCO3
(0.05 mmol) in DMF (10 ml), was heated under reflux at 85e90 ꢁC
for 12 h. After cooling, water was added (10 ml) and the precipitate
was filtered off, washed with water and recrystallized from the
mixture of DMF and H2O to give the final product.
str), 1257 (CeO str), 1148 (piperazine CeN str); 1H NMR,
d ppm
(DMSO-d6): 1.23e1.27 (t, 3H, C1eCH3), 3.35e3.58 (m, 8H, C2e60),
4.52 (q, 2H, C1eCH2e), 7.12e7.14 (d, 1H, C8, J ¼ 7.2), 7.85e8.05 (m,
3H, C5 & 2AreH), 8.32e8.34 (m, 2H, AreH), 8.88 (s, 1H, C2), 14.89 (s,
1H, eCOOH); Anal. Cal%: C, 56.69; H, 4.16; N, 16.53. Found%: C,
56.31; H, 4.21; N, 16.48.
4.3.1. 1-Ethyl-6-fluoro-4-oxo-7-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)
piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (I)
4.3.7. 1-Cyclopropyl-7-(4-(5-(3,4-dinitrophenyl)-1,3,4-oxadiazol-
2-yl)piperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid (XI)
IR (cmꢀ1, KBr): 3050 (aromatic CeH stretch), 1724 (carboxylic
acid C]O str), 1629 (pyridinone C]O str), 1590 (pyridinone ring
C]C str), 1219 (CeO str), 1176 (piperazine CeN str); 1H NMR,
d
ppm
IR (cmꢀ1, KBr): 3048 (aromatic CeH stretch), 1724 (carboxylic
C]O str), 1633 (pyridinone C]O str), 1582 (pyridinone ring C]C
(DMSO-d6): 1.31e1.33 (t, 3H, C1eCH3), 3.29e3.48 (m, 8H, C2e60),
4.58 (q, 2H, C1eCH2), 7.09e7.11 (d, 1H, C8 J ¼ 7 Hz), 7.42e7.53 (m,
3H, AreH), 8.01e8.05(m, 3H, C5 & 2AreH), 9.12 (s, 1H, C2), 14.86 (s,
1H, eCOOH); MS-ESI: 463.17 (Mþ), 464.17 (Mþ þ 1), 465.17
(Mþ þ 2); Anal. Cal%: C, 62.20; H, 4.78; N, 15.11. Found%: C, 62.86; H,
4.96; N, 14.99.
str), 1248 (CeO str), 1133 (CeN str); 1H NMR,
d ppm (DMSO-d6):
1.19e1.23 (m, 4H, C1eCH2e), 3.32e3.56 (m, 8H, C2e60), 3.73e3.76
(m, 1H, C1eCHe), 7.18e7.20 (d, 1H, C8), 7.85e7.89 (d, 1H, C5),
8.12e8.14 (d, 1H, AreH), 8.52e8.54 (d, 1H, AreH), 8.63 (s, 1H,
AreH), 8.69 (s, 1H, C2), 14.69 (s, 1H, eCOOH).
