Synthesis and antimycobacterial activity of prodrugs of indeno[2,1-c]quinoline derivatives

Article abstract of DOI:10.1016/j.ejmech.2011.01.053

Recently we have reported anti-TB properties of a new class of conformationally-constrained indeno[2,1-c]quinolines, which are although considerably active (MIC 0.39-0.78 μg/mL) suffered from intense solubility problems. We thought of improving their bioavailability by prodrugs approach. Accordingly esters of the "Lead" indeno[2,1-c]quinolines 1, 15 and 27 derivatives were synthesized and their prodrug nature at the physiological pH were confirmed. Prodrugs were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv by MABA assay to show that they have 2- to 4-fold improved anti-TB activities, increased aqueous solubility and superior selectivity index over their respective parent compounds. MIC of these prodrugs was in the range of <0.20-6.0 μg/mL, and in general, no cytotoxicity was observed in VERO cells.

Full text of DOI:10.1016/j.ejmech.2011.01.053

European Journal of Medicinal Chemistry 46 (2011) 1306e1324
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antimycobacterial activity of prodrugs of indeno[2,1-c]quinoline
derivatives
Ram Shankar Upadhayaya a, Popat D. Shinde a, Sandip A. Kadam a, Amit N. Bawane a, Aftab Y. Sayyed a,
Ramakant A. Kardile a, Pallavi N. Gitay a, Santosh V. Lahore a, Shailesh S. Dixit a, András Földesi b,
,
Jyoti Chattopadhyaya b
*
a Institute of Molecular Medicine, Pune 411 057, India
b Chemical Biology Program, Department of Cell and Molecular Biology, Biomedical Centre, Uppsala University, SE-75123 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Recently we have reported anti-TB properties of a new class of conformationally-constrained indeno[2,1-
Received 13 January 2011
Received in revised form
24 January 2011
Accepted 25 January 2011
Available online 3 February 2011
c]quinolines, which are although considerably active (MIC 0.39e0.78 mg/mL) suffered from intense
solubility problems. We thought of improving their bioavailability by prodrugs approach. Accordingly
esters of the “Lead” indeno[2,1-c]quinolines 1, 15 and 27 derivatives were synthesized and their prodrug
nature at the physiological pH were confirmed. Prodrugs were evaluated for their antimycobacterial
activity against Mycobacterium tuberculosis H37Rv by MABA assay to show that they have 2- to 4-fold
improved anti-TB activities, increased aqueous solubility and superior selectivity index over their
Keywords:
respective parent compounds. MIC of these prodrugs was in the range of <0.20e6.0 mg/mL, and in
general, no cytotoxicity was observed in VERO cells.
Anti-tuberculosis drugs
Indeno[2,1-c]quinoline
Prodrug approach
MABA assay
Ó 2011 Elsevier Masson SAS. All rights reserved.
Mosmans MTT assay
1. Introduction
a multiple drug regimen given over a long duration of time (6e12
months). It combines isoniazid (INH), rifampin (RIF), pyrazinamide
(PZA), and ethambutol (EMB). These antibiotics are effective in
active, drug-susceptible TB, provided that patients complete the
course. Non-compliance of patients has contributed to the
appearance of multidrug resistant (MDR) and extensively drug
resistant TB (XDR-TB) strains. These suggest that there is an urgent
need for new anti-TB drugs with novel mechanism of action, which
are synthetically feasible, with minimal side effects, and have
required physicochemical properties allowing oral administration
with reduced treatment time. Recently, many novel inhibitors such
as those for ATP synthase [9,10], cell wall assembly [11], isocitrate
lyase [12] and protein synthesis [13] have emerged as anti-TB
targets. Quinoline-based anti-TB compound TMC207 bearing
a bulky biaryl side chain at position C3, is a highly potent anti-TB
agent, has novel mode of action, with very promising activity
against MDR-TB [9,14].
Based on molecular dissection of TMC207 (Fig. 1), we have
recently reported design, synthesis and biological activity of rela-
tively less complex quinoline derivatives, which show potent anti-
TB activity [15e19]. In these efforts, we have discovered a new class
of conformationally-locked indeno[2,1-c]quinoline compounds
which posses excellent antimycobacterial activity, such as those of
compounds 1, 15 and 27 (Fig. 1) which, respectively, showed 91, 99,
Mycobacterium tuberculosis (M. TB) is the leading bacterial
infectious agent in humans, and is responsible for death of almost 3
million people each year [1], which has been a major global health
problem for decades. The resurgence of TB is associated with the
emergence of HIV/AIDS epidemic [2] and the fast development of
multidrug resistant TB bacterial strains [3,4]. A current first-line TB
drug regimen is more than 40 years old, and consists primarily of
rifampicin and isoniazid. Single drug therapy is now known to
result in the rapid emergence of drug resistant M. tuberculosis bacilli
[5] due to the sequential accumulation of spontaneous genetic
mutations [6e8]. Current conventional directly observed treatment
short course (DOTS) therapy, which has been used for decades, is
Abbreviations: DCM, dichloromethane; DMF, N,N-dimethylformamide; DMAP,
4-dimethylaminopyridine; DMSO, dimethyl sulfoxide; EDC.HCl, N-Ethyl-N0-(3-
Dimethylaminopropyl) carbodiimide hydrochloride; MDR, multidrug resistance;
MIC, minimum inhibitory concentration; mp, melting point; MeOH, methanol;
NMR, nuclear magnetic resonance; SI, selectivity index; SAR, structureeactivity
relationship; TB, tuberculosis; THF, tetrahydrofuran; TLC, thin layer chromatog-
raphy; XDR, extensive drug resistance.
* Corresponding author. Tel.: þ46 18 4714577; fax: þ46 18 554495.
E-mail address: jyoti@boc.uu.se (J. Chattopadhyaya).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.01.053

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
1307
R1
O
OH
Br
Br
O
Me
Me
N
N
N
N
N
N
1 : MIC 0.78 µg/mL
2-14 : MIC 0.42-6.0 µg/mL
OH
Br
N
N
O
R1
OH
O
Br
N
Br
N
O
TMC207
MIC 0.06 µg/mL
N
R
N
R
15 : R= Imidazole
16-26 : R= Imidazole
MIC 0.39 µg/mL
27 : R= 2-pyridyl-piperazine
MIC 6.25 µg/mL
MIC <0.20-3.0 µg/mL
28-54 : R= 2-pyridyl-piperazine
MIC 1.47-6.0 µg/mL
Fig. 1. Conformationally-constrained compounds 1, 15 and 27, which are relatively structurally simpler than the parent TMC207, have shown to be considerably active against
Mycobacterium tuberculosis in our lab, see Refs [14e18]; they have been transformed to their corresponding ester derivatives 2e14, 16e26 and 28e54, respectively, as prodrugs,
which are more potent (compare MICs) than their parents.
and 90% growth inhibition of M. tuberculosis H37Rv with minimum
inhibitory concentration (MIC) of 0.78 g/mL (2 M), <0.39 g/mL
(1 M), and 6.25 g/mL (12.8 M) [18].
Antimycobacterial activity of these molecules is comparable to
in dry DMF at 0 ꢀC to room temperature for 15 h. The ester deriv-
atives 2e13 were obtained in moderate to good yields (12e67%).
Various conditions were employed to prepare amino esters deriv-
atives of compound 1, but we succeeded to prepare only ester of
Boc-glycine, i.e. compound 14 which was prepared by treating
compound 1 with n-BuLi and Boc-glycine-N-hydroxysuccinimide
ester in dry THF at ꢁ78 ꢀC in 28% yield.
m
m
m
m
m
m
the standard drug isoniazid. However these molecules are facing
the problem of poor aqueous solubility, as inadequate aqueous
solubility is an important factor limiting parenteral, percutaneous,
and oral bioavailability. To overcome the problem of aqueous
solubility we herein report the preparation of the ester derivatives
(prodrugs) of these molecules, which are deemed to have optimum
balance between hydrophilicity and lipophilicity thereby
enhancing bioavailability and, consequently, improving anti-
mycobacterial activity. Among the three series of 51 different ester
derivatives of indeno[2,1-c]quinolines 1, 15 and 27, 33 esters were
found to have anti-TB activity with MIC [up to 99% inhibition in vitro
determined by Microplate Alamar Blue Assay (MABA)] varying in
Esters 16, 17 and 26 were prepared by treating oxime 15 with
NaH (3 eq) in dry DMF and corresponding acid chlorides (3 eq) in
moderate yield (40e49%). Other esters derivatives, compounds
18e25 were prepared by treating corresponding acids with oxime
15 using EDC.HCl, DMAP in DMF in good yields (26e76%) [20].
Esters of compound 15 were unstable, and hydrolyzed to their
parent oxime 15 during aqueous work-up. By quenching reaction
with phosphate buffer (pH ¼ 6.5e7.0) and extracting it with ethyl
acetate avoided the problem of ester hydrolysis (40e50%).
the range of <0.20e6.0
m
g/mL. Their partition coefficients in
Aliphatic esters 28, 29 and 39 [18] were prepared by treating
oxime 27 with NaH (3 eq) in dry DMF and corresponding acid
chlorides, in moderate yields (60%). Other aliphatic ester deriva-
tives, compound 30e38 and 40e42 and all amino esters,
compound 43e54 were prepared by treating corresponding
aliphatic acids, Boc/Fmoc-amino acids with oxime 27 using
EDC.HCl, DMAP in dry DMF in good yields (27e96%) [20].
octanolewater mixture at pH 7.4 were determined. The ester
derivatives of compound 15 however displayed superior anti-TB
activity and the selectivity index (SI), in that compound 16 (MIC
<0.20 mg/mL, SI >71.52) and 18 (MIC <0.20 mg/mL, SI > 200) were
the most active. In general, ester derivatives of compounds 1 and 15
showed more improved aqueous solubility and lipophilicity than
the parent compounds. Hence, the ester derivatives of these con-
formationally-constrained indeno[2,1-c]quinolines, compounds 1,
15 and 27, represent highly potent, selective and non-toxic anti-TB
compounds which are attractive leads for further anti-TB drug
development.
2.2. Biology
All synthesized ester derivatives of compounds 1, 15 and 27
(Scheme 1) were evaluated against M. tuberculosis H37Rv in
a Microplate Alamar Blue Assay (MABA) method [21]. Cell viability
in the presence or in the absence of test compounds was deter-
mined by Mosmans’s MTT assay [22] for the most active
compounds.
2. Results
2.1. Chemistry
Compounds 1, 15 and 27 (Scheme 1) that served as starting
materials were prepared according to published method [18].
Compounds 2e13 were synthesized by treatment of compound 1
with sodium hydride (3 eq) and corresponding acid chlorides (3 eq)
2.2.1. Esters of compound 1
The results of growth inhibition of ester derivatives 2e14 of
compound 1 (Scheme 1) against M. tuberculosis H37Rv are shown in
Table 1. Out of 13 esters, 9 esters displayed good to excellent activity

1308
R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
11
11
10
10
12
12
9
R1
9
OH
O
5
5
4
4
Br
3
Br
3
2
(i) or (ii)
O
Me
6
Me
6
2
15
15
7
7
N
N
N
N
8
N
8
N
1
1
13
13
14
14
1
2-14
2: R1 = -CH3; 3: R1 = -CH2CH3; 4: R1 = -(CH21)2CH3; 5: R1 = -(CH2)3CH3; 6: R1 = -(CH2)4CH3;
1
1
1
7
8
9
10
: R = -(CH2)5CH3; : R = -(CH2)6CH3; : R = -(CH2)7CH3;
R = -(CH2)12CH3;
1
1
1
1
11
12
13
14
: R = -(CH2)13CH3; : R = -N(CH3)2; : R = -CH2CF3; : R = -CH2NHBoc
10
4
11
11
10
9
12
12
9
R1
O
N
OH
5
8
5
8
4
Br
Br
N
N
3
3
(ii) or (iii)
O
6
6
7
2
2
15
15
7
N
N
N
N
N
1
1
13
13
14
14
15
16 - 26
16: R1 = -CH3; 17: R1 = -CH2CH3; 18: R1 = -(CH21)2CH3; 19: R1 = -(CH21)3CH3;
1
1
20
21
22
23
: R = -(CH2)4CH3; : R = -(CH2)5CH3; : R = -(CH2)7CH3; : R = -(CH2)8CH3;
1
1
1
24
25
26
: R = -(CH2)12CH3; : R = Boc-proline; : R = -N(CH3)2
11
11
10
4
10
4
12
12
9
9
R1
OH
O
5
5
Br
N
Br
N
3
3
(ii) or (iii)
6
7
6
7
O
2
2
N
N
N
N
8
8
1
1
N
N
N
N
16
15
16
15
27
28- 54
13
13
14
14
28: R1 = -CH3; 29: R1 = -CH2CH3; 30: R1 = -(CH21)2CH3; 31: R1 = -(CH21)3CH3; 32: R1 = -(CH2)4CH3;
1
1
33
37
41
34
35
36
: R = -(CH2)5CH3; : R = -(CH2)7CH3; : R = -(CH2)8CH3; : R = -(CH2)10CH3;
1
1
1
1
38
39
40
: R = -(CH2)13CH3; : R = -(CH2)3CH2Br; : R = -N(CH3)2; : R = -Cyclopropyl;
1
1
1
1
42
43
44
: R = (E)-3-(furan-2-yl)acryloyl; : R = -CH2NHAc; : R = Boc-proline; : R = tert-butyl 1-
methylcyclopentylcarbamate-1yl; 45: R1 = -CH2NHBoc; 46: R1 = Boc-alanine; 47: R1 = Boc-leucine;
48: R1 = Boc-tert-leucine; 49: R1 = Boc-methionine; 50: R1 = tert-butyl-2-(3-fluorophenyl)
1
1
51
52
ethylcarbamate-1-yl; : R = tert-butyl 2-phenylethylcarbamate-1-yl; : R = -CH2NHFmoc;
1
1
53
54
: R = Fmoc-leucine; : R = Fmoc-valine
Scheme 1. Reagents and conditions: (i) dry THF, n-BuLi, Boc-glycine-N-hydroxysuccinimide ester, ꢁ78 ꢀC, 2 h then room temperature. 1 h. (for compound 14) (ii) dry DMF, NaH
(3 eq), R1COCl (3 eq), 0 ꢀC to room temperature, 15 h. (iii) dry DMF, EDC.HCl (1.5 eq), DMAP, R1COOH, room temperature, 4 h. Note that we have used arbitrary systematic position
numbering of protons for the sake of easier comparison within the same structural scaffold. The IUPAC nomenclature of compounds is used throughout the text in the experimental
section.

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
1309
against M. tuberculosis H37Rv, MIC in the range of 0.42 (7,
H37Rv by MABA assay [21]. Out of 11 ester derivatives of
compound 15, 10 compounds were found to be active, having MIC
between <0.20 (16: R1 ¼ methyl and 18: R1 ¼ propyl)e3.0 (23:
R1 ¼ hexyl)e6.0 (12, R1 ¼ dimethylamino)
mg/mL. Compounds 7 and
13 (R1 ¼ 2,2,2-trifluoroethyl) are almost 2-fold more potent than
parent alcohol 1. It was found that compounds having aliphatic side
chain (R1-group in 1, Scheme 1) from C-4 to C-8 gave most potent
compounds. The heptanoic ester derivative 7, showed excellent
R1 ¼ nonyl)
m
g/mL. Compounds 16e22 having chain length (R1-
group) C-1eC-9 were found to be active. Compounds having C-
1eC-8 (shorter) aliphatic chains showed more impressive activity
(Table 2, Compounds 16e22), whereas further increase in
the chain length of R1-group resulted in decrease (C-9, 23) or loss
(C-13, 24) of activity. Moving from aliphatic acid esters to
amino acid ester (25) or carbamoyl derivative (26) regains the
activity.
All the ester derivatives of compound 15 are being hydrolyzed
to parent compound in blood serum (pH 7.4) as well as in
aqueous ammonia (pH 8.0), with half-lives (t1/2) in the range of
1e10 h, except compound 26. With increase in the aliphatic chain
length 17, 18, 19 and 20 there is a gradual increase in t1/2 values
3.5 h, 4.0 h, 6.0 h, 10 h. The difference in the stability of these
compounds must be attributed to the structural variation in the
side chain, leading to steric, electronic as well as the solubility
effects in compounds 16e22. These data suggest that compounds
having t1/2 in the range of (1e4 h) are more active (i.e.
compounds 16 and 18) compared to other analogs. Compound 15
was thus proven to be an attractive candidate to synthesize
prodrugs, by improvement of aqueous solubility, lipophilicity in
order to steer to the better activity with good selectivity index.
Cytotoxicity data (Table 2) of these compounds suggest that these
compounds are non-toxic to normal human cell lines compared
to compound 15.
activity (MIC ¼ 0.42
mg/mL). By increasing the chain length from C-7
(as in compound 7) to C-8 (as in compound 8) resulted in 8-fold
decrease in the antimycobacterial activity. Compounds 10 and 11
having long aliphatic chain (R1-group) C-13 and C-14, respectively,
were found to be inactive. Compound 13 having eCH2CF3 group was
found to be 1.5-fold more potent than the parent compound 1. Table
1 shows that compound 7 and 13 have better SI than other active
compounds, as well as that of the parent alcohol 1. Hydrolysis study
of ester derivatives of compound 1 suggests that they are not being
hydrolyzed in blood serum (pH 7.4) except ester 13. While in
aqueous ammonia (pH 8.0) all ester derivatives hydrolyzed to
compound 1 except compound 12 (R1 ¼ dimethylamino, least active
in the series with MIC of 6.0 mg/mL) which perhaps may be owing to
the stable chemical nature of the amide bond. Compounds 13 and 14
are hydrolyzed almost completely to parent compound 1 in aqueous
ammonia (pH 8.0). Cytotoxicity data of active prodrugs of compound
1 suggest that these compounds are non-toxic to normal human cell
lines (Table 1).
2.2.2. Esters of compound 15
Table 2 presents the results of growth inhibition of ester
derivatives 16e26 vis-à-vis their parent 15 against M. tuberculosis
Table 1
Esters of compound 1 e MIC, toxicity, hydrolysis and partition coefficient study.
Comp No.
R1
MIC,a
mg/mL
% Cell viabilityb after
72 h
SI
Hydrolyzed compound (1)
formed in 12 days, at 37 ꢀC
t
½
in days
Partition coefficient
Concentration (
m
g/mL)
20
Blood serumc (%)
Aq. NH3d (%)
Blood serum
Aq. NH3
Pc
log P
ClogP
1.25
5.0
10
1
2
3
4
5
6
7
8
e
0.78
1.88
Inactive
Inactive
1.53
1.60
0.42
3.42
1.56
Inactive
Inactive
6.0
0.50
2.03
93
94
e
64
90
e
64
63
e
37
35
e
4.3
7.5
e
e
e
e
e
e
e
e
e
e
e
e
e
e
20
e
e
54.25
481.5
e
1.7
2.7
e
3.77
4.62
e
eCH3
Nd
e
90
e
10
e
eCH2CH3
eCH2)2CH3
e(CH2)3CH3
e(CH2)4CH3
e(CH2)5CH3
e(CH2)6CH3
e(CH2)7CH3
e(CH2)12CH3
e(CH2)13CH3
eN(CH3)2
eCH2CF3
e
e
e
e
e
e
e
e
e
e
e
e
91
85
85
87
86
e
75
77
83
72
75
e
48
54
68
52
71
e
4
5.6
Nd
Nd
Nd
Nd
Nd
e
90
90
86
90
90
e
12
12
13
11
12
e
42.8
25.7
50.7
63.1
39.3
e
1.7
1.4
1.7
1.8
1.6
e
6.21
6.74
7.27
7.80
8.33
e
15
54
17
50
e
6.1
40.2
2.5
11.4
e
9
10
11
12
13
14
e
e
e
e
e
e
e
e
e
e
e
63
92
90
e
69
62
62
e
e
Nd
50
Nd
Nd
96
97
e
80.3
67.6
61.1
1.9
1.8
1.8
4.87
4.92
5.45
80
83
26
28
22.4
6.0
1
1
eCH2NHBoc
t
is the time required for 50% hydrolysis at 37 ꢀC.
½
Pc is the apparent partition coefficient between 1-octanol and water at room temperature (25 ꢀC). SI, Selectivity Index of compound.
a
MIC Minimum Inhibitory Concentration, determined by Microplate Alamar Blue Assay (MABA) [21] (see Experimental section for details)
Determined by Mosmans’s MTT assay [22] (see Experimental section for details)
The enzymatic hydrolysis of each compound (1 mg) was carried out in 80% human blood serum/phosphate buffer (pH 7.4) incubated at 37 ꢀC. The rate of enzymatic
b
c
hydrolysis was determined by LC-MS/TLC following the literature procedure [23].
d
The rates of chemical hydrolysis of compounds were studied in aqueous ammonia solution (10 % aqueous ammonia in methanol, pH 8) at 37 ꢀC determined by LC-MS. Nd
represents for those molecules which have not been hydrolyzed.

