Synthesis, anti-tuberculosis activity and 3D-QSAR study of amino acid conjugates of 4-(adamantan-1-yl) group containing quinolines

Article abstract of DOI:10.1016/j.ejmech.2008.10.004

The synthesis, antimycobacterial activity and 3D-QSAR study of two series of 4-(adamantan-1-yl) group containing quinolines conjugated to amino acids are described. The most potent analogs displayed in vitro antimycobacterial activity ranging between 1.00

Full text of DOI:10.1016/j.ejmech.2008.10.004

European Journal of Medicinal Chemistry 44 (2009) 2017–2029
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European Journal of Medicinal Chemistry
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Original article
Synthesis, anti-tuberculosis activity and 3D-QSAR study of amino acid
conjugates of 4-(adamantan-1-yl) group containing quinolines
,
,
a,
**
Amit Nayyar a 1, Sanjay R. Patel a, Mushtaque Shaikh b, Evans Coutinho b , Rahul Jain
*
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 Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai 400 098, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis, antimycobacterial activity and 3D-QSAR study of two series of 4-(adamantan-1-yl) group
containing quinolines conjugated to amino acids are described. The most potent analogs displayed in
vitro antimycobacterial activity ranging between 1.00 and 3.125 mg/mL. To understand the relationship
between structure and activity, a 3D-QSAR analysis has been carried out by Comparative Molecular Field
Analysis (CoMFA). The activities of molecules in the test sets were nicely predicted by the CoMFA model
generated with field alignment. The best model was obtained using atom-fit alignment. Based on the
molecular fields the relationships between structure and activity were easily rationalized.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Received 8 April 2008
Received in revised form
19 September 2008
Accepted 2 October 2008
Available online 11 October 2008
Keywords:
Tuberculosis
Ring-substituted quinolines
CoMFA
Amino acid conjugates
Anti-tuberculosis
1. Introduction
patients, and possess activity against drug-resistant strains of
commonly used anti-TB drugs.
In 1993, the World Health Organization (WHO) declared
tuberculosis (TB) a global public health emergency. The disease has
advanced, and currently causes approximately 2 million deaths
annually [1]. Several interlinked factors contribute to this
progression: (a) development of strains resistant to most
commonly used drugs such as isoniazid and rifampicin; (b) the
spread of the HIV/AIDS pandemic (one third of the approximately
40 million HIV cases worldwide are coinfected with Mycobacterium
tuberculosis, and for these individuals, the risk of developing clinical
TB is about 10% per year); (c) the difficulty of TB detection in
infected individuals (less than 40% of TB cases are detected); and
finally; (d) the rising incidence of multidrug-resistant (MDR) TB. To
overcome shortcomings of existing regimens of anti-TB drugs, new
structural classes of drugs acting via novel biochemical pathways
are required [2–4]. Ideally, the new classes of anti-TB drugs must be
of low molecular weight, inexpensive for easy availability to poor
Previously, we had reported the discovery of ring-substituted
quinolines as a new structural class of anti-TB compounds [5]. The
lead compound 2,8-dicyclopentyl-4-methylquinoline (DCMQ)
synthesized in one-step is a promising inhibitor and exhibited
encouraging activities against drug-sensitive and several single
drug-resistant strains (SDR) of M. tuberculosis. The promising
activity against SDR strains of several of the currently used anti-TB
agents suggests that ring-substituted quinolines exemplified by
DCMQ possibly act by new and yet unknown biochemical path-
way(s). In attempts to modify the structure of the lead compound
DCMQ, we have synthesized several new series of ring-substituted
quinolines [6–10]. In one such study, we have reported the
synthesis and promising anti-tuberculosis activity of a series of
ring-substituted quinolinecarbohydrazides/carboxamides [7]. The
most active compounds 4-(adamantan-1-yl)-2-quinolinecarbohy-
drazide and 4-(adamantan-1-yl)-2-quinolinecarboxamide (Fig. 1)
have displayed 99% and 98% inhibition at 6.25
mg/mL, respectively
against drug-sensitive M. tuberculosis H37Rv strain. Both
compounds were synthesized using a facile three-step synthetic
process in high yields. Therefore, both compounds were considered
ideally suited for further structural optimization. In continuation of
our anti-tuberculosis drug discovery program and structural
diversification of ring-substituted quinolines, herein we report
synthesis of various amino acid derivatives (series 1–2, Fig. 2) of 4-
* Corresponding author. Tel.: þ91 22 26670905; fax: þ91 22 26670816.
** Corresponding author. Tel.: þ91 172 2214682; fax: þ91 172 2214692.
E-mail addresses: evans@bcpindia.org (E. Coutinho), rahuljain@niper.ac.in (R.
Jain).
Present address: Laboratory of Clinical Infectious Diseases, NIAID, National
Institutes of Health, Bethesda, MD 20852, USA.
1
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.10.004

2018
A. Nayyar et al. / European Journal of Medicinal Chemistry 44 (2009) 2017–2029
(SOCl2) and triethylamine (Et3N) in dichloroethane (DCE) as solvent
at 80 ꢀC also failed. We reasoned that SOCl2 mediated reaction
failed presumably due to the instability of the in situ formed acid
chloride at elevated temperature. Finally, a highly efficient one-pot
protocol for the reaction of 5 with amino acids was devised. In this
method, compound 5 upon treatment with SOCl2 in the presence of
pyridine and DCM as solvent for 1 min at ambient temperature
produced 4-(1-adamantyl)-2-quinolinecarbonyl chloride in situ.
This intermediate upon reaction with suitably side chain protected
NHNH2
NH2
N
N
O
O
L-amino acid methyl esters in the presence of DMAP in DCM
Fig. 1. Structure of promising ring-substituted quinolines.
successfully provided methyl 2-[4-(adamantan-1-yl)-2-quino-
nylcarboxamido]alkanoates 32–44 (Scheme 1). Compounds 32–38,
40–41 and 44 upon reaction with hydrazine hydrate in the presence
of abs. ethanol for 48 h at ambient temperature produced N2-[1-
hydrazino-carbonylalkyl]-4-(adamantan-1-yl)-2-quinolinecarbox-
amides 45–51, 53–54 and 57. For, remaining compounds 39 and 42–
43 (where the side chain functionality was protected, i.e. in cases of
Orn, Lys with carbobenzyloxy and Tyr with benzyl) an additional
deprotection step was performed. The deprotection at the side
chain was achieved by reaction of 39 and 42–43 with 33% HBr in
acetic acid at ambient temperature for 30 min to produce N2-[1-
hydrazinocarbonylalkyl]-4-(adamantan-1-yl)-2-quinolinecarbox-
amides 52 and 55–56 as their hydrobromide salts (Scheme 1).
(adamantan-1-yl)-2-quinolinecarbohydrazide and 4-(adamantan-
1-yl)-2-quinolinecarboxamide. Amino acids used were chosen in
a way to study the effect of various lipophilic, hydrophilic and
cationic groups present on their side chain on the biological
activity. As remarked earlier, the exact molecular target for the
ring-substituted quinolines remains unknown. Ligand-based
techniques have been employed successfully by us and other
research groups in the past to help in designing newer classes of
antimicrobial agents [8,11–15]. Therefore, we have used the ligand-
based approach of 3D-QSAR (CoMFA) for a better understanding of
the structure activity relationship of the synthesized ring-
substituted quinolines.
2.2. Biological activity
2. Results and discussion
In vitro activities of the synthesized derivatives (Series 1–2)
against M. tuberculosis H37Rv strain (ATCC 27294, susceptible both
to rifampicin and isoniazid) were initially carried out using the
Microplate Alamar Blue Assay (MABA) at a concentration of
6.25 mg/mL [16]. Compounds exhibiting fluorescence were then
tested in the BACTEC 460 radiometric system [17] and the (%)
inhibition are summarized in Tables 1 and 2. Compounds demon-
2.1. Chemistry
4-(Adamantan-1-yl)-2-quinolinecarbohydrazide
(4)
was
synthesized in three convenient steps from commercially available
quinoline-2-carboxylic acid (1) as described earlier [7]. The latter
compound 4 upon reaction with suitably side chain protected
strating ꢁ90% inhibition at 6.25
were further evaluated at the lower concentration of 3.125 and
1.0 g/mL to determine MIC value that is the minimum concen-
tration exhibiting 99% inhibition. Isoniazid (99% inhibition,
MIC ¼ 1 g/mL) was included, as a standard drug, for comparison.
From Series 1, analogs
[R ¼ H, R1 ¼ CO2C(CH3)3],
[R ¼ CH2CH(CH3)2,
mg/mL in the primary screening
commercially available Boc-L-amino acids in the presence of 1,3-
dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine
(DMAP) in anhydrous dichloromethane (DCM) as solvent for 8 h at
ambient temperature afforded {1-[N0-(4-adamantan-1-yl-quino-
line-2-carbonyl)hydrazinocarbonyl]alkyl carbamic acid tert-butyl
esters 6–18 (Scheme 1). Compounds 6–18 upon reaction with 33%
hydrogen bromide (HBr) solution in acetic acid at ambient
temperature for 30 min easily and cleanly produced 4-(adamantan-
1-yl)-quinoline-2-carboxylic N0-(2-aminoalkyl)hydrazides 19–31 as
hydrobromide salts (Scheme 1).
The key intermediate 4-(adamantan-1-yl)-2-quinolincarboxylic
acid (5) required for the synthesis of compounds described in Series
2 was synthesized in three steps from commercially available
quinoline-2-carboxylic acid (1) as described earlier [10]. We next
m
m
7
8
[R ¼ CH(CH3)CH2CH3, R1 ¼ CO2C(CH3)3],
9
R1 ¼ CO2C(CH3)3], 12 [R ¼ CH2C6H5, R1 ¼ CO2C(CH3)3], 25
(R ¼ CH2C6H5, R1 ¼ H), 28 (R ¼ 1H-imidazol-4-yl-methyl, R1 ¼ H),
and 31 [R ¼ (CH2)3NHC(]NH)NH2, R1 ¼ H] exhibited inhibition
that ranged between 81 and 92% of M. tuberculosis H37Rv at
6.25
m
g/mL. While, analogs 14 [R ¼ 1H-indol-2-yl-methyl,
R1 ¼ CO2C(CH3)3],
R1 ¼ CO2C(CH3)3],
15
and
[R ¼ 1H-imidazol-4-yl-methyl,
[R ¼ (CH2)3NHC(]NH)NH2,
18
R1 ¼ CO2C(CH3)3] were more potent and displayed 99% inhibition of
attempted reaction of 5 with side chain protected L-amino acid
M. tuberculosis H37Rv at the lower tested concentration of 3.125
mg/
methyl esters. Conventional methods using DCC or 1,3-diispro-
pylcarbodiimide (DIC) as coupling reagents in DCM or N,N-dime-
thylformamide (DMF) as solvent failed. In situ generated acid
chloride mediated coupling method using 5, thionyl chloride
mL. These analogs upon evaluation at the lower dose of 1 g/mL
m
inhibited the growth of mycobacteria by <50%. All remaining
analogs displayed inhibition that ranged between 36 and 78%
against M. tuberculosis H37Rv at 6.25 mg/mL. A general observation
of the structure activity relationship indicated that the presence of
t-Boc [NHCO2C(CH3)3] group produced compounds with higher
potency when compared to compounds with free amino group at
the side chain. For example, analog 14 containing a t-Boc group was
active at 3.125
27 containing an amino group was comparatively less potent and
displayed 56% inhibition at 6.25 g/mL. Similarly, other t-Boc group
containing analogs 7, 8, 9, 12, 14, 15 and 18 were more potent than
their amino group containing counterparts (Table 1).
From Series 2, analogs 34 [R ¼ CH(CH3)CH2CH3, R1 ¼ OCH3], 35
[R ¼ CH2CH(CH3)2, R1 ¼ OCH3], 36 [R ¼ (CH2)2SCH3, R1 ¼ OCH3]
and 54 (R ¼ 1H-imidazolyl-4-ethyl, R1 ¼ NHNH2) displayed inhi-
bition that ranged between 83 and 99% of M. tuberculosis H37Rv at
mg/mL (99% inhibition), while its counterpart analog
H
R
N
R1
O
m
H
N
H
N
N
N
O
N
R1
H
O
R
O
Series 1
Series 2
Fig. 2. General structure of newly synthesized ring-substituted quinolines.

