Ring-substituted quinolines. Part 2: Synthesis and antimycobacterial activities of ring-substituted quinolinecarbohydrazide and ring-substituted quinolinecarboxamide analogues

Article abstract of DOI:10.1016/j.bmc.2004.09.017

The antimycobacterial activities of ring-substituted quinolinecarbohydrazide and ring-substituted quinolinecarboxamide analogues (series 1-5) against M. tuberculosis H37Rv strains are described. The most effective analogues have exhibited excellent antimy

Full text of DOI:10.1016/j.bmc.2004.09.017

Bioorganic & Medicinal Chemistry 12 (2004) 6465–6472
Ring-substituted quinolines. Part 2: Synthesis and
antimycobacterial activities of ring-substituted
quinolinecarbohydrazide and ring-substituted
quinolinecarboxamide analoguesI
Vikramdeep Monga,a Amit Nayyar,a Balasubramanian Vaitilingam,a Prakash B. Palde,a
Sarbjit Singh Jhamb,b Sukhraj Kaur,b Prati Pal Singhb and Rahul Jaina,*
aDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar,
Punjab 160 062, India
bDepartment of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67,
S.A.S. Nagar, Punjab 160 062, India
Received 27 August 2004; revised 14 September 2004; accepted 14 September 2004
Available online 2 October 2004
Abstract—Additional structural modifications of the new chemical entity, 2,8-dicyclopentyl-4-methylquinoline (DCMQ;
MIC = 6.25lg/mL, M. tuberculosis H37Rv) resulted in the synthesis of four new series of the ring-substituted quinolinecarbohy-
drazides (series 1–4) constituting 22 analogues. All new derivatives were evaluated for in vitro antimycobacterial activities against
drug-sensitive M. tuberculosis H37Rv strain. Certain ring-substituted-2-quinolinecarbohydrazide analogues described herein showed
good inhibitory activity. In particular, analogues 4-(1-adamantyl)-2-quinolinecarbohydrazide (2d), 4,5-dicyclopentyl-2-quinoline-
carbohydrazide (2e), 4,8-dicyclopentyl-2-quinolinecarbohydrazide (2f), and 4,5-dicyclohexyl-2-quinolinecarbohydrazide (2g) have
exhibited the MIC value of 6.25lg/mL. Further investigation of the most suitable lead prototype, 4-(1-adamantyl)-2-quinolinecar-
bohydrazide (2d, series 1) led to the synthesis of N2-alkyl/N2,N2-dialkyl/N2-aryl-4-(1-adamantyl)-2-quinolinecarboxamides (series
5) consisting of 13 analogues. Some of the synthesized carboxamides 7a, 7h, and 7m reported herein have exhibited excellent anti-
mycobacterial activities in the range of 6.25–3.125lg/mL against drug-sensitive and drug-resistant M. tuberculosis H37Rv strains.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
ing data4 of M. tuberculosis for the discovery of new
specific targets is still not fully developed and may take
many more years to provide potentially useful target(s)
based anti-tuberculosis drugs.5–7
Despite the worldwide public health impact of tubercu-
losis, no new structural class of drug specifically target-
ing the causative organism, Mycobacterium tuberculosis
is introduced in the market during the past 40years.2
Worldwide emergence of the multi-drug resistant strains
of the M. tuberculosis, and resurgence of the disease
especially in the immuno-compromised individuals are
considered as the major factors for increase in the num-
ber of mortality cases.3 The use of the genomic sequenc-
Previously, through a structural-directed antimycobac-
terial drug-screening program we have reported the dis-
covery of ring-substituted quinolines as a new structural
class of anti-tuberculosis agent.8 The most promising
analogue, 2,8-dicyclopentyl-4-methylquinoline (DCMQ)
has exhibited interesting anti-tuberculosis activities
against both drug-sensitive and drug-resistant M. tuber-
culosis H37Rv strains.8 Although, DCMQ itself is an
attractive molecule for drug development and synthe-
sized via a one-step transformation from lepidine, it suf-
fers due to low yield (24%). With a view to overcome
this drawback, we have undertaken a systematic study
into the chemical optimization of DCMQ in order to de-
fine and determine more suitable pharmacophore(s) that
Keywords: Tuberculosis; Ring-substituted quinolinecarbohydrazides;
Ring-substituted quinolinecarboxamides; 2,8-Dicyclopentyl-4-methyl-
quinoline (DCMQ); 4-(1-Adamantyl)-2-quinolinecarbohydrazide
(AQCH).
q See Ref. 1.
*
Corresponding author. Tel.: +91 0172 221 4682; fax: +91 0172 221
4692; e-mail: rahuljain@niper.ac.in
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.09.017

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V. Monga et al. / Bioorg. Med. Chem. 12 (2004) 6465–6472
O
O
NHNH2
R1
R4 R3
NHNH2
R1
R3
O
NHNH2
NHNH2
R1
N
N
N
N
N
R1
O
R5
O
R5
Series 3
Series 4
Series 2
Series 1
Series 5
Figure 1.
CO2CH3/C2H5
(CH2)n
CONHNH2
(CH2)n
NH2NH2.H2O
80 oC, 8h
R
R
N
N
1
2-5
n= 0, 1
Scheme 1.
could also result in overall improvement in the biologi-
cal activity. Initially, we have decided to replace only
the methyl group in DCMQ with other easily derivatized
functional groups while at the same time retaining the
cycloalkyl groups placed at the various positions of
the quinoline ring. This strategy seemed particularly
appealing since it has demonstrated that replacement
of the methyl group by other functionalities like an
amino, a nitro, or an ester group largely preserves or en-
hances the biological activity of the resulting ana-
logues.1,9 These results have encouraged us to further
explore other functionalities as the replacement of
methyl group. Herein, we describe synthesis and anti-
mycobacterial activities of several ring-substituted
quinolinecarbohydrazides (series 1–4, Fig. 1). It is
worthwhile to mention that some of the ring-substituted
quinoline esters used for the preparation of ring-substi-
tuted quinolinecarbohydrazides reported herein have
produced good anti-tuberculosis activities as reported
earlier.1 Preliminary biological activity data indicated
that the analogue 4-(1-adamantyl)-2-quinolinecarbo-
hydrazide (2d, series 1) has exhibited interesting biolog-
ical results. In addition, analogue 2d is synthesized in
three convenient steps from commercially available 2-
quinolinecarboxylic acid in high overall yields. Hence,
analogue 2d is considered as an excellent lead prototype,
and ideally suited to emulate while designing new ana-
logues. Keeping these observations in mind, we decided
to further investigate 2d for structural optimization by
synthesizing congeners, which may exhibit potent anti-
tuberculosis activities. Thus, herein, we also report
synthesis and antimycobacterial activities of several
ring-substituted quinolinecarboxamides (series 5, Fig. 1).