4.3.2. 1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-4-(5-(4-
nitrophenyl)-1,3,4-oxadiazol-2-yl)piperazin-1-yl)-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid (III)
4.3.8. 1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-4-(5-
phenyl-1,3,4-oxadiazol-2-yl)piperazin-1-yl)-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid (XV)
IR (cmꢀ1, KBr): 3048 (aromatic CeH stretch), 1728 (carboxylic
acid C]O str), 1632 (pyridinone C]O str), 1595 (pyridinone ring
IR (cmꢀ1, KBr): 3040 (aromatic CeH stretch), 1720 (carboxylic
C]O str), 1617 (pyridinone C]O str), 1555 (pyridinone ring C]C
C]C str), 1211 (CeO str), 1160 (piperazine CeN str); 1H NMR,
(DMSO-d6): 1.10e1.15 (m, 3H, C3 eCH3), 1.19e1.39 (m, 4H,
d
ppm
str), 1278 (CeO str), 1112 (CeN str); 1H NMR,
1.10e1.14 (m, 3H, C3 eCH3), 1.17e1.38 (m, 4H, C1eCH2e), 3.08e3.12
d
ppm (DMSO-d6):
0
0
0
0
C1eCH2e), 3.08e3.12 (m, 1H, C3 ), 3.38e3.65 (m, 6H, C2,5e60), 3.73
(m, 1H, C3 ), 3.32e3.51 (m, 6H, C2,5e60), 3.76 (s, 3H, C8eOCH3),
(s, 3H, C8eOCH3), 3.78e3.81 (m, 1H, C1eCHe), 7.48e7.50 (d, 2H,
AreH), 7.85e7.89 (d, 1H, C5), 8.31e8.33 (d, 2H, AreH), 8.73 (s, 1H,
C2), 14.83 (s, 1H, eCOOH).
3.73e3.78 (m, 1H, C1eCHe), 7.32e7.48 (m, 3H, AreH), 7.56e7.58 (d,
2H, AreH), 7.63e7.67 (d, 1H, C5), 8.52 (s, 1H, C2), 14.74 (s, 1H,
eCOOH); Anal. Cal%: C, 56.69; H, 4.16; N, 16.53. Found%: C, 56.58; H,
4.24; N, 16.51.
4.3.3. 1-Cyclopropyl-6-fluoro-7-(4-(5-(4-methoxyphenyl)-1,3,4-
oxadiazol-2-yl)piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid (V)
4.3.9. 1-Cyclopropyl-7-(4-(5-(3,4-dinitrophenyl)-1,3,4-oxadiazol-
2-yl)-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid (XVIII)
IR (cmꢀ1, KBr): 3041 (aromatic CeH stretch),1719 (carboxylic C]O
str), 1627 (pyridinone C]O str), 1582 (pyridinone ring C]C str), 1256
IR (cmꢀ1, KBr): 3052 (aromatic CeH stretch), 1724 (carboxylic
acid C]O str), 1629 (pyridinone C]O str), 1590 (pyridinone ring
(CeO str), 1133 (CeN str); 1H NMR,
d ppm (DMSO-d6): 1.17e1.37 (m,
4H, C1eCH2e), 3.32e3.45 (m, 8H, C2e60), 3.71 (s, 3H, eOCH3),
3.78e3.84 (m,1H, C1eCHe), 6.91e6.93(m, 2H, AreH), 7.14e7.16 (d, 1H,
C8), 7.76e7.93 (m, 3H, C5 & 2AreH), 8.64 (s, 1H, C2), 14.82 (s, 1H,
eCOOH); MS-ESI: 505.18 (Mþ), 506.08 (Mþ þ 1), 507.08(Mþ þ 2); Anal.
Cal%: C, 61.78; H, 4.79; N, 13.85. Found%: C, 61.33; H, 4.63; N, 13.81.
C]C str),1239 (CeO str),1146 (piperazine CeN str); 1H NMR,
d
ppm
0
(DMSO-d6): 1.13e1.17 (m, 3H, C3 eCH3), 1.19e1.29 (m, 4H,
0
C1eCH2e), 3.03e3.08 (m, 1H, C3 ), 3.28e3.53 (m, 6H, C2,5e60), 3.76
(s, 3H, C8eOCH3), 3.77e3.84 (m, 1H, C1eCHe), 7.56e7.59 (d, 1H, C5),
8.13e8.15 (d, 1H, AreH), 8.49 (s, 1H, C2), 8.51e8.53 (d, 1H, AreH),
8.68 (s, 1H, AreH), 14.76 (s, 1H, eCOOH).