A. Nayyar et al. / European Journal of Medicinal Chemistry 44 (2009) 2017–2029
2019
ii
i
OH
OC2H5
OC2H5
N
N
iv
N
O
O
O
2
1
3
iii
R
NHBoc
O
v
H
H
N
N
OH
N
NH2
N
N
H
N
O
O
O
6-18
4
5
vi
vii
R
NH2
O
viii
NHNH2
O
O
H
N
H
H
N
N
N
N
H
N
OCH3
N
O
19-31
O
32-44
R
R
O
45-57
Scheme 1. (i) Abs. EtOH, HCl gas, 4 ꢀC, 2 h; (ii) 1-adamantanecarboxylic acid, AgNO3, (NH4)2S2O8, CH3CN, 10% H2SO4, 70–80 ꢀC, 15 min; (iii) NH2NH2$H2O, 95% EtOH, 80 ꢀC, 8 h; (iv)
6 N HCl, 100 ꢀC, 8 h; (v) DCC, DMAP, BocNH-R-CO2H, DCM, 8 h, rt; (vi) 33% HBr–AcOH, 30 min, rt; (vii) SOCl2, C5H5N, DCM, 1 min, rt; DMAP, H2N–R–OMe, DCM, 20 min, rt; (viii)
NH2NH2$H2O, abs. EtOH, 48 h, rt; 33% HBr–AcOH, 30 min, rt.
6.25
m
g/mL. At the same time, analogs 41 (R ¼ 1H-imidazolyl-4-
None of the compounds were found to exhibit cytotoxic effects up
to highest test concentration of 50 mg/mL.
ethyl, R1 ¼ OCH3), 44 [R ¼ (CH2)3NHC( ¼ NH)NH2, R1 ¼ OCH3] were
comparatively more active, and produced 99% inhibition at the
lower tested concentration of 3.125
m
g/mL. The most potent
2.3. Computational study
compound of both series 57 [R ¼ (CH2)3NHC(]NH)NH2,
R1 ¼ NHNH2] displayed promising activity (99% inhibition) against
Earlier we had reported the 3D-QSAR studies of analogous
molecules based on Comparative Molecular Field analysis (CoMFA)
[8–10]. On similar lines, we have employed Comparative Molecular
Field Analysis (CoMFA) [18] to understand the structure activity
relationship of amino acid derivatives of 4-(adamantan-1-yl)-2-
substituted quinolines.
drug-sensitive M. tuberculosis H37Rv strain at 1.00 mg/mL and was
comparable to standard drug used in this study, isoniazid. The
remaining analogs produced inhibition that ranged between 26%
and 75% against M. tuberculosis H37Rv at 6.25
we observed that quinoline derivatives conjugated with basic
heteroaromatic residue like -histidine and highly cationic
mg/mL. In this series,
L
L-
arginine residue were more potent compared to the derivatives
conjugated to hydrophobic and other residues. However, quino-
2.3.1. Data set
The molecules were grouped into three sets for the QSAR
analysis. The first group (Set I) was composed of 4-(adamantan-1-
yl)-2-quinolinecarbohydrazide derivatives (Table 1) while the
second set (Set II) comprised 4-(adamantan-1-yl)-2-quinoline-
carboxamide derivatives (Table 2). The 52 molecules listed in Tables
1 and 2 were collected into the third set (Set III). The three indi-
vidual sets were further divided into test and training sets based on
chemical as well as biological diversity. For dividing a given set into
training and test sets, the chemical characteristics were the inter-
action energies calculated between a probe and the molecules
aligned in a 3D grid and the biological activity was the second
property. These two attributes were used to separate the molecules
line derivatives (42–43 and 55–56) conjugated to cationic
and -ornithine residues were exceptions to this observation
(Table 2).
L-lysine
L
The most active derivative, N2-[(1S)-4-amino(imino)-
methylamino-1-hydrazinocarbonylbutyl]-4-(adamantan-1-yl)-2-
quinolinecarboxamide (57), was also evaluated for anti-
mycobacterial activity against isoniazid-resistant strain of M.
tuberculosis H37Rv and exhibited promising activity (99% inhibition
at 3.125 mg/mL), and (60% inhibition at 1.00 mg/mL). The most active
compounds 14, 15, 18, 41, 44 and 57 were further evaluated in vitro
for cytotoxicity (IC50) in mammalian kidney fibroblast (Vero) cells.

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A. Nayyar et al. / European Journal of Medicinal Chemistry 44 (2009) 2017–2029
Table 1
In vitro antimycobacterial activity and pIC50s of {1-[N0-(4-adamantan-1-yl-quinoline-2-carbonyl)hydrazinocarbonyl]alkyl carbamic acid tert-butyl esters 6–18 and 4-ada-
mantan-1-yl-quinoline-2-carboxylic acid N0-(2-aminoalkyl)hydrazides 19–31 (Series 1, Set I) against drug-sensitive M. tuberculosis H37Rv strain.
H
N
R
R1
H
N
N
N
H
O
O
Compound No.
R
R1
Test Conc. (
m
g/mL)
(%) inhibition
pIC50
6
7
8
9
10
11
H
CH3
CO2C(CH3)3
CO2C(CH3)3
CO2C(CH3)3
CO2C(CH3)3
CO2C(CH3)3
CO2C(CH3)3
6.25
6.25
6.25
6.25
6.25
6.25
60
88
90
90
56
51
5.06
5.76
5.89
5.89
5.05
4.96
CH(CH3)CH2CH3
CH2CH(CH3)2
(CH2)2SCH3
(CH2)2CONH2
12
CO2C(CH3)3
6.25
85
5.71
Bzl
O
13
CO2C(CH3)3
6.25
42
4.89
14
15
CO2C(CH3)3
3.125
3.125
99
99
7.29
7.25
NH
NH
N
CO2C(CH3)3
16
17
18
19
20
21
22
23
24
(CH2)3NHZ
(CH2)4NHZ
(CH2)3NHC(]NH)NH2
H
CO2C(CH3)3
CO2C(CH3)3
CO2C(CH3)3
H
H
H
H
H
H
6.25
6.25
3.125
6.25
6.25
6.25
6.25
6.25
6.25
75
73
99
35
41
75
75
59
45
5.51
5.47
7.26
4.52
4.64
5.32
5.32
5.02
4.77
CH3
CH(CH3)CH2CH3
CH2CH(CH3)2
(CH2)2SCH3
(CH2)2CONH2
25
26
H
H
6.25
6.25
81
48
5.50
4.86
OH
27
H
6.25
56
5.01
NH
N
NH
28
H
6.25
88
5.73
29
30
31
(CH2)3NH2
(CH2)4NH2
(CH2)3NHC(]NH)NH2
H
H
H
6.25
6.25
6.25
26
66
92
4.39
5.14
5.94

A. Nayyar et al. / European Journal of Medicinal Chemistry 44 (2009) 2017–2029
2021
Table 2
In vitro antimycobacterial activity and pIC50s of methyl 2-[4-(adamantan-1-yl)-2-quinonylcarboxamido]alkanoates 32–44 and N2-[1-hydrazinocarbonylalkyl]-4-(adamantan-
1-yl)-2-quinolinecarboxamides 45–57 (Series 2, Set II) against drug-sensitive M. tuberculosis H37Rv strain.
O
H
N
N
R1
O
R
Compound No.
R
R1
Test conc. (
m
g/mL)
(%) Inhibition
pIC50
32
33
34
35
36
37
H
CH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
6.25
6.25
6.25
6.25
6.25
6.25
52
73
90
83
86
55
4.81
5.23
5.79
5.53
5.64
4.94
CH(CH3)CH2CH3
CH2CH(CH3)2
(CH2)2SCH3
(CH2)2CONH2
38
OCH3
6.25
60
5.05
Bzl
O
39
OCH3
6.25
58
5.10
40
41
OCH3
OCH3
6.25
75
99
5.38
7.16
NH
NH
N
3.125
42
43
44
45
46
47
48
49
50
(CH2)3NHZ
(CH2)4NHZ
(CH2)3NHC(]NH)NH2
H
OCH3
OCH3
OCH3
NHNH2
NHNH2
NHNH2
NHNH2
NHNH2
NHNH2
6.25
6.25
3.125
6.25
6.25
6.25
6.25
6.25
6.25
66
78
99
70
82
70
83
68
50
5.23
5.50
6.87
5.15
5.45
5.21
5.53
5.18
4.85
CH3
CH(CH3)CH2CH3
CH2CH(CH3)2
(CH2)2SCH3
(CH2)2CONH2
51
52
NHNH2
NHNH2
6.25
6.25
50
44
4.87
4.78
OH
53
NHNH2
6.25
60
5.08
NH
N
NH
54
NHNH2
6.25
99
6.86
55
56
57
(CH2)3NH2
(CH2)4NH2
(CH2)3NHC(]NH)NH2
NHNH2
NHNH2
NHNH2
6.25
6.25
1.00
48
36
99
4.91
4.71
7.67