methyl 2-substituted-4-quinolinecarboxylates or methyl/
ethyl 2-(2-substituted/2,8-disubstituted-4-quinolyl)ace-
tates 1,1 upon reaction with hydrazine hydrate in 95%
ethyl alcohol at 80ꢁC for 8h produced 4-substituted/
4,5-disubstituted/4,8-disubstituted-2-quinolinecarbohydr-
azides 2a–h (series 1), 2-substituted/2,4-disubstituted-3-
quinolinecarbohydrazides 3a–d (series 2), 2-substituted-
4-quinolinecarbohydrazides 4a–d (series 3), and
2-(2-substituted/2,8-disubstituted-4-quinolyl)ethanohydr-
azides 5a–f (series 4), respectively, in quantitative yields
(Scheme 1).
As discussed above, further structural optimization of
analogue 2d was accomplished by synthesizing various
carboxamide analogues 7a–m. Thus, methyl 4-(1-ada-
mantyl)-2-quinolinecarboxylate1 upon reaction with
7N NH3/MeOH for 12h at reflux temperature readily
provided
4-(1-adamantyl)-2-quinolinecarboxamide
(7a). On the other hand, 4-(1-adamantyl)-2-quinoline-
carboxylic acid (6) required for the synthesis of N2-al-
kyl/N2,N2-dialkyl/N2-aryl-4-(1-adamantyl)-2-quinolin-
ecarboxamides 7b–m was prepared in three steps from
commercially available 2-quinolinecarboxylic acid as de-
scribed earlier.1 Carboxylic acid 6 upon reaction with
the excess of thionyl chloride in dichloroethane (DCE)
at 80ꢁC for 1h easily afforded the corresponding acid
chloride, which upon reaction with the several commer-
cially available primary and secondary alkyl amines and
the aryl amines in dichloromethane (DCM) at 4ꢁC in
the presence of triethylamine (Et3N), followed by
stirring for 12h at ambient temperature afforded N2-al-
kyl/N2,N2-dialkyl/N2-aryl-4-(1-adamantyl)-2-quinolin-
ecarboxamides 7b–m (series 5) in satisfactory yields
(Scheme 2).
2. Chemistry
3. Biological activity
Various methyl 4-substituted/4,5-disubstituted/4,8-
disubstituted-2-quinolinecarboxylates or methyl 2-
substituted/2,4-disubstituted-3-quinolinecarboxylates or
In vitro activity of the synthesized analogues (series 1–5)
for tuberculosis inhibition against M. tuberculosis

V. Monga et al. / Bioorg. Med. Chem. 12 (2004) 6465–6472
6467
SOCl2, DCE, 80 oC, 1h
R1
RNH2/R,R'NH, Et3N, DCM
oC to rt, 12 h
N
CO2H
N
O
4
6
7b-m
Scheme 2.
H37Rv strain (ATCC 27294, susceptible both to rif-
ampicin and isoniazid) was initially carried out using
the Microplate Alamar Blue Assay (MABA) at a con-
centration of 6.25lg/mL.10 Compounds exhibiting fluo-
rescence were then tested in the BACTEC 460
radiometric system,11 and activities expressed as mini-
mum inhibitory concentration (MIC, lg/mL) are sum-
marized in Tables 1 and 2. Compounds demonstrating
P90% inhibition at a concentration of 6.25lg/mL in
the initial screen were then retested at the lower concen-
trations of 3.125, 1.562, 1.0, 0.5, and 0.25lg/mL to
determine the actual MIC value that is defined as the
lowest concentration exhibiting P90% inhibition.
Several derivatives (3c, 5e, and 5f) appeared to have
exhibited moderate inhibitory antimycobacterial activity
(<70% inhibition, MICs > 6.25lg/mL) against drug-
sensitive M. tuberculosis H37Rv strain (Table 1). Four
derivatives, 4-(1-adamantyl)-2-quinolinecarbohydrazide
(2d), 4,5-dicyclopentyl-2-quinolinecarbohydrazide (2e),
4,8-dicyclopentyl-2-quinolinecarbohydrazide (2f), and
4,5-dicyclohexyl-2-quinolinecarbohydrazide (2g) exhib-
ited excellent inhibitory activity against M. tuberculosis
H37Rv and produced MIC value of 6.25lg/mL (series
1, Table 1). In general it is observed that ring-substituted
quinoline analogues containing hydrazide group placed
at the C-3 and C-4 position of the quinoline ring are less
Table 1. In vitro antimycobacterial activity data of ring-substituted quinolinecarbohydrazides 2a–h (series 1), 3a–d (series 2), 4a–d (series 3), and 5a–f