1310
R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
Table 2
Esters of compound 15 e MIC, toxicity, hydrolysis and partition coefficient study.
Comp No.
R1
MIC,a
m
g/mL
% Cell viabilityb after
72 h
SI
Hydrolyzed compound (15)
t
½
in hours
Partition coefficient
formed in 24 h, 37 ꢀC
Concentration (
m
g/mL)
20
Blood serumc (%)
Aq. NH3d (%)
Blood serum
Aq. NH3
Pc
log P
ClogP
1.25
5.0
10
77
15
16
17
18
19
20
21
22
23
24
25
26
e
<0.39
<0.2
0.29
<0.2
0.28
1.5
0.36
0.39
3.0
100
87
84
85
85
81
85
87
100
e
91
78
86
88
82
e
77
42
67
70
51
e
>5
e
e
e
e
1.7
0.2
1.1
1.2
1.5
1.6
2.1
1.5
1.9
1.4
e
4.90
4.34
4.87
5.40
5.93
6.46
6.99
8.05
8.57
e
eCH3
59
75
69
75
100
67
77
81
e
>71
>137
>200
60
94
90
90
90
85
85
95
90
e
95
95
95
90
90
95
95
90
e
3.5
3.5
4.0
6.0
10
8.0
3.0
6.0
e
2.0
2.0
1.5
3.0
6.0
2.0
1.0
1.0
e
13.0
17.4
30.9
43.8
129.9
33.0
83.8
28.2
e
eCH2CH3
e(CH2)2CH3
e(CH2)3CH3
e(CH2)4CH3
e(CH2)5CH3
e(CH2)7CH3
e(CH2)8CH3
e(CH2)12CH3
Boc-proline
eN(CH3)2
e
80
85
e
60
72
e
>111
>102
e
Inactive
0.39
0.27
e
e
e
87
77
86
82
74
61
78
50
>102
49
95
Nd
90
Nd
1.0
Nd
0.5
Nd
19.0
14.7
1.3
1.1
6.25
4.40
t
is the time required for 50% hydrolysis at 37 ꢀC.
½
Pc is the apparent partition coefficient between 1-octanol and water at room temperature (25 ꢀC). SI is Selectivity Index.
a
MIC Minimum Inhibitory Concentration determined by Microplate Alamar Blue Assay (MABA) [21] (see Experimental section for details)
Determined by Mosmans’s MTT assay [22] (see Experimental section for details)
The enzymatic hydrolysis of each compound (1 mg) was carried out in 80% human blood serum / phosphate buffer (pH 7.4) incubated at 37 ꢀC. The rate of enzymatic
b
c
hydrolysis was determined by LC-MS/TLC following the literature procedure [23].
d
The rates of chemical hydrolysis of compounds were studied in aqueous ammonia solution (10 % aqueous ammonia in methanol, pH 8) at 37 ꢀC determined by LC-MS. Nd
represents for those molecules which have not been hydrolyzed.
2.2.3. Esters of compound 27
comparable antimycobacterial activity. Compound 50 having
3-fluoro group on the phenyl ring is more potent than 51 (Table 3),
suggesting that fluoro group is imparting in biological activity. It
was found that the aliphatic ester derivatives of compound 27
exhibited excellent antimycobacterial activity than the amino ester
derivatives (Table 3).
Hydrolysis study of esters of compound 27 shows that in blood
serum (pH 7.4) the rate of hydrolysis of these esters is slow. Only
Boc-amino acid esters 42, 45 and 50 are being hydrolyzed upto 95%
over 24 h. Compound 50 having Boc-3-fluorophenylalanine
13 Aliphatic ester derivatives of compound 27 have been
prepared (Table 3) and evaluated for their antimycobacterial
activity against M. TB H37Rv. Four ester derivatives (29, 32, 38 and
41) having small aliphatic chain (R1 ¼ ethyl, pentyl, 4-bromobutyl
and E-2-(furan-2-yl)ethenyl, respectively) were found active,
whereas compounds possessing long aliphatic chain from C6 to C14
(33e37) were found to be inactive as they became hydrophobic in
nature. Compound 39 with carbamoyl group (R1 ¼ eN(CH3)2) was
found to be equipotent as to the parent oxime 27.
(MIC ¼ 2.98
serum (pH 7.4) as compared to 51 having ester of Boc-phenylala-
g/mL). This suggests that the fluoro group is
contributing to hydrolysis as well as imparting in biological activity.
Cytotoxicity data of these compounds showed that they are not
toxic to human cells (Table 3).
Table 4 represents the MIC and structures of active compounds
from three different series i.e. esters of compound 1, 15 and 27. In
total 33 ester derivatives were found active against M. tuberculosis
mg/mL) was more susceptible to hydrolysis in blood
2.2.4. Amino acid esters of compound 27
The amino acids used to prepare chemically diverse ester
derivatives of compound 27 are aliphatic amino acids: Boc-alanine,
Fmoc-valine, Boc-leucine, Boc-glycine, Boc-methionine, aromatic
amino acids, Boc-phenylalanine, Boc-3-fluorophenylalanine,
secondary amino acids such as Boc-proline, and some unnatural
amino acids like 1-(Boc-amino)cyclopentanecarboxylic acid, Boc-
tert-leucine etc. Accordingly, various N-protected amino acids (with
N-acetylglycine (42), Boc-proline (43), Boc-glycine (45), Boc-
alanine (46), Boc-leucine (47), Boc-tert-leucine (48), Boc-methio-
nine (49), Boc-3-fluorophenylalanine (50), Boc-phenylalanine (51),
Fmoc-glycine (52), Fmoc-leucine (53) and Fmoc-valine (54)) esters
were synthesized.
nine (MIC ¼ 6.0
m
H37Rv which are having MIC in the range of 0.2e6.0
Two ester derivatives of compound 1, i.e. heptanoic acid
ester g/mL) and 3,3,3-trifluoropropanoate 13
(MIC ¼ 0.42
(MIC ¼ 0.50 g/mL) were found to exhibit improved activity,
mg/mL.
7
m
m
whereas eight ester derivatives (R1 ¼ methyl (16), ethyl (17), propyl
(18), butyl (19), hexyl (21), octyl (22), N-Boc-pyrrolidin-2-yl (25),
dimethylamino (26)) of compound 15, were found to possess better
to comparable activity as that of 15. Ten ester derivatives (R1 ¼ ethyl
(29), pentyl (32), 4-bromobutyl (38), dimethylamino (39), N-Boc-
pyrrolidin-2-yl (43), N-Boc-aminomethyl (45), (48), 1-(N-Boc-
Four amino ester derivatives, compound 43 (MIC ¼ 1.53
45 (MIC ¼ 1.55 g/mL), 48 (MIC ¼ 1.52 g/mL) and 54 (MIC ¼
1.47 g/mL) exhibited better antimycobacterial activity than
parent compound 27. Esters of aromatic amino acid like compound
50 (MIC ¼ 2.98 g/mL) and 51 (MIC ¼ 3.47 g/mL) also have
mg/mL),
m
m
m
m
m

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
1311
Table 3
Esters of Compound 27 e MIC, toxicity, hydrolysis and partition coefficient study.
Comp No. R1
MIC,a
6.25
Inactive
3.13
Inactive
Inactive
3.16
Inactive
Inactive
Inactive
Inactive
Inactive
2.03
m
g/mL % Cell viabilityb after
72 h
SI
Hydrolyzed compound (27)
t
in hours
Partition coefficient
½
formed in 24 h, 37 ꢀC
Concentration (
1.25 5.0 10
56 49
m
g/mL)
Blood serumc (%) Aq. NH3d (%) Blood serum Aq. NH3 Pc
log P ClogP
20
27
28
29
30
31
32
33
34
35
36
37
38
39
e
100
e
100
e
71
e
e
e
e
e
e
2053
3.3
5.95
eCH3
eCH2CH3
e
e
e
e
e
e
e
e
83
e
88
e
81 83 >13 13
e
95
e
Nd
e
6
447.4 2.7
5.92
e
e(CH2)2CH3
e(CH2)3CH3
e(CH2)4CH3
e(CH2)5CH3
e(CH2)7CH3
e(CH2)8CH3
e(CH2)10CH3
e(CH2)13CH3
e(CH2)3CH2Br
eN(CH3)2
e
e
e
e
e
24
e
e
e
e
e
4
e
e
e
e
e
e
e
e
e
e
e
e
e
96
e
86
e
85 87 >13
5
95
e
Nd
e
115.1 2.1
7.51
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
99
100
94
100
79 80 >20 10
68 47
95
Nd
Nd
Nd
29.3 1.5
216.8 2.3
6.83
5.45
1.56
88 Nd
e
40
Inactive
6.0
e
e
e
e
e
e
e
e
e
e
e
e
41
100
e
85
77
e
e
e
e
Nd
95
95
Nd
4
27.1 1.4
15.0 1.2
6.96
42
43
CH2NHAc
Boc-proline
6.0
1.53
83
86
e
95
95
8
Nd
6
1
4.25
7.29
75
61 69 >26 13
198
2.3
44
Inactive
e
e
e
e
e
e
e
e
e
e
e
e
45
46
47
48
49
eCH2NHBoc
Boc-alanine
Boc-leucine
Boc-tert-leucine 1.52
Boc-methionine Inactive
1.55
6.0
Inactive
87
100
e
82
63 49
22 95
95
95
e
1
20
e
0.15
2
5.0 0.7
49.1 1.7
e
6.11
6.42
e
100
e
e
e
66
e
e
e
e
e
e
e
92
e
86
e
87
e
82 >26 11
e
95
e
Nd
e
2
e
31.9 1.5
e
7.75
e
e
e
50
2.98
3.47
92
90
87
79 84 >13 95
95
6
3
13.8 1.1
7.98
51
87
71 73 >12 70
98
18
3
16.0 1.2
7.84
52
53
54
eCH2NHFmoc
Fmoc-leucine
Fmoc-valine
6.0
Inactive
1.47
68
e
73
e
e
e
29
e
7
90
e
Nd
e
1.5
e
24.1 1.4
e
8.40
e
e
e
e
85
89
81 80 >27
96
Nd
1
66.0 1.8
9.63
t
is the time required for 50% hydrolysis at 37 ꢀC.
½
Pc is the apparent partition coefficient between 1-octanol and water at room temperature (25 ꢀC). SI, Selectivity Index of compound.
a
MIC Minimum Inhibitory Concentration determined by Microplate Alamar Blue Assay (MABA) [21] (see Experimental section for details)
determined by Mosmans’s MTT assay [22] (see Experimental section for details)
The enzymatic hydrolysis of each compound (1 mg) was carried out in 80% human blood serum/phosphate buffer (pH 7.4) incubated at 37 ꢀC. The rate of enzymatic
b
c
hydrolysis was determined by LC-MS/TLC following the literature procedure [23].
d
The rates of chemical hydrolysis of compounds were studied in aqueous ammonia solution (10% aqueous ammonia in methanol, pH 8) at 37 ꢀC determined by LC-MS. Nd
represents for those molecules which have not been hydrolyzed.

1312
R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
Table 4
MICsa of active ester derivatives of compound 1, 15 and 27.
Comp no.
Structure
MIC
0.78
mg/mL
Comp no.
Structure
MIC
1.56
mg/mL
(CH2)7CH3
Me O
OH
Me
O
Br
Br
1
9
N
N
N
N
N
N
N
O
Br
Me O
2
1.88
12
6.0
N
N
N
(CH2)3CH3
Me O
CF3
O
O
Br
Br
Br
Br
Me O
5
1.53
13
0.50
N
N
N
N
N
N
N
N
N
N
(CH2)4CH3
Me O
NHBoc
O
O
Br
Me O
6
1.60
14
2.03
N
N
N
N
(CH2)5CH3
Me O
O
7
0.42
15
0.39
N
(CH2)6CH3
Me O
O
O
Br
N
Br
O
8
3.42
16
0.2
N
N
N
N
N
N

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
1313
Table 4 (continued ).
Comp no.
Structure
MIC
m
g/mL
Comp no.
Structure
MIC mg/mL
(CH2)8CH3
O
O
O
Br
Br
N
N
O
17
0.29
23
3.0
N
N
N
N
N
N
N
(CH2)2CH3
O
O
Boc
O
Br
N
Br
N
O
18
0.2
25
0.39
N
N
N
N
N
N
(CH2)3CH3
O
N
O
O
Br
Br
N
N
O
19
0.28
26
0.27
N
N
N
N
N
N
(CH2)4CH3
O
O
Br
N
20
1.5
27
6.25
N
N
N
(CH2)5CH3
O
O
Br
N
21
0.36
29
3.13
N
N
N
(continued on next page)

1314
R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
Table 4 (continued ).
Comp no.
Structure
MIC
mg/mL
Comp no.
Structure
MIC mg/mL
(CH2)4CH3
O
O
(CH2)7CH3
O
Br
N
O
Br
N
22
0.39
32
3.16
N
N
N
N
N
N
N
H3C
NHBoc
O
Br
N
O
38
2.03
46
6.0
N
N
N
N
39
1.56
48
1.52
41
6.0
50
2.98
42
6.0
51
3.47

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
1315
Table 4 (continued ).
Comp no.
Structure
MIC
m
g/mL
Comp no.
Structure
MIC mg/mL
43
1.53
52
6.0
45
1.55
54
1.47
a
MIC Minimum Inhibitory Concentration determined by Microplate Alamar Blue Assay (MABA) [21] (see Experimental section for details).
amino)-2-(3-fluorophenyl)ethyl (50), 1-(Boc-amino)-2-(phenyl)
ethyl (51), 1-(Fmoc-amino)-2-methylpropyl (54)) were found to
exhibit better activity, than their parent compound 27. In general,
the esters (as prodrugs) of compound 15 exhibited excellent anti-
microbial activity and selectivity index because of improved
solubility.
1 are having log P values in the range of 1.4e2.7. Compound 7 is
having log P 1.7, MIC ¼ 0.42 g/mL, and log P 1.8, MIC ¼ 0.50 g/mL
for compound 13 while compound 1 is having log P 1.7 and
MIC ¼ 0.78 g/mL.
m
m
m
P values for the esters of compound 15 ranged from 13.0 for the
least lipophilic compound 16 (R1 ¼ methyl) to 129.9 for the most
lipophilic compound 19 (pentanoic ester derivative). Thus the
increase in lipophilicity of 5e76 times that of the parent compound
15 (P ¼ 1.7) was achieved through conversion to the ester deriva-
tives. The log P value for the compound 15 is 0.2, while all the active
esters of compound 15 are having log P values in the range of
1.1e2.1. Thus the 5e10 times improvement in the lipophilicity
of molecules was achieved, which enhanced biological activity of
3. Measurement of the partition coefficient of all ester
derivatives
All the active ester derivatives were studied for their aqueous
solubility, by measuring the partition coefficient values in 1-octa-
nol/water mixture. The prodrug nature of these active esters was
determined from their efficient prodrug to drug (parent
compound) conversion at physiological pH.
compounds by 2-fold, compound 15 (MIC ¼ 0.39
mg/mL, log
P ¼ 0.2), while compound 16 (MIC ¼ 0.2 g/mL, log P ¼ 1.1), 17
m
(R1 ¼ ethyl, MIC ¼ 0.29
m
g/mL, log P ¼ 1.2), 18 (R1 ¼ propyl,
MIC ¼ 0.2
m
g/mL, log P ¼ 1.5), 19 (R1 ¼ butyl, MIC ¼ 0.28
mg/mL, log
4. Aqueous solubility and lipophilicity
P ¼ 1.6) and 26 (R1 ¼ dimethylamino, MIC ¼ 0.27
g/mL, log P ¼ 1.1).
m
It was suggested, in the design of drug, compounds having log P
values in the range of 1e3 are appropriate [25].
Drug lipophilicity is a very important factor that influences the
pharmacokinetic and pharmaco-dynamic behavior of compounds.
Partitioning within a biological system and biological activity are
governed by recognition forces that are, among others, defined by
hydrophobic interactions. High lipophilicity often goes with poor
aqueous solubility. This can bring with it many challenges often
making development of a seemingly promising drug candidate very
difficult. Thus drug molecule should possess optimum balance
between hydrophilic and lipophilic properties.
P values for the esters of compound 27 ranged from 5.0 for the
least lipophilic Boc-glycine ester 45 to 447.4 for the most lipophilic
propionic ester 29. The log P value for compound 27 is 3.3
(MIC ¼ 6.25
having log P values in the range of 0.7e2.7, all the esters are having
better MIC values in the range of 1.47e6.0 g/mL. Among the amino
mg/mL) which is slightly higher, while its prodrugs are
m
ester derivatives, compound 43 esterified with Boc-proline is
having higher P value (198).
Partition coefficient (P) was determined [24] for all the active
ester derivatives of compound 1, compound 15 and 27 using
mixture of octanol and phosphate buffer solution (pH 7.4) at room
temperature. The P values for the esters of compound 1 ranged
from 25.7 to 481.5. The most lipophilic compound in this series is
acetate 2 (481.5) which is 9 times more lipophilic than the parent
alcohol 1 (54.25). The most active compounds in this series are
5. Hydrolysis in human serum/aqueous solution
Rates of hydrolysis for active esters were studied in human
blood serum at 37 ꢀC which was diluted to 80% with 0.16 M phos-
phate buffer (pH 7.4) as human serum or plasma is a commonly
used medium to determine the ester hydrolysis of prodrugs for
topical drug delivery [26,27]. The ester derivatives of compound 1
compound 7 (R1 ¼ hexyl, MIC 0.42
m
g/mL) and 13 (R1 ¼ 2,2,2-Tri-
fluoroethyl, MIC 0.50 mg/mL). Active ester derivatives of compound