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A. Nayyar et al. / European Journal of Medicinal Chemistry 44 (2009) 2017–2029
into training and test sets based on the Tanimoto similarity coef-
ficient [19].
2.3.5. CoMFA interaction energy calculation
The steric and electrostatic fields in CoMFA were calculated at
each lattice intersection of a regularly spaced grid of 2.0 Å in all
three dimensions within the defined region. A methyl cation with
charge þ1.0 was used as the probe. The van der Waals potential and
Columbic energy between the probe and the molecules were
calculated. A distance-dependent dielectric constant of 1.0r was
used in the calculation of the electrostatics. The steric field was
truncated at points where the value exceeded ꢄ30.0 kcal/mol, and
the electrostatic fields were ignored at those lattice points where
the steric interactions were high.
2.3.2. Biological data
For the QSAR study, the percent inhibition values were trans-
formed, as follows [20].
Activity [ Llog cD log it
where c is molar concentration ¼ concentration ( g/mL) ꢂ 0.001/
m
(molecular weight) and log it ¼ log[% inhibition/(100 ꢃ %
inhibition)].
2.3.6. Predictive correlation coefficient
2.3.3. Molecular modeling
The predictive ability of each 3D-QSAR model was determined
from a set of test molecules not included in the model generation.
The predictive correlation coefficient (r2pred) based on the test set
molecules, is defined as
The CoMFA studies were carried out with the Sybyl suite of
programs [21] installed on a Pentium 2.8 GHz PC running under the
Linux OS (RedHat Enterprise WS 4.0).
The 4-(adamantan-1-yl)quinoline unit is a rigid moiety. At
the C2-position of the quinoline ring, two primary structures
–CONHNHCO–amino acid and –CONH–aminoacid, are present.
The geometries of the quinolone–CONHNHCO/–CONH segments
were based on the crystal structure-sg6059 shown in Fig. 3
[22].
r2pred [ ðSD L PRESSÞ=SD
where SD is the sum of squared deviations between the biological
activity of the test set and the mean activity of the training set
molecules and the PRESS is the sum of squared deviations between
predicted and actual activity values for every molecule in the test
set.
The structures of the molecules were built with the Builder
module in Insight II [23] and energy minimized with the Discover
module using the steepest descents (SD) and conjugate gradient
(CG) methods and the CFF91 [24] force field. The geometries of the
R and R1 groups (refer Tables 1 and 2) were optimized by sub-
jecting the molecules to a molecular dynamics (MD) simulation
while constraining the 4-(adamantan-1-yl)quinoline moiety and
–CONHNHCO or –CONH units to the crystallographic conforma-
tion. The MD simulation was carried out through a heating stage to
700 K for 1 ps followed by slowly annealing to 300 K in steps of
100 K for 1 ps at each new temperature. In the simulation, the MD
step size was 1 fs and snapshots from the trajectory were captured
every 5 fs. The structure in the MD trajectory with the lowest
energy (the global minima) was sent through a final round of
minimization involving both SD and CG minimizations. The
minimization was terminated at a maximum value of 0.01 kcal/
mol/Å for the gradient. The molecules were then imported into the
Sybyl framework and again subjected to constrained minimization
where only the amino acid group was allowed to relax. This
minimization was done using the Tripos force field and the Gas-
teiger Hu¨ckel charges, until a maximum gradient 0.05 kcal/mol/Å
was achieved. These conformations of the molecules were utilized
for CoMFA studies.
2.3.7. Discussion
CoMFA (Comparative Molecular Field Analysis) studies were
initially started with a training set of 20 molecules for both the Sets
I and II, which were aligned by the atom-fit and field-fit methods.
The remaining molecules composed the test set. Some of the
molecules (41, 43, and 50) were found to be outliers in the QSAR
study implying that the global minimum energy structures of such
molecules is an inappropriate conformation for the QSAR study. For
such molecules an alternative conformation (a local minima) was
introduced into the dataset and QSAR analysis repeated.
For Set I the best CoMFA model (Model 2, Table 3) was that
derived from field-fit alignment, with a correlation coefficient (r2)
of 0.991 and cross-validated r2(q2) of 0.434. For Set II, a model with
a correlation coefficient of 0.985 and cross-validated r2(q2) of 0.450
was obtained again with field-fit alignment of molecules (Model 4,
Table 3). The CoMFA model (Model 5, Table 3) generated by atom-fit
alignment is a robust model for Set III, as revealed by the statistical
parameters (Table 3). Fig. 5 shows plots of predicted versus
experimental activity for molecules in the training set based on
these three best models.
The CoMFA models were tested for their predictivity on the test
sets. The r2pred of 0.416 for Set I, using Model 2 and 0.45 for Set II
based on Model 4 establishes the superiority of these models over
their respective atom-fit models (Models 1 and 3, Table 3). Likewise
Model 5 obtained by atom-fit alignment was better for Set III with
an r2pred of 0.255. Though the rp2red is not high, the other statistical
parameters repose a high confidence in Model 5. Model 5 was
established for the two classes of molecules jointly considered; it
represents a unified picture for the exposition of activity of mole-
cules of both types. The steric and electrostatic contours associated
with the molecules in Sets I and II are described in the following
paragraphs. For the molecules in Set I (e.g. molecule 14) electro-
positive contours (blue color) are seen near the Ca and the Cb
positions of the amino acid side chain. Electropositive contours are
also seen around the acyl hydrazide (–CONHNHCO–) functionality
(Fig. 6a). Similarly, for Set II molecules (e.g. molecule 57) an
improvement in the activity will occur if an electronegative
substitution is made in the amino acid side chain, especially at the
Cb and Cg positions (Fig. 6b). If the amino acid side chains have an
2.3.4. Alignment
For Set I, molecule 14 (Table 1) was chosen as the template. For
both Sets II and III, the template was molecule 57 (Table 2) and all
other molecules aligned using the ATOM-FIT alignment method in
Sybyl (Fig. 4a). The molecules were aligned with reference to the
quinoline ring. A second technique of alignment was also carried
out using the FIELD-FIT method, wherein the steric and electro-
static fields around the molecules were superimposed over the
same fields of the template molecule (Fig. 4b).
O
H
N
N
H
CH3
O
Fig. 3. Structure of sg6059, whose X-day data was used for building the conformation
of the molecules.
aromatic ring, it p-stacks on to the quinoline ring and according to

A. Nayyar et al. / European Journal of Medicinal Chemistry 44 (2009) 2017–2029
2023
Fig. 4. A view of the molecules of Set III aligned using (a) Atom-Fit, and (b) Field-Fit.
this model such aromatic side chains need to contain electroposi-
tive groups.
helped to correlate the fine relationship between substitutions on
the amino acid side chain of the 4-adamantan-2-substituted
quinolines and their anti-tuberculosis activity. The 3D-QSAR study
also suggested some novel molecules which may be more potent
with aromatic amino acid side chains bearing an electropositive
group or aliphatic side chains with electronegative side substitu-
tions. Any increase in the molecular steric bulk appears to affect for
the potency. In conclusion, amino acid derivatives of 4-(ada-
mantan-1-yl)-2-substituted quinolines show promising outcomes
as anti-tuberculosis agents.
With regards to the steric contours, for molecules in Set I, the
replacement of the hydrogens (*) at the Ca and the N atom bearing
the t-Boc group (i.e. CaH*; NH*-t-Boc) with bulky groups will dis-
favored activity; the t-Boc group seems to satisfy the need for
a bulky group in these molecules for good activity (as discussed
earlier). No substitution is recommended at the acyl hydrazide
functionality (Fig. 7a). The steric contours for Set II show bulky
groups at the amino acid side chain are favored but the NH group of
the amino acid needs small protecting groups. Similarly bulky
groups are also disfavored in the vicinity of the parent structure 4-
(adamantan-1-yl)-2-quinolinecarboxamide (Fig. 7b).
4. Experimental
Melting points were recorded on a Mettler DSC 851 instrument
or a capillary melting point apparatus and are uncorrected. 1H
spectra were recorded on a 300 MHz Bruker FT-NMR (Avance
DPX300) spectrometer using tetramethylsilane as internal standard
3. Conclusions
In the present study, our efforts were directed primarily
towards structural optimization of our earlier reported lead
compounds, 4-(adamantan-1-yl)-2-quinolinecarbohydrazide and
4-(adamantan-1-yl)-2-quinolinecarboxamide. Analogs 14, 15, 18,
and the chemical shifts are reported in
d units. Mass spectra were
recorded on a HRMS (Finnigan Mat LCQ) spectrometer (ESI/APCI)
mode or MALDI (Bruker Daltonics, Ultraflux MALDI-tof/tof).
Elemental analyses were carried out on an Elementar Vario EL
spectrometer. Chromatographic purifications were carried out with
silica gel 60 (230–400 mesh) and TLC (silica gel) was done on silica
gel coated (Merck Kiesel 60 F254, 0.2 mm thickness) sheets. All
chemicals were purchased from Aldrich Chemical Ltd (Milwaukee,
WI, USA). Solvents used for the chemical synthesis were acquired
from commercial sources, were of analytical grade and used
without further purification unless otherwise stated.
41 and 44 produced inhibitory activity of 99% at 3.125
most potent analog 57 displayed 99% inhibition at 1.00
against drug-sensitive strain, while it exhibited 99% inhibition at
3.125 g/mL against drug-resistant strain. None of the analog dis-
m
g/mL. The
mg/mL
m
played cytotoxicity when tested in mammalian Vero cell line. In
general, quinolines conjugated to basic and heteroaromatic resi-
dues were more active compared to their hydrophobic and other
counterparts. The various 3D-QSAR models built using CoMFA
Table 3
A summary of the statistics of the 3D-QSAR models.
Parameters
Set I
Set II
Set III
AF Model 1
FF Model 2
AF Model 3
FF Model 4
AF Model 5
FF Model 6
n
26
26
26
26
52
52
N
4
4
6
6
7
7
r2
0.987
0.407
0.111
0.991
0.434
0.093
408
0.416
0.994 ꢄ 0.005
0.988
0.246
0.029
2411
0.345
0.995 ꢄ 0.001
0.985
0.450
0.028
2541
0.45
0.994 ꢄ 0.001
0.996
0.429
0.058
1114
0.255
0.997 ꢄ 0.002
0.996
0.336
0.063
956
0.177
0.997 ꢄ 0.002
rc2v
SEE
F-value
r2pred
r2bs
284
0.366
0.991 ꢄ 0.007
Contributions (%)
Steric
Electrostatic
56
44
55
45
41
59
40
60
46
54
43
57
AF, atom-fit alignment; FF, field-fit alignment; n, number of molecules; N, optimum number of components; rc2v, cross-validated correlation coefficient; r2, conventional (non-
cross-validated) correlation coefficient; SEE, standard error of estimate; r2pred, predictive (test molecules) correlation coefficient; rb2s, correlation coefficient after 100 runs of
bootstrapping analysis; SD, standard deviation from 100 bootstrapping runs.