(series 4) against drug-sensitive strain of M. tuberculosis H37Rv
R4 R3
R2
R1
N
R5
S. No.
R1
R2
R3
R4
R5
(%) Inhibition
MIC (lg/mL)
Series 1
2a
2b
CONHNH2
CONHNH2
CONHNH2
CONHNH2
CONHNH2
CONHNH2
CONHNH2
CONHNH2
H
H
H
H
H
H
H
H
H
H
H
0
0
>6.25
>6.25
>6.25
6.25
c-C5H9
c-C6H11
H
H
2c
2d
H
H
0
1-Adamantyl
c-C5H9
c-C5H9
H
H
99
90
92
91
23
2e
c-C5H9
H
H
6.25
6.25
2f
2g
c-C5H9
H
c-C6H11
c-C6H11
c-C6H11
c-C6H11
H
6.25
>6.25
2h
Series 2
3a
3b
H
CONHNH2
CONHNH2
CONHNH2
CONHNH2
H
H
H
H
H
H
H
H
H
0
32
56
44
>6.25
>6.25
>6.25
>6.25
1-Adamantyl
c-C5H9
c-C6H11
H
3c
3d
c-C5H9
c-C6H11
Series 3
4a
4b
H
H
H
H
H
CONHNH2
CONHNH2
CONHNH2
CONHNH2
H
H
H
H
H
H
H
H
0
2
>6.25
>6.25
>6.25
>6.25
c-C5H9
c-C6H11
1-Adamantyl
4c
4d
2
17
Series 4
5a
5b
H
H
H
H
H
H
H
CH2CONHNH2
CH2CONHNH2
CH2CONHNH2
CH2CONHNH2
CH2CONHNH2
CH2CONHNH2
H
H
H
H
H
H
H
9
1
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
6.25
c-C5H9
c-C6H11
1-Adamantyl
c-C5H9
c-C6H11
H
5c
5d
H
12
31
67
56
100
99
H
5e
5f
c-C5H9
c-C6H11
DCMQ
Isoniazid
1.00

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V. Monga et al. / Bioorg. Med. Chem. 12 (2004) 6465–6472
Table 2. In vitro antimycobacterial activity data of N2-alkyl/N2,N2-
dialkyl/N2-aryl-4-(1-adamantyl)-2-quinolinecarboxamides 7a–m (ser-
ies 5) against drug-sensitive strain of M. tuberculosis H37Rv
exhibited excellent antimycobacterial activity and pro-
duced 99% inhibition at a concentration of 3.125lg/
mL (MIC) (Table 2).
Two of the most effective derivatives, N2-phenyl-4-(1-
adamantyl)-2-quinolinecarboxamide (7h) and N2-benz-
yl-4-(1-adamantyl)-2-quinolinecarboxamide (7m) were
also evaluated for antimycobacterial activity against
isoniazid resistant strain of M. tuberculosis H37Rv and
derivative 7h exhibited promising activity (99% inhibi-
tion, MIC = 6.25lg/mL).
R1
N
O
S. No.
R1
(%) Inhibition
MIC (lg/mL)
7a
7b
7c
7d
7e
7f
NH2
98
3
6.25
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
NH(CH2)2CH3
NH(CH2)3CH3
NH(CH2)4CH3
NH(CH2)5CH3
NH(CH2)6CH3
N(CH2CH3)2
4. Conclusions
22
14
12
1
We have earlier reported the discovery of the 2,8-dicyclo-
pentyl-4-methylquinoline (DCMQ) as a new anti-tuber-
culosis chemical entity. Our present studies on the
systematic structural optimization of the DCMQ led to
the synthesis and discovery of 4-(1-adamantyl)-2-quino-
linecarbohydrazide (AQCH, 2d) as another new chemi-
cal entity. As discussed earlier although, DCMQ itself
is an attractive molecule for drug development; it suffers
due to low yield. On the other hand, AQCH is equally
potent compared to DCMQ, and is synthesized in high
overall yields in three convenient steps. Thus, in our
opinion AQCH is a more suitable molecule for lead opti-
mization compared to DCMQ. Earlier we have observed
that only dialkylated quinolines exhibit superior anti-
mycobacterial activities as illustrated by DCMQ. The
current study has established that a suitable bulky alkyl
group containing quinolinecarbohydrazide 2d also
exhibits potent antimycobacterial activity. The results
of this study also show that analogue 2d is attractive
for further lead optimization as observed from excellent
anti-tuberculosis activities produced by two ring-substi-
tuted quinolinecarboxamides 7h and 7m. Our inves-
tigations on the further structural diversification of
7g
2
7h
7i
7j
99
35
35
3.125
>6.25
>6.25
N
H
OCH3
N
H
OCH3
N
H
Cl
NO2
7k
7l
43
40
99
>6.25
>6.25
3.125
N
H
N
N
H
H
N
7m
4-(1-adamantyl)-2-quinolinecarbohydrazide
are currently underway and results of these studies will
be reported in the due course of time.
(AQCH)
DCMQ
Isoniazid
100
99
6.25
1.00
effective compared to the analogues in which hydrazide
moiety is placed at the C-2 position. Interestingly
though not surprisingly, carbohydrazide analogues 2a,
3a, 4a, and 5a where quinoline ring is not alkylated were
found to be completely inactive. This affirms our earlier
observation that the placement of suitable alkyl groups
in the quinoline ring is utmost important for anti-tuber-
culosis activity.
5. Experimental
Melting points were recorded on Mettler DSC 851 or cap-
illary melting point apparatus and are uncorrected. H
1
spectra were recorded on 300MHz Bruker FT-NMR
(Avance DPX300) spectrometer using tetramethylsilane
as internal standard and the chemical shifts are reported
in d units. Mass spectra were recorded on either GCMS
(Shimadzu QP 5000 spectrometer) auto sampler/direct
injection (EI/CI) or HRMS (Finnigan Mat LCQ spec-
trometer) (APCI/ESI). Elemental analyses were recorded
on Elementar Vario EL spectrometer. All chromato-
graphic purification was performed with silica gel 60
(230–400mesh), whereas all TLC (silica gel) development
New chemical entity, 4-(1-adamantyl)-2-quinolinecarbo-
hydrazide (AQCH, 2d) was further investigated, and a
series of 13 analogues representing N2-alkyl/N2,N2-
dialkyl/N2-aryl-4-(1-adamantyl)-2-quinolinecarboxamides
7a–m was synthesized (series 5). Biological activity data
revealed that one analogue 4-(1-adamantyl)-2-quinoline-
carboxamide (7a) has exhibited good efficacy and exhib-
ited 98% inhibition at a concentration of 6.25lg/mL
(MIC). Whereas, two analogues N2-phenyl-4-(1-ada-
mantyl)-2-quinolinecarboxamide (7h) and N2-benzyl-4-
was performed on silica gel coated (Merck Kiesel 60 F254
,
0.2mm thickness) sheets. All chemicals were purchased
from Aldrich Chemical Ltd (Milwaukee, WI, USA). Sol-
vents used for the chemical synthesis acquired from com-
mercial sources were of analytical grade, and were used
without further purification unless otherwise stated.