1316
R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
were stable in blood serum, they did not hydrolyze at pH 7.4 in 24 h.
Only compound 13, having trifluoro propionic group was being
hydrolyzed (4%) to parent alcohol 1 after 24 h. In order to test the
stability/hydrolyzeability of these compounds within the time-
frame of a typical screening assay, we have further incubated these
compounds (active esters) with blood serum for 12 consecutive
days at 37 ꢀC, but these compounds were not hydrolyzed, except
compound 13 which was hydrolyzed up to 50%. The rates of
chemical hydrolysis of these compounds were also studied in 10%
aqueous ammonia solution (pH 8) at 37 ꢀC for 24 h, ester deriva-
tives 13 and 14 (R1 ¼ N-Boc-aminomethyl) were hydrolyzed to the
parent compound 1, whereas the ester derivatives 5e9 (R1 ¼ from
butyl to octyl) were hydrolyzed only in the range of 11e13%.
Compound 2 with acetyl ester and compound 13, with dime-
thylcarbamoyl group, were stable even in 10% aqueous ammonia
solution (pH 8).
other suitable prodrugs which will have required pharmacokinetic
properties for animal studies to explore new anti-TB agents.
7. Experimental section
7.1. Biology
The MICs were determined by using M. TB H37Rv ATCC 27294 in
MABA [20] according to published procedure. Reported MICs are an
average of three individual measurements.
7.1.1. Microplate Alamar Blue Assay (MABA) [21]
The test compound MICs against M. TB H37Rv (ATCC# 27294)
were assessed by the MABA using rifampin and isoniazid as positive
controls. Compound stock solutions were prepared in DMSO at
a concentration of 12.8 mM, and the final test concentrations
With an increase in the esters aliphatic chain length (C2eC5),
ranged from 128
were prepared in Middlebrook 7H12 medium (7H9 broth con-
taining 0.1% w/v casitone, 5.6 g/mL palmitic acid, 5 mg/mL bovine
serum albumin, 4 mg/mL catalase, filter sterilized) in a volume of
100 L in 96-well microplates (BD OptiluxÔ, 96-well Microplates,
mM to 0.5 mM. Two fold dilutions of compounds
as in 17 (MIC 0.29
mg/mL) to 18 (MIC 0.20
mg/mL) to 19 (MIC
0.28 g/mL), and to 20 (MIC 1.50
m
mg/mL), there is gradual increase
m
in the stability of the corresponding ester group as seen in their
respective t1/2 values of 3.5 h, 4.0 h, 6.0 h and 10.0 h. Thus, the
comparison of MIC with the t1/2 shows that the MIC of 17e19 is
clearly associated with their bioavailability. In addition to that,
m
black/clear flat bottom). TB cultures (100 mL inoculum of
2 ꢂ 105 cfu/mL) were added, yielding a final testing volume of
Boc-proline ester 25 (MIC 0.39
mg/mL) having t1/2 (1 h) further
200 m
L. The plates were incubated at 37 ꢀC. On the seventh day
indicates that t1/2 of ester hydrolysis is a critical factor for bio-
logical activity of prodrugs. Above data suggest that the molecules
with short t1/2 are more active than compounds with higher
of incubation 12.5 mL of 20% Tween 80, and 20 mL of Alamar Blue
(Invitrogen BioSourceÔ) were added to the wells of test plate. After
incubation at 37 ꢀC for 16e24 h, fluorescence of the wells was
measured (ex 530, em 590 nm). The MICs were defined as the
lowest concentration effecting a reduction in fluorescence of ꢃ90%
relative to the mean of replicate bacteria-only controls.
(longer) t1/2
.
The rates of chemical hydrolysis of esters of compound 15 were
studied in aqueous ammonia solution at pH 8.0 at 37 ꢀC for 24 h. All
ester derivatives except compound 26 (R1 ¼ dimethylamino) were
getting hydrolyzed to parent compound 15, having the half-lives
(t1/2) from 0.5 to 6 h.
Similarly hydrolysis studies of esters of compound 27 were
carried out in blood serum at pH 7.4 and in aqueous ammonia at pH
8.0. In blood serum the rate of hydrolysis of these esters was rather
slow. Only Boc-amino ester derivatives 42 (N-acetylglycine ester,
7.1.2. Cytotoxicity assay
Cell viability in the presence and absence of test compounds
was determined by Mosmans’s MTT assay [22] for the most
active compounds from our data set. The cells (human monocytic
cell line U937) were plated in flat-bottomed 96-well plates
(1 ꢂ105 cells/mL), cultured for 1 h in controlled atmosphere (CO2
5% at 37 ꢀC), and non-adherent cells were washed by gentle
flushing with RPMI 1640. Adherent cells were cultured in the
presence of medium alone, Tween 20 (3%) (live and dead controls,
respectively) or different concentration of compounds (depending
upon the solubility) in a triplicate assay. After completion of the
MIC 6.0
m
g/mL), 45 (N-Boc-glycine ester, MIC 1.55
mg/mL) and 50
(N-Boc-3-fluorophenylalanine ester, MIC 2.98
mg/mL) were hydro-
lyzed up to 95% within 24 h. Compounds 42, 45 and 50 are having
half life (t1/2) of 8,1 and 6 h respectively. Interestingly compound 50
(MIC 2.98
mg/mL, t1/2 6 h, Boc-3-fluorophenylalanine) is more active
than 51 (MIC 3.47
m
g/mL, t1/2 18 h, Boc-phenylalanine), which is
experiment protocol 10
Phosphate Buffer Saline) was added in each well. Plates were
incubated for 3 h in CO2 incubator at 37 ꢀC. Then 100
L solubilizing
solution (0.4 M HCl in isopropanol) was added to solubilize the
formazan crystals formed by the surviving cells. Finally the absor-
bance was read at 600 nm in a microplate reader (Bio-Rad-i Mark)
using acidified isopropanol as blank. The results were presented as
percentage cell viability.
mL of MTT solution (5 mg/mL solution in
having fluoro substitution on meta-position of the phenyl ring.
These results clearly indicate that fluoro group contributes to
hydrophilic and electrostatic interactions which lead to superior
biological activity over compound 51. These data also suggest that
the molecules with short t1/2 are more active than other
m
compounds with higher t1/2
.
All the ester derivatives of compound 27 are getting hydrolyzed in
aqueous ammonia (pH 8.0) except compound 39, which is having
dimethylcarbamoyl group. It is remarkable that compounds having
dimethylcarbamoyl ester group are stable in blood serum (pH 7.4) as
well in aqueous ammonia (pH 8.0) in all three series of compounds.
7.1.3. Experimental procedure for partition coefficient
measurements [24]
1-Octanol/aqueous phase partition coefficients were deter-
mined at room temperature using the shake flask method. The
standard solution of water saturated with 1-octanol prepared by
shaking them for 24 h. Solution of compound (10ꢁ4 M concentra-
tion) in the equal amounts of 1-octanol and water was prepared
from previously saturated solution of 1-octanol/aqueous phase and
shaken vigorously for 1 h, and the contents were allowed to stand
for 15 min. Sample was centrifuged for 10 min with 10,000 rpm to
avoid emulsions. Recorded the blank readings and the UV absor-
bance for both the phases at 280 nm. The partition coefficients
were calculated from the ratio of the absorbance between the
octanol and water phases.
6. Conclusion
In conclusion the prodrugs of parent compound 1, i.e. 7
(MIC ¼ 0.42
m
g/mL) and 13 (MIC ¼ 0.50
mg/mL) are having better
antimycobacterial activity, selectivity index and improved solu-
bility. Similarly prodrugs 16e22 and 25e26 are showing better
antimycobacterial activity (MIC 0.2e1.5 mg/mL) and excellent
selectivity index as compared to parent compound 15. Biological
results of these prodrugs further suggest that parent compounds 1
and 15 are scaffolds of considerable promise as targets to make

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
1317
7.1.4. Hydrolysis study
119.8 (C15), 122.2 (Ar-C), 122.4 (C12), 124.6 (C9), 125.2 (C4a), 126.6
(C5), 129.7 (C10, C14), 130.8 (C11), 131.7 (C8), 132.9 (C3), 134.1 (C7),
136.7 (Ar-C), 145.2 (C9a), 146.9 (C4), 147.0 (C8a), 148.5 (C12a), 168.7
(CaO). ESI-MS m/z of [M þ H]þ 434.00, 436.00 was obtained for
a calculated mass of 434.05, 436.05.
7.1.4.1. Hydrolysis in aqueous solution. The rates of chemical
hydrolysis of prodrugs were studied in aqueous ammonia solution
at pH 8 at 37 ꢀC. An appropriate amount (1 mg) of prodrugs was
dissolved (1 mL, 10% aqueous ammonia in methanol). The solutions
were placed in a thermostatically controlled water bath at 37 ꢀC.
Hydrolysis rate was monitored by TLC as well as LC-MS.
7.2.2.2. 2-Bromo-6-(1H-imidazol-1-yl)-7-methyl-7H-indeno[2,1-c]
quinolin-7-yl propionate (3) Procedure B, yield 22%. Light-brown
7.1.4.2. Hydrolysis in human serum. The rates of hydrolysis for
prodrugs were studied in human serum at 37 ꢀC which was diluted
to 80% with 0.16 M phosphate buffer of pH 7.4. The reactions were
initiated by dissolving an appropriate amount (1 mg) of prodrugs in
1 mL ethanol, and preheated human blood serum in phosphate
solid; mp 244e245 ꢀC, 1H-NMR (600 MHz, CDCl3):
d 1.02 (t,
J ¼ 7.2 Hz, 3 H, CH2CH3), 1.62 (s, 3 H, CCH3), 2.34 (q, J ¼ 7.2 Hz, 2 H,
CH2CH3), 7.29 (s, 1 H, H14), 7.56e7.61 (m, 4 H, H10, H11, H12 and
H15), 7.88 (dd, J ¼ 1.8, 9.0 Hz, 1H, H7), 8.00 (d, J ¼ 9.0 Hz, 1 H, H8),
8.14 (s, 1 H, H13), 8.31 (d, J ¼ 7.2 Hz, 1 H, H9), 8.85 (d, J ¼ 2.4 Hz, 1 H,
buffer (200
m
L) was added. The solutions were kept in a water bath
H5). 13C-NMR (150.9 MHz, CDCl3):
d 8.7 (CH2CH3), 23.7 (CCH3), 28.1
at 37 ꢀC, sample centrifuged for 10 min at 10,000 rpm, the super-
natant was analyzed for remaining prodrugs, monitored by TLC as
well as LC-MS.
(CH2CH3), 83. 7 (CH3C), 119.8 (C15), 122.2 (Ar-C), 122.3 (C12), 124.6
(C9), 125.2 (C4a), 126.6 (C5), 129.7 (C10 and C14), 130.8 (C11), 131.7
(C8), 133.0 (C3), 134.1 (C7), 136.7 (Ar-C), 137.5 (C13), 145.2 (C9a),
146.9 (C4), 146.95 (C8a), 148.7 (C12a), 172.2 (CaO). ESI-MS m/z of
[M þ H]þ 448.20, 450.20 was obtained for a calculated mass of
448.06, 450.06.
7.2. Chemistry
Purification and drying of reagents and solvents were carried
out according to literature procedures [28]. Thin layer chromato-
graphic analysis was performed on E-Merck 60 F 254 precoated
aluminium thin layer chromatographic plates. All air-sensitive
reactions were carried out under nitrogen atmosphere. Melting
points were determined on a Büchi melting point B-540 instrument
and are uncorrected. 1H-NMR and 13C-NMR spectra were recorded
on Bruker Biospin 400 MHz, Bruker Avance DRX500 and DRX600
spectrometers with TMS as an internal standard. The values of
chemical shifts are expressed in ppm and the coupling constants (J)
in Hertz (Hz). Mass spectra were recorded on API 2000 LC/MS/MS
system spectrometer upto 2 decimals. IR spectra were recorded on
PerkineElmer Spectrum RX1 instrument.
7.2.2.3. 2-Bromo-6-(1H-imidazol-1-yl)-7-methyl-7H-indeno[2,1-c]
quinolin-7-yl butyrate (4) Procedure B, yield 19%. White solid; mp
214e215 ꢀC, 1H-NMR (600 MHz, CDCl3):
d
0.86 (t, J ¼ 7.2 Hz, 3 H,
CH3CH2), 1.49e1.56 (m, 2 H, CH3CH2), 1.62 (s, 3 H, CH3C), 2.24e2.37
(m, 2 H, COCH2), 7.29 (s, 1 H, H14), 7.51e7.63 (m, 4 H, H10, H11, H12
and H15), 7.87 (dd, J ¼ 1.8, 9.0 Hz,1 H, H7), 8.00 (d, J ¼ 9 Hz,1 H, H8),
8.17 (s, 1 H, H13), 8.30 (d, J ¼ 7.8 Hz, 1 H, H9), 8.85 (d, J ¼ 1.8 Hz, 1 H,
H-5). 13C-NMR (150.9 MHz, CDCl3):
d 13.5 (CH3CH2), 18.0 (CH3CH2),
23.7 (CH3C), 36.6 (COCH2), 83.6 (CH3C), 119.8 (C15), 122.1 (Ar-C),
122.3 (C12), 124.6 (C9), 125.2 (C4a), 126.6 (C5), 129.6 (C10), 129.7
(C14), 130.8 (C11), 131.7 (C8), 132.9 (C3), 134.1 (C7), 136.7 (Ar-C),
137.5 (C13), 145.1 (C9a), 146.9 (C4), 147.0 (C8a), 148.7 (C12a), 171.4
(C ¼ O). ESI-MS m/z of [M þ H]þ 462.30, 464.30 was obtained for
a calculated mass of 462.08, 464.08.
7.2.1. General procedure A
Oxime compounds 15 or compound 27 (1 eq), EDC.HCl (1.5 eq)
and DMAP (1.5 eq) were stirred in dry DMF for 20 min at room
temperature. Corresponding acid (1.5 eq) was added and reaction
was further stirred for 4 h. Reaction was quenched with water and
extracted with DCM. Organic layer was washed with brine, dried
over sodium sulfate; filtered and solvents were evaporated under
reduced pressure. Crude product was washed with pentane to
obtain pure compound.
7.2.2.4. 2-Bromo-6-(1H-imidazol-1-yl)-7-methyl-7H-indeno[2,1-c]
quinolin-7-yl pentanoate (5) Procedure B, yield 21%. Gray solid; mp
140e143 ꢀC, 1H-NMR (500 MHz, CDCl3):
d
0.85 (t, J ¼ 7.5 Hz, 3 H,
CH3CH2), 1.21e1.30 (m,
2
H, CH3CH2), 1.43e1.52 (m, H,
2
OCOCH2CH2), 1.61 (s, 3 H, CCH3), 2.26e2.39 (m, 2 H, OCOCH2), 7.29
(s, 1 H, H14), 7.51e7.62 (m, 4 H, H10, H11, H12 and H15), 7.88 (dd,
J ¼ 2.5, 9.5 Hz,1 H, H7), 8.00 (d, J ¼ 9.0 Hz,1 H, H8), 8.16 (s,1 H, H13),
8.31 (d, J ¼ 8.0 Hz, 1 H, H9), 8.84 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR
7.2.2. General procedure B
(125.8 MHz, CDCl3): d 13.6 (CH3CH2), 22.1 (CH3CH2CH2), 23.6
To a cooled (0 ꢀC) solution of oxime compound 15 or compound
27 (1 eq) in dry DMF, sodium hydride (3 eq) was added under
nitrogen atmosphere and stirred for 30 min. Reaction mixture color
changed from yellow to dark red with evolution of hydrogen gas.
Corresponding acid chloride (3 eq) was added and reaction was
stirred for 15 h at room temperature after which reaction was
quenched with ice. Reaction mixture was extracted with DCM,
washed by brine. Organic layer was dried over sodium sulfate,
filtered and solvents were evaporated under reduced pressure to
get crude product. Crude product was washed with pentane several
times to get pure compound.
(CCH3), 26.5 (CH3CH2CH2), 34.4 (COCH2), 83.6 (CCH3), 119.8 (C15),
122.1 (Ar-C), 122.2 (C12), 124.6 (C9), 125.2 (C4a), 126.6 (C5), 129.7
(C15), 130.8 (C11), 131.7 (C8), 132.9 (C3), 134.1 (C7), 136.7 (Ar-C),
137.5 (C13), 145.2 (C9a), 146.9 (C4), 147.0 (C8a), 148.7 (C12a), 171.6
(CaO). ESI-MS m/z of [M þ H]þ 475.80, 477.80 was obtained for
a calculated mass of 476.09, 478.09.
7.2.2.5. 2-Bromo-6-(1H-imidazol-1-yl)-7-methyl-7H-indeno[2,1-c]
quinolin-7-yl hexanoate (6) Procedure B, yield 56%. Off-white solid;
mp 108e110 ꢀC. IRn
(KBr, cmꢁ1) 1744.48; 1H-NMR (500 MHz,
max
CDCl3):
d
0.83 (t, J ¼ 7.0 Hz, 3 H, CH3CH2), 1.18e1.30 (m, 4 H, (CH2)2),
1.44e1.52 (m, 2 H, OCOCH2CH2), 1.61 (s, 3 H, CCH3), 2.23e2.39 (m, 2
H, OCOCH2), 7.29 (s, 1 H, H14), 7.50e7.63 (m, 4 H, H10, H11, H12 and
H15), 7.88 (dd, J ¼ 2.4, 9.0 Hz, 1 H, H7), 8.00 (d, J ¼ 9.0 Hz, 1 H, H8),
8.16 (s, 1 H, H13), 8.31 (d, J ¼ 7.5 Hz, 1 H, H9), 8.85 (d, J ¼ 2.0 Hz, 1 H,
7.2.2.1. 2-Bromo-6-(1H-imidazol-1-yl)-7-methyl-7H-indeno[2,1-c]
quinolin-7-yl acetate (2) Procedure B, yield 23%. Light-brown solid;
mp 237e238 ꢀC, IRn
(KBr, cmꢁ1) 1742.69; 1H-NMR (500 MHz,
max
CDCl3):
d
1.62 (s, 3 H, CH3), 2.05 (s, 3 H, OCOCH3), 7.30 (s, 1 H, H14),
H5). 13C-NMR (125.8 MHz, CDCl3):
d 13.8 (CH3CH2), 22.2
7.51e7.62 (m, 4 H, H10, H11, H15 and H12), 7.88 (dd, J ¼ 2.0, 9.0 Hz,1
H, H7), 8.00 (d, J ¼ 9.0 Hz, 1 H, H8), 8.15 (s, 1 H, H13), 8.31 (d,
J ¼ 7.5 Hz, 1 H, H9), 8.85 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR
(CH3CH2CH2), 23.6 (CCH3), 24.2 (CH3CH2CH2CH2), 31.0
(CH3CH2CH2), 34.7 (COCH2), 83.7 (CCH3), 119.8 (C15), 122.1 (Ar-C),
122.2 (C12), 124.6 (C9), 125.2 (C4a), 126.6 (C5), 129.6 (C10), 129.7
(C14), 130.8 (C11), 131.7 (C8), 132.9 (C3), 134.1 (C7), 136.5 (Ar-C),
(125.8 MHz, CDCl3):
d 21.8 (CH3COO), 23.7 (CH3C), 83.9 (CH3eC),