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A. Nayyar et al. / European Journal of Medicinal Chemistry 44 (2009) 2017–2029
Fig. 5. Predicted versus experimental activity for molecules in the training set based on (a) Model 2, (b) Model 4, and (c) Model 5.
4.1. General procedure for the synthesis of {1-[N0-(4-adamantan-1-
yl-quinoline-2-carbonyl)hydrazinocarbonyl]alkyl carbamic acid
tert-butyl esters (6–18)
4.1.1. {2-[N0-(4-Adamantan-1-yl-quinoline-2-carbonyl)hydrazino]-
2-oxoethyl}carbamic acid tert-butyl ester (6)
Yield: 71%; mp: 155–156 ꢀC (dec.); 1H NMR (CDCl3):
d 8.63 (d,
1H, J ¼ 8.6 Hz), 8.14 (m, 2H), 7.60 (m, 1H), 7.51 (m, 1H), 3.85 (m, 2H),
1.89 (m, 15H), 1.43 (s, 9H); MALDIMS: m/z 479 (M þ 1); Anal. Calcd
for C27H34N4O4 (478.6): C, 67.76; H, 7.16; N, 11.71. Found: C, 68.04;
H, 7.01; N, 11.89.
To a solution of 4-(adamantan-1-yl)quinoline-2-carbohydrazide
(4, 0.1 g, 0.31 mmol) in DCM (15 mL), N-a-Boc protected L-amino
acid (0.08 g, 0.35 mmol), DCC (0.07 g, 0.35 mmol) and DMAP
(0.02 mg, 0.16 mmol) were added. The reaction mixture was stirred
for 8 h at ambient temperature. The solvent was removed under
reduced pressure to afford a semi-solid residue. This residue was
dissolved in ethyl acetate (5 mL) and kept in the refrigerator for 8 h.
The precipitated dicyclohexylurea was removed by filtration, and
solvent evaporated under reduced pressure to afford the crude
product, which upon column chromatographic purification over
silica gel (230–400 mesh) using ethyl acetate/hexanes (8:92) gave
6–18.
4.1.2. (S)-{2-[N0-(4-Adamantan-1-yl-quinoline-2-
carbonyl)hydrazino]-1-methyl-2-oxoethyl}carbamic acid tert-butyl
ester (7)
Yield: 65%; mp: 173–175 ꢀC (dec.); 1H NMR (CDCl3):
d 8.61 (d,
1H, J ¼ 8.6 Hz), 8.10 (m, 2H), 7.64 (m, 1H), 7.54 (m, 1H), 4.56 (m, 1H),
1.88 (m, 15H), 1.51 (d, 3H, J ¼ 6.7 Hz), 1.44 (s, 9H); MALDIMS: m/z
493 (M þ 1); Anal. Calcd for C28H36N4O4 (492.6): C, 68.27; H, 7.37;
N, 11.37. Found: C, 68.29; H, 7.39; N, 11.42.
Fig. 6. CoMFA contours based on Model 5 for electrostatic fields drawn around molecules (a) 14 and (b) 57. The red contour shows regions where electronegative substituents are
favored, while the blue contour is associated with positions where electropositive substituents improve activity. (For interpretation of the references to color in this figure legend,
the reader is referred to the web version of this article.)

A. Nayyar et al. / European Journal of Medicinal Chemistry 44 (2009) 2017–2029
2025
Fig. 7. CoMFA contours based on Model 5 for steric fields drawn around molecules (a) 14 and (b) 57. The green colored contour favors steric bulk while sites where steric bulk is
disfavored are shown in yellow. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
4.1.3. (S)-{1-[N0-(4-Adamantan-1-yl-quinoline-2-
carbonyl)hydrazinocarbonyl]-2-methylbutyl}carbamic acid tert-
butyl ester (8)
4.1.8. (S)-[2-[N0-(4-Adamantan-1-yl-quinoline-2-
carbonyl)hydrazino]-1-(4-benzyloxy-benzyl)-2-oxoethyl]carbamic
acid tert-butyl ester (13)
Yield: 62%; mp: 134–136 ꢀC (dec.); 1H NMR (CDCl3):
d
8.61 (d,
Yield: 68%; mp: 173–175 ꢀC (dec.); 1H NMR (CDCl3):
d 10.29 (br s,
1H, J ¼ 8.8 Hz), 8.12 (m, 2H), 7.60 (m, 1H), 7.54 (m, 1H), 4.60 (m,
1H), 2.62 (m, 1H), 1.88 (m, 15H), 1.42 (s, 9H), 1.32 (m, 2H), 0.99 (m,
6H); MALDIMS: m/z 535 (M þ 1); Anal. Calcd for C31H42N4O4S
(534.7): C, 69.64; H, 7.92; N, 10.48. Found: C, 69.79; H, 8.12; N,
10.31.
1H), 8.66 (d, 1H, J ¼ 8.7 Hz), 8.16 (m, 2H), 7.70 (m, 1H), 7.58 (m, 1H),
7.36 (m, 5H), 7.23 (d, 2H, J ¼ 8.5 Hz), 6.92 (d, 2H, J ¼ 8.5 Hz), 5.02 (s,
2H), 4.55 (m, 1H), 3.15 (d, 2H, J ¼ 6.5 Hz), 1.88 (m, 15H), 1.42 (s, 9H);
MALDIMS: m/z 675(M þ 1); Anal. Calcd for C41H46N4O5 (674.8): C,
72.97; H, 6.87; N, 8.30. Found: C, 72.95; H, 6.82; N, 8.35.
4.1.4. (S)-{1-[N0-(4-Adamantan-1-yl-quinoline-2-
carbonyl)hydrazinocarbonyl]-3-methylbutyl}carbamic acid tert-
butyl ester (9)
4.1.9. (S)-[2-[N0-(4-Adamantan-1-yl-quinoline-2-
carbonyl)hydrazino]-1-(1H-indol-2-yl-methyl)-2-
oxoethyl]carbamic acid tert-butyl ester (14)
Yield: 66%; mp: 121–123 ꢀC (dec.); 1H NMR (CDCl3):
d
8.58 (d,
Yield: 52%; mp: 176–178 ꢀC (dec.); 1H NMR (CDCl3):
d 10.19 (br s,
1H, J ¼ 8.6 Hz), 8.11 (m, 2H), 7.62 (m, 1H), 7.50 (m, 1H), 4.56 (m,
1H), 2.01 (m, 1H), 1.94 (m, 2H), 1.88 (m, 15H), 1.42 (s, 9H), 1.08 (m,
6H); MALDIMS: m/z 535 (M þ 1); Anal. Calcd for C31H42N4O4S
(534.7): C, 69.64; H, 7.92; N, 10.48. Found: C, 69.43; H, 7.66; N,
10.31.
1H), 8.65 (d, 1H, J ¼ 8.7 Hz), 8.22 (br s, 1H), 8.14 (m, 2H), 7.69 (m,
2H), 7.52 (m, 1H), 7.50 (m, 3H), 7.37 (d, 1H, J ¼ 7.7 Hz), 4.20 (m, 1H),
2.20 (s, 2H), 1.88 (m, 15H), 1.43 (s, 9H); MALDIMS: m/z 608 (M þ 1);
Anal. Calcd for C36H41N5O4 (607.7): C, 71.15; H, 6.80; N, 11.52.
Found: C, 71.18; H, 6.85; N, 11.55.
4.1.5. (S)-{1-[N0-(4-Adamantan-1-yl-quinoline-2-
carbonyl)hydrazinocarbonyl]-3-methylsulfanylpropyl}carbamic
acid tert-butyl ester (10)
4.1.10. (S)-[2-[N0-(4-Adamantan-1-yl-quinoline-2-
carbonyl)hydrazino]-1-(1H-imidazol-4-yl-methyl)-2-
oxoethyl]carbamic acid tert-butyl ester (15)
Yield: 60%; mp: 175–177 ꢀC (dec.); 1H NMR (CDCl3):
d
8.63 (d,
Yield: 40%; mp: 182–184 ꢀC (dec.); 1H NMR (CDCl3):
d 8.67 (d,
1H, J ¼ 8.7 Hz), 8.14 (m, 2H), 7.62 (m, 1H), 7.51 (m, 1H), 4.51 (m,
1H), 2.62 (m, 2H), 2.21 (m, 2H), 2.15 (s, 3H), 1.88 (m, 15H), 1.42 (s,
9H); MALDIMS: m/z 553 (M þ 1); Anal. Calcd for C30H40N4O4S
(552.7): C, 65.19; H, 7.29; N, 10.14. Found: C, 65.23; H, 7.33; N,
10.45.
1H, J ¼ 8.7 Hz), 8.20 (s, 1H), 8.14 (d, 1H, J ¼ 8.1 Hz), 7.70 (m, 1H), 7.58
(m, 2H), 6.90 (s, 1H), 5.62 (br s, 1H), 4.57 (m, 1H), 3.10 (m, 2H), 1.88
(m, 15H), 1.47 (s, 9H); MALDIMS: m/z 559 (M þ 1); Anal. Calcd for
C31H38N6O4 (558.6): C, 66.65; H, 6.86; N, 15.04. Found: C, 66.69; H,
6.89; N, 15.09.
4.1.6. 4.1.6. (S)-{1-[N0-(4-Adamantan-1-yl-quinoline-2-
carbonyl)hydrazinocarbonyl]-3-carbamoylpropyl}carbamic acid
tert-butyl ester (11)
4.1.11. (S)-{5-[N0-(4-Adamantan-1-yl-quinoline-2-
carbonyl)hydrazino]-4-tert-butoxy-carbonylamino-5-
oxopentyl}carbamic acid tert-butyl ester (16)
Yield: 55%; mp: 173–175 ꢀC (dec.); 1H NMR (CDCl3):
d
9.88 (br
Yield: 75%; mp: 175–177 ꢀC (dec.); 1H NMR (CDCl3):
d 10.11 (br s,
s, 1H) 8.67 (d, 1H, J ¼ 8.7 Hz), 8.15 (m, 2H), 7.70 (m, 1H), 7.59 (m,
1H), 4.56 (m, 1H), 1.88 (m, 15H), 1.67 (m, 2H), 1.47 (s, 9H), 1.16 (m,
2H); MALDIMS: m/z 550 (M þ 1); Anal. Calcd for C30H39N5O5
(549.7): C, 65.55; H, 7.15; N, 12.74. Found: C, 65.59; H, 7.12; N,
12.72.
1H), 9.25 (br s, 1H), 8.65 (d, 1H, J ¼ 8.6 Hz), 8.14 (m, 2H), 7.69 (m,
1H), 7.57 (m, 1H), 4.51 (m, 1H), 3.14 (m, 2H), 1.88 (m, 15H), 1.44 (s,
18H), 1.28 (m, 4H); MALDIMS: m/z 636 (M þ 1); Anal. Calcd for
C35H49N5O6 (635.7): C, 66.12; H, 7.77; N, 11.02. Found: C, 66.18; H,
7.79; N, 11.05.
4.1.7. (S)-{2-[N0-(4-Adamantan-1-yl-quinoline-2-
carbonyl)hydrazino]-1-benzyl-2-oxoethyl}carbamic acid tert-butyl
ester (12)
4.1.12. (S)-{6-[N0-(4-Adamantan-1-yl-quinoline-2-
carbonyl)hydrazino]-5-tert-butoxy-carbonylamino-6-
oxohexyl}carbamic acid benzyl ester (17)
Yield: 75%; mp: 167–169 ꢀC (dec.); 1H NMR (CDCl3):
d
10.27 (br
Yield: 77%; mp: 178–180 ꢀC (dec.); 1H NMR (CDCl3):
d 9.48 (br s,
s, 1H), 9.03 (br s, 1H), 8.63 (d, 1H, J ¼ 8.2 Hz), 8.13 (m, 2H), 7.67 (m,
1H), 7.55 (m, 1H), 7.22 (m, 5H), 4.56 (m, 1H), 3.18 (d, 2H, J ¼ 6.4 Hz),
1.88 (m, 15H), 1.38 (s, 9H); MALDIMS: m/z 569 (M þ 1); Anal. Calcd
for C34H40N4O4 (568.7): C, 71.81; H, 7.09; N, 9.85. Found: C, 71.84; H,
7.05; N, 9.80.
1H), 8.65 (d, 1H, J ¼ 8.7 Hz), 8.19 (m, 2H), 7.69 (m, 1H), 7.58 (m, 1H),
7.31 (m, 5H), 5.08 (s, 2H), 4.35 (m, 1H), 3.19 (m, 2H), 1.88 (m, 15H),
1.52 (m, 6H), 1.42 (s, 9H); MALDIMS: m/z 684 (M þ 1); Anal. Calcd
for C39H49N5O6 (683.8): C, 68.50; H, 7.22; N, 10.24. Found: C, 68.54;
H, 7.25; N, 10.29.

