Synthesis, biological evaluation and 3D-QSAR study of hydrazide, semicarbazide and thiosemicarbazide derivatives of 4-(adamantan-1-yl)quinoline as anti-tuberculosis agents

Article abstract of DOI:10.1016/j.ejmech.2014.07.100

We report synthesis, anti-tuberculosis activity and 3D-QSAR study of forty nine hydrazide, semicarbazide and thiosemicarbazide derivatives of 4-(adamantan-1-yl)quinoline. The most potent compounds upon evaluation for anti-tuberculosis activity exhibited M

Full text of DOI:10.1016/j.ejmech.2014.07.100

European Journal of Medicinal Chemistry 85 (2014) 255e267
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, biological evaluation and 3D-QSAR study of hydrazide,
semicarbazide and thiosemicarbazide derivatives of 4-(adamantan-1-
yl)quinoline as anti-tuberculosis agents
,
*
Sanjay R. Patel a, Rahul Gangwal b, Abhay T. Sangamwar b, Rahul Jain a
a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India
b Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We report synthesis, anti-tuberculosis activity and 3D-QSAR study of forty nine hydrazide, semicarbazide
and thiosemicarbazide derivatives of 4-(adamantan-1-yl)quinoline. The most potent compounds upon
Received 30 August 2013
Received in revised form
25 February 2014
Accepted 26 July 2014
Available online 29 July 2014
evaluation for anti-tuberculosis activity exhibited MIC99 of 3.125
mg/mL against Mycobacterium tuber-
culosis H37Rv strain. We applied the in silico technique of 3D-QSAR to study structure activity rela-
tionship of the synthesized compounds. The developed CoMFA model exhibited excellent r2
of 0.971,
ncv
and r2cv of 0.543. The predicted r2pred of 0.883 showed that the predicted values were in good agreement
with the experimental values. Further, the contour map analysis, suggested that the sterically bulky and
electronegative substitutions at the para position of the phenyl ring are favorable for anti-tuberculosis
activity.
Keywords:
Tuberculosis
Quinolines
© 2014 Elsevier Masson SAS. All rights reserved.
CoMFA
Hydrazide
Semicarbazide
Thiosemicarbazide
1. Introduction
starting material in a convenient three-step synthesis, making it an
ideal structural prototype around which additional structural
The appearance of extreme drug resistance and totally drug
resistance strains of tuberculosis (TB) created a need for the new
anti-TB agents, which can effectively cure all forms of the disease
[1]. The numbers of TB cases are still at a high level with 8.8 million
cases annually, and approximately 1.45 million deaths, worldwide
[2]. Moreover, development of TB in conjunction with AIDS has
further intensified the problems associated with its cure, because
both diseases (TB and AIDS) speed up each other progression [3].
The current chemotherapy is inadequate in meeting emerging
challenges in the treatment of TB, underling the importance of the
discovery process in identifying new classes of compounds.
optimization could be initiated. Moreover, the presence of a novel
structure suggests cross-resistance to this structurally different
anti-tuberculosis compound with the existing TB drugs is dimin-
ished to a greater extent. Therefore, 2 can be considered suitable for
the further structural optimization. The semicarbazides and thio-
semicarbazide derivatives are known as the effective pharmaco-
phore for anti-tuberculosis activity [5e10]. For example, Fox et al.,
identified thiosemicarbazones of isonicotinaldehyde (derivative of
isoniazid) as the potential anti-TB agents with activity comparable
to that of isoniazid [11]. Sriram et al., reported oxazolyl thio-
semicarbazones as potent anti-TB compounds, with most prom-
We have earlier identified 4-(adamantan-1-yl)quinoline-2-
carbohydrazide (2, Scheme 1) as a promising antimycobacterial
from a series of ring-substituted quinoline-carbohydrazides/car-
boxamides [4]. The compound 2 exhibited MIC99 of 3.125 mg/mL,
when tested against Mycobacterium tuberculosis H37Rv strain. The
compound 2 was synthesized in good yield from the inexpensive
ising analogue exhibiting MIC of 0.05 mg/mL, against MTB and MDR-
TB in vitro [12]. The thiosemicarbazide derivatives of quinoline,
when evaluated against a variety of Gram-positive and Gram-
negative bacteria and yeast, exhibited activity comparable with
the standard drugs used in the assay [13]. Keeping these observa-
tions in mind, we have designed a series of hydrazide, thio-
semicarbazide and semicarbazide derivatives of 4-(adamantan-1-
yl)quinoline-2-carbohydrazide (2), and herein, we report their
synthesis, antimycobacterial activity and 3D-QSAR studies.
* Corresponding author.
E-mail address: rahuljain@niper.ac.in (R. Jain).
http://dx.doi.org/10.1016/j.ejmech.2014.07.100
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

256
S.R. Patel et al. / European Journal of Medicinal Chemistry 85 (2014) 255e267
Scheme 1. (i) NH2NH2$H2O, CH3OH, 70 ꢁC, 8 h; (ii) RCOCl, Et3N, CH2Cl2, RT, 2 h; (iii) R-NCS, THF, RT, 4 h; (iv) R-NCO, THF, RT, 4 h.
2. Result and discussion
rifampicin, which exhibited MIC99 at the concentrations of 0.1
mL and 0.2 g/mL, respectively.
mg/
m
2.1. Chemistry
The carbohydrazide derivatives 3e17, in general exhibited
moderate anti-TB activities (Table 1). The most active compound 16
(R ¼ 2-naphthyl) exhibited 90% inhibition, while compound 13
Methyl 4-(adamantan-1-yl)quinoline-2-carboxylate (1, Scheme
1) was conveniently synthesized using a method previously
described, using a silver-catalyzed homolytic free radical alkylation
reaction [4,14]. The compound 1 was converted to 4-(adamantan-1-
yl)quinoline-2-carbohydrazide (2, Scheme 1) by reaction with hy-
drazine hydrate in CH3OH under reflux temperature for 8 h. Com-
pound 2 upon reaction with various alkyl/aryl/heteroaryl acid
chlorides in the presence of triethylamine (Et3N) in anhydrous
CH2Cl2 at ambient temperature gave N0-alkyl/aryl/heteroaryl-4-
(adamantan-1-yl)quinoline-2-carbohydrazides (3e17, Series 1,
Scheme 1). The reaction of 2 with a library of alkyl/aryl iso-
thiocyanates at ambient temperature cleanly afforded N-alkyl/aryl-
2-{[4-(adamantan-1-yl)quinolin-2-yl]carbonyl}hydrazinecarbo-
thioamides (18e36, Series 2, Scheme 1). Likewise, 2 upon reaction
with alkyl/aryl isocyanates afforded N-alkyl/aryl-2-{[4-(ada-
mantan-1-yl)quinolin-2-yl]carbonyl}hydrazinecarboxamides
(37e51, Series 3, Scheme 1).
(R ¼ 1-naphthyl) exhibited 88% inhibition at 6.25
mg/mL. The
replacement of the naphthyl ring with a phenyl ring (10) resulted in
the reduction in activity (12% inhibition). The introduction of a 3-
pyridyl and 4-pyridyl ring (12 and 14, respectively) resulted in an
increase in activity (56% and 75% inhibition, respectively) at
6.25
mg/mL. The compounds bearing electron-withdrawing sub-
stituent on the phenyl ring, such as 7 (R ¼ pentafluorophenyl) and
11 (R ¼ 3-trifluoromethylphenyl) exhibited modest activity (88%
and 69% inhibition at 6.25 mg/mL, respectively). Compounds con-
taining the five membered heteroaromatic rings in the side chain (5
and 8) were inactive. On the other hand, the aliphatic side chain
containing compounds 3 (R ¼ undecanoyl), 4 (R ¼ undec-10-enoyl)
and 6 (R ¼ pentadecanoyl) exhibited moderate inhibitory activity of
32%, 50% and 79% at 6.25
mg/mL, respectively; while, compound 15
(R ¼ adamantan-1-yl) exhibited 87% inhibition at 6.25
m
g/mL.
From Series 2, the most active compound 27 (R ¼ 2-chloro-4-
nitrophenyl) exhibited 96% inhibition at the test concentration of
2.2. Biological activity
6.25
35 (R
inhibitory activity of 94% and 89%, respectively, at 6.25
compounds bearing chloro group such as 21 (R
dichlorophenyl) and 23 (R ¼ 2,5-dichlorophenyl) exhibited 74%
and 43% inhibition at 6.25 g/mL, respectively. The 2-ethylphenyl
group-containing compound (26) exhibited 89% inhibition at
6.25 g/mL; while, 2,6-dimethylphenyl ring containing analogue
(25) exhibited moderate activity (51% inhibition) at 6.25 g/mL. The
compound 22 (R ¼ 2,5-dimethoxyphenyl) showed inhibitory ac-
tivity of 81% whereas compound 28 (R 2-methoxy-5-
methylphenyl) exhibited only 12% inhibition at 6.25 g/mL. The
m
g/mL (Table 2). The compounds 29 (R ¼ 4-nitrophenyl) and
4-trifluoromethoxyphenyl) also exhibited promising
g/mL. The
2,3-
¼
In vitro activity of the synthesized analogues for the tuberculosis
inhibition against M. tuberculosis H37Rv strain (susceptible both to
rifampicin and isoniazid) were initially carried out using the
Microplate Alamar Blue Assay (MABA) at a concentration of 6.25
mL [15]. The compounds exhibiting fluorescence were then tested
m
¼
m
g/
m
in the BACTEC 460 radiometric system [16], and activities expressed
m
as Minimum Inhibitory Concentration (MIC,
rized in Tables 1e3. The compounds demonstrating ꢀ90% inhibi-
tion at 6.25 g/mL in the initial screen were retested at the lower
concentrations of 3.125 and 1.56 g/mL to determine the actual MIC
m
g/mL) are summa-
m
m
¼
m
m
value that is defined as the lowest concentration exhibiting ꢀ90%
introduction of alkyl groups as in compounds 30 (R ¼ ethyl), 31
inhibition. Standard drugs used for testing were isoniazid and
(R ¼ allyl) and 32 (R ¼ tert-butyl) resulted in 72%, 77% and 90%

S.R. Patel et al. / European Journal of Medicinal Chemistry 85 (2014) 255e267
257
Table 1
Table 2
In vitro antimycobacterial activity and pIC50s of N0-alkyl/aryl/heteroaryl-4-(tricyclo
[3.3.1.13,7]dec-1-yl)quinoline-2-carbohydrazides (3e17, Series 1) against drug-
sensitive M. tuberculosis H37Rv strain.
In vitro antimycobacterial activity and pIC50s of N-alkyl/aryl-2-{[4-(tricyclo[3.3.1.13,7
]
dec-1-yl)quinolin-2-yl]carbonyl}hydrazinecarbothioamides (18e36, Series 2)
against drug-sensitive M. tuberculosis H37Rv strain.
Compound no.
R
(%) Inhibition MIC (
m
g/mL) pIC50
4.07
Compound no.
R
(%) Inhibition MIC (
m
g/mL) pIC50
3
4
32
50
6.25
6.25
4.60
4.89
18
12
0
6.25
6.25
6.25
5
6
0
6.25
6.25
e
19
20
e
79
5.47
44
4.72
7
88
6.25
5.66
21
22
23
74
81
43
6.25
6.25
6.25
5.15
5.55
4.85
8
9
9
3
6.25
6.25
3.83
3.53
10
12
6.25
4.25
11
12
69
56
6.25
6.25
5.30
4.58
24
23
6.25
4.34
13
88
6.25
5.35
25
26
51
89
6.25
6.25
5.08
5.82
14
15
74
87
6.25
6.25
5.33
5.67
27
28
96
12
6.25
6.25
6.38
4.14
16
17
90
5
6.25
6.25
5.33
3.42
INH
RIF
99
99
0.1
0.2
(continued on next page)