1318
R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
137.5 (C13), 145.1 (C9a), 146.9 (C4), 147.0 (C8a), 148.7 (C12a), 171.6
(CaO). ESI-MS m/z of [M þ H]þ 489.90, 491.90 was obtained for
a calculated mass of 490.11, 492.11.
122.13 (Ar-C), 122.19 (Ar-C), 124.6 (Ar-C), 125.1 (Ar-C), 126.5 (Ar-C),
129.36 (Ar-C), 129.67 (Ar-C), 130.7 (Ar-C), 131.6 (Ar-C), 132.8 (Ar-C),
134.1 (Ar-C), 134.6 (Ar-C), 145.0 (Ar-C), 146.8 (Ar-C), 147.0 (Ar-C),
148.6 (Ar-C),171.7 (CaO). ESI-MS m/z of [M þ H]þ 602.10, 603.90 was
obtained for a calculated mass of 602.23, 604.23.
7.2.2.6. 2-Bromo-6-(1H-imidazol-1-yl)-7-methyl-7H-indeno[2,1-c]
quinolin-7-yl heptanoate (7) Procedure B, yield 40%. Off-white solid;
mp 120e122 ꢀC, 1H-NMR (600 MHz, CDCl3):
d
0.84 (t, J ¼ 7.2 Hz, 3 H,
7.2.2.10. 2-Bromo-6-(1H-imidazol-1-yl)-7-methyl-7H-indeno[2,1-c]
quinolin-7-yl pentadecanoate (11) Procedure B, yield 12%. White
CH3CH2), 1.18e1.28 (m,
6
H, (CH2)3), 1.44e1.53 (m, H,
2
OCOCH2CH2), 1.61 (s, 3 H, CCH3), 2.25e2.39 (m, 2 H, OCOCH2), 7.29
(s, 1 H, H14), 7.51e7.63 (m, 4 H, H10, H11, H12 and H15), 7.88 (dd,
J ¼ 1.8, 9.0 Hz,1 H, H7), 8.00 (d, J ¼ 9.0 Hz,1 H, H8), 8.16 (s, 1 H, H13),
8.31 (d, J ¼ 7.8 Hz, 1 H, H9), 8.85 (d, J ¼ 2.4 Hz, 1 H, H5). 13C-NMR
solid; mp 67e69 ꢀC. 1H-NMR (600 MHz, CDCl3):
d
0.87 (t, J ¼ 7.2 Hz,
3 H, CH3CH2), 1.16e1.33 (m, 22 H, CH2), 1.43e1.52 (m, 2 H,
COCH2CH2), 1.60 (s, 3 H, CCH3), 2.27e2.40 (m, 2 H, COCH2), 7.30 (s, 1
H, H14), 7.52e7.63 (m, 4 H, H10, H11, H12 and H15), 7.88 (dd, J ¼ 1.8,
9.0, Hz, 1 H, H7), 8.00 (d, J ¼ 9.0 Hz, 1 H, H8), 8.16 (s, 1 H, H13), 8.32
(d, J ¼ 9.0 Hz, 1 H, H9), 8.85 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR
(150.9 MHz, CDCl3):
d 14.0 (CH2CH3), 22.4 (CH2), 23.6 (CCH3), 24.5
(CH2), 28.7 (CH2), 31.4 (CH2), 34.8 (COCH2), 83.7 (CCH3), 119.8 (C15),
122.1 (Ar-C), 122.3 (C12), 124.6 (C9), 125.2 (C4a), 126.6 (C5), 129.7
(C10 and C14), 130.8 (C11), 131.7 (C8), 132.9 (C3), 134.1 (C7), 136.8,
145.2 (C9a), 146.9 (C4), 147.0 (C8a), 148.7 (C12a), 171.6 (CaO). ESI-
MS m/z of [M þ H]þ 504.00, 505.90 was obtained for a calculated
mass of 504.12, 506.12.
(150.9 MHz, CDCl3):
d 14.0 (CH3CH2), 22.7 (CH3CH2), 23.5 (CH2),
24.5 (CH3C), 28.9 (CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 29.5
(CH2), 29.61 (CH2), 29.64 (CH2), 29.7 (CH2), 31.9 (COCH2CH2), 34.7
(COCH2CH2), 83.5 (CH3C), 119.7 (C15), 122.1 (Ar-C), 122.2 (C12),
124.6 (C9), 125.1 (C4a), 126.5 (C5), 129.64 (C10), 129.68 (C14), 130.8
(C11), 131.6 (C8), 132.8 (C3), 134.1 (C7), 136.6 (Ar-C), 137.5 (C13),
145.0 (C9a), 146.8 (C4), 146.9 (C8a), 148.5 (C12a), 171.7 (CaO). ESI-
MS m/z of [M þ H]þ 616.40, 618.50 was obtained for a calculated
mass of 616.25, 618.25.
7.2.2.7. 2-Bromo-6-(1H-imidazol-1-yl)-7-methyl-7H-indeno[2,1-c]
quinolin-7-yl octanoate (8) Procedure B, yield 45%. Off-white solid,
mp 121e123 ꢀC. IRn
(KBr, cmꢁ1) 1743.95; 1H-NMR (500 MHz,
max
CDCl3):
d
0.82 (t, J ¼ 7.5 Hz, 3 H, CH3CH2), 1.14e1.31 (m, 8 H, (CH2)4),
1.44e1.54 (m, 2 H, OCOCH2CH2), 1.61 (s, 3 H, CCH3), 2.24e2.38 (m, 2
H, OCOCH2), 7.29 (s, 1 H, H14), 7.51e7.62 (m, 4 H, H10, H11, H12 and
H15), 7.88 (dd, J ¼ 2.0, 9.0 Hz, 1 H, H7), 8.00 (d, J ¼ 9.0 Hz, 1 H, H8),
8.15 (s, 1 H, H13), 8.31 (d, J ¼ 8.0 Hz, 1 H, H9), 8.84 (d, J ¼ 2.0 Hz, 1 H,
7.2.2.11. 2-Bromo-6-(1H-imidazol-1-yl)-7-methyl-7H-indeno[2,1-c]
quinolin-7-yl dimethylcarbamate (12) Procedure B, yield 55%. white
solid, mp 241e243 ꢀC. 1H-NMR (400 MHz, CDCl3):
d 1.53 (s, 3 H,
CCH3), 2.73 (s, 3 H, CH3N), 3.03 (s, 3 H, CH3N), 7.26 (s, 1 H, Ar-H).
7.45e7.62 (m, 4 H, Ar-H), 7.85 (dd, J ¼ 2.0, 9.0 Hz, 1 H, Ar-H), 7.98 (s,
1 H, Ar-H), 8.0 (d, J ¼ 2.5 Hz, 1 H, Ar-H), 8.29 (d, J ¼ 7.1 Hz,1 H, Ar-H),
H5). 13C-NMR (125.8 MHz, CDCl3):
d 14.0 (CH3CH2), 22.5
(CH3CH2CH2), 23.6 (CCH3), 24.5 (CH3CH2), 28.8 (COCH2CH2), 28.9
(COCH2CH2), 31.6 (CH2), 34.7 (CH2), 83.7 (CCH3), 119.7 (C15), 122.1
(Ar-C), 122.2 (C12), 124.6 (C9), 125.2 (C4a) , 126.6 (C5), 129.68 (C10),
129.69 (C14), 130.7 (C11), 131.7 (C8), 132.9 (C3), 134.1 (C7), 136.7
(Ar-C), 137.5 (C13), 145.1 (C9a), 146.9 (C4), 147.0 (C8a), 148.7 (Ar-C),
171.6 (CaO). ESI-MS m/z of [M]þ 517.70, 519.70 was obtained for
a calculated mass of 517.13, 519.13.
8.83 (d, J ¼ 2.0 Hz, 1 H, Ar-H). 13C-NMR (100.6 MHz, CDCl3):
d 24.11
(CH3C), 36.3 (NCH3), 83.3 (CH3C), 119.8 (Ar-C), 121.9 (Ar-C), 122.0
(Ar-C), 124.6 (Ar-C), 125.3 (Ar-C), 126.5 (Ar-C), 129.3 (Ar-C), 129.5
(Ar-C), 130.6 (Ar-C), 131.6 (Ar-C), 133.8 (Ar-C), 134.5 (Ar-C), 136.4
(Ar-C), 137.4 (Ar-C), 144.1 (Ar-C), 146.5 (Ar-C), 146.8 (Ar-C), 149.2
(Ar-C), 153.5 (CaO). ESI-MS m/z of [M þ H]þ 462.90, 464.70 was
obtained for a calculated mass of 463.07, 465.07.
7.2.2.8. 2-Bromo-6-(1H-imidazol-1-yl)-7-methyl-7H-indeno[2,1-c]
quinolin-7-yl nonanoate (9) Procedure B, yield 67%. Off-white solid,
7.2.2.12. 2-Bromo-6-(1H-imidazol-1-yl)-7-methyl-7H-indeno[2,1-c]
mp 81e82 ꢀC. IRn
(KBr, cmꢁ1) 1745.73; 1H-NMR (600 MHz,
quinolin-7-yl 3,3,3-trifluoropropanoate (13) Procedure B, yield
max
CDCl3):
d
0.85 (m, 3 H, CH3CH2), 1.16e1.28 (m, 10 H, (CH2)5),
27%. Off-white solid; mp 195e206 ꢀC. IRn
(KBr, cmꢁ1) 1766.03;
max
1.44e1.52 (m, 2 H, OCOCH2CH2), 1.60 (s, 3 H, CCH3), 2.26e2.40 (m, 2
H, OCOCH2), 7.30 (t, J ¼ 1.2 Hz, 1 H, H14), 7.51e7.63 (m, 4 H, H10,
H11, H12 and H15), 7.88 (dd, J ¼ 1.8, 9.0 Hz, 1 H, H7), 8.00 (d,
J ¼ 9.0 Hz, 1 H, H8), 8.16 (d, J ¼ 1.2 Hz, 1 H, H13), 8.32 (d, J ¼ 7.8 Hz, 1
H, H9), 8.85 (d, J ¼ 2.4 Hz, 1 H, H5). 13C-NMR (150.9 MHz, CDCl3):
1H-NMR (500 MHz, CDCl3):
d 1.67 (s, 3 H, CCH3), 3.05e3.25 (m, 2 H,
CH2CF3), 7.31 (s, 1 H, H14), 7.49e7.64 (m, 4 H, H10, H11, H12 and
H15), 7.90 (dd, J ¼ 2.0, 9.0 Hz, 1 H, H7), 8.01 (d, J ¼ 9.0 Hz, 1 H, H8),
8.06 (s, 1 H, H13), 8.31 (d, J ¼ 8.0 Hz, 1 H, H9), 8.84 (d, J ¼ 2.0 Hz, 1 H,
H5). 13C-NMR (125.8 MHz, CDCl3):
d 23.9 (CH3), 39.8 (CF3CH2), 40.0
d
14.1 (CH3CH2), 22.6 (CH3CH2), 23.5 (CH3C), 24.5 (CH2), 28.9 (CH2),
(CF3CH2), 40.3 (CF3CH2), 40.5 (CF3CH2), 85.5 (CH3C), 119.7 (C15),
121.9 (Ar-C), 122.4 (C12), 122.5 (Ar-C), 124.0 (Ar-C), 124.8 (C9), 125.2
(C4a), 126.6 (C5), 129.8 (C10, C14), 130.2 (C10), 131.0 (C11), 131.8
(C8), 132.2 (Ar-C), 134.5 (C7), 136.7 (Ar-C), 137.3 (C13), 145.0 (C9a),
147.1 (Ar-C), 147.14 (Ar-C), 147.4 (Ar-C), 161.9 (CaO). ESI-MS m/z of
[M þ H]þ 501.80, 503.70 was obtained for a calculated mass of
502.03, 504.03.
29.0 (CH2), 29.1 (CH2), 31.7 (CH3CH2CH2), 34.7 (COCH2), 83.5
(CCH3), 119.7 (C15), 122.1 (Ar-C), 122.2 (C12), 124.6 (C9), 125.1 (C4a),
126.5 (C10), 129.5 (C15), 129.7 (C10, C14), 130.8 (C11), 131.6 (C8),
132.7 (C3), 134.1 (C7), 136.6 (Ar-C), 137.4 (C13), 145.0 (C9a), 146.8
(C4), 146.9 (C8a), 148.5 (C12a), 171.7 (CaO). ESI-MS m/z of [M þ H]þ
531.60, 533.60 was obtained for a calculated mass of 531.15, 533.15.
7.2.2.9. 2-Bromo-6-(1H-imidazol-1-yl)-7-methyl-7H-indeno[2,1-c]
7.2.2.13. 2-Bromo-6-(1H-imidazol-1-yl)-7-methyl-7H-indeno[2,1-c]
quinolin-7-yl tetradecanoate (10) Procedure B, yield 33%. Off-white
quinolin-7-yl 2-(tert butoxycarbonylamino)acetate (14). A mixture
solid, mp 77e79 ꢀC. 1H-NMR (400 MHz, CDCl3):
d
0.82e0.88 (m, 3 H,
of compound
1
(1.0 g, 2.55 mmol), Boc-glycine-N-hydrox-
CH3CH2), 1.15e1.38 (m, 20 H, CH3(CH2)10), 1.40e1.52 (m, 2 H,
CH2CH2CO), 1.59 (s, 3 H, CCH3), 2.25e2.38 (m, 2 H, COCH2), 7.29 (s, 1
H, Ar-H), 7.40e7.68 (m, 4 H, Ar-H), 7.87 (dd, J ¼ 2.0, 9.0 Hz,1 H, Ar-H),
7.99 (d, J ¼ 9.0 Hz, 1 H, Ar-H), 8.18 (s, 1 H, Ar-H), 8.30 (d, J ¼ 7.5 Hz, 1
H, Ar-H), 8.83 (d, J ¼ 1.9 Hz,1 H, Ar-H). 13C-NMR (100.6 MHz, CDCl3):
ysuccinimide ester (2.08 g, 7.66 mmol) in dry THF (80 mL) was
cooled to ꢁ78 ꢀC then n-BuLi (4.5 mL, 3.82 mmol) was added,
reaction mixture stirred for 30 min at same temperature and then
allowed to warm at room temperature and stirred for 1 h, color of
the reaction changed from yellow to dark red. Reaction was
quenched with aqueous ammonium chloride. Reaction mixture
was diluted with ethyl acetate (100 mL), washed with brine
(3 ꢂ 50 mL) and dried over anhydrous sodium sulfate. Organic layer
d
14.1 (CH3CH2), 22.7 (CH3CH2), 23.6 (CH3C), 24.5 (CH2), 28.9 (CH2),
29.2 (CH2), 29.33 (CH2), 29.37 (CH2), 29.47 (CH2), 29.53 (CH2), 29.60
(CH2), 29.63 (CH2), 31.9 (CH2), 34.7 (CH2), 83.6 (CH3C), 119.8 (Ar-C),