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4.1.13. (S)-{1-[N0-(4-Adamantan-1-yl-quinoline-2-
carbonyl)hydrazinocarbonyl]-4-(N,N0-bis-
benzyloxycarbonylguanidinobutyl)}carbamic acid tert-butyl ester
(18)
(m, 1H), 4.05 (m, 1H), 2.37 (m, 4H), 1.90 (m, 15H); MALDIMS: m/z
450 (M þ 1); Anal. Calcd for C25H33Br2N5O3 (611.4): C, 49.11; H,
5.44; N, 11.46. Found: C, 49.32; H, 5.25; N, 11.37.
Yield: 37%; mp: 180–182 ꢀC (dec.); 1H NMR (CDCl3):
d
9.60 (br s,
4.2.7. (S)-4-Adamantan-1-yl-quinoline-2-carboxylic acid N0-(2-
amino-3-phenylpropionyl)hydrazide$2HBr (25)
1H), 9.45 (br s, 1H), 9.34 (br s, 1H), 9.13 (br s, 1H), 8.66 (d, 1H,
J ¼ 8.7 Hz), 8.11 (m, 2H), 7.70 (m, 1H), 7.58 (m, 1H), 7.25 (m, 10H),
5.25 (s, 2H), 5.23 (s, 2H), 4.45 (m, 1H), 2.04 (m, 2H), 1.88 (m, 15H),
1.72 (m, 2H), 1.45 (s, 9H), 1.33 (m, 2H); MALDIMS: m/z 846 (M þ 1);
Anal. Calcd for C47H55N7O8 (845.9): C, 66.73; H, 6.55; N, 11.59.
Found: C, 66.79; H, 6.49; N, 11.55.
Yield: 90%; mp: 172–174 ꢀC (dec.); 1H NMR (CD3OD):
d 8.78 (d,
1H, J ¼ 8.7 Hz), 8.25 (d, 1H, J ¼ 8.2 Hz), 8.14 (s, 1H), 7.81 (m, 1H),
7.71 (m, 1H), 7.44 (m, 5H), 4.32 (m, 1H), 3.18 (d, 2H, J ¼ 6.4 Hz), 1.88
(m, 15H); MALDIMS: m/z 469 (M þ 1); Anal. Calcd for
C29H34Br2N4O2 (630.4): C, 55.25; H, 5.44; N, 8.89. Found: C, 55.21;
H, 5.44; N, 8.93.
4.2. General method for the synthesis of 4-adamantan-1-yl-
quinoline-2-carboxylic acid N0-(2-aminoalkyl)hydrazides (19–31)
4.2.8. (S)-4-Adamantan-1-yl-quinoline-2-carboxylic acid N0-[2-
amino-3-(4-hydroxyphenyl)propionyl]hydrazide$2HBr (26)
A solution of 33% HBr in glacial acetic acid (3 mL) was added to
6–18 (0.1 mmol), and the reaction mixture was stirred at ambient
temperature for 30 min. The solvent was removed under reduced
pressure to afford 19–31 as hydrobromide salts.
Yield: 90%; mp: 173–175 ꢀC (dec.); 1H NMR (CD3OD):
d 8.89 (d,
1H, J ¼ 8.8 Hz), 8.33 (d, 1H, J ¼ 8.5 Hz), 8.24 (s, 1H), 7.90 (m,1H), 7.79
(m, 1H), 7.22 (d, 2H, J ¼ 8.1 Hz), 6.82 (d, 2H, J ¼ 8.2 Hz), 4.20 (m, 1H),
1.96 (d, 2H, J ¼ 6.5 Hz), 1.88 (m, 15H); MALDIMS: m/z 575 (M þ 1);
Anal. Calcd for C29H34Br2N4O3 (646.4): C, 53.88; H, 5.30; N, 8.67.
Found: C, 53.84; H, 5.32; N, 8.69.
4.2.1. 4-Adamantan-1-yl-quinoline-2-carboxylic acid N0-(2-
aminoacetyl)hydrazide$2HBr (19)
Yield: 95%; mp: 160–162 ꢀC (dec.); 1H NMR (CD3OD):
d
8.84 (d,
4.2.9. (S)-4-Adamantan-1-yl-quinoline-2-carboxylic acid N0-[2-
amino-3-(1H-indol-2-yl)propionyl]hydrazide$2HBr (27)
1H, J ¼ 8.7 Hz), 8.40 (d, 1H, J ¼ 8.4 Hz), 8.27 (s, 1H), 7.91 (m, 1H), 7.85
(m, 1H), 4.03 (m, 2H), 1.88 (m, 15H); MALDIMS: m/z 379 (M þ 1);
Anal. Calcd for C22H28Br2N4O2 (540.3): C, 48.91; H, 5.22; N, 10.37.
Found: C, 49.08; H, 5.04; N, 10.55.
Yield: 94%; mp: 176–178 ꢀC (dec.); 1H NMR (CD3OD):
d 8.78 (d,
1H, J ¼ 8.6 Hz), 8.24 (d, 1H, J ¼ 8.3 Hz), 8.16 (s, 1H), 7.78 (m, 3H),
7.42 (m, 1H), 7.34 (s, 1H), 7.11 (m, 2H), 4.30 (m, 1H), 2.30 (s, 2H),
1.88 (m, 15H); MALDIMS: m/z 507 (M þ 1); Anal. Calcd for
C31H35Br2N5O2 (749.4): C, 49.69; H, 4.71; N, 9.35. Found: C, 49.63;
H, 4.67; N, 9.33.
4.2.2. (S)-4-Adamantan-1-yl-quinoline-2-carboxylic acid N0-(2-
aminopropionyl)hydrazide$2HBr (20)
Yield: 91%; mp: 175–177 ꢀC (dec.); 1H NMR (CD3OD):
d 8.89 (d,
1H, J ¼ 8.6 Hz), 8.37 (d,1H, J ¼ 8.4 Hz), 8.25 (s, 1H), 7.93 (m, 1H), 7.86
(m, 1H), 4.14 (m, 1H), 1.88 (m, 15H), 1.57 (d, 3H, J ¼ 6.8 Hz); MAL-
DIMS: m/z 393 (M þ 1); Anal. Calcd for C23H30Br2N4O2 (554.3): C,
49.84; H, 5.46; N, 10.11. Found: C, 49.87; H, 5.49; N, 10.15.
4.2.10. (S)-4-Adamantan-1-yl-quinoline-2-carboxylic acid N0-[2-
amino-3-(1H-imidazol-4-yl)propionyl]hydrazide$3HBr (28)
Yield: 95%; mp: 165–167 ꢀC (dec.); 1H NMR (CD3OD):
d 8.77 (d,
1H, J ¼ 8.7 Hz), 8.34 (d, 1H, J ¼ 8.1 Hz), 8.25 (s, 1H), 7.75 (m, 1H),
7.62 (m, 2H), 6.92 (s, 1H), 4.37 (m, 1H), 2.91 (m, 2H), 1.88 (m, 15H);
MALDIMS: m/z 459 (M þ 1); Anal. Calcd for C26H33 Br3N6O2
(701.2): C, 44.53; H, 4.74; N, 11.98. Found: C, 44.56; H, 4.78; N,
11.97.
4.2.3. (S)-4-Adamantan-1-yl-quinoline-2-carboxylic acid N0-(2-
amino-3-methyl-pentanoyl)hydrazide$2HBr (21)
Yield: 90%; mp: 170–172 ꢀC (dec.); 1H NMR (CD3OD):
d 8.92 (d,
1H, J ¼ 8.4 Hz), 8.40 (d,1H, J ¼ 8.4 Hz), 8.29 (s, 1H), 7.97 (m, 1H), 7.83
(m, 1H), 4.10 (m, 1H), 2.88 (m, 1H), 1.88 (m, 15H), 1.40 (m, 2H), 1.02
(m, 6H); MALDIMS: m/z 435 (M þ 1); Anal. Calcd for C26H36Br2N4O2
(596.4): C, 52.36; H, 6.08; N, 9.39. Found: C, 52.12; H, 6.36; N, 9.21.
4.2.11. (S)-4-Adamantan-1-yl-quinoline-2-carboxylic acid N0-(2,5-
diaminopentanoyl)hydrazide$3HBr (29)
Yield: 90%; semi-solid; 1H NMR (CD3OD):
d 8.76 (d, 1H,
J ¼ 8.6 Hz), 8.25 (d, 1H, J ¼ 8.3 Hz), 8.14 (s, 1H), 7.77 (m, 1H), 7.71 (m,
1H), 4.11 (m, 1H), 3.07 (m, 2H), 2.10 (m, 2H), 1.88 (m, 15H), 1.28 (m,
2H); MALDIMS: m/z 436 (M þ 1); Anal. Calcd for C25H36Br3N5O6
(678.3): C, 44.27; H, 5.35; N, 10.32. Found: C, 44.23; H, 5.31; N,
10.28.
4.2.4. (S)-4-Adamantan-1-yl-quinoline-2-carboxylic acid N0-(2-
amino-4-methyl-pentanoyl)hydrazide$2HBr (22)
Yield: 90%; mp: 171–173 ꢀC (dec.); 1H NMR (CD3OD):
d 8.91 (d, 1H,
J ¼ 8.4 Hz), 8.40 (d, 1H, J ¼ 8.4 Hz), 8.30 (s, 1H), 7.95 (m, 1H), 7.84 (m,
1H), 4.11 (m, 1H), 2.10 (m, 1H), 1.99 (m, 2H), 1.88 (m, 15H), 1.10 (d, 6H,
J ¼ 6.8 Hz); MALDIMS: m/z 435 (M þ 1); Anal. Calcd for C26H36Br2N4O2
(596.4): C, 52.36; H, 6.08; N, 9.39. Found: C, 52.66; H, 6.21; N, 9.54.
4.2.12. (S)-4-Adamantan-1-yl-quinoline-2-carboxylic acid N0-(2,6-
diaminohexanoyl)hydrazide$3HBr (30)
Yield: 92%; mp: 172–174 ꢀC (dec.); 1H NMR (CD3OD): 8.99 (d,
1H, J ¼ 8.7 Hz), 8.33 (d, 1H, J ¼ 8.7 Hz), 8.23 (s, 1H), 7.90 (m, 1H),
7.79 (m, 1H), 4.13 (m, 1H), 3.04 (m, 2H), 2.07 (m, 2H), 1.88 (m, 15H),
1.30 (m, 4H); MALDIMS: m/z 450 (M þ 1); Anal. Calcd for
C26H38Br3N5O2 (692.3): C, 45.11; H, 5.53; N, 10.12. Found: C, 45.07;
H, 5.49; N, 10.09.
4.2.5. (S)-4-Adamantan-1-yl-quinoline-2-carboxylic acid N0-(2-
amino-4-methylsulfanyl-butyryl)hydrazide$2HBr (23)
Yield: 93%; mp: 173–175 ꢀC (dec.); 1H NMR (CD3OD):
d 8.76 (d,
1H, J ¼ 8.3 Hz), 8.33 (d, 1H, J ¼ 8.3 Hz), 8.14 (s, 1H), 7.77 (m, 1H), 7.70
(m, 1H), 4.20 (m, 1H), 2.60 (m, 2H), 2.25 (m, 2H), 2.15 (s, 3H), 1.88
(m, 15H); MALDIMS: m/z 453 (M þ 1); Anal. Calcd for
C25H34Br2N4O2S (614.4): C, 48.87; H, 5.58; N, 9.12. Found: C, 48.93;
H, 5.61; N, 9.14.
4.2.13. (S)-{5-[N0-(4-Adamantan-1-yl-2-carbonyl)hydrazino]-4-
amino-5-oxopentyl}-guanidine$3HBr (31)
Yield: 95%; mp: 140–142 ꢀC (dec.); 1H NMR (CD3OD):
d 9.15 (br s,
4.2.6. (S)-5-[N0-(4-Adamantan-1-yl-quinoline-2-
carbonyl)hydrazino]-4-amino-5-oxopentanoic acid amide$2HBr
(24)
1H), 8.88 (d, 1H, J ¼ 7.9 Hz), 8.57 (br s, 1H), 8.33 (m, 1H, J ¼ 8.4 Hz),
8.23 (s, 1H), 7.90 (m, 1H), 7.80 (m, 1H), 4.20 (m, 1H), 2.04 (m, 2H),
1.88 (m, 15H), 1.72 (m, 2H), 1.33 (m, 2H); MALDIMS: m/z 478
(M þ 1); Anal. Calc for C26H38Br3N7O2 (720.3): C, 43.35; H, 5.32; N,
13.61. Found: C, 43.32; H, 5.35; N, 13.64.
Yield: 95%; mp: 142–144 ꢀC (dec.); 1H NMR (CD3OD):
d
8.80 (d,
1H, J ¼ 8.4 Hz), 8.39 (d, 1H, J ¼ 8.4 Hz), 8.20 (s, 1H), 7.82 (m, 1H), 7.74