258
S.R. Patel et al. / European Journal of Medicinal Chemistry 85 (2014) 255e267
Table 2 (continued )
2.3. Quantitative structure activity relationship (QSAR) study
Compound no.
R
(%) Inhibition MIC (mg/mL) pIC50
Earlier, we have reported the 3D-QSAR studies of a number of
promising ring-substituted quinolines based upon a Comparative
Molecular Field Analysis (CoMFA) [18e21]. Similarly, herein, we
have employed Comparative Molecular Field Analysis (CoMFA) to
understand the structure activity relationship of newly synthesized
ring-substituted quinolines.
29
94
6.25
6.04
30
31
72
77
6.25
6.25
5.11
5.39
2.3.1. Dataset
For 3D-QSAR studies, the molecules were divided into test and
training sets based upon structural and biological diversity. The
number of molecules in training set was 38, while in the test set 9
molecules were selected. Molecules 5 and 19 were not considered
for the QSAR study, as they are inactive. The test compounds were
selected manually considering the structural diversity and wide
range of activity in the dataset.
32
33
90
47
6.25
6.25
5.91
4.66
2.3.2. Biological data
For the QSAR study, the percent inhibition values were trans-
formed into pIC50 values using equation given below [22].
34
35
79
89
6.25
6.25
5.54
5.91
pIC50 ¼ ꢂlog c þ logit
where,
c
is the molar concentration
¼
concentration (mg/
mL) ꢃ 0.001/(molecular weight) and log it ¼ log[% inhibition/
(100 ꢂ % inhibition)].
2.3.3. Molecular modeling
All the molecular modeling calculations were performed using
SYBYL-X1.2 installed on HP Z800 workstation running under the
Linux OS (CentOS 5.4). The 3D structures of all compounds were
constructed using the Sketch Molecule module of SYBYL. Com-
pound 40 was selected as a template molecule for the sketching
and alignment of all the compounds. Further, applying the Tripos
molecular mechanics force field, with conjugate gradient method,
minimized the molecules. The minimization was terminated when
the energy gradient convergence criterion of 0.05 kcal/mol was
reached or when the 10,000-step minimization cycle was exceeded.
Finally, Gasteiger-Hückel charges were applied to all the com-
pounds in the dataset, and it was subsequently used for CoMFA
studies.
36
46
6.25
4.84
INH
RIF
99
99
0.1
0.2
inhibition of M. tuberculosis H37Rv at 6.25
remaining compounds of the series exhibited <50% inhibition of
M. tuberculosis H37Rv at the primary test concentration of 6.25 mg/
mL.
mg/mL, respectively. The
The Table 3 showed in vitro biological activity of semi-
carbazide derivatives 37e51. The most active compound 40
(R ¼ 4-trifluoromethoxyphenyl) exhibited MIC99 at a concen-
2.3.4. Molecular alignment
tration of 3.125
butoxyphenyl), 48 (R
m
g/mL. Other interesting compounds 47 (R ¼ 4-
The most important input for the CoMFA is the alignment of
molecules. The molecule with the highest biological activity and
least conformational flexibility was chosen as the template and all
other molecules were aligned to it using the database alignment
method in SYBYL. Molecule 40 was taken as a template for align-
ment and all molecules in the dataset were aligned with reference,
4-(adamantan-1yl)quinoline (Fig. 1).
¼
4-fluorophenyl), 49 (R
¼
3-
methoxyphenyl) and 51 (R ¼ 3-fluorophenyl) exhibited moder-
ate anti-TB activity (61%, 68%, 78% and 78% inhibition, respec-
tively). It is observed that the compounds containing
a
cycloalkyl group, for example, 44 (R ¼ cyclopentyl) and 46
(R ¼ cyclododecyl) in general exhibited increased activity when
compared to acyclic aliphatic groups containing compounds [for
example, 37 (R
(R hexadecyl)]. The compounds 39 (R
trimethoxyphenyl), 41 (R 4-tert-butylphenyl) and 45
(R ¼ 2,6-diethylphenyl) exhibited weak anti-TB activity (22%,
37% and 27% inhibition, respectively) at 6.25 g/mL. The most
¼
pentyl), 42 (R
¼
hexyl) and 43
¼
¼
3,4,5-
2.3.5. CoMFA interaction energy calculation
¼
For aligned training set, the steric and electrostatic CoMFA fields
at each lattice intersection of a regularly spaced grid of 2.0 Å were
calculated using the default probe, a sp3 carbon atom with a charge
of þ1, and a van der Waals radius of 1.52 Å. The Lennard-Jones
potentials and coulombic terms, which represent steric and elec-
trostatic fields, respectively, were calculated using Tripos force
field, in which their energy values were truncated at 30 kcal/mol.
The minimum column filtering was set to 2.0 kcal/mol to improve
the signal-to-noise ratio by omitting the lattice points, whose en-
ergy variation was below this threshold.
m
active compound 40 of the series, exhibited 50% inhibition of
M. tuberculosis H37Rv at the lowest tested concentration of
1.56
mg/mL. All active compounds were further screened for
cytotoxicity using an MTT assay with mouse fibroblasts using a
procedure described earlier [17]. None of the compounds
showed cytotoxic effects up to the highest test concentration
used (200 mg/mL), confirming their safety profile.

S.R. Patel et al. / European Journal of Medicinal Chemistry 85 (2014) 255e267
259
Table 3
In vitro antimycobacterial activity and pIC50s of N-alkyl/aryl-2-{[4-(tricyclo[3.3.1.13,7
]
dec-1-yl)quinolin-2-yl]carbonyl}hydrazinecarboxamides (37e51, Series 3) against
drug-sensitive M. tuberculosis H37Rv strain.
Compound no.
R
(%) Inhibition MIC (
m
g/mL) pIC50
4.90
37
55
34
6.25
6.25
38
39
4.70
4.35
22
99
6.25
Fig. 1. Alignment of molecules used for CoMFA model generation.
2.3.6. Partial least squares (PLS) analysis
40a
3.125
6.42
The PLS analysis was used to linearly correlate the CoMFA fields
to the inhibitory activity. The cross validation analysis was per-
formed using the leave-one-out (LOO) method. The non-cross-
validated conventional analysis was produced with the optimal
number of components equal to that yielding the highest q2, and
the corresponding conventional correlation coefficient (r2), its
standard error, and the F ratio were also calculated.
41
42
37
47
6.25
6.25
4.65
4.92
2.3.7. Predictive correlation coefficient
43
44
16
84
6.25
6.25
4.18
5.48
The predictive ability of each 3D-QSAR model was determined
from a set of test molecules not included in the model generation.
The activity values for the test molecules were predicted by using
the developed CoMFA model. The predictive correlation coefficient
(r2pred) based on the test set molecules, is defined as.
45
46
27
87
6.25
6.25
4.37
5.85
rp2red ¼ ðSD ꢂ PRESSÞ=SD
where, SD is the sum of the squared deviations between the
inhibitory activities of the test set and mean activities of the
training molecules and PRESS is the sum of squared deviations
between predicted and actual activity values for each molecule in
the test set.
47
48
61
68
6.25
6.25
5.11
5.42
2.3.8. CoMFA contour maps
The contour maps were generated as a scalar product of the
coefficients and standard deviation (StDev * Coeff) associated with
each column. The favored and disfavored levels, fixed at 60.40% and
39.60%, respectively, were used to display the steric and the elec-
trostatic fields. The contours for the steric fields are shown in green
(more bulk favored) and yellow (less bulk favored), while the
electrostatic field contours are displayed in red (electronegative
substituent favored) and blue (electropositive substituent favored)
colors.
49
50
51
78
77
78
6.25
6.25
6.25
5.42
5.30
5.32
2.3.9. Discussion
The 3D-QSAR model was developed using 38 training set mol-
ecules (Table 4), while 9 molecules were kept in the test set
(Table 5). The best CoMFA model exhibited correlation coefficient
(r2) of 0.971 and cross-validated correlation coefficient (r2cv) of
0.543 (Table 6). The optimum number of components was 7 and
column filtering was set to 2. The steric factor contributed about
60.40%, and the electronic factor contributed 39.60% towards the
INH
RIF
99
99
0.1
0.2
a
Exhibited 50% inhibition at the test concentration of 1.56 mg/mL.

260
S.R. Patel et al. / European Journal of Medicinal Chemistry 85 (2014) 255e267
Table 4
Table 6
The experimental and predicted pIC50 values of the training set compounds.
Summary of the statistical parameter for 3D-QSAR analysis.
Compound no.
(%) Inhibition
MIC
g/mL)
Experimental
pIC50
Predicted pIC50
Parameters
(
m
n (no. of molecules)
47
3
4
6
7
32
50
79
88
3
12
69
56
74
87
5
12
44
74
81
43
51
89
96
12
94
72
90
47
89
55
34
22
99
47
16
84
27
87
68
78
77
78
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
3.125
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
4.57
4.89
5.52
5.78
3.33
3.97
5.24
4.94
5.29
5.71
3.49
4.00
4.80
5.38
5.55
4.80
4.91
5.80
6.31
4.04
6.10
5.23
5.80
4.84
5.84
4.93
4.61
4.38
6.37
4.80
4.25
5.56
4.47
5.75
5.19
5.43
5.41
5.42
4.60
4.89
5.47
5.66
3.53
4.25
5.30
4.58
5.33
5.67
3.42
4.07
4.72
5.15
5.55
4.85
5.08
5.82
6.38
4.14
6.04
5.11
5.91
4.66
5.91
4.90
4.70
4.35
6.42
4.92
4.18
5.48
4.37
5.85
5.42
5.42
5.30
5.32
Molecule used for alignment
Total number of training set molecules
Total number of test set molecules
Total number of outlier molecules
N (optimum component)
Column filtering use
Compound 40
38
9
0
7
2
0.971
0.543
0.14
141.107
0.883
9
10
11
12
14
15
17
18
20
21
22
23
25
26
27
28
29
30
32
33
35
37
38
39
40
42
43
44
45
46
48
49
50
51
r2 (non-cross-validated r2)
r2cv (cross-validated r2)
SEE (standard error of estimate)
F-Value
r2pred (test molecules correlation coefficient)
Contributions (%)
Steric
60.40%
39.60%
Electrostatics
compound 32 is in the proximity of two green regions, and as a
result this compound exhibits good inhibitory activity. The good
inhibitory activity of the compound 26 may be due to the alkyl
substituent at ortho position of the phenyl ring, which is completely
buried under green region. Similarly, naphthyl ring of 13 and 16,
adamantan-1-yl ring of 15, cyclopentyl ring of 44 and cyclododecyl
ring of 46, also lies in the green contour and hence, these com-
pounds are active. The phenyl ring of 18 and 33 is close to the
sterically not favored yellow contour, thus these compounds show
moderate activity. Likewise, OCH3 and CH3 substituents of 28 also
fall under the yellow region and therefore, this molecule exhibit
moderate inhibitory activity. The electrostatic contour (Fig. 4)
shows six red colored contours and three blue colored contours. A
big red colored contour near the C-4 and C-3 position of the phenyl
ring is observed, which indicates that the electron-withdrawing
groups are favored at this position. The p-NO2 of 27 and 29 and
p-OCF3 of 35 and 40 lie near to red contour and hence, these
compounds exhibited promising anti-TB activity. Whereas, tert-
butyl and CH3 groups at the para position of the phenyl ring in the
compounds 41 and 24, also lie down near the red contour, which is
favored by electronegative group but not by electropositive sub-
stituents and therefore, these compounds possess moderate anti-
activity. The Fig. 2 shows plot of predicted versus experimental
activity for molecules in the training set based on the best model.
The CoMFA model was tested for their predictivity on the test set.
The model showed r2pred of 0.883, while the F-value and SEE were
141.107 and 0.14, respectively (Table 6). The steric and electronic
contours for the compound 40 are shown in Figs. 3 and 4. The
analysis of steric contour of 40 (Fig. 3) reveals two green contours
(sterically favored) lying on two opposite phase of the phenyl ring
and a very small green contour near the p-OCF3 group of the phenyl
ring. The four yellow contours (sterically not favored) are also
observed in the steric contour of 40. Like 40, p-OCF3 group of the
phenyl ring of 35 also lies in the green sterically favored region and
hence, accounts for good anti-TB activity. The tert-butyl group of
Table 5
The experimental and predicted pIC50 values of the test set compounds.
Compound no. (%) Inhibition MIC (mg/mL) Experimental pIC50 Predicted pIC50
8
9
88
90
23
77
79
46
37
61
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
6.25
3.83
5.75
5.84
4.35
5.35
5.50
4.87
4.67
5.11
3.83
5.35
5.33
4.34
5.39
5.54
4.84
4.65
5.11
13
16
24
31
34
36
41
47
Fig. 2. A graph of predicted versus experimental pIC50 values.