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
1319
was filtered and solvents were evaporated under reduced pressure
to obtain a gum as a crude product. Crude product was purified by
column chromatography (silica gel 100e200 mesh, eluent: 2%
methanol in DCM) to give pure compound 14 (0.38 g, 28%) as an off-
7.2.2.17. 2-Bromo-6-(1H-imidazol-1-yl)-7H-indeno[2,1-c]quinolin-
7-one O-pentanoyl oxime (19) Procedure A, yield 60%. Light-brown
solid; mp 230e232 ꢀC. IRn (KBr, cmꢁ1 1765.72; 1H-NMR
0.94 (t, J ¼ 7.3 Hz, 3 H, CH3CH2), 1.39e1.44 (m, 2
)
max
(400 MHz, CDCl3):
d
white solid; mp 197e198 ꢀC. IRn
(KBr, cmꢁ1) 1770.99; 1H-NMR
H, CH3CH2), 1.63e1.72 (m, 2 H, CH3CH2CH2), 2.57 (t, J ¼ 7.5 Hz, 2 H,
COCH2), 7.22 (d, J ¼ 0.9 Hz, 1 H, H14), 7.59e7.71 (m, 3 H, H10, H11
and H15), 7.90 (dd, J ¼ 2.0, 9.0 Hz, 1 H, H7), 7.99 (d, J ¼ 9.0 Hz, 1H,
H8), 8.23 (s, 1 H, H13), 8.29 (d, J ¼ 7.7 Hz, 1 H, H9), 8.55 (d, J ¼ 7.4 Hz,
1 H, H12), 8.74 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR (100.6 MHz, CDCl3):
max
(500 MHz, CDCl3):
d 1.37 (s, 9 H, Boc), 1.63 (s, 3 H, CCH3), 3.83 (dd,
J ¼ 6.0, 18.5 Hz, 1 H, CH2NHBoc), 3.93 (dd, J ¼ 6.0, 18.5 Hz, 1 H,
CH2NHBoc), 4.84 (bs, 1 H, NH, D2O exchangeable), 7.30 (s, 1 H, H14),
7.52e7.63 (m, 4 H, H10, H11, H12 and H15), 7.89 (dd, J ¼ 2.0, 9.0 Hz,
1 H, H7), 8.00 (d, J ¼ 9.0 Hz, 1 H, H8), 8.10 (s, 1 H, H13), 8.30 (d,
J ¼ 7.5 Hz, 1 H, H9), 8.84 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR
d
13.7 (CH3CH2), 22.1 (CH3CH2), 26.4 (CH3CH2CH2), 31.9 (COCH2),
119.6 (Ar-C), 120.4 (Ar-C), 122.5 (Ar-C), 123.8 (Ar-C), 124.3 (Ar-C),
126.1 (Ar-C), 128.8 (Ar-C), 129.5 (Ar-C), 130.7 (Ar-C), 131.4 (Ar-C),
131.8 (Ar-C), 132.8 (Ar-C), 135.0 (Ar-C), 137.9 (Ar-C), 138.6 (Ar-C),
144.3 (Ar-C), 147.4 (Ar-C), 148.6 (Ar-C), 154.4 (Ar-C), 172.1 (CaO).
ESI-MS m/z of [M þ H]þ 474.90, 476.90 was obtained for a calcu-
lated mass of 475.07, 477.07.
(125.8 MHz, CDCl3): d 23.7 (CH3C), 28.2 (NHBoc), 43.0 (COCH2), 80.1
((CH3)3C), 84.8 (CH3C), 119.9 (C15), 122.4 (Ar-C), 122.7 (C12), 124.7
(C9), 125.2 (C4a) , 126.6 (C5), 129.8 (C10), 129.9 (C15), 131.9 (C8),
132.7 (C3), 134.3 (C7), 136.7 (Ar-C), 137.6 (C13), 145.2(C9a), 147.1
(C8a), 147.9 (C12a), 155.5 (CO(CH3)3), 168.4 (CaO). ESI-MS m/z of
[M þ H]þ 548.70, 550.70 was obtained for a calculated mass of
549.11, 551.11.
7.2.2.18. 2-Bromo-6-(1H-imidazol-1-yl)-7H-indeno[2,1-c]quinolin-
7-one O-hexanoyl oxime (20) Procedure A, yield 46%. Yellow solid;
mp, compound decomposed above 151 ꢀC. 1H-NMR (500 MHz,
7.2.2.14. 2-Bromo-6-(1H-imidazol-1-yl)-7H-indeno[2,1-c]quinolin-
7-one O-acetyl oxime (16) Procedure B, yield 47%. Light-brown solid;
CDCl3):
d
0.92 (t, J ¼ 7.0 Hz, 3 H, CH3CH2), 1.33e1.43 (m, 4 H,
mp 243e245 ꢀC. IRn
(KBr, cmꢁ1) 1783.56; 1H-NMR (600 MHz,
2 ꢂ CH2), 1.68e1.75 (m, 2 H, COCH2CH2), 2.57 (t, J ¼ 7.5 Hz, 2 H,
COCH2), 7.25 (s, 1 H, H14), 7.59e7.63 (m, 1 H, H11), 7.68e7.73 (m, 2
H, H10 and H15), 7.90 (dd, J ¼ 2.0, 9.0 Hz,1 H, H7), 7.99 (d, J ¼ 9.0 Hz,
1 H, H8), 8.26e8.32 (m, 2 H, H9 and H13), 8.54 (d, J ¼ 7.5 Hz, 1 H,
H12), 8.73 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR (150.9 MHz, CDCl3):
max
DMSO-d6):
d 2.26 (s, 3 H, CH3CO), 7.08 (s, 1 H, H14), 7.71 (t,
J ¼ 7.6 Hz, 1 H, H10), 7.75e7.81 (m, 2 H, H11 and H15), 8.00 (d,
J ¼ 9.0 Hz, 1 H, H8), 8.07 (dd, J ¼ 1.8, 9.0 Hz, 1 H, H7), 8.32 (s, 1 H,
H13), 8.45 (d, J ¼ 7.5 Hz, 1 H, H12), 8.62 (d, J ¼ 7.8 Hz, 1 H, H9), 8.88
(d, J ¼ 1.8 Hz, 1 H, H5). 13C-NMR (150.9 MHz, DMSO-d6):
d
19.1
d 13.9 (CH3), 22.4 (CH2), 24.1 (CH2), 31.1 (CH2), 32.2 (COCH2), 119.7
(CH3CO), 119.9 (C15), 120.7 (Ar-C), 122.1 (Ar-C), 123.4 (Ar-C), 125.5
(C9), 126.2 (C5), 128.0 (C14), 128.9 (C12a), 130.1 (C12), 131.6 (C8 and
C11), 133.3 (C10), 135.2 (C7), 137.8 (C9a), 137.9 (C13), 144.2 (Ar-C),
146.9 (C8a), 148.3 (C4), 154.5 (C3a), 169.2 (CaO). ESI-MS m/z of
[M þ H]þ 432.70, 434.80 was obtained for a calculated mass of
433.03, 435.03.
(C15), 120.7 (Ar-C), 122.7 (Ar-C), 124.2 (Ar-C), 124.6 (C9), 126.3 (C5),
128.5 (C14), 129.8 (C12a), 130.9 (C12), 131.5 (C11), 132.0 (C8), 132.9
(C10), 135.2 (C7), 137.8 (C13), 138.9 (C9a), 144.6 (Ar-C), 147.7 (C8a),
148.9 (C4), 154.6 (C3a), 172.1 (CaO). ESI-MS m/z of [M þ H]þ 489.00,
490.90 was obtained for a calculated mass of 489.09, 491.09.
7.2.2.19. 2-Bromo-6-(1H-imidazol-1-yl)-7H-indeno[2,1-c]quinolin-
7-one O-heptanoyl oxime (21) Procedure A, yield 58%. Yellow solid;
mp, compound decomposed above 153 ꢀC. 1H-NMR (400 MHz,
7.2.2.15. 2-Bromo-6-(1H-imidazol-1-yl)-7H-indeno[2,1-c]quinolin-
7-one O-propionyl oxime (17) Procedure B, yield 40%. Light-brown
solid; mp 246e248 ꢀC. 1H-NMR (400 MHz, DMSO-d6):
d
1.11 (t,
CDCl3)
d
: 0.89 (t, J ¼ 7.0 Hz, 3 H, CH3CH2), 1.24e1.45 (m, 6 H, (CH2)3),
J ¼ 7.4 Hz, 3 H, CH3CH2), 2.62 (q, J ¼ 7.4 Hz, 2 H, CH3CH2), 7.09 (s,1 H,
H14), 7.54e7.52 (m, 1 H, H11), 7.73e7.82 (m, 2 H, H10 and H15), 7.99
(d, J ¼ 9.0 Hz,1 H, H8), 8.06 (dd, J ¼ 1.4, 10.5 Hz,1 H, H7), 8.32 (s, 1 H,
H13), 8.43 (d, J ¼ 7.4 Hz, 1 H, H9), 8.61 (d, J ¼ 7.7 Hz, 1 H, H12), 8.86
1.62e1.75 (m, 2 H, COCH2CH2), 2.56 (t, J ¼ 7.5 Hz, 2 H, COCH2CH2),
7.22 (s, 1 H, Ar-H), 7.57e7.64 (m, 1 H, Ar-H), 7.65e7.75 (m, 2 H, Ar-
H), 7.90 (dd, J ¼ 2.0, 9.0 Hz,1 H, H7), 7.80 (d, J ¼ 9.0 Hz,1 H, H8), 8.24
(s, 1 H, Ar-H), 8.31 (d, J ¼ 7.6 Hz, 1 H, Ar-H), 8.55 (d, J ¼ 7.4 Hz, 1 H,
Ar-H), 8.75 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR (100.6 MHz, CDCl3):
(s, 1 H, H5). 13C-NMR (100.6 MHz, DMSO-d6):
d 8.2 (CH3CH2), 24.6
(CH3CH2), 119.6 (Ar-C), 120.1 (Ar-C), 121.7 (Ar-C), 122.9 (Ar-C), 125.0
(Ar-C), 125.8 (Ar-C), 127.6 (Ar-C), 128.4 (Ar-C), 129.7 (Ar-C), 131.1
(Ar-C), 131.2 (Ar-C), 132.9 (Ar-C), 134.8 (Ar-C), 137.42 (Ar-C), 137.44
(Ar-C), 143.8 (Ar-C), 146.4 (Ar-C), 147.8 (Ar-C), 154.1 (Ar-C), 171.8
(CaO). ESI-MS m/z of [M þ H]þ 446.70, 448.80 was obtained for
a calculated mass of 447.04, 449.04.
d 14.0 (CH3), 22.5 (CH2), 24.4 (CH2), 28.6 (CH2), 31.4 (CH2), 32.2
(COCH2), 119.6 (Ar-C), 120.6 (Ar-C), 122.6 (Ar-C), 124.1 (Ar-C), 124.5
(Ar-C), 126.3 (Ar-C), 128.9 (Ar-C), 129.7 (Ar-C), 130.8 (Ar-C), 131.5
(Ar-C),131.9 (Ar-C),132.9 (Ar-C),135.2 (Ar-C),137.9 (Ar-C),138.8 (Ar-
C), 144.5 (Ar-C), 147.6 (Ar-C), 148.8 (Ar-C), 154.6 (Ar-C), 172.2 (CaO).
ESI-MS m/z of [M þ H]þ 503.10, 505.00 was obtained for a calcu-
lated mass of 503.10, 505.10.
7.2.2.16. 2-Bromo-6-(1H-imidazol-1-yl)-7H-indeno[2,1-c]quinolin-
7-one O-butyryl oxime (18) Procedure A, yield 43%. Yellow solid; mp
7.2.2.20. 2-Bromo-6-(1H-imidazol-1-yl)-7H-indeno[2,1-c]quinolin-
7-one O-nonanoyl oxime (22) Procedure A, yield 55%. Yellow solid;
190e191 ꢀC, 1H-NMR (600 MHz, DMSO-d6):
d
0.96 (t, J ¼ 7.2 Hz, 3 H,
CH3CH2), 1.58e1.67 (m, 2 H, CH3CH2), 2.58 (t, J ¼ 7.2 Hz, 2 H,
COCH2CH2), 7.08 (t, J ¼ 1.2 Hz, 1 H, H14), 7.68 (t, J ¼ 7.8 Hz, 1 H, H11),
7.74 (dt, J ¼ 1.2, 7.8 Hz, 1 H, H10), 7.77 (t, J ¼ 1.2 Hz,1 H, H15), 7.97 (d,
J ¼ 9.0 Hz, 1 H, H8), 8.03 (dd, J ¼ 1.8, 9.0 Hz, 1 H, H7), 8.30 (d,
J ¼ 1.2 Hz, 1 H, H13), 8.39 (dd, J ¼ 0.6, 7.2 Hz, 1 H, H9), 8.54 (d,
J ¼ 7.8 Hz, 1 H, H12), 8.80 (d, J ¼ 1.8 Hz, 1 H, H5). 13C-NMR
mp 147e149 ꢀC. 1H-NMR (600 MHz, CDCl3):
d
0.87 (t, J ¼ 7.0 Hz, 3 H,
CH3CH2), 1.20e1.35 (m, 10 H, CH3(CH2)5), 1.68e1.75 (m, 2 H,
CH2CH2), 2.58 (t, J ¼ 7.4 Hz, 2 H, COCH2CH2), 7.27 (s, 1 H, H14),
7.60e7.65 (m, 1 H, H11), 7.70e7.75 (m, 2 H, H15 and H10), 7.92 (dd,
J ¼ 2.0, 9.0 Hz, 1 H, H7), 8.00 (d, J ¼ 9.0 Hz, 1 H, H8), 8.31 (s, 1 H, H9),
8.37 (s, 1 H, H13), 8.55 (d, J ¼ 7.4 Hz, 1 H, H12), 8.76 (d, J ¼ 2.0 Hz, 1
(150.9 MHz, DMSO-d6):
d
13.9 (CH3CH2), 18.1 (CH3CH2), 33.8
H, H5). 13C-NMR (150.9 MHz, CDCl3):
d 14.1 (CH3CH2), 22.6 (CH2),
(COCH2), 120.5 (C15), 121.3 (Ar-C), 122.7 (Ar-C), 124.0 (Ar-C), 126.1
(C9), 126.6 (C5), 128.7 (C14), 129.6 (C12a), 130.7 (C12), 132.2 (C8 and
C11), 134.0 (C10), 135.1 (Ar-C), 135.9 (C7), 138.4 (C13), 138.5 (C9a),
144.9 (Ar-C), 147.6 (C8a), 148.9 (Ar-C), 155.3 (C3a), 171.8 (CaO). ESI-
MS m/z of [M þ H]þ460.80, 462.70 was obtained for a calculated
mass of 461.06, 463.06.
24.5 (CH2), 29.0 (CH2), 29.09 (CH2), 29.25 (CH2), 31.8 (CH2), 32.2
(COCH2), 120.0 (C15), 120.6 (Ar-C), 122.9 (Ar-C), 124.31 (Ar-C),
124.65 (C9), 126.2 (C5), 129.7 (C12a), 130.9 (C12), 131.5 (C11), 132.0
(C8), 132.9 (C10), 135.2 (C7), 137.5 (C13), 138.8 (C9a), 147.6 (C8a),
149.0 (C4), 154.6 (C3a), 172.2 (CaO). ESI-MS m/z of [M þ H]þ 531.10,
533.10 was obtained for a calculated mass of 531.13, 533.13.