(1-adamantyl)-2-quinolinecarboxamide
(7m)
have

V. Monga et al. / Bioorg. Med. Chem. 12 (2004) 6465–6472
6469
5.1. Typical procedure for the synthesis of various 4-
substituted/4,5-disubstituted/4,8-disubstituted-2-quino-
linecarbohydrazides 2a–h, 2-substituted/2,4-disubstituted-
3-quinolinecarbohydrazides 3a–d, 2-substituted-4-quino-
linecarbohydrazides 4a–d, and 2-(2-substituted/2,8-disub-
stituted-4-quinolyl)ethanohydrazides 5a–f
7.67 (d, 1H, J = 8.7Hz), 7.87 (m, 2H), 8.17 (s, 1H),
8.20 (br s, 1H); ESI MS m/z 324 (M+1); Anal. Calcd
for C20H25N3O (323.4): C, 74.27; H, 7.79; N, 12.99.
Found: C, 74.21; H, 7.85; N, 12.83.
5.1.7. 4,5-Dicyclohexyl-2-quinolinecarbohydrazide (2g).
1
Yield: 90%; mp 112–113ꢁC; H NMR (CDCl3): d 1.65
To a solution of methyl 4-substituted/4,5-disubstituted/
4,8-disubstituted-2-quinolinecarboxylate or methyl 2-
substituted/2,4-disubstituted-3-quinolinecarboxylate or
methyl 2-substituted-4-quinolinecarboxylate1 or methyl/
ethyl 2-(2-substituted/2,8-disubstituted-4-quinolyl)ace-
tate (1, 5mmol) in 95% ethyl alcohol (10mL) hydrazine
hydrate (10mL) was added and reaction mixture was
heated under reflux for 8h. The hydrazides 2a–h, 3a–d,
4a–d, and 5a–f were obtained in quantitative yields di-
rectly after evaporation of the reaction solution without
any additional purification step.
(m, 20H), 3.41 (m, 1H), 4.01 (m, 1H), 4.11 (br s, 2H),
7.66 (d, 1H, J = 8.4Hz), 7.85 (m, 1H), 8.15 (s, 1H),
8.19 (br s, 1H), 8.30 (d, 1H, J = 8.4Hz); ESI MS m/z
352 (M+1); Anal. Calcd for C22H29N3O (351.5): C,
75.18; H, 8.32; N, 11.96. Found: C, 75.27; H, 8.47; N,
11.85.
5.1.8. 4,8-Dicyclohexyl-2-quinolinecarbohydrazide (2h).
1
Yield: 97%; mp 114–115ꢁC; H NMR (CDCl3): d 1.72
(m, 20H), 3.30 (m, 1H), 4.12 (m, 1H), 4.17 (br s, 2H),
7.69 (d, 1H, J = 8.3Hz), 7.81 (m, 2H), 8.15 (s, 1H),
8.20 (br s, 1H); ESI MS m/z 352 (M+1); Anal. Calcd
for C22H29N3O (351.5): C, 75.18; H, 8.32; N, 11.96.
Found: C, 75.09; H, 8.31; N, 11.91.
5.1.1. 2-Quinolinecarbohydrazide (2a). Yield: 95%; mp
1
101–102ꢁC; H NMR (CDCl3): d 5.81 (br s, 2H), 6.71
(m, 1H), 7.40 (br s, 1H), 7.48 (m, 1H), 7.72 (d, 1H,
J = 8.35Hz), 7.91 (d, 1H, J = 8.60Hz), 8.40 (d, 1H,
J = 8.35Hz); EI MS m/z 187 (M+); Anal. Calcd for
C10H9N3O (187.2): C, 64.16; H, 4.85; N, 22.45. Found:
C, 63.87; H, 5.10; N, 22.27.
5.1.9. 3-Quinolinecarbohydrazide (3a). Yield: 99%; mp
87–88ꢁC; 1H NMR (CDCl3): d 4.99 (br s, 2H), 7.11
(m, 1H), 7.40 (m, 1H), 8.01 (d, 1H, J = 8.3Hz), 8.11
(d, 1H, J = 8.4Hz), 8.51 (s, 1H), 9.31 (s, 1H); EI MS
m/z 187 (M+); Anal. Calcd for C10H9N3O (187.2): C,
64.16; H, 4.85; N, 22.45. Found: C, 64.22; H, 4.97; N,
22.51.
5.1.2. 4-Cyclopentyl-2-quinolinecarbohydrazide (2b).
1
Yield: 98%; mp 110–111ꢁC; H NMR (CDCl3): d 1.63
(m, 8H), 3.30 (m, 1H), 4.11 (br s, 2H), 7.62 (m, 1H),
7.73 (m, 1H), 8.12 (m, 2H), 8.15 (br s, 1H), 8.35 (d,
1H, J = 8.5Hz); EI MS m/z 255 (M+); Anal. Calcd for
C15H17N3O (255.3): C, 70.56; H, 6.71; N, 16.46. Found:
C, 70.55; H, 6.68; N, 16.39.
5.1.10. 2-(1-Adamantyl)-3-quinolinecarbohydrazide (3b).
1
Yield: 100%; mp 101–102ꢁC; H NMR (CDCl3): d 2.00
(m, 15H), 5.16 (br s, 2H), 7.28 (m, 1H), 7.87 (m, 1H),
8.05 (d, 1H, J = 8.3Hz), 8.20 (d, 1H, J = 8.2Hz), 8.61
(s, 1H); EI MS m/z 321 (M+); Anal. Calcd for
C20H23N3O (321.4): C, 74.74; H, 7.21; N, 13.07. Found:
C, 74.89; H, 7.43; N, 13.21.