S.R. Patel et al. / European Journal of Medicinal Chemistry 85 (2014) 255e267
261
MIC99 of 3.125
lower tested concentration of 1.56
29 and 32 exhibited MIC of 6.25 g/mL, when tested in vitro against
mg/mL, and later also produced 50% inhibition at the
mg/mL. Other analogues 16, 27,
m
drug-sensitive strain. None of the active analogues exhibited
cytotoxicity in an MTT assay using mouse fibroblasts up to the
highest tested concentration of 200 mg/mL. The 3D-QSAR model
developed using CoMFA exhibits good statistical significance with
all values in an acceptable range. The results indicate that the ste-
rically bulky or electronegative substitution at the para position of
phenyl ring is required for good anti-TB activity.
4. Experimental
The synthesized compounds were checked for their purity on
pre-coated silica gel G254 TLC plates (Merck) and the spots were
visualized under UV spectrophotometer and then by exposing
them to iodine vapors. Flash chromatography purification was
carried out on Merck silica gel (230e400 mesh) using Biotage® SP1
automated flash chromatography system equipped with a UV de-
tector. Melting points were recorded on capillary melting point
apparatus or on the Perkin Elmer DSC instrument and are uncor-
rected. All solvents used for synthesis were of analytical grade and
used without any further purification unless otherwise stated. 1H
and 13C NMR spectra were recorded on 400 MHz Bruker FT-NMR
spectrometer using tetramethylsilane as internal standard and
Fig. 3. The steric field distribution around compound 40.
TB activity. The Cl and F groups at the meta position of the phenyl
ring of 21 and 51, respectively, lies in the red colored contour and
thus, these compounds show good inhibitory activity. The blue
colored contour near the ortho position of the phenyl ring favored
by electropositive substituents like ethyl (26) and methyl (50), and
hence these molecules possess promising anti-TB activity. The
adamantan-1-yl, naphthyl and tert-butyl groups of compounds 15,
16 and 32, respectively, are buried under a blue colored contour,
which is reasoned for the exhibition of promising activity.
the chemical shifts are reported in
d units. All NMR spectra were
processed on the 1H NMR/13C NMR module of ACD 12.0 software.
The IR spectra (nmax in cmꢂ1) were recorded on Nicolet FT-IR Impact
410 instrument either in neat or in KBr pellet. The HRMS spectra
were recorded on the Bruker Maxis mass spectrometer. Elemental
analyses were recorded on Elementar Vario EL spectrometer.
4.1. General method for the synthesis of N0-alkyl/aryl/heteroaryl-4-
(tricyclo[3.3.1.13,7]dec-1-yl)quinoline-2-carbohydrazides (3e17)
To the ice-cold solution of 2 (10 mmol) and Et3N (20 mmol) in
dry CH2Cl2 (10 mL), alkyl/aryl/heteroaryl acid chloride (12 mmol)
was added slowly under N2 atmosphere. The ice bath was removed
and the reaction was allowed to proceed at ambient temperature
for 2 h. The reaction mixture was poured onto crushed ice and
extracted with CH2Cl2 (3 ꢃ 25 mL). The combined organic extract
was washed with brine (20 mL), dried over sodium sulfate and
evaporated under reduced pressure to afford carbohydrazide de-
rivatives 3e17, which were purified through flash column chro-
matography using EtOAc/hexanes as mobile phase.
3. Conclusion
The hydrazide, semicarbazide and thiosemicarbazide de-
rivatives of 4-(adamantan-1-yl)quinoline-2-carbohydrazide have
exhibited promising anti-tuberculosis activity, when tested against
M. tuberculosis H37Rv, in vitro. Most active analogue 40 exhibited
4.1.1. 4-(Tricyclo[3.3.1.13,7]dec-1-yl)-N0-undecanoylquinoline-2-
carbohydrazide (3)
Yield: 63%; white solid; mp: 168e173 ꢁC; IR (KBr): 2925,
1642 cmꢂ1 1H NMR (CDCl3):
; d 10.51 (br s, 1H), 8.90 (br s, 1H),
8.64e8.71 (m, 1H), 8.14e8.19 (m, 2H), 7.64e7.76 (m, 1H), 7.58 (ddd,
J ¼ 1.3, 6.9, 8.6 Hz,1H), 2.20e2.42 (m,11H),1.89 (br s, 6H),1.68e1.78
(m, 2H), 1.65 (br s, 2H), 1.21e1.41 (m, 12H), 0.83e0.96 (m, 3H); 13
C
NMR (CDCl3):
d 169.8, 161.2, 157.7, 148.0, 147.5, 131.9, 128.8, 128.3,
126.5, 126.3, 115.7, 42.2, 39.1, 36.8, 34.4, 31.8, 29.7, 29.4, 29.4, 29.4,
29.3, 29.0, 25.5, 22.6, 14.1; HRMS (ESI): m/z calcd for C31H43N3NaO2
[MþNa]þ: 498.3096, found: 498.3094; Anal. Calcd for C31H43N3O2
(476.1): C, 76.03; H, 8.85; N, 8.58; Found: C, 76.00; H, 8.86; N, 8.55.
4.1.2. 4-(Tricyclo[3.3.1.13,7]dec-1-yl)-N0-(undec-10-enoyl)quinoline-
2-carbohydrazide (4)
Yield: 71%; light brown solid; mp: 155e161 ꢁC; IR (KBr): 2921,
1640 cmꢂ1; 1H NMR (CDCl3):
d 10.63 (br s, 1H), 9.58 (br s, 1H), 8.65
(d, J ¼ 8.8 Hz, 1H), 8.12e8.20 (m, 2H), 7.69 (t, J ¼ 7.6 Hz, 1H),
Fig. 4. The electrostatic filed distribution around analogue compound 40.
7.52e7.61 (m, 1H), 5.67e5.87 (m, 1H), 4.85e5.08 (m, 2H), 2.42 (t,

262
S.R. Patel et al. / European Journal of Medicinal Chemistry 85 (2014) 255e267
J ¼ 7.4 Hz, 2H), 2.28e2.34 (m, 6H), 2.22 (br s, 3H), 1.96e2.07 (m,
2H), 1.88 (br s, 6H), 1.74 (q, J ¼ 7.5 Hz, 2H), 1.21e1.41 (m, 10H); 13C
1H), 7.52e7.61 (m, 1H), 3.67e3.76 (m, 4H), 3.52e3.60 (m, 4H),
2.27e2.39 (m, 6H), 2.21 (br s, 3H), 1.87 (br s, 6H); 13C NMR (CDCl3):
d 163.1, 157.1, 156.3, 147.6, 147.5, 131.6, 128.3, 127.8, 126.1, 125.9,
NMR (CDCl3):
d
170.0, 161.0, 157.6, 148.0, 147.4, 139.1, 131.9, 128.8,
128.2, 126.5, 126.2, 115.6, 114.1, 114.1, 42.1, 39.1, 36.8, 34.2, 33.7, 29.3,
29.3, 29.3, 29.2, 29.2, 29.1, 29.0, 28.9, 28.9, 25.5; HRMS (ESI): m/z
calcd for C31H41N3NaO2 [MþNa]þ: 510.3096, found: 510.3083; Anal.
Calcd for C31H41N3O2 (487.3): C, 76.35; H, 8.47; N, 8.62; Found: C,
76.33; H, 8.48; N, 8.60.
115.4, 66.1, 43.8, 41.8, 38.7, 36.5, 28.6; HRMS (ESI): m/z calcd for
C
C
25H30N4NaO3 [MþNa]þ: 457.2216, found: 457.2216; Anal. Calcd for
25H30N4O3 (434.3): C, 69.10; H, 6.96; N, 12.89; Found: C, 69.05; H,
6.95; N, 12.86.
4.1.8. N0-Benzoyl-4-(tricyclo[3.3.1.13,7]dec-1-yl)quinoline-2-
carbohydrazide (10)
4.1.3. N0-(Furan-2-ylcarbonyl)-4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinoline-2-carbohydrazide (5)
Yield: 77%; yellow solid; mp: 82e84 ꢁC; IR (KBr): 2907,
Yield: 63%; white solid; mp: 223e228 ꢁC; IR (KBr): 2921,
1704 cmꢂ1; 1H NMR (CDCl3):
d
10.30 (s, 1H), 8.64 (d, J ¼ 8.5 Hz, 1H),
1633 cmꢂ1
;
1H NMR (CDCl3):
d
9.04 (br s, 1H), 8.91 (br s, 2H), 8.69
8.19 (s, 1H), 8.12 (dd, J ¼ 1.4, 8.4 Hz, 1H), 7.83e7.90 (m, 3H), 7.68