A. Nayyar et al. / European Journal of Medicinal Chemistry 44 (2009) 2017–2029
2027
4.3. General procedure for the synthesis of methyl 2-[4-
(adamantan-1-yl)-2-quinonylcarboxamido]alkanoates (32–44)
4.98 (m, 1H), 3.85 (s, 3H), 2.82 (m, 4H), 1.89 (m, 15H); ESIMS: m/z
450 (M þ 1); Anal. Calcd for C26H31N2O4 (449.5): C, 69.47; H, 6.95;
N, 9.35. Found: C, 69.27; H, 7.21; N, 9.24.
To a mixture of 4-(adamantan-1-yl)-2-quinolincarboxylic acid
(5, 0.324 g, 0.94 mmol) and pyridine (112
mL, 148 mmol) in anhy-
4.3.7. Methyl (2S)-2-[4-(adamantan-1-yl)-2-
drous DCM (15 mL), SOCl2 (95 L, 1.35 mmol) was added under N2
atmosphere. The reaction mixture was stirred at ambient temper-
ature for 1 min. To the intermediate acid chloride was added drop
m
quinonylcarboxamido]-3-phenylpropanoate (38)
Yield: 74%; oil; IR (neat, cmꢃ1): 3350, 1720; 1H NMR (CDCl3):
d
8.75 (br s, 1H), 8.65 (d, 1H, J ¼ 8.7 Hz), 8.22 (s, 1H), 8.15 (d, 1H,
wise
a
solution of the desired
L-amino acid methyl ester
J ¼ 8.4 Hz), 7.72 (m, 1H), 7.56 (m, 1H), 7.30 (m, 5H), 5.04 (m, 1H),
3.82 (s, 3H), 3.39 (m, 2H), 1.88 (m, 15H); ESIMS: m/z 469 (M þ 1);
Anal. Calcd for C30H32N3O2 (468.6), calcd: C, 76.90; H, 6.88; N, 5.98.
Found: C, 76.69; H, 6.49; N, 5.78.
(0.82 mmol) and DMAP (0.81 mmol) in DCM (10 mL) via a syringe
during a period of 5 min under N2 atmosphere. The reaction
mixture was stirred for another 20 min at ambient temperature.
The reaction mixture was diluted with DCM (50 mL) and washed
with water (2 ꢂ 25 mL) and brine solution (1 ꢂ 25 mL). The organic
layer was dried over Na2SO4 and concentrated under reduced
pressure to produce the crude product, which was purified by
column chromatography on silica gel using ethyl acetate/hexanes
(10:90) as eluant to provide methyl 2-[4-(adamantan-1-yl)-2-qui-
nonylcarboxamido]alkanoates 32–44.
4.3.8. Methyl (2S)-2-[4-(adamantan-1-yl)-2-
quinonylcarboxamido]-3-(4-benzyloxyphenyl)propanoate (39)
Yield: 50%; oil; IR (neat, cmꢃ1): 3344, 1718; 1H NMR (CDCl3):
d
8.78 (br s, 1H), 8.67 (d, 1H, J ¼ 8.7 Hz), 8.21 (s, 1H), 8.13 (d, 1H,
J ¼ 8.3 Hz), 7.69 (m, 1H), 7.57 (m, 1H), 7.36 (m, 5H), 7.15 (d, 2H,
J ¼ 8.5 Hz), 6.91 (d, 2H, J ¼ 8.6 Hz), 5.06 (s, 2H), 4.08 (m, 1H), 3.74 (s,
3H), 3.23 (m, 2H), 1.88 (m, 15H); ESIMS: m/z 575 (M þ 1); Anal.
Calcd for C37H38N2O4 (574.7), calcd: C, 77.33; H, 6.66; N, 4.87.
Found: C, 77.18; H, 6.52; N, 4.80.
4.3.1. Methyl 2-[4-(adamantan-1-yl)-2-
quinonylcarboxamido]acetate (32)
Yield: 65%; oil; IR (neat, cmꢃ1): 3380, 1741; 1H NMR (CDCl3):
d
8.75 (br s, 1H), 8.61 (d, 1H, J ¼ 8.5 Hz), 8.24 (m, 2H), 7.75 (m, 1H),
4.3.9. Methyl (2S)-2-[4-(adamantan-1-yl)-2-
7.58 (m, 1H), 4.17 (m, 2H), 3.81 (s, 3H), 1.88 (m, 15H); ESIMS: m/z
393 (M þ 1); Anal. Calcd for C23H26N2O3 (378.5), calcd: C, 72.99; H,
6.92; N, 7.40. Found: C, 72.63; H, 6.68; N, 7.77.
quinonylcarboxamido]-3-(1H-indolyl)propanoate (40)
Yield: 57%; oil; IR (neat, cmꢃ1): 3382, 1725; 1H NMR (CDCl3):
d
8.75 (br s, 1H), 8.61 (d, 1H, J ¼ 8.4 Hz), 8.22 (m, 2H), 7.68 (m, 1H),
7.55 (m, 1H), 7.27 (m, 4H), 6.94 (s, 1H), 5.03 (m, 1H), 3.77 (s, 3H),
3.22 (m, 2H), 1.88 (m, 15H); ESIMS: m/z 508 (M þ 1); Anal. Calcd for
C32H33N3O3 (507.6), calcd: C, 75.71; H, 6.55; N, 8.28. Found: C,
75.64; H, 6.44; N, 8.47.
4.3.2. Methyl (2S)-2-[4-(adamantan-1-yl)-2-
quinonylcarboxamido]propanoate (33)
Yield: 50%; oil; IR (neat, cmꢃ1): 3380, 1741; 1H NMR (CDCl3):
d
8.69 (br s, 1H), 8.66 (d, 1H, J ¼ 8.7 Hz), 8.20 (m, 2H), 7.69 (m, 1H),
7.55 (m, 1H), 4.21 (m, 1H), 3.80 (s, 3H), 1.88 (m, 15H), 1.60 (d, 3H,
J ¼ 6.8 Hz); ESIMS: m/z 393 (M þ 1); Anal. Calcd for C24H28N2O3
(392.4): C, 73.44; H, 7.19; N, 7.14. Found: C, 73.32; H, 7.17; N, 12.19.
4.3.10. Methyl (2S)-2-[4-(adamantan-1-yl)-2-
quinonylcarboxamido]-(1H-4-imidazol-yl)propaonoate (41)
Yield: 58%; oil; IR (neat, cmꢃ1): 3352, 1703; 1H NMR (CDCl3):
d
9.12 (br s, 1H), 8.72 (d, 1H, J ¼ 8.7 Hz), 8.25 (d, 1H, J ¼ 9.8 Hz), 8.17
4.3.3. Methyl (2S,3S)-2-[4-(adamantan-1-yl)-2-
quinonylcarboxamido]-3-methylpentanoate (34)
(s, 1H), 7.90 (s, 1H), 7.76 (m, 1H), 7.67 (m, 1H), 6.25 (s, 1H), 4.20 (m,
1H), 3.86 (s, 3H), 2.28 (m, 2H), 1.88 (m, 15H); ESIMS: m/z 459
(M þ 1); Anal. Calcd for C24H30N4O3 (458.6): C, 70.72; H, 6.59; N,
12.22. Found; C, 70.54; H, 5.47; N, 12.17.
Yield: 54%; oil; IR (neat, cmꢃ1): 3391, 1701; 1H NMR (CDCl3):
d 8.74
(br s,1H), 8.66 (d,1H, J ¼ 8.7 Hz), 8.21 (m, 2H), 7.70 (m,1H), 7.60 (m,1H),
4.83 (m, 1H), 3.78 (s, 3H), 1.88 (m, 15H), 1.33 (m, 1H), 1.25 (m, 2H), 1.10
(m, 6H); ESIMS: m/z435 (M þ 1); Anal. Calcd for C27H34N2O3 (434.5): C,
74.62; H, 7.89; N, 6.45. Found: C, 74.64; H, 7.75; N, 6.38.
4.3.11. Methyl (2S)-2-[4-(adamantan-1-yl)-2-
quinonylcarboxamido]-5-(benzyloxycarbonylamino)pentanoate
(42)
4.3.4. Methyl (2S)-2-[4-(adamantan-1-yl)-2-
Yield: 69%; oil; IR (neat, cmꢃ1): 3400, 1715; 1H NMR (CDCl3):
quinonylcarboxamido]-4-methylpentanoate (35)
d
8.72 (br s, 1H), 8.65 (d, 1H, J ¼ 8.7 Hz), 8.20 (m, 2H), 7.69 (m, 1H),
Yield: 64%; oil; IR (neat, cmꢃ1): 3412, 1720; 1H NMR (CDCl3):
7.57 (m, 1H), 7.33 (m, 5H), 5.08 (s, 2H), 4.84 (m, 1H), 3.70 (s, 3H),
3.26 (m, 2H), 1.88 (m, 15H), 1.24 (m, 4H); APCIMS: m/z 570 (M þ 1);
Anal. Calcd for C34H39N3O5 (569.7): C, 71.68; H, 6.90; N, 7.38. Found:
C, 71.62; H, 6.55; N, 7.32.
d
8.66 (d, 1H, J ¼ 8.7 Hz), 8.59 (br s, 1H), 8.24 (s, 1H), 8.19 (d, 1H,
J ¼ 7.6 Hz), 7.70 (m, 1H), 7.57 (m, 1H), 4.89 (m, 1H), 3.78 (s, 3H), 1.88
(m, 15H), 1.81 (m, 2H), 1.25 (m, 1H), 1.10 (m, 6H); ESIMS: m/z 435
(M þ 1); Anal. Calcd for C27H34N2O3 (434.5): C, 74.62; H, 7.89; N,
6.45. Found: C, 74.65; H, 7.83; N, 6.38.
4.3.12. Methyl (2S)-2-[4-(adamantan-1-yl)-2-
quinonylcarboxamido]-6-(benzyloxycarbonylamino)hexanoate (43)
4.3.5. Methyl (2S)-2-[4-(adamantan-1-yl)-2-
Yield: 65%; oil; IR (neat, cmꢃ1): 3381, 1728; 1H NMR (CDCl3):
quinonylcarboxamido]-4-methylsulfanylbutanoate (36)
d
8.72 (br s, 1H), 8.65 (d, 1H, J ¼ 8.7 Hz), 8.20 (m, 2H), 7.69 (m, 1H),
Yield: 54%; oil; IR (neat, cmꢃ1): 3379, 1731; 1H NMR (CDCl3):
7.57 (m,1H), 7.30 (m, 5H), 5.05 (s, 2H), 4.87 (m,1H), 3.79 (s, 3H), 3.18
(m, 2H), 1.88 (m, 15H), 1.48 (m, 6H); ESIMS: m/z 584 (M þ 1); Anal.
Calcd for C35H41N3O5 (583.7): C, 72.02; H, 7.08; N, 7.20. Found: C,
72.09; H, 7.15; N, 7.25.
d
8.78 (br s, 1H), 8.66 (d, 1H, J ¼ 8.7 Hz), 8.20 (m, 2H), 7.70 (m, 1H),
7.57 (m, 1H), 4.97 (m, 1H), 3.82 (s, 3H), 2.13 (s, 3H), 1.88 (m, 15H),
1.59 (m, 2H), 1.25 (m, 2H); ESIMS: m/z 453 (M þ 1); Anal. Calcd for
C26H32N2O3S (452.2): C, 68.99; H, 7.13; N, 6.19. Found: C, 68.93; H,
7.07; N, 6.15.
4.3.13. Methyl (2S)-2-[4-(adamantan-1-yl)-2-
quinonylcarboxamido]-5-[amino(imino)methylamino]pentanoate
(44)
4.3.6. Methyl (2S)-2-[4-(adamantan-1-yl)-2-
quinonylcarboxamido]-4-carbamoylbutanoate (37)
Yield: 41%; oil; IR (neat, cmꢃ1): 3380, 1730; 1H NMR (CDCl3):
8.75 (br s, 1H), 8.67 (d, 1H, J ¼ 8.6 Hz), 8.25 (m, 2H), 7.70 (m, 1H),
Yield: 61%; oil; IR (neat, cmꢃ1): 3385, 1730; 1H NMR (CDCl3):
d
d
8.70 (d, 1H, J ¼ 8.4 Hz), 8.25 (m, 2H), 7.74 (m, 1H), 7.52 (m, 1H),
7.52 (m, 1H), 5.01 (M, 1H), 3.78 (s, 3H), 2.90 (m, 2H), 2.03 (m, 2H),