5.1.3. 4-Cyclohexyl-2-quinolinecarbohydrazide (2c). Yield:
1
98%; mp 112ꢁC; H NMR (CDCl3): d 1.60 (m, 10H),
3.36 (m, 1H), 4.11 (br s, 2H), 7.65 (m, 1H), 7.78 (m,
1H), 8.19 (m, 2H), 8.25 (br s, 1H), 8.37 (d, 1H,
J = 8.3Hz); EI MS m/z 269 (M+); Anal. Calcd for
C16H19N3O (269.3): C, 71.35; H, 7.11; N, 15.60. Found:
C, 71.32; H, 7.04; N, 15.66.
5.1.11. 2,4-Dicyclopentyl-3-quinolinecarbohydrazide (3c).
1
Yield: 95%; mp 99–100ꢁC; H NMR (CDCl3): d 1.70
(m, 16H), 3.22 (m, 1H), 3.99 (m, 1H), 5.15 (br s, 2H),
7.75 (m, 1H), 7.81 (m, 1H), 8.11 (d, 1H, J = 8.1Hz),
8.24 (d, 1H, J = 8.4Hz); ESI MS m/z 324 (M+1); Anal.
Calcd for C20H25N3O (323.4): C, 74.27; H, 7.79; N,
12.99. Found: C, 74.44; H, 7.61; N, 13.11.
5.1.4. 4-(1-Adamantyl)-2-quinolinecarbohydrazide (2d).
1
Yield: 97%; mp 178ꢁC; H NMR (CDCl3): d 1.88 (m,
15H), 4.13 (br s, 2H), 7.57 (m, 1H), 7.69 (m, 1H), 8.11
(d, 1H, J = 8.3Hz), 8.19 (s, 1H), 8.66 (d, 1H,
J = 8.7Hz), 9.19 (br s, 1H); ESI MS m/z 322 (M+1);
Anal. Calcd for C20H23N3O (321.4): C, 74.74; H, 7.21;
N, 13.07. Found: C, 74.77; H, 7.19; N, 13.02.
5.1.12. 2,4-Dicyclohexyl-3-quinolinecarbohydrazide (3d).
1
Yield: 98%; mp 104–105ꢁC; H NMR (CDCl3): d 1.65
(m, 20H), 3.19 (m, 1H), 3.97 (m, 1H), 5.05 (br s, 2H),
7.71 (m, 1H), 7.86 (m, 1H), 8.14 (d, 1H, J = 8.2Hz),
8.21 (d, 1H, J = 8.3Hz); ESI MS m/z 352 (M+1); Anal.
Calcd for C22H29N3O (351.5): C, 75.18; H, 8.32; N,
11.96. Found: C, 75.09; H, 8.31; N, 11.97.
5.1.5. 4,5-Dicyclopentyl-2-quinolinecarbohydrazide (2e).
1
Yield: 92%; mp 107–108ꢁC; H NMR (CDCl3): d 1.70
(m, 16H), 3.22 (m, 1H), 3.99 (m, 1H), 4.20 (br s, 2H),
7.53 (d, 1H, J = 8.7Hz), 7.87 (m, 1H), 8.11 (s, 1H),
8.17 (br s, 1H), 8.25 (d, 1H, J = 8.5Hz); ESI MS m/z
324 (M+1); Anal. Calcd for C20H25N3O (323.4): C,
74.27; H, 7.79; N, 12.99. Found: C, 74.55; H, 7.68; N,
13.05.
5.1.13. 4-Quinolinecarbohydrazide (4a). Yield: 99%;
mp 92–93ꢁC; 1H NMR (CDCl3): d 5.14 (br s, 2H),
7.55 (m, 1H), 7.65 (m, 1H), 7.70 (s, 1H), 8.05 (d, 1H,
J = 8.4Hz), 8.15 (d, 1H, J = 8.4Hz), 9.14 (s, 1H); EI
MS m/z 187 (M+); Anal. Calcd for C10H9N3O (187.2):
C, 64.16; H, 4.85; N, 22.45. Found: C, 64.08; H, 4.77;
N, 22.37.
5.1.6. 4,8-Dicyclopentyl-2-quinolinecarbohydrazide (2f).
1
Yield: 95%; mp 104–105ꢁC; H NMR (CDCl3): d 1.68
(m, 16H), 3.21 (m, 1H), 4.02 (m, 1H), 4.15 (br s, 2H),

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V. Monga et al. / Bioorg. Med. Chem. 12 (2004) 6465–6472
5.1.14. 2-Cyclopentyl-4-quinolinecarbohydrazide (4b).
Yield: 100%; mp 87ꢁC; H NMR (CDCl3): d 1.56 (m,
8H), 3.20 (m, 1H), 4.23 (br s, 2H), 7.3 (s, 1H), 7.54
(m, 1H), 7.73 (m, 1H), 8.09 (d, 1H, J = 8.4Hz), 8.13
(d, 1H, J = 8.4Hz); ESI MS m/z 256 (M+1); Anal. Calcd
for C15H17N3O (255.3): C, 70.56; H, 6.71; N, 16.46.
Found: C, 70.77; H, 6.56; N, 16.44.
1H), 7.87 (d, 1H, J = 8.4Hz); ESI MS m/z 338 (M+1);
Anal. Calcd for C21H27N3O (337.5): C, 74.74; H, 8.06;
N, 12.45. Found: C, 74.88; H, 8.21; N, 12.37.
1
5.1.22. 2-(2,8-Dicyclohexyl-4-quinolyl)ethanohydrazide
(5f). Yield: 97%; mp 92–93ꢁC; 1H NMR (CDCl3): d
1.35 (m, 20H), 3.11 (m, 1H), 3.74 (m, 3H), 3.99 (s,
2H), 6.47 (br s, 1H), 7.15 (s, 1H), 7.57 (m, 1H), 7.77
(m, 1H), 7.90 (d, 1H, J = 8.3Hz); ESI MS m/z 366
(M+1); Anal. Calcd for C23H31N3O (365.5): C, 75.58;
H, 8.55; N, 11.50. Found: C, 75.41; H, 8.37; N, 11.77.
5.1.15. 2-Cyclohexyl-4-quinolinecarbohydrazide (4c).