(ddd, J ¼ 1.3, 7.0, 8.3 Hz, 1H), 7.58 (ddd, J ¼ 1.5, 6.9, 8.7 Hz, 1H),
7.41e7.51 (m, 1H), 7.32e7.41 (m, 2H), 2.26e2.34 (m, 6H), 2.20 (br s,
(d, J ¼ 8.8 Hz, 1H), 8.17e8.23 (m, 2H), 7.73 (t, J ¼ 7.2 Hz, 1H),
7.57e7.64 (m, 1H), 7.52e7.56 (m, 1H), 7.24 (d, J ¼ 3.5 Hz, 1H),
6.53e6.59 (m, 1H), 2.35 (br s, 6H), 2.24 (br s, 3H), 1.91 (br s, 6H); 13
C
3H), 1.87 (br s, 6H); 13C NMR (CDCl3):
d 171.8, 164.6, 157.7, 147.9,
NMR (CDCl3):
d
161.7, 157.7, 155.5, 148.0, 147.4, 145.8, 145.5, 144.9,
147.1, 133.8, 132.5, 131.9, 128.9,128.8,128.5,128.4,126.7, 126.3, 116.1,
42.1, 39.1, 36.8, 28.9; HRMS (ESI): m/z calcd for C27H27N3NaO2
[MþNa]þ: 448.2001, found: 448.1994; Anal. Calcd for C27H27N3O2
(425.2): C, 76.21; H, 6.40; N, 9.87; Found: C, 76.18; H, 6.38; N, 9.85.
144.8, 131.9, 128.8, 128.3, 126.5, 126.3, 116.24, 116.0, 115.8, 112.3,
42.2, 39.2, 36.8, 29.7, 28.9; HRMS (ESI): m/z calcd for C25H25N3NaO3
[MþNa]þ: 438.1794, found: 438.1788; Anal. Calcd for C25H25N3O3
(415.2): C, 72.27; H, 6.06; N,10.11; Found: C, 72.22; H, 6.00; N,10.08.
4.1.9. 4-(Tricyclo[3.3.1.13,7]dec-1-yl)-N0-[3-(trifluoromethyl)
benzoyl]quinoline-2-carbohydrazide (11)
4.1.4. N0-Pentadecanoyl-4-(tricyclo[3.3.1.13,7]dec-1-yl)quinoline-2-
carbohydrazide (6)
Yield: 40%; white solid; mp: 184e187 ꢁC; IR (KBr): 2914,
Yield: 66%; white solid; mp: 150e154 ꢁC; IR (KBr): 2919,
1647 cmꢂ1
;
1H NMR (CDCl3):
d
10.44 (br s, 1H), 8.65 (d, J ¼ 7.8 Hz,
1641 cmꢂ1; 1H NMR (CDCl3):
d
10.48 (br s, 1H), 8.62e8.70 (m, 2H),
1H), 8.16 (br s, 1H), 8.01e8.12 (m, 3H), 7.98 (br s, 1H), 7.64e7.80 (m,
8.14e8.22 (m, 2H), 7.70 (t, J ¼ 7.2 Hz, 1H), 7.56e7.63 (m, 1H),
2.30e2.41 (m, 8H), 2.23 (br s, 3H), 1.89 (br s, 6H), 1.75 (t, J ¼ 7.4 Hz,
2H), 1.20e1.41 (m, 20H), 0.88 (t, J ¼ 6.8 Hz, 3H); 13C NMR (CDCl3):
2H), 7.59 (br s,1H), 7.53 (br s,1H), 2.29 (br s, 6H), 2.21 (br s, 3H),1.88
(br s, 6H); 13C NMR (CDCl3):
d 170.5, 164.9, 158.0, 147.8, 147.7, 134.4,
131.9, 131.7, 131.6, 129.2, 129.0, 127.0, 126.3, 125.72, 116.0, 60.41,
42.2, 39.2, 36.8, 28.9; HRMS (ESI): m/z calcd for C28H26F3N3NaO2
[MþNa]þ: 516.1875, found: 516.1864; Anal. Calcd for C28H26F3N3O2
(493.2): C, 68.14; H, 5.31; N, 8.51; Found: C, 68.10; H, 5.34; N, 8.47.
d
169.8, 161.2, 157.7, 148.0, 147.4, 131.9, 128.8, 128.3, 126.5, 126.3,
115.7, 42.2, 39.1, 36.8, 34.4, 31.9, 29.7, 29.7, 29.6, 29.6, 29.5, 29.3,
29.3, 28.9, 25.5, 22.7, 14.1; HRMS (ESI): m/z calcd for C35H51N3NaO2
[MþNa]þ: 554.3722, found: 554.3715; Anal. Calcd for C35H51N3O2
(532.4): C, 77.02; H, 9.42; N, 7.70; Found: C, 76.98; H, 9.40; N, 7.68.
4.1.10. N0-(Pyridin-4-ylcarbonyl)-4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinoline-2-carbohydrazide (12)
4.1.5. N0-(Pentafluorobenzoyl)-4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinoline-2-carbohydrazide (7)
Yield: 60%; yellow solid; mp: 122e126 ꢁC; IR (KBr): 2905,
1629 cmꢂ1; 1H NMR (DMSO-d6):
d 10.84e11.01 (m, 2H), 8.68e8.85
Yield: 80%; white solid; mp: 256e260 ꢁC; IR (KBr): 2907,
(m, 3H), 8.21 (d, J ¼ 8.0 Hz, 1H), 8.04 (s, 1H), 7.82e7.90 (m, 3H),
1654 cmꢂ1
;
1H NMR (CDCl3):
d
9.81 (br s, 1H), 8.68 (d, J ¼ 8.8 Hz,
7.66e7.80 (m, 1H), 2.28 (br s, 6H), 2.18 (br s, 3H), 1.77e1.95 (m, 6H);
1H), 8.14e8.22 (m, 1H), 8.05e8.11 (m, 1H), 7.68e7.76 (m, 1H),
7.58e7.66 (m, 1H), 2.31 (br s, 6H), 2.17 (br s, 3H), 1.79e1.97 (m, 9H);
13C NMR (DMSO-d6):
d 164.4, 164.1, 157.2, 150.8, 149.0, 147.9, 139.9,
131.7, 129.7, 127.6, 127.5, 126.8, 121.7, 115.8, 42.0, 38.6, 36.5, 28.7;
HRMS (ESI): m/z calcd for C26H26N4NaO2 [MþNa]þ: 449.1953,
found: 449.1950; Anal. Calcd for C26H26N4O2 (426.2): C, 73.22; H,
6.14; N, 13.14; Found: C, 73.23; H, 6.11; N, 13.12.
13C NMR (CDCl3):
d 161.7, 158.1, 148.0, 146.7, 131.9, 129.1, 128.5,
126.9, 126.4, 115.5, 42.2, 39.2, 36.8, 28.9; HRMS (ESI): m/z calcd for
C
27H22F5N3NaO2 [MþNa]þ: 538.1530, found: 538.1517; Anal. Calcd
for C27H22F5N3O2 (515.2): C, 62.91; H, 4.30; N, 8.15; Found: C, 62.92;
H, 4.33; N, 8.13.
4.1.11. N0-(Naphthalen-1-ylcarbonyl)-4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinoline-2-carbohydrazide (13)
4.1.6. N0-(Thiophen-2-ylcarbonyl)-4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinoline-2-carbohydrazide (8)
Yield: 76%; white solid; mp: 246e249 ꢁC; IR (KBr): 2906,
1637 cmꢂ1; 1H NMR (CDCl3):
d 10.71 (br s, 1H), 8.88 (s, 1H), 8.69 (d,
Yield: 69%; yellow solid; mp: 224e232 ꢁC; IR (KBr): 2905,
J ¼ 8.5 Hz, 1H), 8.51 (d, J ¼ 8.5 Hz, 1H), 8.22 (dd, J ¼ 1.3, 8.5 Hz, 1H),
8.18 (s, 1H), 7.97 (d, J ¼ 8.3 Hz, 1H), 7.88 (d, J ¼ 7.5 Hz, 1H), 7.84 (dd,
J ¼ 1.0, 7 Hz, 1H), 7.70e7.78 (m, 1H), 7.45e7.65 (m, 4H), 2.29e2.40
1635 cmꢂ1; 1H NMR (CDCl3):
d 10.53 (br s, 1H), 9.51 (br s, 1H), 8.67
(d, J ¼ 8.3 Hz, 1H), 8.14e8.24 (m, 2H), 7.78 (dd, J ¼ 0.88, 3.6 Hz, 1H),
7.71 (ddd, J ¼ 1.1, 6.9, 8.3 Hz, 1H), 7.59 (ddd, J ¼ 1.5, 6.9, 8.7 Hz, 1H),
7.49e7.56 (m, 1H), 7.11 (dd, J ¼ 3.8, 5.0 Hz, 1H), 2.28e2.41 (m, 6H),
(m, 6H), 2.23 (br s, 3H), 1.82e1.95 (m, 6H); 13C NMR (CDCl3):
d 166.1,
161.8, 157.7, 148.1, 147.4, 133.7, 132.0, 131.7, 130.9, 130.4, 128.9, 128.4,
128.3, 127.6, 126.7, 126.6, 126.6, 126.3, 126.1, 125.3, 124.6, 115.8, 42.2,
39.2, 36.9, 29.0; HRMS (ESI): m/z calcd for C31H30N3O2 [MþH]þ:
476.2338, found: 476.2330; Anal. Calcd for C31H29N3O2 (475.3): C,
78.29; H, 6.15; N, 8.84; Found: C, 78.22; H, 6.18; N, 8.85.
2.14e2.26 (m, 3H), 1.81e1.96 (m, 6H); 13C NMR (CDCl3):
d 170.5,
157.7, 148.0, 147.4, 131.9, 131.1, 128.9, 128.3, 127.9, 126.6, 126.3, 115.8,
42.1, 39.2, 36.8, 28.9; HRMS (ESI): m/z calcd for C31H30N3NaO2S
[MþNa]þ: 454.1565, found: 454.1558; Anal. Calcd for C25H25N3O2S
(431.2): C, 69.58; H, 5.84; N, 9.74; Found: C, 69.53; H, 5.81; N, 9.72.
4.1.12. N0-(Pyridin-3-ylcarbonyl)-4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinoline-2-carbohydrazide (14)
4.1.7. N0-(Morpholin-4-ylcarbonyl)-4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinoline-2-carbohydrazide (9)
Yield: 79%; yellow solid; mp: 129e133 ꢁC; IR (KBr): 2908,
Yield: 80%; white solid; mp: 286e290 ꢁC; IR (KBr): 2906,
1646 cmꢂ1; 1H NMR (CDCl3):
d 10.69 (br s, 1H), 9.85 (br s, 1H), 9.16
1689 cmꢂ1
;
1H NMR (CDCl3):
d
10.12 (br s, 1H), 8.64 (d, J ¼ 8.8 Hz,
(d, J ¼ 1.7 Hz, 1H), 8.77 (dd, J ¼ 1.5, 4.8 Hz, 1H), 8.67 (d, J ¼ 8.3 Hz,
1H), 8.47 (br s, 1H), 8.10e8.19 (m, 2H), 7.68 (ddd, J ¼ 1.0, 6.9, 8.3 Hz,
1H), 8.21e8.28 (m, 1H), 8.14e8.21 (m, 2H), 7.72 (dt, J ¼ 1.1, 7.6 Hz,