1320
R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
7.2.2.21. 2-Bromo-6-(1H-imidazol-1-yl)-7H-indeno[2,1-c]quinolin-
d 36.6 (NCH3), 37.5 (NCH3), 120.1 (C15), 120.3 (Ar-C), 122.2 (Ar-C),
7-one O-decanoyl oxime (23) Procedure A, yield 47%. Yellow solid;
123.7 (Ar-C), 124.4 (C9), 126.0 (C5), 128.7 (C14), 129.3 (C12), 129.5
(C12a), 131.0 (C11), 131.7 (C8), 132.5 (C10), 134.8 (C7), 138.5 (C13),
131.1 (C9a), 144.9 (Ar-C), 147.6 (C8a), 148.3 (C4), 153.8 (CaO), 154.6
(C3a), (CaO). ESI-MS m/z of [M þ H]þ 461.80, 463.90 was obtained
for a calculated mass of 462.05, 464.05.
mp 147e148 ꢀC; 1H-NMR (400 MHz, CDCl3):
d
0.86 (t, J ¼ 6.7 Hz, 3
H, CH3CH2), 1.17e1.42 (m, 12 H, CH3(CH2)6), 1.61e1.77 (m, 2 H,
CH2CH2), 2.56 (t, J ¼ 7.5 Hz, 2 H, COCH2CH2), 7.22 (s, 1 H, H14),
7.58e7.65 (m, 1 H, H11), 7.69 (d, J ¼ 1.0 Hz,1 H, H15), 7.70e7.74 (m, 1
H, H10), 7.91 (dd, J ¼ 2.0, 9.0 Hz,1 H, H7), 7.99 (d, J ¼ 9.0 Hz,1 H, H8),
8.24 (s, 1 H, H13), 8.31 (d, J ¼ 7.8 Hz, 1 H, H9), 8.55 (d, J ¼ 7.4 Hz, 1 H,
H12), 8.75 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR (100.6 MHz, CDCl3):
7.2.2.25. 2-Bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-7H-indeno
[2,1-c]quinolin-7-one O-acetyl oxime (28) Procedure B, yield
60%. Brown solid; mp 213e214 ꢀC. IRnmax (KBr, cmꢁ1) 1785.38; 1H-
d
14.1 (CH3CH2), 22.7 (CH3CH2), 24.4 (CH2), 28.95 (CH2), 29.28
(CH2), 31.85 (CH2), 32.24 (COCH2), 119.6 (Ar-C), 120.7 (Ar-C), 122.6
(Ar-C), 124.1 (Ar-C), 125.6 (Ar-C), 126.3 (Ar-C), 129.0 (Ar-C), 129.7
(Ar-C),130.9 (Ar-C),131.4 (Ar-C),131.9 (Ar-C),132.9 (Ar-C),135.2 (Ar-
C), 137.9 (Ar-C), 138.8 (Ar-C), 144.6 (Ar-C), 147.7 (Ar-C), 148.9 (Ar-C),
154.6 (Ar-C), 172.2 (CaO). ESI-MS m/z of [M þ H]þ 544.70, 546.70
was obtained for a calculated mass of 545.15, 547.15.
NMR (500 MHz, CDCl3): d 2.42 (s, 3 H, CH3), 3.70e3.95 (m, 8 H,
piperizine-CH2), 6.64 (dd, J ¼ 5.5, 7.0 Hz, 1 H, H15), 6.76 (d,
J ¼ 8.5 Hz,1 H, H13), 7.48e7.56 (m, 2 H, H11 and H14), 7.58e7.65 (m,
1 H, H10), 7.73 (dd, J ¼ 2.0, 9.0 Hz, 1 H, H7), 7.78 (d, J ¼ 9.0 Hz, 1 H,
H8), 8.20 (d, J ¼ 7.5 Hz, 2 H, H9, H16), 8.22e8.26 (m, 1 H, H16), 8.40
(d, J ¼ 7.5 Hz, 1 H, H12), 8.56 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR
(125.8 MHz, CDCl3):
d 19.6 (COCH3), 45.4 (piperazine-CH2), 49.5
7.2.2.22. 2-Bromo-6-(1H-imidazol-1-yl)-7H-indeno[2,1-c]quinolin-
(piperazine-CH2), 113.1 (C15), 118.4 (Ar-C), 118.9 (Ar-C), 121.9 (Ar-C),
124.2 (C9), 126.1 (C5), 130.1 (C12), 130.2 (C14), 130.6 (C8), 132.3
(C10), 134.1 (C7), 140.1 (Ar-C), 148.0 (C16), 148.6 (Ar-C), 156.5 (Ar-C),
157.5 (Ar-C), 167.2 (CaO). ESI-MS m/z of [M þ H]þ 528.5, 530.5 was
obtained for a calculated mass of 528.10, 530.10.
7-one O-tetradecanoyl oxime (24) Procedure A, yield 26%. Yellow
solid; mp 240e242 ꢀC. IRn
(KBr, cmꢁ1 1769.50; 1H-NMR
)
max
(400 MHz, CDCl3):
d
0.86 (t, J ¼ 6.6 Hz, 3 H, CH3CH2), 1.20e1.31 (m,
18 H, CH3(CH2)9), 1.34e1.41 (m, 2 H, COCH2CH2CH2), 1.65e1.70 (m, 2
H, COCH2CH2), 2.56 (t, J ¼ 7.5 Hz, 2 H, COCH2), 7.22 (s, 1 H, H14), 7.61
(t, J ¼ 7.6 Hz, 1 H, H11), 7.67 (d, J ¼ 1.2 Hz, 1 H, H15), 7.72 (dd, J ¼ 0.8,
7.56 Hz, 1 H, H10), 7.90 (dd, J ¼ 2.0, 9.0 Hz, 1 H, H7), 7.99 (d,
J ¼ 9.0 Hz, 1 H, H8), 8.24 (s, 1 H, H13), 8.30 (d, J ¼ 7.8 Hz, 1 H, H9),
8.55 (d, J ¼ 7.5 Hz, 1 H, H12), 8.74 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR
7.2.2.26. 2-Bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-7H-indeno
[2,1-c]quinolin-7-one O-propionyl oxime (29) Procedure B, yield
60%. Yellow solid; mp 196e199 ꢀC. IRnmax (KBr, cmꢁ1) 1789.32; 1H-
NMR (500 MHz, CDCl3):
d
1.35 (t, J ¼ 7.5 Hz, 3 H, CH3), 2.69 (q,
(126.8 MHz, CDCl3):
d
13.5 (CH3CH2), 24.6 (CH3CH2), 24.9 (CH2),
J ¼ 7.5 Hz, 2 H, CH3CH2), 3.67e3.76 (m, 4 H, piperizine-CH2),
3.83e3.96 (m, 4 H, piperizine-CH2), 6.62 (dd, J ¼ 5.0, 7.0 Hz, 1 H,
H15), 6.76 (d, J ¼ 8.5 Hz, 1 H, H13), 7.47e7.55 (m, 2 H, H11 and H14),
7.60 (t, J ¼ 7.5 Hz,1 H, H10), 7.72 (dd, J ¼ 2.0, 9.0 Hz, 1 H, H7), 7.78 (d,
J ¼ 9.0 Hz, 1 H, H8), 8.19 (d, J ¼ 7.5 Hz, 1 H, H9), 8.22 (dd, J ¼ 1.5,
5.0 Hz, 1 H, H16), 8.41 (d, J ¼ 8.0 Hz, 1 H, H12), 8.56 (d, J ¼ 2.0 Hz, 1
29.0 (CH2), 29.2 (CH2), 29.3 (CH2), 29.35 (CH2), 29.4 (CH2), 29.5
(CH2), 29.69 (CH2), 29.70 (CH2), 32.0 (COCH2CH2), 32.3 (COCH2CH2),
119.7 (C15), 120.9 (Ar-C), 122.7 (Ar-C), 124.2 (Ar-C), 124.6 (C9), 126.4
(C5), 128.9 (C14), 129.9 (Ar-C), 130.9 (C12), 131.5 (C11), 132.1 (C8),
132.9 (C10), 135.2 (C7), 138.0 (C13), 139.0 (Ar-C), 144.8 (Ar-C), 147.9
(Ar-C), 148.9 (Ar-C), 154.8 (Ar-C), 172.19 (CaO). ESI-MS m/z of
[M þ H]þ 601.20, 603.10 was obtained for a calculated mass of
601.21, 603.21.
H, H5). 13C-NMR (125.8 MHz, CDCl3):
d 9.1 (CH3), 26.2 (COCH2CH3),
45.1 (piperazine-CH2), 49.5 (piperazine-CH2), 107.4 (C13), 113.0
(C15), 118.4 (Ar-C), 119.0 (Ar-C), 121.9 (Ar-C), 124.1 (C9), 126.1 (C5),
130.1 (C12), 130.2 (C11), 130.6 (C8), 132.2 (C10), 134.0 (C7), 137.8
(C14), 140.1 (Ar-C), 147.9 (C16 and C4), 148.5 (C8a), 156.6 (C2), 157.5
(C3a), 170.8 (CaO). ESI-MS m/z of [M þ H]þ 542.10, 544.10 was
obtained for a calculated mass of 542.11, 544.1.
7.2.2.23. tert-Butyl
2-((2-bromo-6-(1H-imidazol-1-yl)-7H-indeno
[2,1-c]quinolin-7-ylideneaminooxy)carbonyl)pyrrolidine-1-carbox-
ylate (25) Procedure A, yield 76%. Light-brown solid; mp
219e222 ꢀC. IRn
(KBr, cmꢁ1) 1784.66; Rotamers in the ratio of
max
(1:1), 1H-NMR (400 MHz, DMSO-d6):
d
1.24 (s, 4.5 H, (CH3)3C), 1.38
7.2.2.27. 2-Bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-7H-indeno
[2,1-c]quinolin-7-one O-butyryl oxime (30) Procedure A, yield
52%. Brown solid; mp 190e191 ꢀC. 1H-NMR (500 MHz, CDCl3):
(s, 4.5 H, (CH3)3C), 1.83e1.93 (m, 3 H, CH2CH2CH2), 2.10e2.30 (m, 1
H, CHCH2CH2), 3.36e3.42 (m, 2 H, CH2CH2N), 4.50e4.65 (m, 1 H,
NCHCO), 7.08 (s, 1 H, Ar-H), 7.72 (d, J ¼ 6.4 Hz, 1 H, Ar-H), 7.75e7.79
(m, 2 H, Ar-H), 7.95e8.03 (m, 1 H, Ar-H), 8.04e8.10 (m, 1 H, Ar-H),
8.29e8.34 (m, 1 H, Ar-H), 8.39e8.45 (m, 1 H, Ar-H), 8.66 (d,
J ¼ 7.6 Hz, 1 H, Ar-H), 8.91 (s, 1 H, H5). 13C-NMR (100.6 MHz, DMSO-
d
1.09 (t, J ¼ 7.5 Hz, 3 H, CH3), 1.82e1.95 (m, 2 H, CH2CH3), 2.65 (t,
J ¼ 7.5 Hz, 2 H, COCH2), 3.67e3.78 (m, 4 H, piperizine-CH2),
3.85e3.97 (m, 4 H, piperizine-CH2), 6.58e6.67 (m, 1 H, H15), 6.76
(d, J ¼ 7.5 Hz, 1 H, H13), 7.46e7.56 (m, 2 H, H11 and H14), 7.58e7.65
(m, 1 H, H10), 7.73 (dd, J ¼ 2.0, 9.0 Hz, 1 H, H7), 7.78 (d, J ¼ 9.0 Hz, 1
H, H8), 8.18e8.26 (m, 2 H, H9 and H16), 8.41 (d, J ¼ 7.5 Hz, 1 H, H12),
d6): d 22.8, 24.0, 27.3, 27.5, 29.1, 29.8, 29.4, 45.8, 46.1, 56.9 (NCHCO),
78.8 ((CH3)3C), 119.5 (Ar-C), 120.1 (Ar-C), 121.7 (Ar-C), 122.9 (Ar-C),
125.2 (Ar-C), 125.8 (Ar-C), 127.6 (Ar-C), 128.5 (Ar-C), 129.8 (Ar-C),
131.2 (Ar-C), 133.2 (Ar-C), 134.9 (Ar-C), 137.3 (Ar-C), 137.6 (Ar-C),
143.8 (Ar-C), 146.5 (Ar-C), 148.0 (Ar-C), 152.2 (Ar-C), 153.0 (Ar-C),
155.4 (Ar-C), 161.8 (NeCaO), 170.0 (CHeCaO). ESI-MS m/z of
[M þ H]þ 587.90, 589.70 was obtained for a calculated mass of
588.12, 590.12.
8.57 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR (125.8 MHz, CDCl3):
d 13.8
(CH2CH3), 18.4 (CH2CH3), 34.7 (COCH2), 45.3 (piperazine-CH2), 49.5
(piperazine-CH2),113.0 (C15),118.4 (Ar-C),119.0 (Ar-C),122.0 (Ar-C),
124.1 (C9), 126.1 (C5), 130.1 (C12), 130.2 (C11), 130.6 (C8), 132.2
(C10), 134.0 (C7), 140.1 (Ar-C), 147.9 (Ar-C), 148.5 (C16), 157.5 (Ar-C),
169.8 (CaO). ESI-MS m/z of [M þ H]þ 556.10, 558.10 was obtained
for a calculated mass of 556.13, 558.13.
7.2.2.24. 2-Bromo-6-(1H-imidazol-1-yl)-7H-indeno[2,1-c]quinolin-
7-one O-dimethylcarbamoyl oxime (26) Procedure B, yield
7.2.2.28. 2-Bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-7H-indeno
[2,1-c]quinolin-7-one O-pentanoyl oxime (31) Procedure A, yield
76%. Yellow solid; mp 167e169 ꢀC. 1H-NMR (600 MHz, CDCl3):
49%. Light-brown solid; mp 270e272 ꢀC. IRn
(KBr, cmꢁ1
)
max
1750.47; 1H-NMR (600 MHz, CDCl3):
d 3.10 (s, 3 H, NCH3), 3.20 (s, 3
H, NCH3), 7.25 (s, 1 H, H14), 7.59 (t, J ¼ 7.8 Hz, 1 H, H10), 7.67e7.73
(m,1 H, H11), 7.84e7.91 (m, 2 H, H7 and H15), 7.99 (d, J ¼ 8.4 Hz,1 H,
H8), 8.31 (d, J ¼ 7.8 Hz, 1 H, H9), 8.40 (d, J ¼ 7.2 Hz, 1 H, H12), 8.46 (s,
1 H, H13), 8.73 (d, J ¼ 1.8 Hz, 1 H, H5). 13C-NMR (150.9 MHz, CDCl3):
d
0.99 (t, J ¼ 7.2 Hz, 3 H, CH2CH3), 1.45e1.55 (m, 2 H, CH2CH3),
1.76e1.87 (m, 2 H, CH2CH2CH3), 2.67 (t, J ¼ 7.2 Hz, 2 H, COCH2),
3.70e3.76 (m, 4 H, piperazine-CH2), 3.85e3.94 (m, 4 H, pipera-
zine-CH2), 6.60e6.65 (m, 1 H, H15), 6.76 (d, J ¼ 7.8 Hz, 1 H, H13),