1
Yield: 100%; mp 96ꢁC; H NMR (CDCl3): d 1.25 (m,
10H), 3.13 (m, 1H), 4.60 (br s, 2H), 7.38 (s, 1H), 7.54
(m, 1H), 7.72 (m, 1H), 8.08 (d, 1H, J = 8.3Hz), 8.13
(d, 1H, J = 8.3Hz); ESI MS m/z 270 (M+1); Anal. Calcd
for C16H19N3O (269.3): C, 71.35; H, 7.11; N, 15.60.
Found: C, 71.51; H, 7.37; N, 15.78.
5.2. Synthesis of 4-(1-adamantyl)-2-quinolinecarbox-
amide (7a)
A solution of methyl 4-(1-adamantyl)-2-quinolinecarb-
oxylate1 (500mg, 1.5mmol) in 7N NH3/MeOH
(50mL) was refluxed for 12h. The desired product 7a
was obtained directly after evaporation of the solvent
without any additional purification step. Yield: 94%;
5.1.16. 2-(1-Adamantyl)-4-quinolinecarbohydrazide (4d).
Yield: 100%; mp 108ꢁC; H NMR (CDCl3): d 1.95 (m,
15H), 4.42 (br s, 2H), 7.51 (m, 2H), 7.71 (m, 1H), 8.11
(m, 2H); ESI MS m/z 322 (M+1); Anal. Calcd for
C20H23N3O (321.4): C, 74.74; H, 7.21; N, 13.07. Found:
C, 74.63; H, 7.08; N, 13.11.
1
1
semi-solid; H NMR (CDCl3): d 1.89 (m, 15H), 5.89
(br s, 2H), 7.58 (m, 1H), 7.70 (m, 1H), 8.13 (m, 1H),
8.25 (s, 1H), 8.67 (d, 1H, J = 8.6Hz); ESI MS m/z 307
(M+1); Anal. Calcd for C20H22N2O (306.4): C, 78.40;
H, 7.24; N, 9.14. Found: C, 78.63; H, 7.21; N, 9.27.
5.1.17. 2-(4-Quinolyl)ethanohydrazide (5a). Yield: 91%;
1
mp 101ꢁC; H NMR (CDCl3 + DMSO-d6): d 3.81 (br
s, 2H), 3.97 (s, 2H), 7.41 (d, 1H, J = 8.4Hz), 7.58
(m, 1H), 7.72 (m, 1H), 8.09 (d, 1H, J = 8.8Hz), 8.13
(d, 1H, J = 8.4Hz), 8.87 (d, 1H, J = 8.4Hz), 8.99 (br s,
1H); ESI MS m/z 202 (M+1); Anal. Calcd for
C11H11N3O (201.2): C, 65.66; H, 5.51; N, 20.88. Found:
C, 65.39; H, 5.43; N, 20.78.
5.3. Typical procedure for the synthesis of N2-alkyl/
N2,N2-dialkyl/N2-aryl-4-(1-adamantyl)-2-quinolinecar-
boxamides (7b–m)
To a mixture of 4-(1-adamantyl)-2-quinolinecarboxylic
acid hydrochloride1 (6, 5mmol) in dichloroethane
(5mL), thionyl chloride (10mL) was added and the reac-
tion mixture was heated with stirring at 80ꢁC for 1h.
Solvent and excess of SOCl2 were removed under re-
duced pressure to afford acid chloride. The intermediate
acid chloride was immediately dissolved in anhydrous
CH2Cl2 (5mL) and cooled to 4ꢁC. Alkyl/aryl amine
(5.5mmol) and Et3N (15mmol) were added to the pre-
cooled solution. Reaction mixture was allowed to attain
room temperature and stirred for 12h. The solvent was
removed under reduced pressure, and residue was dis-
solved in chloroform (50mL). Organic layer was washed
with water (2 · 5mL) and brine (2 · 5mL). The organic
layer was dried (Na2SO4). The solvent was removed un-
der reduced pressure and the crude product was purified
by column chromatography using EtOAc/hexanes
(20:80) to afford N2-alkyl/N2,N2-dialkyl/N2-aryl-4-(1-
adamantyl)-2-quinolinecarboxamides 7b–m in satisfac-
tory yields.
5.1.18. 2-(2-Cyclopentyl-4-quinolyl)ethanohydrazide (5b).
Yield: 89%; mp 112ꢁC; NMR (CDCl3): d 1.99 (m, 8H),
3.77 (m, 1H), 3.85 (br s, 2H), 4.00 (s, 2H), 6.57 (br s,
1H), 7.21 (s, 1H), 7.53 (m, 1H), 7.70 (m, 1H), 7.89 (d,
1H, J = 8.4Hz), 8.07 (d, 1H, J = 8.4Hz); APCI MS m/
z 270 (M+1); Anal. Calcd for C16H19N3O (269.3): C,
71.35; H, 7.11; N, 15.60. Found: C, 71.67; H, 7.37; N,
15.74.
5.1.19. 2-(2-Cyclohexyl-4-quinolyl)ethanohydrazide (5c).
1
Yield: 88%; mp 105ꢁC; H NMR (CDCl3): d 1.71 (m,
10H), 3.10 (m, 1H), 3.89 (br s, 2H), 4.08 (s, 2H), 6.54
(br s, 1H), 7.12 (s, 1H), 7.54 (m, 1H), 7.65 (m, 1H),
7.99 (d, 1H, J = 8.3Hz), 8.05 (d, 1H, J = 8.5Hz); ESI
MS, m/z 284 (M+1); Anal. Calcd for C17H21N3O
(283.4): C, 72.06; H, 7.47; N, 14.83. Found: C, 72.31;
H, 7.33; N, 14.67.
5.1.20.
2-[2-(1-Adamantyl)-4-quinolyl]ethanohydrazide
5.3.1.