S.R. Patel et al. / European Journal of Medicinal Chemistry 85 (2014) 255e267
263
1H), 7.60 (ddd, J ¼ 1.3, 6.9, 8.6 Hz, 1H), 7.41 (dd, J ¼ 4.8, 7.9 Hz, 1H),
2.29e2.41 (m, 6H), 2.22 (br s, 3H), 1.80e1.95 (m, 3H); 13C NMR
d 181.2, 164.6, 156.7, 149.4, 147.8, 139.6, 131.7, 129.6, 128.8, 128.4,
127.8, 126.8, 126.0, 125.3, 124.8, 124.1, 115.9, 42.1, 39.2, 36.8, 28.9,
25.1; HRMS (ESI): m/z calcd for C27H28N4NaOS [MþNa]þ: 479.1882,
found: 479.1871; Anal. Calcd for C27H28N4OS (456.2): C, 71.02; H,
6.18; N, 12.27; Found: C, 71.06; H, 6.24; N, 12.30.
(CDCl3):
d 162.7, 162.1, 157.9, 153.0, 148.6, 148.0, 147.2, 135.2, 132.0,
129.0, 128.4, 127.6, 126.7, 126.3, 123.5, 115.8, 77.2, 42.2, 39.2, 36.8,
29.7, 28.9; HRMS (ESI): m/z calcd for C26H26N4NaO2 [MþNa]þ:
449.1953, found: 449.1950; Anal. Calcd for C26H26N4O2 (426.2): C,
73.22; H, 6.14; N, 13.14; Found: C, 73.20; H, 6.15; N, 13.15.
4.2.2. N-Cyclohexyl-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)quinolin-2-
yl]carbonyl}hydrazinecarbothioamide (19)
4.1.13. 4-(Tricyclo[3.3.1.13,7]dec-1-yl)-N0-(tricyclo[3.3.1.13,7]dec-1-
ylcarbonyl)quinoline-2-carbohydrazide (15)
Yield: 75%; colorless solid; mp: 217e220 ꢁC; IR (KBr):
1634 cmꢂ1; 1H NMR (CDCl3):
d
10.05 (br s, 1H), 8.68 (d, J ¼ 8.7 Hz,
Yield: 80%; white solid; mp: 249e252 ꢁC; IR (KBr): 2905,
1H), 8.15e8.19 (m, 2H), 8.07 (br s, 1H), 7.39 (t, J ¼ 7.2 Hz, 1H), 7.61 (t,
J ¼ 7.3 Hz, 1H), 6.54 (br s, 1H), 4.23e4.26 (m, 1H), 2.31 (br s, 6H),
2.22 (br s, 3H), 2.03e2.13 (m, 2H), 1.88 (br s, 6H), 1.64e1.73 (m, 6H),
1638 cmꢂ1; 1H NMR (CDCl3):
d
10.54 (br s, 1H), 8.66 (d, J ¼ 8.5 Hz,
1H), 8.53 (br s, 1H), 8.12e8.20 (m, 2H), 7.70 (ddd, J ¼ 1.1, 6.9, 8.3 Hz,
1H), 7.58 (ddd, J ¼ 1.5, 6.9, 8.7 Hz, 1H), 2.29e2.38 (m, 6H), 2.22 (br s,
3H), 2.11 (br s, 3H), 2.01 (d, J ¼ 2.7 Hz, 6H), 1.89 (br s, 6H), 1.72e1.81
1.33e1.46 (m, 2H), 1.10e1.25 (m, 6H); 13C NMR (CDCl3):
d 180.9,
163.5, 158.1, 148.0, 147.3, 131.9, 129.1, 128.5, 126.8, 126.4, 115.8, 53.6,
(m, 6H); 13C NMR (CDCl3):
d
173.8, 160.8, 157.6, 148.1, 147.5, 131.9,
42.2, 39.2, 36.8, 32.7, 29.7, 28.9, 25.5, 24.8; HRMS (ESI): m/z calcd for
128.8,128.2,126.4,126.3,115.6, 42.1, 40.3, 39.1, 38.9, 38.9, 36.8, 36.4,
28.9, 27.9; HRMS (ESI): m/z calcd for C31H37N3NaO2 [MþNa]þ:
506.2783, found: 506.2779; Anal. Calcd for C31H37N3O2 (483.3): C,
76.98; H, 7.71; N, 8.69; Found: C, 76.94; H, 7.70; N, 8.64.
C
27H34N4NaOS [MþNa]þ: 485.2351, found: 485.2348; Anal. Calcd
for C27H34N4OS (462.3): C, 70.09; H, 7.41; N, 12.11; Found: C, 70.04;
H, 7.37; N, 12.09.
4.2.3. N-(Naphthalen-1-yl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinolin-2-yl]carbonyl}-hydrazinecarbothioamide (20)
4.1.14. N0-(Naphthalen-2-ylcarbonyl)-4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinoline-2-carbohydrazide (16)
Yield: 83%; colorless solid; mp: 227e230 ꢁC; IR (KBr): 2906,
Yield: 71%; white solid; mp: 226e229 ꢁC; IR (KBr): 2905,
1690 cmꢂ1; 1H NMR (DMSO-d6):
d 10.01 (s, 1H), 9.92 (br s, 1H), 8.75
1644 cmꢂ1; 1H NMR (CDCl3):
d
10.85 (br s, 1H), 9.92 (br s, 1H), 8.66
(d, J ¼ 8.8 Hz,1H), 8.23 (d, 1H, J ¼ 8.3 Hz), 8.06e8.15 (m, 2H), 7.99 (d,
J ¼ 7.3 Hz, 1H), 7.86e7.94 (m, 2H), 7.70e7.83 (m, 1H), 7.52e7.64 (m,
3H), 7.42 (br s,1H), 2.34 (br s, 6H), 2.24 (br s, 3H),1.80e1.93 (m, 6H);
(d, J ¼ 8.5 Hz, 1H), 8.48 (s, 1H), 8.18e8.25 (m, 1H), 8.16 (s, 1H),
7.95e8.02 (m, 1H), 7.80e7.92 (m, 3H), 7.72 (t, J ¼ 7.3 Hz, 1H),
7.45e7.63 (m, 3H), 2.23e2.34 (m, 6H), 2.19 (br s, 3H), 1.86 (br s, 6H);
13C NMR (DMSO-d6):
d 182.8, 158.6, 156.7, 149.7, 147.8, 133.7, 131.3,
13C NMR (CDCl3):
d
164.3,161.6,157.7,148.1,147.5,135.1,132.5,132.0,
129.5,128.2,128.0,127.5,127.4,127.1,126.7,126.4,125.7,125.4,116.0,
41.8, 38.5, 36.1, 28.3; HRMS (ESI): m/z calcd for C31H30N4NaOS
[MþNa]þ: 529.2038, found: 529.2028; Anal. Calcd for C31H30N4OS
(506.2): C, 73.49; H, 5.97; N,11.06; Found: C, 73.43; H, 5.95; N,11.02.
129.2, 128.9, 128.8, 128.6, 128.3, 128.3, 128.0, 127.7, 126.8, 126.6,
126.3, 123.5, 115.8, 42.1, 39.1, 36.8, 28.9; HRMS (ESI): m/z calcd for
C
C
31H30N3O2 [MþH]þ: 476.2338, found: 476.2334; Anal. Calcd for
31H29N3O2 (475.2): C, 78.29; H, 6.15; N, 8.84; Found: C, 78.24; H,
6.12; N, 8.82.
4.2.4. N-(2,3-Dichlorophenyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinolin-2-yl]carbonyl}-hydrazinecarbothioamide (21)
4.1.15. N0-Acetyl-4-(tricyclo[3.3.1.13,7]dec-1-yl)quinoline-2-
carbohydrazide (17)
Yield: 76%; red solid; mp: 198e201 ꢁC; IR (KBr): 2918,
1668 cmꢂ1; 1H NMR (DMSO-d6):
d 10.92 (br s, 1H), 10.05 (br s, 1H),
Yield: 66%; colorless solid; mp: 204e207 ꢁC; IR (KBr): 2907,
9.76 (br s,1H), 8.76 (d, J ¼ 8.3 Hz,1H), 8.21 (d,1H, J ¼ 8.5 Hz), 8.06 (s,
1H), 7.85 (d, J ¼ 7.4 Hz, 1H), 7.71e7.76 (m, 1H), 7.74 (s, 1H), 7.38 (s,
1H), 7.42 (s, 1H), 2.29 (br s, 6H), 2.19 (br s, 3H), 1.80e1.94 (m, 6H);
1727 cmꢂ1; 1H NMR (CDCl3):
d
10.03 (s, 1H), 8.69 (d, J ¼ 8.3 Hz, 1H),
8.21 (s, 1H), 8.16 (dd, J ¼ 1.4, 8.4 Hz, 1H), 7.68e7.78 (m, 1H),
7.55e7.66 (m, 1H), 2.52 (s, 3H), 2.33 (d, J ¼ 2.3 Hz, 6H), 2.23 (br s,
13C NMR (DMSO-d6):
d 182.3, 164.6, 156.8, 149.7, 147.8, 139.4, 131.9,
3H), 1.89 (t, J ¼ 2.8 Hz, 6H); 13C NMR (CDCl3):
d
171.6, 165.0, 157.9,
131.7, 130.2, 129.5, 128.8, 127.8, 127.4, 126.7, 116.0, 41.8, 38.5, 36.5,
28.7; HRMS (ESI): m/z calcd for C27H26Cl2N4NaOS [MþNa]þ:
547.1102, found: 547.1100; Anal. Calcd for C27H26Cl2N4OS (524.1): C,
61.71; H, 4.99; N, 10.66; Found: C, 61.68; H, 4.95; N, 10.62.
147.9, 147.1, 131.9, 128.9, 128.6, 126.8, 126.4, 116.0, 42.1, 39.2, 36.8,
28.9, 25.1; HRMS (ESI): m/z calcd for C22H25N3NaO2 [MþNa]þ:
386.1844, found: 386.1842; Anal. Calcd for C22H25N3O2: C, 72.70; H,
6.93; N, 11.56; Found: C, 72.68; H, 6.90; N, 11.54.
4.2.5. N-(2,5-Dimethoxyphenyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinolin-2-yl]carbonyl}-hydrazinecarbothioamide (22)
4.2. General method for the synthesis of N-alkyl/aryl-2-{[4-(tricyclo
[3.3.1.13,7]dec-1-yl)quinolin-2-yl]carbonyl}
hydrazinecarbothioamides (18e36)
Yield: 90%; colorless solid; mp: 164e167 ꢁC; IR (KBr): 2903,
1523 cmꢂ1; 1H NMR (CDCl3):
d 10.98 (br s, 1H), 8.72 (br s, 1H), 8.67
(d, J ¼ 8.8 Hz, 1H), 8.24 (d, J ¼ 8.5 Hz, 1H), 8.13 (s, 1H), 7.98 (br s, 1H),
7.74 (t, J ¼ 7.6 Hz, 1H), 7.54e7.66 (m, 1H), 6.74e6.85 (m, 2H),
6.63e6.72 (m,1H), 3.68e3.83 (m, 6H), 3.63 (br s,1H), 2.26 (br s, 6H),
The alkyl/aryl isothiocyanate (1.2 mmol) was added drop wise to
a stirred solution of 2 (1 mmol) in tetrahydrofuran (THF, 5 mL) at
ambient temperature. The reaction mixture was stirred at ambient
temperature for 4 h. The solvent was evaporated, and the residue
was suspended in C2H5OH. The precipitated solid was filtered,
washed with C2H5OH and dried under vacuum to produce 18e36.
2.17 (br s, 3H), 1.81e1.94 (m, 6H); 13C NMR (CDCl3):
d 180.0, 157.1,
152.6,149.0,147.8,145.7131.7,129.7,128.9,127.6,127.55,126.7,119.6,
114.7, 113.5, 111.4, 110.23, 109.9, 79.5, 67.3, 56.7, 55.7 42.7, 38.9, 36.5,
28.7; HRMS (ESI): m/z calcd for
539.2093, found: 539.2089; Anal. Calcd for C29H32N4O3S (516.2): C,
67.42; H, 6.24; N, 10.84; Found: C, 67.49; H, 6.32; N, 10.86.
C
29H32N4NaO3S [MþNa]þ:
4.2.1. N-Phenyl-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)quinolin-2-yl]
carbonyl}hydrazinecarbothioamide (18)
Yield: 77%; white solid; mp: 224e228 ꢁC; IR (KBr): 1637 cmꢂ1
;
4.2.6. N-(2,5-Dichlorophenyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinolin-2-yl]carbonyl}-hydrazinecarbothioamide (23)
1H NMR (DMSO-d6):
d
9.94 (br s, 2H), 8.91 (d, J ¼ 8.5 Hz, 1H), 8.34,
(d, J ¼ 8.3 Hz), 8.19 (s, 1H), 7.99 (t, J ¼ 7.2 Hz, 1H), 7.87 (t, J ¼ 7.4 Hz,
1H), 7.60 (s, 1H), 7.46 (t, J ¼ 7.8 Hz, 1H), 7.29 (t, J ¼ 7.3 Hz, 1H), 2.43
(br s, 6H), 2.33 (br s, 3H), 1.90e2.04 (m, 6H); 13C NMR (DMSO-d6)
Yield: 91%; yellow solid; mp: 179e183 ꢁC; IR (KBr): 2906,
1647 cmꢂ1
;
1H NMR (CDCl3):
d
9.09 (br s, 1H), 8.67 (d, J ¼ 8.8 Hz,
1H), 8.38 (br s, 1H), 8.21e8.28 (m, 1H), 8.06 (br s, 1H), 7.72e7.78 (m,