2028
A. Nayyar et al. / European Journal of Medicinal Chemistry 44 (2009) 2017–2029
1.88 (m, 17H); ESIMS: m/z 478 (M þ 1); Anal. Calcd for C27H35N5O3
(477.6): C, 67.90; H, 7.39; N, 14.66. Found: C, 67.78; H, 7.57; N,
14.41.
4.4.6. N2-[(1S)-3-Carbamoyl-1-hydrazinocarbonylpropyl]-4-
(adamantan-1-yl)-2-quinolinecarboxamide (50)
Yield: 90%; semi-solid; 1H NMR (CDCl3):
d 8.68 (d, 1H,
J ¼ 8.4 Hz), 8.21 (m, 2H), 7.74 (m, 1H), 7.57 (m, 1H), 4.96 (m, 1H),
2.80 (m, 4H), 1.88 (m, 15H); ESIMS: m/z 450 (M þ 1); Anal. Calcd for
C25H31N5O3 (449.6): C, 66.79; H, 6.95; N, 15.58. Found: C, 66.87; H,
7.15; N, 15.23.
4.4. General procedure for the synthesis of N2-[1-
hydrazinocarbonylalkyl]-4-(adamantan-1-yl)-2-
quinolinecarboxamides (45–57)
To the solution of methyl 2-[4-(adamantan-1-yl)-2-quino-
nylcarboxamido]alkanoate (32–44, 0.1 mmol) in abs. ethyl alcohol
(10 mL), hydrazine hydrate (0.5 mL, 12.5 mmol) was added and the
reaction mixture was stirred for 48 h at ambient temperature. The
solvent was removed under reduced pressure to afford 45–51, 53–
54, and 57.
4.4.7. N2-[(1S)-1-Hydrazinocarbonyl-2-phenylethyl]-4-
(adamantan-1-yl)-2-quinolinecarboxamide (51)
Yield: 91%; semi-solid; 1H NMR (CDCl3): 8.69 (d, 1H, J ¼ 8.7 Hz),
8.24 (s, 1H), 8.17 (d, 1H, J ¼ 8.4 Hz), 7.70 (m, 1H), 7.52 (m, 1H), 7.28
(m, 5H), 5.00 (m, 1H), 3.40 (m, 2H), 1.89 (m, 15H); ESIMS: m/z 469
(M þ 1); Anal. Calcd for C29H32N4O2 (468.6): C, 74.33; H, 6.88; N,
11.96. Found: C, 74.10; H, 6.59; N, 11.67.
In certain cases where the side chain of the amino acid in
methyl
2-[4-(adamantan-1-yl)-2-quinonylcarbox-
amido]alkanoates was protected (i.e. Orn, Lys with a carbobenzy-
loxy, and Tyr with a benzyl group), an additional deprotection step
as described below was carried out to obtain desired compounds.
A solution of 33% HBr in acetic acid (2 mL) was added to inter-
mediates 39, and 42–43 (0.1 mmol) and the reaction mixture was
stirred at ambient temperature for 30 min. The solvent was
removed under reduced pressure to afford 52, and 55–56 as
hydrobromide salts.
4.4.8. N2-[(1S)-1-Hydrazinocarbonyl-2-(4-hydroxyphenyl)ethyl]-
4-(adamantan-1-yl)-2-quinolinecarboxamide$2HBr (52)
Yield: 96%; mp: 155–157 ꢀC (dec.); 1H NMR (CD3OD):
d 8.98 (d,
1H, J ¼ 8.8 Hz), 8.37 (d,1H, J ¼ 8.3 Hz), 8.20 (s,1H), 8.02 (m,1H), 7.88
(d, 2H, J ¼ 8.1 Hz), 7.17 (d, 2H, J ¼ 8.1 Hz), 6.74 (d, 2H, J ¼ 7.7 Hz),
3.34 (s, 2H), 1.88 (m, 15H); ESIMS: m/z 485 (M þ 1); Anal. Calcd for
C29H34Br2N4O3 (646.4): C, 53.88; H, 5.30; N, 8.67. Found: C, 53.78;
H, 5.27; N, 8.63.
4.4.1. N2-1-Hydrazinocarbonylmethyl-4-(adamantan-1-yl)-2-
quinolinecarboxamide (45)
4.4.9. N2-[(1S)-1-Hydrazinocarbonyl-2-(1H-indolyl)ethyl]-4-
(adamantan-1-yl)-2-quinolinecarboxamide (53)
Yield: 95%; semi-solid; 1H NMR (CDCl3):
d
9.12 (br s, 1H), 8.67 (d,
Yield: 88%; semi-solid; 1H NMR (CDCl3):
d 8.60 (d, 1H,
1H, J ¼ 8.8 Hz), 8.25 (s, 1H), 8.17 (d, 1H, J ¼ 8.3 Hz), 7.70 (m, 1H), 7.58
(m, 1H), 3.2 (s, 2H), 1.88 (m, 15H); ESIMS: m/z 379 (M þ 1); Anal.
Calcd for C22H26N4O2 (378.5): C, 69.82; H, 6.92; N, 14.80. Found: C,
69.85; H, 6.95; N, 14.78.
J ¼ 8.4 Hz), 8.24 (m, 2H), 7.65 (m, 1H), 7.52 (m, 1H), 7.29 (m, 4H),
6.96 (s, 1H), 5.05 (m, 1H), 3.20 (m, 2H), 1.88 (m, 15H); ESIMS: m/z
508 (M þ 1); Anal. Calcd for C31H33N5O2 (507.6): C, 73.35; H, 6.55;
N, 13.80. Found: C, 73.64; H, 6.40; N, 13.90.
4.4.2. N2-[(1S)-1-Hydrazinocarbonylethyl]-4-(adamantan-1-yl)-2-
quinolinecarboxamide (46)
4.4.10. N2-[(1S)-1-Hydrazinocarbonyl-2-(1H-4-imidazolyl)ethyl]-
4-(adamantan-1-yl)-2-quinolinecarboxamide (54)
Yield: 95%; semi-solid; 1H NMR (CDCl3):
d
8.66 (d, 1H,
Yield: 99%; semi-solid; 1H NMR (CDCl3):
d 8.71 (d, 1H,
J ¼ 8.7 Hz), 8.53 (br s, 1H), 8.18 (m, 2H), 7.73 (m, 1H), 7.58 (m, 1H),
4.71 (m, 1H), 1.88 (m, 15H), 1.60 (d, 3H, J ¼ 6.8 Hz); ESIMS: m/z 393
(M þ 1); Anal. Calcd for C23H28N4O2 (392.4): C, 70.38; H, 7.19; N,
14.27. Found: C, 70.42; H, 7.21; N, 14.31.