4.3.4. 7-(4-(5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl)piperazin-1-
yl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
(VII)
4.3.10. 1-Cyclopropyl-7-(4-(5-(3,4-dimethoxyphenyl)-1,3,4-
oxadiazol-2-yl)piperazin-1-yl)-6-fluoro-4-oxo-1,4-
IR (cmꢀ1, KBr): 3058 (aromatic CeH stretch), 1728 (carboxylic
C]O str), 1632 (pyridinone C]O str), 1578 (pyridinone ring C]C
dihydroquinoline-3-carboxylic acid (XX)
IR (cmꢀ1, KBr): 3055 (aromatic CeH stretch), 1718 (C]O str,
carboxylic acid), 1628 (pyridinone C]O str), 1581 (pyridinone ring
C]C str), 1259 (CeO, str), 1137 (CeN, str, piperazine); 1H NMR,
str), 1243 (CeO str), 1156 (CeN str); 1H NMR,
d ppm (DMSO-d6):
1.21e1.24 (t, 3H, C1eCH3), 3.28e3.56 (m, 8H, C2e60), 4.55e4.62 (m,
2H, C1eCH2e), 7.18e7.20 (d, 1H, C8), 7.38e7.74 (m, 4H, AreH),
7.84e7.88 (d, 1H, C5), 8.74 (s, 1H, C2), 14.76 (s, 1H, eCOOH).
d
ppm (DMSO-d6): 1.19e1.28 (m, 4H, C1eCH2e), 3.29e3.47 (m, 8H,
C2e60), 3.76 (s, 6H, AreOCH3), 3.82e3.87 (m, 1H, C1eCHe),
6.93e6.99 (m, 2H, AreH), 7.14e7.16 (d, 1H, C8), 7.48e7.50 (d, 1H,
AreH), 7.82e7.86 (d, 1H, C5), 8.62 (s, 1H, C2), 14.82 (s, 1H, eCOOH);
MS-ESI: 535.19 (Mþ), 536.19 (Mþ þ 1), 537.19 (Mþ þ 2); Anal Cal%:
C, 60.56; H, 4.89; N, 13.08. Found%: C, 60.28; H, 4.76; N, 12.97.
4.3.5. 1-Cyclopropyl-6-fluoro-4-oxo-7-(4-(5-phenyl-1,3,4-
oxadiazol-2-yl)piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic
acid (VIII)
IR (cmꢀ1, KBr): 3052 (aromatic CeH stretch), 1721 (carboxylic
C]O str), 1635 (pyridinone C]O str), 1572 (pyridinone ring C]C
4.4. Antibacterial activity
str), 1243 (CeO str), 1133 (CeN str); 1H NMR,
d ppm (DMSO-d6):
1.21e1.37 (m, 4H, C1eCH2e), 3.29e3.58 (m, 8H, C2e60), 3.74e3.79
(m, 1H, C1eCHe), 7.18e7.20 (d, 1H, C8), 7.44e7.76 (m, 5H, AreH),
7.84e7.88 (d, 1H, C5), 8.62 (s, 1H, C2), 14.64 (s, 1H, eCOOH).
All the synthesized compounds were evaluated for their in vitro
antibacterial activities against aerobic Gram positive bacteria e S.
aureus subsp. aureus (MTCC 1430) i.e. Strain type Serovar 3, B.

3550
R. Kumar et al. / European Journal of Medicinal Chemistry 46 (2011) 3543e3550
subtilis (MTCC 2423) and Gram negative bacterium e E. coli (MTCC
739) by two fold tube dilution method [22,23]. DMSO was used as
negative control while ciprofloxacin was used as a positive control
showing inhibition of growth of microbes. According to the values
of control, the results were evaluated.
providing the gift samples of norfloxacin, ciprofloxacin and gati-
floxacin. We also acknowledge Prof. A. C. Gaudio, for providing
BuildQsar software for regression analysis.
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Acknowledgments
Authors are really grateful to Mr. Avtar Singh, SAIF, Panjab
University, Chandigarh for providing 1H NMR & FTIR spectra.
Authors are thankful to Alkem Laboratories, Bhiwadi, India for