264
S.R. Patel et al. / European Journal of Medicinal Chemistry 85 (2014) 255e267
1H), 7.62 (ddd, J ¼ 1.5, 6.9, 8.7 Hz, 1H), 7.28e7.37 (m, 1H), 7.24 (d,
J ¼ 2.3 Hz,1H), 7.13 (dd, J ¼ 2.3, 8.5 Hz,1H), 2.21 (br s, 6H), 2.13 (br s,
4.2.11. N-(2-Methoxy-5-methylphenyl)-2-{[4-(tricyclo[3.3.1.13,7
]
dec-1-yl)quinolin-2-yl]-carbonyl}hydrazinecarbothioamide (28)
3H), 1.74e1.90 (m, 6H); 13C NMR (CDCl3):
d 161.9, 158.3, 146.7, 136.0,
Yield: 88%; colorless solid; mp: 172e175 ꢁC; IR (KBr): 2908,
132.8,130.9,130.1,129.2,128.5,128.0,126.9,126.6,126.4,115.5, 42.2,
1655 cmꢂ1; 1H NMR (CDCl3):
d 10.93 (br s, 1H), 9.27 (br s, 1H), 8.68
39.3, 36.8, 32.0, 29.7, 29.4, 29.0, 22.7, 14.1; HRMS (ESI): m/z calcd for
C
for C27H26Cl2N4OS (524.2): C, 61.71; H, 4.99; N, 10.66; Found: C,
61.70; H, 4.96; N, 10.62.
(d, J ¼ 8.5 Hz, 1H), 8.41 (br s, 1H), 8.19e8.29 (m, 1H), 8.09e8.17 (m,
1H), 7.84 (br s, 1H), 7.74 (dt, J ¼ 1.1, 7.6 Hz, 1H), 7.61 (ddd, J ¼ 1.3, 6.7,
8.6 Hz, 1H), 6.92e7.04 (m, 1H), 6.76e6.85 (m, 1H), 3.66e3.78 (m,
3H), 2.34 (s, 3H), 2.24e2.32 (m, 6H), 2.19 (br s, 3H), 1.80e1.94 (m,
27H26Cl2N4NaOS [MþNa]þ: 547.1102, found: 547.1102; Anal. Calcd
6H); 13C NMR (CDCl3):
d
178.0, 158.4, 149.8, 148.6, 147.7, 131.0, 129.5,
128.9, 127.8, 127.2, 126.9, 126.4, 125.2, 116.2, 111.8, 56.4, 42.7, 39.7,
4.2.7. N-(4-Methylphenyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinolin-2-yl]carbonyl}-hydrazinecarbothioamide (24)
37.4, 29.5, 21.3; HRMS (ESI): m/z calcd for
C29H32N4NaO2S
[MþNa]þ: 523.2144, found: 523.2144; Anal. Calcd for C29H32N4O2S
Yield: 90%; pale yellow solid; mp: 225e228 ꢁC; IR (KBr): 2905,
(500.2):C, 69.57; H, 6.44; N, 11.19; Found: C, 69.50; H, 6.38; N, 11.11.
1664 cmꢂ1 1H NMR (DMSO-d6):
; d 10.86 (br s, 1H), 9.70 (br s, 1H),
8.74 (d, J ¼ 9.0 Hz, 1H), 8.18 (d, J ¼ 8.5 Hz, 1H), 8.03 (s, 1H), 7.83 (t,
J ¼ 7.5 Hz, 1H), 7.66e7.75 (m, 1H), 7.25e7.37 (m, 2H), 7.11 (d,
J ¼ 7.5 Hz, 2H), 2.26 (br s, 10H), 2.17 (br s, 3H), 1.90 (d, J ¼ 12.0 Hz,
4.2.12. N-(4-Nitrophenyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinolin-2-yl]carbonyl}-hydrazinecarbothioamide (29)
Yield: 79%; yellow solid; mp: 205e209 ꢁC; IR (KBr): 1637 cmꢂ1
;
3H), 1.81 (d, J ¼ 12.0 Hz, 3H); 13C NMR (DMSO-d6):
d 181.2, 164.6,
1H NMR (DMSO-d6):
d
10.11 (br s, 1H), 8.75 (d, J ¼ 8.5 Hz, 1H), 8.19
156.8, 148.4, 147.8, 137.0, 134.4,131.7,129.6,128.8,127.5,127.4, 126.7,
(d, J ¼ 9.0 Hz, 3H), 8.05 (s, 1H), 7.91 (d, J ¼ 8.0 Hz, 2H), 7.83 (t,
J ¼ 7.8 Hz, 1H), 7.66e7.77 (m, 1H), 3.33 (s, 1H), 2.28 (br s, 6H), 2.18
(br s, 3H), 1.91 (d, J ¼ 11.5 Hz, 3H), 1.82 (d, J ¼ 12.1 Hz, 3H); 13C NMR
125.8, 115.9, 41.8, 38.9, 36.5, 28.7, 20.8; HRMS (ESI): m/z calcd for
C
28H30N4NaOS [MþNa]þ: 493.2039, found: 493.2037; Anal. Calcd
for C28H30N4OS (470.6): C, 71.46; H, 6.43; N, 11.90; Found: C, 71.42;
H, 6.39; N, 11.88.
(DMSO-d6):
d 180.2, 156.6, 155.3, 148.5, 147.3, 145.6, 142.9, 131.1,
128.9, 127.1, 126.8, 126.1, 125.9, 123.6, 122.9, 115.2, 112.2, 42.3, 38.4,
36.0, 28.2; HRMS (ESI): m/z calcd for C29H32N4NaO2S [MþNa]þ:
524.1733, found: 524.1733; Anal. Calcd for C29H32N4O2S (501.2): C,
64.65; H, 5.43; N, 13.96; Found: C, 64.69; H, 5.48; N, 13.97.
4.2.8. N-(2,6-Dimethylphenyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinolin-2-yl]carbonyl}-hydrazinecarbothioamide (25)
Yield: 79%; colorless solid; mp: 207e210 ꢁC; IR (KBr): 2918,
1634 cmꢂ1
;
1H NMR (CDCl3):
d
10.97 (br s, 1H), 8.65 (d, J ¼ 8.8 Hz,
4.2.13. N-Ethyl-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)quinolin-2-yl]
carbonyl}hydrazinecarbothioamide (30)
1H), 8.16e8.26 (m, 1H), 8.05 (br s, 1H), 7.72 (t, J ¼ 7.5 Hz, 1H), 7.59 (t,
J ¼ 7.2 Hz, 1H), 7.12e7.23 (m, 3H), 2.31e2.47 (m, 6H), 2.10e2.31 (m,
Yield: 78%; colorless solid; mp: 226e230 ꢁC; IR (KBr): 2907,
6H), 1.85 (br s, 6H), 1.61 (br s, 3H); 13C NMR (CDCl3):
d 179.2, 160.8,
1655 cmꢂ1
;
1H NMR (CDCl3):
d
9.95 (br s, 1H), 8.67 (d, J ¼ 8.5 Hz,
158.0, 148.2, 146.9, 141.2, 134.8, 132.2, 129.2, 129.0, 128.6, 128.3,
128.2,127.6,127.0,126.7,126.3,115.3, 42.1, 39.1, 36.8, 29.7, 28.9, 24.6,
14.6; HRMS (ESI): m/z calcd for C29H32N4NaOS [MþNa]þ: 507.2195,
found: 507.2190; Anal. Calcd for C29H32N4OS (484.6):C, 71.87; H,
6.66; N, 11.56; Found: C, 71.83; H, 6.62; N, 11.51.
1H), 8.11e8.20 (m, 2H), 8.00 (br s, 1H), 7.73 (dt, J ¼ 1.1, 7.6 Hz, 1H),
7.61 (ddd, J ¼ 1.5, 6.9, 8.7 Hz, 1H), 6.69 (br s, 1H), 3.64e3.76 (m, 2H),
2.25e2.35 (m, 6H), 2.21 (br s, 3H), 1.81e1.90 (m, 6H), 1.17e1.33 (m,
3H); 13C NMR (CDCl3):
d 182.5, 164.2, 158.2, 147.9, 147.3, 131.7, 129.1,
128.5, 126.9, 126.4, 115.9, 42.2, 39.9, 39.2, 36.8, 28.9, 14.2; HRMS
(ESI): m/z calcd for C23H28N4NaOS [MþNa]þ: 431.1882, found:
431.1875; Anal. Calcd for C23H28N4OS (408.2): C, 67.61; H, 6.91; N,
13.71; Found: C, 67.59; H, 6.88; N, 13.68.
4.2.9. N-(2-Ethylphenyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinolin-2-yl]carbonyl}-hydrazinecarbothioamide (26)
Yield: 81%; colorless solid; mp: 204e207 ꢁC; IR (KBr): 2917,
1638 cmꢂ1
;
1H NMR (CDCl3):
d
11.19 (br s, 1H), 8.64 (d, J ¼ 8.8 Hz,
4.2.14. N-(Prop-2-en-1-yl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinolin-2-yl]carbonyl}-hydrazinecarbothioamide (31)
1H), 8.45 (br s, 1H), 8.16e8.26 (m, 1H), 8.00 (s, 1H), 7.67e7.76 (m,
1H), 7.59 (ddd, J ¼ 1.5, 6.7, 8.6 Hz, 1H), 7.41e7.51 (m, 1H), 7.28e7.38
(m, 3H), 7.11e7.24 (m, 1H), 2.62e2.79 (m, 2H), 2.07e2.25 (m, 9H),
Yield: 68%; colorless solid; mp: 234e237 ꢁC; IR (KBr): 2905,
1662 cmꢂ1; 1H NMR [CDCl3:CD3OD (5:1)]:
d
8.62 (d, J ¼ 8.5 Hz, 1H),
1.74e1.89 (m, 6H), 1.14e1.31 (m, 3H); 13C NMR (CDCl3):
d 179.07,
8.05e8.11 (m, 2H), 7.67 (t, J ¼ 7.6 Hz, 1H), 7.51e7.59 (m, 1H),
5.77e5.89 (m, 1H), 5.13e5.21 (m, 1H), 5.05e5.12 (m, 1H), 4.21 (d,
160.7, 157.9, 148.1, 146.9, 141.1, 137.0, 134.9, 132.2, 129.5, 128.9, 128.5,
128.3, 127.9, 127.5, 127.0, 126.7, 126.3, 115.2, 42.0, 39.1, 36.7, 28.9,
25.4, 18.2; HRMS (ESI): m/z calcd for C29H32N4NaOS [MþNa]þ:
507.2195, found: 507.2190; Anal. Calcd for C29H32N4OS (484.2):C,
71.87; H, 6.66; N, 11.56; Found: C, 71.83; H, 6.62; N, 11.51.
J ¼ 5.5 Hz, 2H), 2.24 (br s, 6H), 2.15 (br s, 3H), 1.77e1.86 (m, 6H); 13
C
NMR [CDCl3:CD3OD (5:1)]:
d 182.6, 164.5, 158.4, 147.9, 147.8, 133.3,
131.6, 129.3, 128.5, 127.0, 126.6, 117.0, 116.2, 47.3, 42.7, 39.4, 36.9,
28.9; HRMS (ESI): m/z calcd for C24H28N4NaOS [MþNa]þ: 443.1882,
found: 443.1882; Anal. Calcd for C24H28N4OS (420.2): C, 68.54; H,
6.71; N, 13.32; Found: C, 68.54; H, 6.69; N, 13.31.
4.2.10. N-(2-Chloro-4-nitrophenyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-
yl)quinolin-2-yl]-carbonyl}hydrazinecarbothioamide (27)
Yield: red solid; 86%; mp: 178e182 ꢁC; IR (KBr): 1634 cmꢂ1; 1H
4.2.15. N-tert-Butyl-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)quinolin-2-
yl]carbonyl}hydrazinecarbothioamide (32)
NMR (DMSO-d6):
d 11.09 (br s, 1H), 10.28 (s, 1H), 9.82 (s, 1H), 8.75
(d, J ¼ 8.8 Hz, 1H), 8.29e8.35 (m, 1H), 8.20 (d, J ¼ 7.5 Hz, 2H), 8.04
(br s, 1H), 7.84 (t, J ¼ 7.4 Hz, 2H), 7.73 (t, J ¼ 7.3 Hz, 1H), 2.27 (br s,
6H), 2.18 (br s, 3H), 1.90 (d, J ¼ 11.5 Hz, 3H), 1.81 (d, J ¼ 12.0 Hz,
Yield: 66%; colorless solid; mp: 158e164 ꢁC; IR (KBr): 2907,
1654 cmꢂ1; 1H NMR (CDCl3):
d
10.21 (br s, 1H), 8.68 (d, J ¼ 8.5 Hz,
1H), 8.04e8.22 (m, 3H), 7.73 (ddd, J ¼ 1.3, 7, 8.3 Hz, 1H), 7.61 (ddd,
J ¼ 1.5, 6.9, 8.7 Hz, 1H), 6.60 (br s, 1H), 2.26e2.39 (m, 6H), 2.22 (br s,
3H); 13C NMR (DMSO-d6):
d 181.9, 164.8, 156.9, 149.2, 147.8, 145.8,
143.5, 131.7, 131.1, 129.7, 127.6, 126.8, 124.8, 122.6, 116.6, 41.8, 39.0,
3H), 1.88 (br s, 6H), 1.50e1.60 (m, 9H); 13C NMR (CDCl3):
d 180.4,
36.6, 28.8; HRMS (ESI): m/z calcd for C27H26ClN5NaO3S [MþNa]þ:
163.4, 158.0, 148.0, 147.2, 131.9, 129.0, 128.5, 126.8, 126.4, 115.8, 54.0,
42.2, 39.2, 36.8, 28.9; HRMS (ESI): m/z calcd for C25H32N4NaOS
[MþNa]þ: 459.2195, found: 459.2193; Anal. Calcd for C25H32N4OS
(436.3):C, 68.77; H, 7.39; N,12.83; Found: C, 68.76; H, 7.39; N, 12.82.
558.1343, found: 558.1334; Anal. Calcd for
C27H26ClN5O3S
(535.1):C, 60.50; H, 4.89; N, 13.06; Found: C, 60.44; H, 4.82; N,
13.02.