J ¼ 8.6 Hz), 8.25 (d, 1H, J ¼ 9.6 Hz), 8.17 (s, 1H), 7.91 (s, 1H), 7.75
(m, 1H), 7.65 (m, 1H), 6.23 (s, 1H), 4.19 (m, 1H), 232 (m, 2H), 1.88
(m, 15H); ESIMS: m/z 459 (M þ 1); Anal. Calcd for C26H30N6O2
(458.6): C, 68.10; H, 6.59; N, 18.33. Found; C, 68.08; H, 6.57; N,
18.32.
4.4.3. N2-[(1S,2S)-1-Hydrazinocarbonyl-2-methylbutyl]-4-
(adamantan-1-yl)-2-quinolinecarboxamide (47)
4.4.11. N2-[(1S)-1-Hydrazinocarbonylbutyl]-4-(adamantan-1-yl)-
2-quinolinecarboxamide$3HBr (55)
Yield: 95%; semi-solid; 1H NMR (CDCl3):
d 8.66 (d, 1H,
J ¼ 8.4 Hz), 8.49 (br s, 1H), 8.18 (m, 2H), 7.72 (m, 1H), 7.58 (m,
1H), 4.67 (m, 1H), 1.88 (m, 15H), 1.31 (m, 1H), 1.23 (m, 2H), 1.10
(m, 6H); ESIMS: m/z 435 (M þ 1); Anal. Calcd for C26H34N4O2
(434.5): C, 71.86; H, 7.89; N, 12.89. Found: C, 71.89; H, 7.91; N,
12.85.
Yield: 97%; mp: 121–123 ꢀC (dec.); 1H NMR (CD3OD):
d 9.10 (d,
1H, J ¼ 8.9 Hz), 8.54 (m, 2H), 8.14 (m, 1H), 8.00 (m, 1H), 4.85 (m, 1H),
3.10 (m, 2H), 2.17 (m, 2H), 1.88 (m, 15H), 1.30 (m, 2H); MALDIMS: m/
z 436 (M þ 1); Anal. Calcd for C25H36Br3N5O2 (678.3): C, 44.27; H,
5.35; N, 10.32. Found: C, 44.21; H, 5.28; N, 10.27.
4.4.4. N2-[(1S)-1-Hydrazinocarbonyl-3-methylbutyl]-4-
(adamantan-1-yl)-2-quinoline-carboxamide (48)
4.4.12. N2-[(1S)-1-Hydrazinocarbonylpentyl]-4-(adamantan-1-yl)-
2-quinolinecarboxamide$3HBr (56)
Yield: 95%; semi-solid; 1H NMR (CDCl3):
d
8.67 (d, 1H,
Yield: 98%; mp: 115–117 ꢀC (dec.); 1H NMR (CD3OD):
d 9.00 (d,
J ¼ 8.3 Hz), 8.18 (m, 2H), 7.71 (m, 1H), 7.59 (m, 1H), 7.47 (br s,
1H), 4.44 (m, 1H), 1.88 (m, 15H), 1.61 (m, 2H), 1.25 (m, 1H), 0.99
(m, 6H); ESIMS: m/z 435 (M þ 1); Anal. Calcd for C26H34N4O2
(434.5): C, 71.86; H, 7.89; N, 12.89. Found: C, 71.92; H, 7.95; N,
12.87.
1H, J ¼ 8.8 Hz), 8.41 (d, 1H, J ¼ 8.4 Hz), 8.36 (s, 1H), 7.99 (m, 1H), 7.87
(m, 1H), 4.77 (m, 1H), 2.98 (m, 2H), 2.09 (m, 2H), 1.88 (m, 15H), 1.30
(m, 4H); ESIMS: m/z 450 (M þ 1); Anal. Calcd for C26H38Br3N5O2
(692.3): C, 45.11; H, 5.53; N, 10.12. Found: C, 45.07; H, 5.49; N, 10.07.
4.4.13. N2-[(1S)-4-Amino(imino)methylamino-1-
hydrazinocarbonylbutyl]-4-(adamantan-1-yl)-2-
quinolinecarboxamide (57)
4.4.5. N2-[(1S)-1-Hydrazinocarbonyl-3-methylsulfanylpropyl]-4-
(adamantan-1-yl)-2-quinolinecarboxamide (49)
Yield: 95%; semi-solid; 1H NMR (CDCl3):
d
8.72 (br s,1H), 8.66 (d,
Yield: 95%; semi-solid; 1H NMR (CDCl3):
d 8.68 (d, 1H,
1H, J ¼ 7.9 Hz), 8.17 (m, 2H), 7.69 (m, 1H), 7.59 (m, 1H), 4.85 (m, 1H),
2.64 (m, 2H), 2.13 (s, 3H), 1.88 (m, 15H), 1.25 (m, 2H); ESIMS: m/z
453 (M þ 1); Anal. Calcd for C25H32N4O2S (452.2): C, 66.34; H, 7.13;
N, 12.38. Found: C, 66.37; H, 7.14; N, 12.28.
J ¼ 8.4 Hz), 8.20 (d, 1H, J ¼ 9.2 Hz), 8.17 (s, 1H), 7.75 (m, 1H), 7.65 (m,
1H), 4.50 (m, 1H), 3.02 (m, 2H), 1.62 (m, 4H), 1.88 (m, 15H); ESIMS:
m/z 478 (M þ 1); Anal. Calcd for C26H35N7O2 (477.6): C, 65.38; H,
7.39; N, 20.53. Found: C, 65.64; H, 7.14; N, 20.23.

A. Nayyar et al. / European Journal of Medicinal Chemistry 44 (2009) 2017–2029
2029
[7] V. Monga, A. Nayyar, B. Vaitilingam, P.B. Palde, S.S. Jhamb, P.P. Singh, R. Jain,
Bioorg. Med. Chem. 12 (2004) 6465–6472.
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The authors are thankful to the Tuberculosis Antimicrobial
Acquisition and Coordination Facility (TAACF), which provided
partial antimycobacterial data through a research and development
contract with the U.S. National Institute of Allergy and Infectious
Diseases. Amit Nayyar and Sanjay R. Patel thank the Council of
Scientific and Industrial Research (CSIR), and the Department of
Biotechnology (DBT, grant no. CSH/GIA/1490), India, respectively,
for the award of Senior Research Fellowship. The computational
facilities at Bombay College of Pharmacy were jointly provided by
the All India Council of Technical Education through grant (F. No.
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and Technology through their FIST program (SR/FST/LSI–163/2003).
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