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
1321
7.47e7.54 (m, 2 H, H11 and H14), 7.59e7.64 (m, 1 H, H10), 7.73 (dd,
J ¼ 1.8, 9.0 Hz, 1 H, H7), 7.78 (d, J ¼ 9.0 Hz, 1 H, H8), 8.20 (d,
J ¼ 7.8 Hz, 1 H, H9), 8.22e8.50 (m, 1 H, H16), 8.41 (d, J ¼ 7.2 Hz, 1 H,
H12), 8.56 (d, J ¼ 2.4 Hz, 1 H, H5). 13C-NMR (150.9 MHz, CDCl3):
29.10 (CH2), 29.17 (CH2), 29.23 (CH2), 31.8 (CH2), 32.8 (COCH2), 45.3
(piperazine-CH2), 49.5 (piperazine-CH2), 113.0 (C15), 118.3 (Ar-C),
119.0 (Ar-C), 121.9 (Ar-C), 124.1 (C9), 126.1(C5), 130.05 (C10), 130.16
(C11), 130.6 (C8), 132.2 (C10), 134.0 (C7), 140.1 (Ar-C), 147.8 (C16),
148.5 (Ar-C), 156.6 (Ar-C), 157.4 (Ar-C), 170.0 (CaO). ESI-MS m/z of
[M þ H]þ 626.00, 628.10 was obtained for a calculated mass of
626.21, 628.21.
d
13.7 (CH2CH3), 22.3 (CH2CH2CH3), 26.9 (CH2CH2CH3), 32.5
(COCH2CH2), 45.3 (piperazine-CH2), 49.5 (piperazine-CH2), 113.0
(C13), 118.4 (Ar-C), 119.1 (Ar-C), 122.0 (Ar-C), 124.1 (C9), 126.1 (C5),
130.05 (C12), 130.17 (Ar-C), 130.19 (C11), 130.6 (C8), 132.2 (C10),
134.0 (C7), 137.9 (Ar-C), 140.1 (Ar-C), 147.9 (C16), 148.5 (Ar-C),
156.6 (Ar-C), 157.5 (Ar-C), 170.0 (CaO). ESI-MS m/z of [M þ H]þ
570.60, 572.50 was obtained for a calculated mass of 570.15,
572.14.
7.2.2.32. 2-Bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-7H-indeno
[2,1-c]quinolin-7-one O-decanoyl oxime (35) Procedure A, yield
60%. Green solid; mp 138e140 ꢀC. IRn
(KBr, cmꢁ1) 1777.24; 1H-
max
NMR (500 MHz, CDCl3):
d
0.88 (t, J ¼ 7.0 Hz, 3 H, CH2CH3), 1.18e1.50
(m,12 H, CH2),1.78e1.88 (m, 2 H, COCH2CH2), 2.66 (t, J ¼ 7.0 Hz, 2 H,
COCH2CH2), 3.66e3.75 (m, 4 H, piperizine-CH2), 3.84e3.92 (m, 4 H,
piperizine-CH2), 6.59e6.65 (m, 1 H, H15), 6.74 (d, J ¼ 8.5 Hz, 1 H,
H13), 7.45e7.54 (m, 2 H, H11 and H14), 7.58e7.63 (m, 1 H, H10), 7.72
(dd, J ¼ 2.0, 9.0 Hz, 1 H, H7), 7.77 (d, J ¼ 9.0 Hz, 1 H, H8), 8.18 (d,
J ¼ 8.0 Hz, 1 H, H9), 8.22 (dd, J ¼ 1.5, 5.0 Hz, 1 H, H16), 8.40 (d,
J ¼ 7.5 Hz, 1 H, H12), 8.55 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR
7.2.2.29. 2-Bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-7H-indeno
[2,1-c]quinolin-7-one O-hexanoyl oxime (32) Procedure A, yield
58%. Green solid; mp 171e172 ꢀC. IRn
(KBr, cmꢁ1) 1780.38; 1H-
max
NMR (600 MHz, CDCl3):
d
0.93 (t, J ¼ 7.2 Hz, 3 H, CH2CH3), 1.35e1.49
(m, 4 H, CH2CH2CH2CH3), 1.80e1.87 (m, 2 H, COCH2CH2CH2), 2.65 (t,
J ¼ 7.2 Hz, 2 H, COCH2CH2), 3.68e3.78 (m, 4 H, piperazine-CH2),
3.85e3.94 (m, 4 H, piperazine-CH2), 6.59e6.65 (m, 1 H, H15), 6.74
(d, J ¼ 8.4 Hz, 1 H, H13), 7.47e7.55 (m, 2 H, H11 and H14), 7.59e7.64
(m, 1 H, H10), 7.72 (dd, J ¼ 2.0, 9.0 Hz, 1 H, H7), 7.78 (d, J ¼ 9.0 Hz, 1
H, H8), 8.20 (d, J ¼ 7.8 Hz, 1 H, H9), 8.21e8.24 (m, 1 H, H16), 8.40 (d,
J ¼ 7.2 Hz, 1 H, H12), 8.56 (d, J ¼ 2.4 Hz, 1 H, H5). 13C-NMR
(125.8 MHz, CDCl3):
d 14.1 (CH3), 22.7 (CH3CH2), 24.9 (CH2), 29.2
(CH2), 29.26 (CH2), 29.27 (CH2), 29.40 (CH2), 31.9 (CH2), 32.8
(COCH2CH2), 45.2 (piperazine-CH2), 49.5 (piperazine-CH2), 107.3
(C13), 113.1 (C15), 118.4 (Ar-C), 119.0 (Ar-C), 121.9 (Ar-C), 124.1 (C9),
126.1 (C5), 130.0 (C12), 130.1 (C11), 130.6 (C8), 132.2 (C10), 134.0
(C7), 137.5 (C14), 140.1 (Ar-C), 147.8 (C16), 147.9 (Ar-C), 148.5 (Ar-C),
156.6 (Ar-C), 157.5 (Ar-C), 159.8 (Ar-C), 170.0 (CaO). ESI-MS m/z of
[M þ H]þ 639.70, 641.70 was obtained for a calculated mass of
640.22, 642.22.
(150.9 MHz, CDCl3):
d 13.9 (CH2CH3), 22.3 (CH2CH3), 24.6
(CH2CH2CH3), 31.3 (CH2CH2), 32.8 (COCH2), 45.3 (piperizine-CH2),
49.5 (piperizine-CH2), 113.0 (C15), 118.4 (Ar-C), 119.1 (Ar-C), 121.9
(Ar-C), 124.1 (C9), 126.1 (C5), 130.05 (C12), 130.16 (Ar-C), 130.19
(C10), 130.6 (C8), 132.2 (C11), 134.0 (C7), 137.5 (C14), 140.1 (Ar-C),
147.8 (C16), 148.5 (Ar-C), 156.6 (Ar-C), 157.5 (Ar-C), 159.9 (Ar-C),
170.0 (CaO). ESI-MS m/z of [M þ H]þ 583.90, 585.90 was obtained
for a calculated mass of 584.16, 586.16.
7.2.2.33. 2-Bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-7H-indeno
[2,1-c]quinolin-7-one O-dodecanoyl oxime (36) Procedure A, yield
47%. Yellow solid; mp 175e176 ꢀC. 1H-NMR (600 MHz, CDCl3):
d
0.87 (t, J ¼ 7.2 Hz, 3 H, CH2CH3), 1.19e1.50 (m, 16 H), 1.79e1.88 (m,
7.2.2.30. 2-Bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-7H-indeno
[2,1-c]quinolin-7-one O-heptanoyl oxime (33) Procedure A, yield
96%. Yellow solid; mp, compound decomposed above 300 ꢀC. IRn
2 H, COCH2CH2), 2.66 (t, J ¼ 7.2 Hz, 2 H, COCH2), 3.68e3.78 (m, 4 H,
piperizine-CH2), 3.82e3.98 (m, 4 H, piperizine-CH2), 6.60e6.66 (m,
1 H, H15), 6.75 (d, J ¼ 6.0 Hz, 1 H, H13), 7.47e7.55 (m, 2 H, H11 and
H14), 7.61 (t, J ¼ 7.8 Hz,1 H, H10), 7.73 (d, J ¼ 8.4 Hz,1 H, H7), 7.78 (d,
J ¼ 9.0 Hz, 1 H, H8), 8.18e8.25 (m, 2 H, H9 and H16), 8.41 (d,
J ¼ 7.2 Hz,1 H, H12), 8.57 (bs,1 H, H5). 13C-NMR (150.9 MHz, CDCl3):
(KBr, cmꢁ1) 1778.28; 1H-NMR (400 MHz, CDCl3):
d 0.88 (t,
max
J ¼ 7.0 Hz, 3 H, CH2CH3), 1.14e1.42 (m, 4 H, CH2CH2CH3), 1.43e1.48
(m, 2 H, CH2CH2CH2CH3), 1.50e1.84 (m, 2 H, COCH2CH2CH2), 2.65 (t,
J ¼ 7.5 Hz, 2 H, COCH2CH2), 3.68e3.74 (m, 4 H, piperizine-CH2),
3.84e3.90 (m, 4 H, piperizine-CH2), 6.00e6.64 (m, 1 H, Ar-H), 6.74
(d, J ¼ 8.6 Hz,1 H, Ar-H), 7.45e7.56 (m, 2 H, Ar-H), 7.58e7.65 (m,1 H,
Ar-H), 7.73 (dd, J ¼ 2.0, 9.0 Hz, 1 H, H7), 7.78 (d, J ¼ 9.0 Hz, 1 H, H8),
8.21 (d, J ¼ 7.2 Hz, 2 H, Ar-H), 8.41 (d, J ¼ 7.8 Hz, 1 H, Ar-H), 8.57 (d,
d
14.1 (CH2CH3), 22.7 (CH2), 24.9 (CH2), 29.2 (CH2), 29.28 (CH2),
29.33 (CH2), 29.45 (CH2), 29.6 (CH2), 31.9 (CH2), 32.8 (COCH2), 45.3
(piperazine-CH2), 49.5 (piperazine-CH2), 113.0 (C13), 118.4 (Ar-C),
119.1 (Ar-C), 122.0 (Ar-C), 124.1 (C9), 126.1 (C5), 130.06 (C12), 130.16
(Ar-C), 130.20 (C11), 130.60 (C8), 132.2 (C10), 134.0 (C7), 140.2 (Ar-
C), 147.9 (C16), 148.6 (Ar-C), 156.6 (Ar-C), 157.5 (Ar-C), 170.0 (CaO).
ESI-MS m/z of [M þ H]þ 668.50, 670.60 was obtained for a calcu-
lated mass of 668.26, 670.25.
J ¼ 2.0 Hz, 1 H, H5). 13C-NMR (100.6 MHz, CDCl3):
d 14.0 (CH3), 22.5
(CH2), 24.8 (CH2), 28.8 (CH2), 31.4 (CH2), 32.8 (COCH2), 45.2
(piperazine-CH2), 49.5 (piperazine-CH2), 107.2 (Ar-C), 113.1 (Ar-C),
118.3 (Ar-C), 119.0 (Ar-C), 121.9 (Ar-C), 124.1 (Ar-C), 126.1 (Ar-C),
130.03 (Ar-C), 130.14 (Ar-C), 130.53 (Ar-C), 132.2 (Ar-C), 134.0 (Ar-C),
137.4 (Ar-C), 140.1 (Ar-C), 147.81 (Ar-C), 147.93 (Ar-C), 148.5 (Ar-C),
156.6 (Ar-C), 157.4 (Ar-C), 159.8 (Ar-C), 170.0 (CaO). ESI-MS m/z of
[M þ H]þ of 598.50, 600.50 was obtained for calculated mass of
598.18, 600.18.
7.2.2.34. 2-Bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-7H-indeno
[2,1-c]quinolin-7-one O-pentadecanoyl oxime (37) Procedure A, yield
34%. Green solid; mp 115e116 ꢀC. 1H-NMR (500 MHz, CDCl3):
d 0.87
(t, J ¼ 7.0 Hz, 3 H, CH2CH3), 1.17e1.50 (m, 22 H, (CH2)11), 1.78e1.88
(m, 2 H, COCH2CH2), 2.66 (t, J ¼ 7.5 Hz, 2 H, COCH2), 3.68e3.76 (m, 4
H, piperizine-CH2), 3.84e3.93 (m, 4 H, piperizine-CH2), 6.59e6.65
(m, 1 H, H15), 6.74 (d, J ¼ 8.5 Hz, 1 H, H13), 7.47e7.55 (m, 2 H, H10
and H14), 7.58e7.65 (m, 1 H, H11), 7.73 (dd, J ¼ 2.5, 9.0 Hz, 1 H, H7),
7.78 (d, J ¼ 9.0 Hz,1 H, H8), 8.18- 8.25 (m, 2 H, H12 and H16), 8.41 (d,
J ¼ 7.5 Hz, 1 H, H9), 8.56 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR
7.2.2.31. 2-Bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-7H-indeno[2,1-
c]quinolin-7-one O-nonanoyl oxime (34) Procedure A, yield
65%. Green solid; mp 159e160 ꢀC. IRn
(KBr, cmꢁ1) 1776.52; 1H-
max
NMR (500 MHz, CDCl3):
d
0.88 (t, J ¼ 7.5 Hz, 3 H, CH2CH3), 1.22e1.50
(m, 10 H), 1.79e1.88 (m, 2 H), 2.66 (t, J ¼ 7.5, 2 H, COCH2), 3.70e3.80
(m, 4 H, piperizine-CH2), 3.83e3.95 (m, 4 H, piperizine-CH2),
6.60e6.67 (m, 1 H, H15), 6.75 (d, J ¼ 8.0 Hz, 1 H, H13), 7.48e7.55 (m,
2 H, H11 and H14), 7.58e7.65 (m, 1 H, H10), 7.72 (dd, J ¼ 2.5, 8.5 Hz,
1 H, H7), 7.78 (d, J ¼ 9.0 Hz, 1 H, H8), 8.18e8.25 (m, 2 H, H9 and
H16), 8.41 (d, J ¼ 8.0 Hz, 1 H, H12), 8.56 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-
(125.8 MHz, CDCl3): d 14.1 (CH2CH3), 22.7 (CH2), 24.9 (CH2), 29.17
(CH2), 29.28 (CH2), 29.36 (CH2), 29.45 (CH2), 29.61 (CH2), 29.65
(CH2), 29.67 (CH2), 29.69 (CH2), 31.9 (CH2), 32.8 (COCH2), 45.2
(piperazine-CH2), 49.5 (piperazine-CH2), 107.3 (C13), 113.1 (C15),
118.4 (Ar-C), 119.1 (Ar-C), 121.9 (Ar-C), 124.1 (C9), 126.1 (C5), 130.05
(C12), 130.15 (Ar-C), 130.17 (C11), 130.6 (C8), 132.1 (C10), 134.0 (C7),
140.1 (Ar-C), 147.8 (C16), 148.5 (Ar-C), 156.6 (Ar-C), 157.5 (Ar-C),
NMR (125.8 MHz, CDCl3):
d 14.1 (CH3), 22.6 (CH2CH3), 24.9 (CH2),

1322
R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
170.0 (CaO). ESI-MS m/z of [M þ H]þ 709.90, 712.00 was obtained
H), 7.65e7.80 (m, 2 H, Ar-H), 8.14 (d, J ¼ 7.8 Hz,1 H, Ar-H), 8.20e8.30
(m, 1 H, Ar-H), 8.32 (d, J ¼ 7.6 Hz, 1 H, Ar-H), 8.51 (d, J ¼ 1.5 Hz, 1 H,
for a calculated mass of 710.30, 712.30.
H5). 13C-NMR (126.8 MHz, CDCl3):
d 23.0 (COCH3), 40.5 (COCH2),
7.2.2.35. 2-Bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-7H-indeno
[2,1-c]quinolin-7-one O-5-bromopentanoyl oxime (38) Procedure A,
yield 66%. Yellow solid; mp 195e196 ꢀC. IRnmax (KBr, cmꢁ1) 1778.47;
45.4 (piperazine-CH2), 49.5 (piperazine-CH2), 107.7 (Ar-C), 113.2
(Ar-C), 118.6 (Ar-C), 121.9 (Ar-C), 124.2 (Ar-C), 126.2 (Ar-C), 129.9
(Ar-C), 130.4 (Ar-C), 130.6 (Ar-C), 132.5 (Ar-C), 132.8 (Ar-C), 134.3
(Ar-C), 137.8 (Ar-C),140.1 (Ar-C), 147.5 (Ar-C), 148.2 (Ar-C),148.7 (Ar-
C), 156.4 (Ar-C), 158.6 (Ar-C), 167.2 (Ar-C), 170.6 (CaO). ESI-MS m/z
of [M þ H]þ 585.00, 587.10 was obtained for a calculated mass of
585.13, 587.13.
1H-NMR (600 MHz, CDCl3):
d 1.94e2.08 (m, 4 H, CH2CH2),
2.69e2.75 (m, 2 H, COCH2), 3.47 (t, J ¼ 6.6 Hz, 2 H, CH2CH2Br),
3.68e3.77 (m, 4 H, piperizine-CH2), 3.85e3.94 (m, 4 H, piperizine-
CH2), 6.62e6.68 (m, 1 H, H15), 6.75 (d, J ¼ 8.4 Hz, 1 H, H13),
7.48e7.54 (m, 2 H, H11 and H14), 7.59e7.64 (m, 1 H, H10), 7.72 (dd,
J ¼ 2.4, 9.0 Hz, 1 H, H7), 7.77 (d, J ¼ 8.4 Hz, 1 H, H8), 8.19 (d,
J ¼ 7.8 Hz, 1 H, H9), 8.22e8.25 (m, 1 H, H16), 8.39 (d, J ¼ 7.2 Hz, 1 H,
H12), 8.55 (d, J ¼ 2.4 Hz, 1 H, H5). 13C-NMR (150.9 MHz, CDCl3):
7.2.2.39. tert-Butyl 2-((2-bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-
7H-indeno[2,1-c]quinolin-7-ylideneaminooxy)carbonyl)pyrrolidine-
1-carboxylate (43). Rotamers in the ratio of 6:4. Procedure A, yield
d
23.4 (CH2), 31.79 (CH2), 31.82 (COCH2), 32.9 (CH2Br), 45.3
41%. Brown solid; mp 172e174 ꢀC. IRn
(KBr, cmꢁ1) 1779.38; 1H-
max
(piperazine-CH2), 49.5 (piperazine-CH2), 113.0 (Ar-C) 118.4 (Ar-C),
118.9 (Ar-C), 121.9 (Ar-C), 124.2 (C9), 126.1 (C5), 130.08 (C12), 130.13
(Ar-C), 130.22 (C11), 130.6 (C8), 132.3 (C10), 134.1 (C7), 140.2 (Ar-C),
147.9 (Ar-C), 148.6 (Ar-C), 156.5 (Ar-C), 157.7 (Ar-C), 169.4 (CaO).
ESI-MS m/z of [M þ H]þ 647.80, 649.70 was obtained for a calcu-
lated mass of 648.06, 650.05.
NMR (600 MHz, CDCl3): d 1.39 (s, 5 H, N-Boc), 1.49 (s, 4 H, N-Boc),
1.90e2.50 (m, 4 H, proline-CH2), 3.50e4.00 (m, 10 H, piperazine-
CH2CH2, proline-CH2), 4.52e4.60 (m, 0.6 H, proline-CH), 4.69e4.72
(m, 0.4 H, proline-CH), 6.59e6.66 (m, 1 H, Ar-H), 6.70e6.75 (m, 1 H,
Ar-H), 7.45e7.55 (m, 2 H, Ar-H), 7.56e7.64 (m, 1 H, Ar-H), 7.69e7.80
(m, 2 H, Ar-H), 8.10e8.22 (m, 2 H, Ar-H), 8.35 (d, J ¼ 7.8 Hz, 0.6 H, Ar-
H), 8.44 (d, J ¼ 7.8 Hz, 0.4 H, Ar-H), 8.56 (bs, 1 H, Ar-H). 13C-NMR
7.2.2.36. 2-Bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-7H-indeno
(150.9 MHz, CDCl3): d 23.9, 24.6, 26.9, 28.4, 28.5, 30.2, 31.3, 34.7,
[2,1-c]quinolin-7-one O-cyclopropanecarbonyl oxime (40) Procedure
45.2, 45.3, 46.49, 46.6, 46.8, 49.5, 58.2, 58.7, 80.4, 80.7, 107.3 (Ar-C),
112.9 (Ar-C), 113.2 (Ar-C), 118.5 (Ar-C), 118.8 (Ar-C), 118.9 (Ar-C),
121.9 (Ar-C), 124.1 (Ar-C), 124.2 (Ar-C), 126.2 (Ar-C), 130.12 (Ar-C),
130.21 (Ar-C), 130.37 (Ar-C), 130.44 (Ar-C), 130.59 (Ar-C), 132.21 (Ar-
C), 132.42 (Ar-C), 134.04 (Ar-C), 134.16 (Ar-C), 137.58 (Ar-C), 140.12
(Ar-C), 148.0 (Ar-C), 148.11 (Ar-C), 148.68 (Ar-C), 153.6 (Ar-C), 154.5
(Ar-C), 156.5 (Ar-C), 158.3 (Ar-C), 158.4 (Ar-C), 159.5 (Ar-C), 169.5
(CaO). ESI-MS m/z of [M þ H]þ 682.90, 684.90 was obtained for
a calculated mass of 683.19, 685.19.
A, yield 55%. Brown solid; mp 217e219 ꢀC. IRn
(KBr, cmꢁ1
)
max
1765.10; 1H-NMR (600 MHz, CDCl3):
d 1.08e1.14 (m, 2 H, CH2),
1.25e1.30 (m, 2 H, CH2), 1.93e2.00 (m, 1 H, CH), 3.69e3.74 (m, 4 H,
piperizine-CH2), 3.85e3.93 (m, 4 H, piperizine-CH2), 6.61e6.65 (m,
1 H, H15), 6.73 (d, J ¼ 8.4 Hz, 1 H, H13), 7.48e7.55 (m, 2 H, H11 and
H14), 7.59e7.64 (m, 1 H, H10), 7.71 (dd, J ¼ 2.4, 9.0 Hz, 1 H, H7), 7.77
(d, J ¼ 9.0 Hz, 1 H, H8), 8.18e8.24 (m, 2 H, H9 and H16), 8.48 (d,
J ¼ 7.2 Hz, 1 H, H12), 8.55 (d, J ¼ 2.4 Hz, 1 H, H5). 13C-NMR
(150.9 MHz, CDCl3):
d 9.6 (cyclopropyl-CH2), 11.6 (CH), 45.3
(piperazine-CH2), 49.5 (piperazine-CH2), 113.0 (C15), 118.4 (Ar-C),
119.1 (Ar-C), 121.9 (Ar-C), 124.1 (C9), 126.1 (C5), 130.2 (C12), 130.6
(C11), 132.2 (C8), 134.0 (C7), 140.1 (Ar-C), 147.8 (Ar-C), 148.4 (Ar-C),
156.6 (Ar-C), 157.3 (Ar-C), 159.7 (Ar-C), 171.6 (CaO). ESI-MS m/z of
[M]þ 554.60, 556.50 was obtained for a calculated mass of 554.12,
556.12.
7.2.2.40. tert-Butyl 1-((2-bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-
7H-indeno[2,1-c]quinolin-7-ylideneaminooxy)carbonyl)cyclo-
pentylcarbamate (44) Procedure A, yield 49%. Yellow solid; mp
200e201 ꢀC. IRn
(KBr, cmꢁ1 1778.12; 1H-NMR (500 MHz,
)
max
CDCl3): d 1.38 (s, 9 H, N-Boc), 1.80e1.95 (m, 4 H, cyclopentane-CH2),
1.96e2.16 (m, 2 H, cyclopentane-CH2), 2.41e2.52 (m, 2 H, cyclo-
pentane-CH2), 3.69e3.77 (m, 4 H, piperizine-CH2), 3.88e3.96 (m, 4
H, piperizine-CH2), 5.10 (s, 1 H), 6.58e6.65 (m, 1 H, H15), 6.74 (d,
J ¼ 8.5 Hz,1 H, H13), 7.47e7.55 (m, 2 H, H11 and H14), 7.57e7.64 (m,
1 H, H10), 7.72 (dd, J ¼ 2.0, 9.0 Hz, 1 H, H7), 7.78 (d, J ¼ 9.0 Hz, 1 H,
H8), 8.16e8.25 (m, 2 H, H9 and H16), 8.46 (d, J ¼ 8.0 Hz, 1 H, H12),
7.2.2.37. 2-Bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-7H-indeno
[2,1-c]quinolin-7-one O-(E)-3-(furan-2-yl)acryloyl oxime (41) Proce-
dure A, yield 46%. Brown solid; mp 224e225 ꢀC. IRnmax (KBr, cmꢁ1
)
1747.42; 1H-NMR (600 MHz, CDCl3):
d 3.72e3.80 (m, 4 H, piper-
izine-CH2), 3.89e4.00 (m, 4 H, piperizine-CH2), 6.50e6.55 (m, 1 H,
Ar-H), 6.61e6.70 (m, 2 H, H15 and COCHaCH), 6.71e6.81 (m, 2 H,
H13 and Ar-H), 7.48e7.57 (m, 3 H, H11, H14 and Ar-H), 7.59e7.65
(m, 1 H, H10), 7.68e7.75 (m, 2 H, H7 and COCHaCH), 7.78 (d,
J ¼ 9.0 Hz, 1 H, H8), 8.18e8.26 (m, 2 H, H9 and H16), 8.50 (d,
J ¼ 7.5 Hz, 1 H, H12), 8.56 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR
8.56 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR (125.6 MHz, CDCl3):
d 24.3
(cyclopentane-CH2), 28.3 (Boc-CH3), 38.0 (cyclopentane-CH2), 45.2
(piperizine-CH2), 49.5 (piperizine-CH2), 107.4 (C13), 113.0 (Ar-C),
118.3 (Ar-C), 119.1 (Ar-C), 121.9 (C15), 124.1 (C9), 126.1 (C15), 130.1
(C12 and C11), 130.6 (C8), 132.2 (C10), 134.0 (C7), 140.1 (Ar-C), 147.8
(Ar-C), 148.5 (Ar-C), 154.7 (Ar-C), 156.6 (Ar-C), 170.8 (CaO). ESI-MS
m/z of [M þ H]þ 696.90, 698.70 was obtained for a calculated mass
of 697.21, 699.21.
(150.9 MHz, CDCl3): d 45.3 (piperazine-CH2), 49.5 (piperazine-CH2),
112.0 (Ar-C), 112.7 (Ar-C), 113.0 (Ar-C), 116.5 (Ar-C), 118.4 (Ar-C),
119.1 (Ar-C), 121.9 (Ar-C), 124.1 (C9), 126.1 (C5), 130.16 (C12), 130.21
(Ar-C), 130.25 (C11), 130.58 (C8), 132.2 (C10), 133.5 (C7), 134.0 (Ar-
C), 140.1 (Ar-C), 145.4 (Ar-C), 147.8 (C16), 148.5 (Ar-C), 150.8 (Ar-C),
157.6 (Ar-C), 164.3 (CaO). ESI-MS m/z of [M þ H]þ 606.00, 608.00
was obtained for a calculated mass of 606.11, 608.11.
7.2.2.41. tert-Butyl 2-(2-bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-
7H-indeno[2,1-c]quinolin-7-ylideneaminooxy)-2-oxoethylcarbamate
(45) Procedure A, yield 53%. Brown solid; mp 173e175 ꢀC. IRn
max
(KBr, cmꢁ1) 1703.00; 1H-NMR (400 MHz, CDCl3):
d 1.45 (s, 9 H, N-
Boc), 3.65e3.70 (m, 4 H, piperizine-CH2), 3.75e3.80 (m, 4 H,
piperizine-CH2), 4.30 (d, J ¼ 5.7 Hz, 2 H, COCH2NH), 5.20 (d,
J ¼ 4.7 Hz, 1 H, NH), 6.62 (dd, J ¼ 5.7, 6.7 Hz, 1 H, H15), 6.73 (d,
J ¼ 8.6 Hz,1 H, H13), 7.45e7.55 (m, 2 H, H11 and H14), 7.57e7.65 (m,
1 H, H10), 7.72 (dd, J ¼ 2.0, 8.9 Hz, 1 H, H7), 7.77 (d, J ¼ 9.0 Hz, 1 H,
H8), 8.15e8.25 (m, 2 H, H9 and H16), 8.36 (d, J ¼ 7.6 Hz, 1 H, H12),
7.2.2.38. N-(2-(2-Bromo-6-(4-phenylpiperazin-1-yl)-7H- indeno
[2,1-c]quinolin-7-ylideneaminooxy)-2-oxoethyl)acetamide
Procedure A, yield 70%. Red solid; mp 174e176 ꢀC. 1H-NMR
(400 MHz, CDCl3): 2.10 (s, 3 H, NHCOCH3), 3.64e3.74 (m, 4 H,
(42)
d
piperizine-CH2), 3.77e3.87 (m, 4 H, piperizine-CH2), 4.42 (d,
J ¼ 5.0 Hz, 2 H, COCH2NHAc), 6.35e6.42 (m, 1 H, Ar-H), 6.60e6.66
(m, 1 H, Ar-H), 6.74 (d, J ¼ 8.56 Hz, 1 H, Ar-H), 7.45e7.65 (m, 3 H, Ar-
8.55 (d, J ¼ 2.0 Hz, 1 H, H5). 13C-NMR (100.6 MHz, CDCl3):
d 28.3
(Boc), 31.4 (CCH3), 41.6 (COCH2NH), 45.1 (piperazine-CH2), 49.5