S.R. Patel et al. / European Journal of Medicinal Chemistry 85 (2014) 255e267
265
4.2.16. N-(2-Phenylethyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
4.3.1. N-Pentyl-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)quinolin-2-yl]
carbonyl}hydrazinecarboxamide (37)
Yield: 80%; white solid; mp: 208e211 ꢁC; IR (KBr): 3435,
1646 cmꢂ1 1H NMR (CDCl3):
quinolin-2-yl]carbonyl}-hydrazinecarbothioamide (33)
Yield: 82%; white solid; mp: 201e205 ꢁC; IR (KBr): 2908,
1635 cmꢂ1
;
1H NMR (CDCl3):
d
9.84 (br s, 1H), 8.69 (d, J ¼ 8.5 Hz,
;
d
9.83 (br s, 1H), 8.66 (d, J ¼ 8.5 Hz,
1H), 8.10e8.18 (m, 2H), 8.07 (br s, 1H), 7.71e7.79 (m, 1H), 7.63 (ddd,
J ¼ 1.5, 6.9, 8.7 Hz, 1H), 7.08e7.25 (m, 4H), 6.98e7.08 (m, 1H), 6.73
(br s, 1H), 3.81e3.95 (m, 2H), 2.89e2.98 (m, 2H), 2.30 (s, 6H), 2.22
1H), 8.05e8.15 (m, 2H), 7.70 (t, J ¼ 7.3 Hz, 1H), 7.56e7.61 (m, 1H),
7.12 (br s, 1H), 5.52 (br s, 1H), 3.22e329 (m, 2H), 2.34 (br s, 6H), 2.24
(s, 3H), 1.90e1.96 (m, 6H), 1.50e154 (m, 2H), 1.26e131 (m, 4H),
(br s, 3H), 1.89 (br s, 6H); 13C NMR [CDCl3:CD3OD (5:1)]:
d
182.5,
0.84e0.90 (m, 3H); 13C NMR (CDCl3):
d 164.4, 158.0, 157.8, 147.9,
164.5, 158.3, 147.9, 147.8, 138.8, 138.6, 131.7, 129.3, 129.0, 128.9,
128.8, 128.5, 127.0, 126.6, 126.5, 116.2, 46.2, 42.3, 39.4, 36.9, 35.1,
29.1; HRMS (ESI): m/z calcd for C29H32N4NaOS [MþNa]þ: 507.2195,
found: 507.2195; Anal. Calcd for C29H32N4OS (484.2): C, 71.87; H,
6.66; N, 11.56; Found: C, 71.86; H, 6.65; N, 11.55.
147.7, 131.8, 128.9, 128.4, 126.7, 126.4, 115.9, 43.1, 42.2, 40.3, 39.7,
39.2, 36.9, 36.8, 29.8, 28.9, 25.4, 14.0; HRMS (ESI): m/z calcd for
C
26H34N4NaO2 [MþNa]þ: 457.2579, found: 457.2575; Anal. Calcd
for C26H34N4O2 (434.3): C, 71.86; H, 7.89; N, 12.89; Found: C, 71.88;
H, 7.84; N, 12.87.
4.2.17. 2-{[4-(Tricyclo[3.3.1.13,7]dec-1-yl)quinolin-2-yl]carbonyl}-
N-[2-(trifluoromethyl)-phenyl]hydrazinecarbothioamide (34)
Yield: 75%; yellow solid; mp: 190e193 ꢁC; IR (KBr): 2915,
4.3.2. N-(Tricyclo[3.3.1.13,7]dec-1-yl)-2-{[4-(tricyclo[3.3.1.13,7]dec-
1-yl)quinolin-2-yl]-carbonyl}hydrazinecarboxamide (38)
Yield: 90%; yellow solid; mp: 247e250 ꢁC; IR (KBr): 3429, 2929,
1635 cmꢂ1
;
1H NMR (CDCl3):
d
8.86 (br s, 1H), 8.57e8.70 (m, 1H),
1728 cmꢂ1; 1H NMR [CDCl3:CD3OD (5:1)]:
8.05e8.16 (m, 2H), 7.67 (t, J ¼ 7.6 Hz,1H), 7.50e7.60 (m,1H), 2.28 (br
s, 6H), 2.18 (br s, 3H), 2.02 (s, 3H), 1.95 (s, 6H), 1.79e1.89 (m, 6H),
d
8.63 (d, J ¼ 8.8 Hz, 1H),
8.19e8.26 (m, 1H), 8.01 (br s, 1H), 7.95 (br s, 1H), 7.54e7.76 (m, 5H),
7.39 (t, J ¼ 7.5 Hz, 1H), 2.17 (br s, 6H), 2.10 (br s, 3H), 1.73e1.86 (m,
6H); 13C NMR [CDCl3:CD3OD (5:1)]:
d
180.4, 164.5, 158.1, 148.0,
1.62 (s, 6H); 13C NMR [CDCl3:CD3OD (5:1)]:
d 164.7, 157.7, 157.1,
147.2,135.9,133.4,133.1,130.5,129.3,129.1,128.9,127.8,127.0,126.9,
125.9, 121.8, 115.7, 68.0, 43.1, 39.2, 36.8, 29.9; HRMS (ESI): m/z calcd
for C27H28F3N4NaOS [MþNa]þ: 547.1756, found: 547.1753; Anal.
Calcd for C27H28F3N4OS (484.2): C, 64.11; H, 5.19; N,10.68; Found: C,
64.10; H, 5.14; N, 10.66.
147.8, 147.7, 131.4, 128.8, 128.1, 126.5, 126.2, 115.7, 51.1, 51.0, 41.9,
41.6, 39.0, 36.6, 36.1, 29.3, 28.7; HRMS (ESI): m/z calcd for
C
31H38N4NaO2 [MþNa]þ: 521.2892, found: 521.2890; Anal. Calcd
for C31H38N4O2 (498.7): C, 74.67; H, 7.68; N, 11.24; Found: C, 74.62;
H, 7.63; N, 11.20.
4.2.18. 2-{[4-(Tricyclo[3.3.1.13,7]dec-1-yl)quinolin-2-yl]carbonyl}-
N-[4-(trifluoromethoxyphenyl]hydrazinecarbothioamide (35)
Yield: 96%; white solid; mp: 208e211 ꢁC; IR (KBr): 2923,
4.3.3. 2-{[4-(Tricyclo[3.3.1.13,7]dec-1-yl)quinolin-2-yl]carbonyl}-N-
(3,4,5-trimethoxy-phenyl)hydrazinecarboxamide (39)
Yield: 78%; yellow solid; mp: >300 ꢁC; IR (KBr): 3433, 2927,
1665 cmꢂ1
;
1H NMR (DMSO-d6):
d
10.84 (br s, 1H), 9.97 (br s, 1H),
1737 cmꢂ1
;
1H NMR (CDCl3):
d
10.11 (br s, 1H), 8.65 (d, J ¼ 8.8 Hz,
9.85 (br s,1H), 8.74 (d, J ¼ 8.5 Hz, 1H), 8.19 (d, J ¼ 8.5 Hz,1H), 8.04 (s,
1H), 7.82 (t, J ¼ 7.5 Hz, 1H), 7.72 (t, J ¼ 7.8 Hz, 1H), 7.55e7.68 (m, 2H),
7.25e7.37 (m, 2H), 2.27 (br s, 6H), 2.17 (br s, 3H), 1.86e1.94 (m, 3H),
1H), 8.22 (br s, 1H), 8.09e8.18 (m, 2H), 7.98 (s, 1H), 7.65e7.75 (m,
1H), 7.52e7.64 (m, 1H), 6.64 (s, 2H), 3.71 (d, J ¼ 9.8 Hz, 9H), 2.24 (br
s, 6H), 2.17 (br s, 3H),1.85 (br s, 6H); 13C NMR (CDCl3):
d 165.4,158.0,
1.74e1.86 (m, 3H); 13C NMR [CDCl3:CD3OD (5:1)]:
d
181.4, 164.5,
155.4, 153.0, 148.0, 147.3, 134.1, 133.9, 131.9, 129.0, 128.4, 126.8,
126.3, 115.7, 97.7, 60.9, 55.9, 42.1, 39.1, 36.8, 28.9; HRMS (ESI): m/z
calcd for C30H34N4NaO5 [MþNa]þ: 553.2427, found: 553.2415; Anal.
Calcd for C30H34N4O5 (530.6): C, 67.91; H, 6.46; N, 10.56; Found: C,
67.88; H, 6.43; N, 10.52.
156.9, 149.3, 147.8, 145.4, 138.7, 131.7, 129.6, 129.1, 127.5, 127.4, 126.7,
122.3, 121.2, 118.7, 118.3, 115.4, 41.8, 38.9, 36.5, 28.7; HRMS (ESI): m/
z calcd for C27H28F3N4NaO2S [MþNa]þ: 563.1705, found: 563.1702;
Anal. Calcd for C27H28F3N4O2S (540.2): C, 64.35; H, 4.82; N, 10.72;
Found: C, 64.32; H, 4.80; N, 10.70.
4.3.4. 2-{[4-(Tricyclo[3.3.1.13,7]dec-1-yl)quinolin-2-yl]carbonyl}-N-
[4-(trifluoromethoxy)-phenyl]hydrazinecarboxamide (40)
4.2.19. 2-{[4-(Tricyclo[3.3.1.13,7]dec-1-yl)quinolin-2-yl]carbonyl}-
N-(3,4,5-trimethoxyphenyl)hydrazinecarbothioamide (36)
Yield: 88%; white solid; mp: 259e263 ꢁC; IR (KBr): 2904,
Yield: 69%; red solid; mp: 245e248 ꢁC; IR (KBr): 3307, 2921,
1726 cmꢂ1
;
1H NMR (CDCl3):
d
10.19 (br s, 1H), 8.60 (d, J ¼ 8.8 Hz,
1657 cmꢂ1; 1H NMR (CDCl3):
d
8.85 (br s,1H), 8.69 (br s,1H), 8.64 (d,
1H), 8.48 (br s, 2H), 8.13 (dd, J ¼ 1.4, 8.4 Hz, 1H), 8.03 (s, 1H), 7.68 (t,
J ¼ 8.8 Hz, 1H), 8.19 (d, J ¼ 8.3 Hz, 1H), 8.09 (s, 1H), 7.70 (t, J ¼ 7.6 Hz,
1H), 7.59 (t, J ¼ 7.8 Hz, 1H), 6.68e6.85 (m, 3H), 3.78 (d, J ¼ 8.3 Hz,
9H), 2.24 (br s, 6H), 2.14e2.22 (m, 3H), 1.80e1.90 (m, 6H); 13C NMR
J ¼ 7.6 Hz, 1H), 7.57 (t, J ¼ 7.6 Hz, 1H), 7.30e7.33 (m, 2H), 6.90e6.92
(m, 2H), 2.12 (s, 9H), 1.74e1.86 (m, 6H); 13C NMR (CDCl3):
d 165.5,
157.9, 155.1, 147.9, 147.1, 144.4, 136.9, 131.9, 129.0, 128.4, 126.8, 126.3,
121.7, 121.3, 120.2, 115.5, 42.0, 39.0, 36.7, 28.8; HRMS (ESI): m/z
calcd for C28H27F3N4NaO3 [MþNa]þ: 547.1933, found: 547.1928;
Anal. Calcd for C28H27F3N4O3 (524.5): C, 64.11; H, 5.19; N, 10.68;
Found: C, 64.07; H, 5.15; N, 10.64.
(CDCl3):
d 179.5, 175.7, 158.0, 153.2, 153.0, 148.0, 146.9, 136.2, 133.0,
131.9, 129.0, 128.4, 126.8, 126.3, 115.6, 102.5, 101.8, 60.8, 56.2, 56.1,
42.0, 39.1, 36.7, 28.8; HRMS (ESI): m/z calcd for C30H34N4NaO4S
[MþNa]þ: 569.2199, found: 569.2196; Anal. Calcd for C30H34N4O4S
(546.2): C, 65.91; H, 6.27; N, 10.25; Found: C, 65.89; H, 6.23; N,
10.23.
4.3.5. N-(4-tert-Butylphenyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinolin-2-yl]carbonyl}-hydrazinecarboxamide (41)
4.3. General method for the synthesis of N-alkyl/aryl-2-{[4-(tricyclo
[3.3.1.13,7]dec-1-yl)quinolin-2-yl]carbonyl}hydrazinecarboxamides
(37e51)
Yield: 87%; white solid; mp: 208e211 ꢁC; IR (KBr): 3350, 2907,
1720 cmꢂ1
;
1H NMR (CDCl3):
d
9.90 (br s, 1H), 8.68 (d, J ¼ 8.8 Hz,
1H), 8.10e8.21 (m, 2H), 7.72 (t, J ¼ 7.4 Hz, 1H), 7.57e7.65 (m, 2H),
7.42 (d, J ¼ 6.8 Hz, 1H), 7.12e7.22 (m, 2H), 7.13 (br s, 1H), 6.99 (br s,
1H), 2.31 (br s, 6H), 2.16e2.27 (m, 3H), 1.89 (br s, 6H), 1.35e1.47 (m,
To a stirred solution of 2 (1 mmol) in THF (5 mL), alkyl/aryl
isocyanate (1.2 mmol) was added. The reaction mixture was stirred
at ambient temperature for 4 h. The solvent was evaporated and the
residue was suspended in C2H5OH. The precipitated solid was
filtered, washed with C2H5OH and dried under vacuum to afford
37e51.
9H); 13C NMR (CDCl3):
d 163.7, 157.7, 156.0, 148.0, 147.5, 134.9, 131.9,
129.2, 128.9, 128.3, 127.1, 126.8, 126.6, 126.3, 115.8, 77.3, 42.1, 39.1,
36.8, 34.8, 30.7, 30.5, 28.9; HRMS (ESI): m/z calcd for C31H37N4O2
[MþH]þ: 497.2917, found: 497.2911; Anal. Calcd for C31H36N4O2
(496.6): C, 74.97; H, 7.31; N, 11.28; Found: C, 74.93; H, 7.29; N, 11.24.