N2-Propyl-4-(1-adamantyl)-2-quinolinecarbox-
1
1
(5d). Yield: 92%; mp 97ꢁC; H NMR (CDCl3): d 1.88
(m, 15H), 3.84 (br s, 2H), 4.02 (s, 2H), 6.51 (br s, 1H),
7.39 (s, 1H), 7.52 (m, 1H), 7.69 (m, 1H), 7.88 (d, 1H,
J = 8.1Hz), 8.10 (d, 1H, J = 8.3Hz); EI MS m/z 335
(M+); Anal. Calcd for C21H25N3O (335.4): C, 75.19;
H, 7.51; N, 12.53. Found: C, 75.44; H, 7.59; N, 12.41.
amide (7b). Yield: 66%; semi-solid; H NMR (CDCl3):
d 0.85 (m, 3H), 1.45 (m, 2H), 1.89 (m, 15H), 3.48 (q,
2H, J = 6.8Hz), 7.56 (m, 1H), 7.68 (m, 1H), 8.13 (d,
1H, J = 8.7Hz), 8.26 (m, 2H), 8.66 (d, 1H, J = 8.7Hz);
APCI MS m/z 349 (M+1); Anal. Calcd for C23H28N2O
(348.5): C, 79.27; H, 8.10; N, 8.04. Found: C, 79.15;
H, 8.19; N, 8.14.
5.1.21. 2-(2,8-Dicyclopentyl-4-quinolyl)ethanohydrazide
1
(5e). Yield: 100%; mp 88ꢁC; H NMR (CDCl3): d 1.37
5.3.2. N2-Butyl-4-(1-adamantyl)-2-quinolinecarboxamide
(7c). Yield: 75%; semi-solid; H NMR (CDCl3): d 0.85
(t, 3H, J = 6.8Hz), 1.49 (m, 4H), 1.89 (m, 15H), 3.45
1
(m, 16H), 3.13 (m, 1H), 3.77 (m, 3H), 4.00 (s, 2H),
6.51 (br s, 1H), 7.20 (s, 1H), 7.51 (m, 1H), 7.74 (m,

V. Monga et al. / Bioorg. Med. Chem. 12 (2004) 6465–6472
6471
(q, 2H, J = 6.7Hz), 7.52 (m, 1H), 7.67 (m, 1H), 8.15 (d,
1H, J = 8.7Hz), 8.21 (br s, 1H), 8.27 (s, 1H), 8.69 (d, 1H,
J = 8.5Hz); APCI MS m/z 363 (M+1); Anal. Calcd for
C24H30N2O (362.5): C, 79.52; H, 8.34; N, 7.73. Found:
C, 79.81; H, 8.37; N, 7.98.
1H, J = 8.8Hz), 7.60 (m, 1H), 7.74 (m, 2H), 7.92 (s,
1H), 8.20 (d, 1H, J = 8.3Hz), 8.33 (s, 1H), 8.70 (d, 1H,
J = 8.7Hz), 10.14 (br s, 1H); EI MS m/z 446 (M+); Anal.
Calcd for C27H27ClN2O2 (446.9): C, 72.55; H, 6.09; N,
6.27. Found: C, 72.67; H, 6.11; N, 6.34.
5.3.3.
N2-Pentyl-4-(1-adamantyl)-2-quinolinecarbox-
5.3.10. N2-(4-Nitrophenyl)-4-(1-adamantyl)-2-quinoline-
carboxamide (7k). Yield: 48%; mp 191–192ꢁC; 1H
NMR (CDCl3): d 1.91 (m, 15H), 7.62 (m, 1H), 7.74
(m, 3H), 8.32 (m, 3H), 8.69 (d, 1H, J = 8.5Hz), 9.11
(d, 1H, J = 8.4Hz), 13.10 (br s, IH); ESI MS m/z 428
(M+1); Anal. Calcd for C26H25N3O3 (427.5): C, 73.05;
H, 5.89; N, 9.83. Found: C, 73.11; H, 5.79; N, 9.75.
1
amide (7d). Yield: 56%; semi-solid; H NMR (CDCl3):
d 0.92 (m, 7H), 1.40 (m, 2H), 1.89 (m, 15H), 3.51 (q,
2H, J = 6.8Hz), 7.52 (m, 1H), 7.64 (m, 1H), 8.12 (d,
1H, J = 8.3Hz), 8.20 (br s, 1H), 8.27 (s, 1H), 8.64 (d,
1H, J = 8.7Hz); ESI MS m/z 377 (M+1); Anal. Calcd
for C25H32N2O (376.5): C, 79.75; H, 8.57; N, 7.44.
Found: C, 79.76; H, 8.64; N, 7.29.
5.3.11. N2-[3-(Quinolyl)-4-(1-adamantyl)]-2-quinolinecar-
boxamide (7l). Yield: 21%; mp 244–245ꢁC; H NMR
5.3.4.
amide (7e). Yield: 49%; semi-solid; H NMR (CDCl3):
0.91 (m, 7H), 1.88 (m, 19H), 3.52 (q, 2H,
J = 6.7Hz), 7.55 (m, 1H), 7.68 (m, 1H), 8.14 (d, 1H,
J = 8.3Hz), 8.26 (m, 2H), 8.66 (d, 1H, J = 8.7Hz); APCI
MS m/z 391 (M+1); Anal. Calcd for C26H34N2O (390.6):
C, 79.96; H, 8.77; N, 7.17. Found: C, 79.85; H, 8.91; N,
7.09.
N2-Hexyl-4-(1-adamantyl)-2-quinolinecarbox-
1
1
(CDCl3): d 1.92 (m, 15H), 7.62 (m, 3H), 7.77 (m, 1H),
7.88 (d, 1H, J = 7.9Hz), 8.10 (d, 1H, J = 8.2Hz), 8.28
(d, 1H, J = 9.0Hz), 8.39 (s, 1H), 8.72 (d, 1H,
J = 8.7Hz), 9.07 (m, 2H), 10.52 (br s, 1H); ESI MS
m/z 434 (M+1); Anal. Calcd for C29H27N3O (433.5):
C, 80.34; H, 6.28; N, 9.69. Found: C, 80.57; H, 6.15;
N, 9.89.
d
5.3.5.
N2-Heptyl-4-(1-adamantyl)-2-quinolinecarbox-
1
5.3.12.
N2-Benzyl-4-(1-adamantyl)-2-quinolinecarbox-
amide (7f). Yield: 61%; semi-solid; H NMR (CDCl3):
d 0.88 (t, 3H, J = 6.5Hz), 1.35 (m, 8H), 1.66 (m, 2H),
1.88 (m, 15H), 3.51 (q, 2H, J = 6.7Hz), 7.54 (m, 1H),
7.68 (m, 1H), 8.13 (d, 1H, J = 8.4Hz), 8.29 (m, 2H),
8.66 (d, 1H, J = 8.7Hz); ESI MS m/z 405 (M+1); Anal.