266
S.R. Patel et al. / European Journal of Medicinal Chemistry 85 (2014) 255e267
4.3.6. N-Hexyl-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)quinolin-2-yl]
carbonyl}hydrazinecarboxamide (42)
553.3518, found: 553.3499; Anal. Calcd for C33H46N4O2 (530.7): C,
74.68; H, 8.74; N, 10.56; Found: C, 74.63; H, 8.71; N, 10.51.
Yield: 86%; yellow solid; mp: 277e280 ꢁC; IR (KBr): 3343, 2935,
1657 cmꢂ1
;
1H NMR (CDCl3):
d
9.76 (br s, 1H), 8.69 (d, J ¼ 8.8 Hz,
4.3.11. N-(4-Butoxyphenyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinolin-2-yl]carbonyl}-hydrazinecarboxamide (47)
1H), 8.13e8.23 (m, 2H), 7.73 (t, J ¼ 7.2 Hz,1H), 7.62 (t, J ¼ 7.2 Hz,1H),
6.87 (br s, 1H), 5.41 (t, J ¼ 5.6 Hz, 1H), 3.22e3.32 (m, 2H), 2.31 (s,
6H), 2.21 (s, 3H), 1.89 (s, 6H), 1.52 (q, J ¼ 7.2 Hz, 2H), 1.22e1.36 (m,
Yield: 64%; yellow solid; mp: 219e222 ꢁC; IR (KBr): 3333, 2906,
1663 cmꢂ1; 1H NMR [CDCl3:CD3OD (5:1)]:
d
8.68 (d, J ¼ 8.8 Hz, 1H),
6H), 0.78e0.93 (m, 3H); 13C NMR (CDCl3):
d
164.4, 158.0, 157.7,
8.12e8.19 (m, 2H), 7.71 (t, J ¼ 7.5 Hz, 1H), 7.60 (t, J ¼ 7.4 Hz, 1H), 7.32
(d, J ¼ 5.3 Hz, 2H), 6.81 (d, J ¼ 9.0 Hz, 2H), 3.91 (t, J ¼ 6.5 Hz, 2H),
2.30 (br s, 6H), 2.22 (br s, 3H), 1.88 (br s, 6H), 1.67e1.79 (m, 2H),
1.40e1.53 (m, 2H), 0.96 (t, J ¼ 7.4 Hz, 3H); 13C NMR [CDCl3:CD3OD
148.0, 147.7, 131.8, 128.9, 128.3, 126.6, 126.3, 115.8, 42.2, 40.3, 39.1,
36.8, 31.5, 30.1, 28.9, 26.5, 22.6, 14.0; HRMS (ESI): m/z calcd for
C
C
27H34N4NaO2 [MþNa]þ: 471.2736, found: 471.2724; Anal. Calcd for
27H36N4O2 (448.6): C, 72.29; H, 8.09; N, 12.49; Found: C, 72.25; H,
(5:1)]: d 164.9, 158.0, 156.2, 155.6, 148.0, 147.8, 131.7, 131.0, 129.1,
8.06; N, 12.45.
128.4, 126.8, 126.4, 122.1, 121.9, 116.0, 114.9, 68.1, 42.2, 39.2, 36.9,
31.4, 29.0,19.3,13.9; HRMS (ESI): m/z calcd for C31H37N4O2 [MþH]þ:
513.2866, found: 513.2858; Anal. Calcd for C31H36N4O3 (512.6): C,
72.63; H, 7.08; N, 10.93; Found: C, 72.61; H, 7.03; N, 10.90.
4.3.7. N-Hexadecyl-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)quinolin-2-yl]
carbonyl}hydrazinecarboxamide (43)
Yield: 79%; white solid; mp: 99e103 ꢁC; IR (KBr): 2923,
1726 cmꢂ1; 1H NMR [CDCl3:CD3OD (5:1)]:
d
8.66 (d, J ¼ 8.8 Hz, 1H),
4.3.12. N-(4-Fluorophenyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinolin-2-yl]carbonyl}-hydrazinecarboxamide (48)
8.09e8.19 (m, 2H), 7.71 (t, J ¼ 7.4 Hz, 1H), 7.56e7.61 (m, 1H), 3.21 (t,
J ¼ 7.0 Hz, 2H), 2.26e2.44 (m, 6H), 2.21 (br s, 3H), 2.02 (br s, 6H),
1.87 (br s, 6H), 1.48 (d, J ¼ 6.8 Hz, 2H), 1.21e1.23 (m, 20H), 0.86 (t,
Yield: 88%; white solid; mp: 247e250 ꢁC; IR (KBr): 2902,
1654 cmꢂ1; 1H NMR [CDCl3:CD3OD (5:1)]:
d
8.69 (d, J ¼ 8.6 Hz, 1H),
J ¼ 6.7 Hz, 3H); 13C NMR [CDCl3:CD3OD (5:1)]:
d
164.8, 158.5, 158.0,
8.15e8.18 (m, 2H), 7.74 (t, J ¼ 7.4 Hz, 1H), 7.62 (t, J ¼ 7.5 Hz, 1H),
7.38e7.43 (m, 2H), 6.95e7.00 (m, 2H), 2.33 (br s, 6H), 2.23 (br s, 3H),
147.9, 147.8, 131.7, 129.0, 128.4, 126.7, 126.4, 116.0, 42.2, 40.3, 40.2,
39.2, 36.8, 32.0, 30.0, 29.7, 29.7, 29.6, 29.5, 29.4, 29.3, 29.0, 26.9,
1.90 (br s, 6H); 13C NMR [CDCl3:CD3OD (5:1)]:
d 165.3, 158.1, 157.9,
22.7, 14.1; HRMS (ESI): m/z calcd for
589.4482, found: 589.4476; Anal. Calcd for C37H56N4O2 (588.9): C,
75.47; H, 9.59; N, 9.51; Found: C, 75.45; H, 9.54; N, 9.48.
C
37H57N4O2 [MþH]þ:
155.6, 148.1, 148.0, 134.5, 131.7, 129.2, 128.5, 126.9, 126.5, 121.5,
121.4, 116.1,115.6,115.4, 42.2, 39.2, 36.9, 29.0; HRMS (ESI): m/z calcd
for C27H28FN4O2 [MþH]þ: 459.2126, found: 459.2124; Anal. Calcd
for C27H27FN4O2 (458.5): C, 70.72; H, 5.94; N, 12.22; Found: C,
70.69; H, 5.91; N, 12.18.
4.3.8. N-Cyclopentyl-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)quinolin-2-
yl]carbonyl}hydrazinecarboxamide (44)
Yield: 95%; yellow solid; mp: 253e256 ꢁC; IR (KBr): 3318, 2930,
4.3.13. N-(2-Trifluoromethoxyphenyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-
1-yl)quinolin-2-yl]-carbonyl}hydrazinecarboxamide (49)
1642 cmꢂ1
;
1H NMR (CDCl3):
d
9.89 (br s, 1H), 8.68 (d, J ¼ 8.8 Hz,
1H), 8.12e8.21 (m, 2H), 7.72 (t, J ¼ 7.3 Hz, 1H), 7.58e7.62 (m, 1H),
7.27 (s, 1H), 5.51 (br s,1H), 4.11e4.16 (m,1H), 2.31 (br s, 6H), 2.22 (br
s, 3H), 1.94e2.01 (m, 2H), 1.80e1.92 (m, 6H), 1.51e1.71 (m, 4H), 1.43
Yield: 62%; white solid; mp: 216e219 ꢁC; IR (KBr): 2904,
1648 cmꢂ1
;
1H NMR (CDCl3):
d
10.14 (br s, 1H), 8.69 (d, J ¼ 8.8 Hz,
1H), 8.49 (br s, 1), 8.13e8.25 (m, 3H), 8.05 (br s, 1H), 7.72 (dt, J ¼ 0.9,
7.6 Hz, 1H), 7.61 (dt, J ¼ 1.2, 7.9 Hz, 1H), 7.11e7.16 (m, 2H), 6.91e7.01
(m, 1H), 2.31 (br s, 6H), 2.21 (br s, 3H), 1.88 (br s, 6H); 13C NMR
(dd, J ¼ 6.2, 12.4 Hz, 2H); 13C NMR (CDCl3):
d 164.2, 158.0, 157.6,
147.8, 147.6, 131.7, 129.0, 128.4, 126.7, 126.4, 115.9, 52.0, 42.2, 39.2,
36.8, 36.1, 33.3, 28.9, 23.6; HRMS (ESI): m/z calcd for C26H33N4O2
[MþH]þ: 433.2604, found: 433.2594; Anal. Calcd for C26H32N4O2
(432.6): C, 72.19; H, 7.46; N, 12.95; Found: C, 72.15; H, 7.43; N, 12.91.
(CDCl3):
d 164.9, 157.8, 154.5, 148.0, 147.3, 138.0, 138.0, 138.0, 132.0,
131.2, 128.9,128.4,127.3, 126.7, 126.3,122.9,121.8, 121.1, 120.3, 119.2,
115.9, 42.1, 39.1, 36.8, 28.9; HRMS (ESI): m/z calcd for
C
28H27F3N4NaO3 [MþNa]þ: 547.1933, found: 547.1923; Anal. Calcd
4.3.9. N-(2,6-Diethylphenyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinolin-2-yl]carbonyl}-hydrazinecarboxamide (45)
for C28H30N4O3 (470.6): C, 71.47; H, 6.43; N, 11.91; Found: C, 71.44;
H, 6.40; N, 11.88.
Yield: 78%; white solid; mp: 250e254 ꢁC; IR (KBr): 3400, 2929,
1727 cmꢂ1; 1H NMR [CDCl3:CD3OD (5:1)]:
d
8.65 (d, J ¼ 8.8 Hz, 1H),
4.3.14. 2-{[4-(Tricyclo[3.3.1.13,7]dec-1-yl)quinolin-2-yl]carbonyl}-
N-(2,4,6-trimethylphenyl)hydrazinecarboxamide (50)
8.11e8.14 (m, 2H), 7.70 (t, J ¼ 7.4 Hz, 1H), 7.53e7.62 (m, 1H), 7.16 (br
s, 3H), 2.24 (br s, 6H), 2.17 (br s, 3H), 1.85 (br s, 6H), 1.61 (s, 4H),
Yield: 68%; colorless solid; mp: 242e245 ꢁC; IR (KBr): 2925,
1.17e1.31 (m, 6H); 13C NMR [CDCl3:CD3OD (5:1)]:
d
164.7, 158.0,
1725 cmꢂ1; 1H NMR [CDCl3:CD3OD (5:1)]:
d
8.66 (d, J ¼ 8.5 Hz, 1H),
157.3, 148.0, 147.9, 131.7, 129.0, 128.4, 128.0, 126.7, 126.5, 116.0, 77.4,
8.01e8.26 (m, 2H), 7.70 (t, J ¼ 7.2 Hz, 1H), 7.52e7.64 (m, 1H),
42.2, 39.2, 36.9, 29.0, 24.8, 14.6; HRMS (ESI): m/z calcd for
6.80e6.97 (m, 2H), 2.15e2.44 (m, 18H), 1.80e1.95 (m, 6H); 13C NMR
C
C
31H36N4NaO2 [MþNa]þ: 519.2736, found: 519.2735; Anal. Calcd for
[CDCl3:CD3OD (5:1)]: d 164.6, 157.8, 157.1, 147.9, 147.8, 131.6, 128.9,
31H36N4O2 (496.6): C, 74.68; H, 8.74; N, 10.56; Found: C, 74.63; H,
128.3, 126.6, 126.3, 115.9, 42.1, 39.1, 36.7, 28.9, 20.8, 18.0; HRMS
(ESI): m/z calcd for C30H34N4NaO2 [MþNa]þ: 505.2579, found:
505.2571; Anal. Calcd for C30H34N4O2 (482.6): C, 74.66; H, 7.10; N,
11.61; Found: C, 74.61; H, 7.03; N, 11.58.
8.71; N, 10.51.
4.3.10. N-Cyclododecyl-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)quinolin-
2-yl]carbonyl}hydrazinecarboxamide (46)
Yield: 86%; white solid; mp: 214e217 ꢁC; IR (KBr): 2927,
4.3.15. N-(3-Fluorophenyl)-2-{[4-(tricyclo[3.3.1.13,7]dec-1-yl)
quinolin-2-yl]carbonyl}-hydrazinecarboxamide (51)
1726 cmꢂ1
;
1H NMR (CDCl3):
d
9.90 (d, J ¼ 3.3 Hz, 1H), 8.66 (d,
J ¼ 8.8 Hz, 1H), 8.12e8.18 (m, 2H), 7.71 (dt, J ¼ 1, 7.7 Hz, 1H),
7.56e7.61 (m, 1H), 7.34 (br s, 1H), 5.32 (d, J ¼ 8.5 Hz, 1H), 3.90e4.03
(m, 1H), 2.27e2.38 (m, 6H), 2.21 (br s, 3H), 1.84e1.93 (m, 6H),
Yield: 72%; white solid; mp: 244e247 ꢁC; IR (KBr): 2929,
1728 cmꢂ1; 1H NMR [CDCl3:CD3OD (5:1)]:
8.13e8.21 (m, 2H), 7.73 (t, J ¼ 7.4 Hz, 1H), 7.57e7.67 (m, 1H),
7.34e7.43 (m, 1H), 7.17e7.25 (m, 1H), 7.08e7.15 (m, 1H), 6.65e6.77
(m, 1H), 2.32 (br s, 6H), 2.23 (br s, 3H), 1.90 (br s, 6H); 13C NMR
d
8.69 (d, J ¼ 8.8 Hz, 1H),
1.51e1.67 (m, 2H), 1.20e1.50 (m, 22H); 13C NMR (CDCl3):
d 163.9,
157.7, 157.3, 148.0, 147.7, 131.8, 128.9, 128.3, 126.6, 126.3, 115.8, 46.9,
42.2, 39.1, 36.8, 31.8, 30.5, 28.9, 25.6, 23.9, 23.7, 23.5, 23.3, 23.2, 23.1,
21.4, 21.0; HRMS (ESI): m/z calcd for C33H46N4NaO2 [MþNa]þ:
[CDCl3:CD3OD (5:1)]:
d 165.1, 164.4, 162.0, 158.1, 155.6, 148.1, 147.9,
140.2, 131.7, 130.0, 129.9, 129.1, 128.5, 126.9, 126.5, 116.1, 114.6, 114.5,

S.R. Patel et al. / European Journal of Medicinal Chemistry 85 (2014) 255e267
267
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Acknowledgments
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The work was supported by a research grant (DBT/CSH/GIA/
1490) from the Department of Biotechnology, India. Sanjay Patel
thank the Council of Scientific and Industrial Research (CSIR), India
for the award of Research Associate Fellowship.
Appendix A. Supplementary data
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