Calcd for C27H36N2O (404.6): C, 80.15; H, 8.97; N, 6.92.
Found: C, 80.19; H, 8.94; N, 6.78.
amide (7m). Yield: 94%; mp 157–159ꢁC; 1H NMR
(CDCl3): d 1.89 (m, 15H), 4.74 (m, 2H), 7.36 (m, 5H),
7.56 (m, 1H), 7.67 (m, 1H), 8.09 (d, 1H, J = 7.9Hz),
8.30 (s, 1H), 8.61 (br s, 1H), 8.66 (d, 1H, J = 8.5Hz);
APCI MS m/z 397 (M+1); Anal. Calcd for C27H28N2O
(396.5): C, 81.78; H, 7.12; N, 7.06. Found: C, 81.93;
H, 7.02; N, 7.31.
5.3.6. N2,N2-Diethyl-4-(1-adamantyl)-2-quinolinecarbox-
amide (7g). Yield: 44%; semi-solid; 1H NMR (CDCl3): d
1.25 (m, 6H), 1.88 (m, 15H), 3.42 (q, 2H, J = 7.0Hz),
3.62 (q, 2H, J = 7.0Hz), 7.52 (m, 1H), 7.56 (s, 1H),
7.66 (m, 1H), 8.13 (d, 1H, J = 8.2Hz), 8.63 (d, 1H,
J = 8.7Hz); APCI MS m/z 363 (M+1); Anal. Calcd for
C24H30N2O (362.5): C, 79.52; H, 8.34; N, 7.73. Found:
C, 79.31; H, 8.22; N, 7.89.
Acknowledgements
Amit Nayyar thanks the Council of Scientific and Indus-
trial Research (CSIR), India for the award of Senior Re-
search Fellowship.
References and notes
5.3.7.
N2-Phenyl-4-(1-adamantyl)-2-quinolinecarbox-
1
1. For Part 1 of the series, please see: Vaitilingam, B.;
Nayyar, A.; Palde, P. B.; Monga, V.; Jain, R.; Kaur, S.;
Singh, P. P. Bioorg. Med. Chem. 2004, 12, 4179.
2. (a) Mitscher, L. A.; Baker, W. Med. Res. Rev. 1998, 98,
363; (b) Crick, D. C.; Brennan, P. J. Curr. Opin. Anti-
Infect. Invest. Drugs 2000, 2, 154.
3. (a) World Health Organization. Anti-tuberculosis Drug
Resistance in the World. The WHO/IUALTD Global
Project on Anti-Tuberculosis Drug Resistance Surveillance;
World Health Organization (Publication # WHO/TB/
97.229): Geneva, Switzerland, 1997; (b) Fitzgerald, D. W.;
Morse, M. M.; Pape, J. W.; Johnson, W. D., Jr. Clin.
Infect. Dis. 2000, 31, 1495.
amide (7h). Yield: 69%; semi-solid; H NMR (CDCl3):
d 1.90 (m, 15H), 7.16 (m, 1H), 7.42 (m, 2H), 7.60 (m,
1H), 7.73 (m, 1H), 7.86 (m, 2H), 8.22 (d, 1H,
J = 8.1Hz), 8.36 (s, 1H), 8.70 (d, 1H, J = 8.7Hz),
10.24 (br s, 1H); APCI MS m/z 383 (M+1); Anal. Calcd
for C26H26N2O (382.5): C, 81.64; H, 6.85; N, 7.32.
Found: C, 81.93; H, 6.97; N, 7.18.
5.3.8. N2-(4-Methoxyphenyl)-4-(1-adamantyl)-2-quino-
linecarboxamide (7i). Yield: 59%; mp 228–230ꢁC; 1H
NMR (CDCl3): d 1.90 (m, 15H), 3.84 (s, 3H), 6.95 (d,
2H, J = 8.9Hz), 7.59 (m, 1H), 7.74 (m, 3H), 8.21 (d,
1H, J = 8.4Hz), 8.35 (s, 1H), 8.69 (d, 1H, J = 8.6Hz),
10.13 (br s, 1H); ESI MS m/z 413 (M+1); Anal. Calcd
for C27H28N2O2 (412.5): C, 78.61; H, 6.84; N, 6.79.
Found: C, 78.88; H, 6.71; N, 6.58.
4. Cole, S. T.; Brosch, R.; Parkhill, J., et al. Nature 1998,
393, 537.
5. Global Alliance for TB Drug Development. In Scientific
Blueprint for Tuberculosis Drug Development; 2001, see
http://www.tballiance.org/.
6. Long, R. Can. Med. Assoc. J. 2000, 163, 425.
7. Duncan, K. Chem. Ind. 1997, 861.
8. Jain, R.; Vaitilingam, B.; Nayyar, A.; Palde, P. B. Bioorg.
Med. Chem. Lett. 2003, 13, 1051.
5.3.9. N2-(3-Chloro-4-methoxyphenyl)-4-(1-adamantyl)-
2-quinolinecarboxamide (7j). Yield: 66%; mp 242ꢁC; H
NMR (CDCl3): d 1.90 (m, 15H), 3.93 (s, 3H), 6.97 (d,
1

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V. Monga et al. / Bioorg. Med. Chem. 12 (2004) 6465–6472
9. Vangapandu, S.; Jain, M.; Jain, R.; Kaur, S.; Singh, P. P.
Bioorg. Med. Chem. 2004, 12, 2501.
B.; Quenzer, V. K.; Ferguson, R. M.; Gilman, R. H. J.
Clin. Microbiol. 1998, 36, 362.
10. Franzblau, S. G.; Witzig, R. S.; McLaughlin, J. C.; Torres,
P.; Madico, G.; Herandez, A.; Degnan, M. T.; Cook, M.
11. Collins, L.; Franzblau, S. G. Antimicrob. Agents Chemo-
ther. 1997, 41, 1004.