R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
1323
(piperazine-CH2), 80.4 (C(CH3)3), 106.3 (Ar-C), 107.3 (Ar-C), 113.2
(Ar-C), 118.4 (Ar-C), 121.7 (Ar-C), 123.9 (Ar-C), 126.0 (Ar-C), 129.7
(Ar-C), 130.2 (Ar-C), 130.4 (Ar-C), 132.2 (Ar-C), 134.0 (Ar-C), 137.4
(Ar-C),139.8 (Ar-C),147.8 (Ar-C),147.9 (Ar-C),148.4 (Ar-C),155.7 (Ar-
C), 156.3 (Ar-C), 158.2 (CaO), 159.6 (Ar-C), 162.5 (Ar-C), 167.4 (CO).
ESI-MS m/z of [M þ H]þ 643.00, 645.00 was obtained for a calcu-
lated mass of 643.16, 645.16.
(Ar-C), 168.9 (CaO). ESI-MS m/z of [M þ H]þ 699.50, 701.40 was
obtained for a calculated mass of 699.22, 701.22.
7.2.2.45. tert-Butyl 1-(2-bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-
7H-indeno[2,
oxobutan-2-ylcarbamate (49) Procedure A, yield 27%. Yellow solid;
mp 162e163 ꢀC. IRn (KBr, cmꢁ1) 1772.03; 1H-NMR (600 MHz,
1-c]quinolin-7-ylideneaminooxy)-4-(methylthio)-1-
max
CDCl3): d 1.46 (s, 9 H, N-Boc), 2.05e2.10 (m, 1 H), 2.11 (s, 3 H, SCH3),
7.2.2.42. tert-Butyl 1-(2-bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-
7H-indeno[2,1-c]quinolin-7-ylideneaminooxy)-1-oxopropan-2-ylcar-
bamate (46) Procedure A, yield 86%. Yellow solid; mp 186e187 ꢀC.
2.25e2.31 (m, 1 H), 2.60e2.70 (m, 2 H), 3.62e4.0 (m, 8 H, piper-
izine-CH2), 4.84e4.90 (m, 1 H), 5.30 (d, J ¼ 8.4 Hz, 1 H), 6.64 (t,
J ¼ 5.4 Hz, 1 H, H15), 6.76 (d, J ¼ 9.0 Hz, 1 H, H13), 7.46e7.56 (m, 2 H,
H11 and H14), 7.62 (t, J ¼ 7.8 Hz, 1 H, H10), 7.72 (dd, J ¼ 1.8, 9.0 Hz, 1
H, H7), 7.77 (d, J ¼ 9.0 Hz, 1 H, H8), 8.18 (d, J ¼ 7.8 Hz, 1 H, H9), 8.22
(dd, J ¼ 1.2, 4.8 Hz, 1 H, H16), 8.45 (d, J ¼ 7.8 Hz, 1 H, H12), 8.54 (d,
1H-NMR (500 MHz, CDCl3):
d
1.45 (s, 9 H, N-Boc), 1.58 (d, J ¼ 7.0 Hz,
3 H, CHCH3), 3.62e3.90 (m, 8 H, piperazine-CH2), 4.70e4.80 (m, 1
H, CHCH3), 5.19 (d, J ¼ 7.5 Hz, 1 H, NH), 6.63 (dd, J ¼ 1.5, 5.0 Hz, 1 H,
H15), 6.75 (d, J ¼ 8.5 Hz, 1 H, H13), 7.48e7.54 (m, 2 H, H11 and H14),
7.58e7.64 (m, 1 H, H10), 7.72 (dd, J ¼ 2.0, 9.0 Hz, 1 H, H7), 7.77 (d,
J ¼ 9.0 Hz, 1 H, H8), 8.18 (d, J ¼ 8.0 Hz, 1 H, H9), 8.22 (dd, J ¼ 1.5,
5.0 Hz,1 H, H16), 8.41 (d, J ¼ 7.5 Hz,1 H, H12), 8.54 (d, J ¼ 2.0 Hz,1 H,
J ¼ 1.8 Hz, 1 H, H5). 13C-NMR (150.9 MHz, CDCl3):
d 15.6 (SCH3), 28.4
(OC(CH3)3), 30.2 (SCH2), 32.4 (CH2), 45.4 (piperazine-CH2), 49.5
(piperazine-CH2), 51.7 (NHCH), 80.6 (OC(CH3)3), 113.0 (C15), 118.5
(Ar-C), 118.7 (Ar-C), 121.9 (Ar-C), 124.2 (C9), 126.2 (C5), 130.0 (C12),
130.5 (C11), 130.6 (C8), 132.5 (C10), 134.2 (C7), 140.2 (Ar-C), 148.2
(Ar-C), 148.7 (Ar-C), 155.3 (Ar-C), 156.5 (CO), 158.7 (Ar-C), 169.2
(CaO). ESI-MS m/z of [M þ H]þ 717.10, 719.10 was obtained for
a calculated mass of 717.18, 719.18.
H5). 13C-NMR (125.8 MHz, CDCl3):
d 19.0 (CHCH3), 28.3 (Boc-CH3),
45.3 (piperazine-CH2), 48.4 (CHeCH3), 49.5 (piperazine-CH2), 80.4
(C(CH3)3), 107.4 (C13), 113.0 (C15), 118.4 (Ar-C), 118.7 (Ar-C), 121.9
(Ar-C), 124.2 (C9), 126.1 (C5), 130.04 (Ar-C), 130.33 (C12), 130.39
(C11),130.59 (C8),132.4 (C10),134.2 (Ar-C),140.1 (Ar-C),148.1 (C16),
148.7 (Ar-C), 155.0 (Ar-C), 156.5 (Ar-C), 158.5 (Ar-C), 170.0 (CaO).
ESI-MS m/z of [M]þ 656.60, 658.60 was obtained for a calculated
mass of 656.17, 658.17.
7.2.2.46. tert-Butyl 1-(2-bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-
7H-indeno[2,1-c]quinolin-7-ylideneaminooxy)-3-(3-fluorophenyl)-1-
oxopropan-2-ylcarbamate (50) Procedure A, yield 89%. Brown solid;
mp 164e165 ꢀC. IRn
(KBr, cmꢁ1) 1771.63; 1H-NMR (600 MHz,
max
7.2.2.43. tert-Butyl 1-(2-bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-
7H-indeno[2,1-c]quinolin-7-ylideneaminooxy)-4-methyl-1-oxo-
pentan-2-ylcarbamate (47) Procedure A, yield 80%. Brown solid; mp
122e123 ꢀC. IRnmax (KBr, cmꢁ1) 1774.21; 1H-NMR (400 MHz, CDCl3):
CDCl3): d 1.43 (s, 9 H, NHBoc), 3.15e3.33 (m, 2 H, CH2Ph), 3.65e3.75
(m, 4 H, piperizine-CH2), 3.80e3.90 (m, 4 H, piperizine-CH2), 4.92
(d, J ¼ 7.2 Hz, 1 H, CHNH), 5.23 (d, J ¼ 8.4 Hz, 1 H, NH), 6.62e6.66
(m, 1 H, Ar-H), 6.73 (d, J ¼ 8.4 Hz, 1 H, Ar-H), 6.83e6.88 (m, 1 H, Ar-
H), 6.90e7.05 (m, 2 H, Ar-H), 7.19e7.25 (m, 1 H, Ar-H), 7.40e7.44
(m, 1 H, Ar-H), 7.49e7.53 (m, 1 H, Ar-H), 7.55e7.62 (m, 1 H, Ar-H),
7.72 (dd, J ¼ 2.4, 9.0 Hz, 1 H, H7), 7.76 (d, J ¼ 9.0 Hz, 1 H, H7),
8.11e8.21 (m, 2 H, Ar-H), 8.22 (dd, J ¼ 1.8, 4.8 Hz, 1 H, Ar-H), 8.52 (d,
d
0.99 (d, J ¼ 6.32 Hz, 3 H, CH3), 1.02 (d, J ¼ 6.08 Hz, 3 H, CH3), 1.45 (s,
9 H, N-Boc), 1.65e1.85 (m, 3 H, CH2CH(CH3)2), 3.60e3.90 (m, 8 H,
piperizine-CH2), 4.65e4.75 (m, 1 H, CHNH), 5.02 (d, J ¼ 8.64 Hz, 1
H), 6.60e6.65 (m, 1 H, H15), 6.73 (d, J ¼ 8.6 Hz, 1 H, H13), 7.45e7.55
(m, 2 H, H11 and H14), 7.61 (t, J ¼ 8.1 Hz, 1 H, H10), 7.72 (dd, J ¼ 1.9,
8.8 Hz, 1 H, H7), 7.78 (d, J ¼ 9.0 Hz, 1 H, H8), 8.15e8.30 (m, 2 H, H9
and H16), 8.45 (d, J ¼ 7.8 Hz, 1 H, H12), 8.56 (d, J ¼ 1.9 Hz, 1 H, H5).
J ¼ 1.8 Hz, 1 H, H5). 13C-NMR (150.9 MHz, CDCl3):
d 28.3 (OC(CH3)3),
38.8 (CH2Ph), 45.3 (piperazine-CH2), 49.5 (piperazine-CH2), 53.8
(NHCH), 80.6 (OC(CH3)3), 107.4 (Ar-C), 113.1 (Ar-C), 114.2 (Ar-C),
114.3 (Ar-C), 116.3 (Ar-C), 116.5 (Ar-C), 118.4 (Ar-C), 118.7 (Ar-C),
121.9 (Ar-C), 124.1 (Ar-C), 125.1 (Ar-C), 125.2 (Ar-C), 126.2 (Ar-C),
129.7 (Ar-C), 129.9 (Ar-C), 130.2 (Ar-C), 130.3 (Ar-C), 130.6 (Ar-C),
132.4 (Ar-C), 132.8 (Ar-C), 134.2 (Ar-C), 137.6 (Ar-C), 138.1 (Ar-C),
138.2 (Ar-C), 140.1 (Ar-C), 147.7 (Ar-C), 148.2 (Ar-C), 148.8 (Ar-C),
155.0 (Ar-C), 156.1 (Ar-C), 156.5 (Ar-C), 158.8 (Ar-C), 159.7 (Ar-C),
162.1 (Ar-C), 163.7 (Ar-C), 168.8 (CaO). ESI-MS m/z of [M þ H]þ
751.60, 753.60 was obtained for a calculated mass of 751.20, 753.20.
13C-NMR (100.6 MHz, CDCl3):
d 21.9 (CHCH3), 22.9 (CHCH3), 24.8
(CH(CH3)2), 28.3, 28.4, 42.0 (CHCH2), 45.1 (piperazine-CH2), 49.5
(piperazine-CH2), 51.1 (COCH), 80.3 (C(CH3)3), 107.3 (Ar-C), 113.0
(Ar-C), 118.4 (Ar-C), 118.7 (Ar-C), 121.8 (Ar-C), 124.1 (Ar-C), 126.1 (Ar-
C), 130.0 (Ar-C), 130.3 (Ar-C), 130.5 (Ar-C), 132.3 (Ar-C), 134.1 (Ar-C),
137.4 (Ar-C), 140.0 (Ar-C), 147.9 (Ar-C), 148.0 (Ar-C), 148.6 (Ar-C),
155.4 (Ar-C), 156.5 (CaO), 158.5 (Ar-C), 159.7 (Ar-C), 170.1 (CaO).
ESI-MS m/z of [M þ H]þ 699.40, 701.20 was obtained for a calcu-
lated mass of 699.20, 701.22.
7.2.2.47. tert-Butyl 1-(2-bromo-6-(4-(pyridin-2-yl) piperazin-1-yl)-
7H-indeno[2,1-c]quinolin-7-ylideneaminooxy)-1-oxo-3-phenyl-
propan-2-ylcarbamate (51) Procedure A, yield 37%. Yellow solid; mp
167e168 ꢀC. IRnmax (KBr, cmꢁ1) 1776.25; 1H-NMR (400 MHz, CDCl3):
7.2.2.44. tert-Butyl 1-(2-bromo-6-(4-(pyridin-2-yl)piperazin-1-yl)-
7H-indeno[2,1-c]quinolin-7-ylideneaminooxy)-3,3-dimethyl-1-oxo-
butan-2-ylcarbamate (48) Procedure A, yield 53%. Yellow solid; mp
156e157 ꢀC. IRnmax (KBr, cmꢁ1) 1776.47; 1H-NMR (500 MHz, CDCl3):
d
1.42 (s, 9 H, NHBoc), 3.15e3.30 (m, 2 H, CH2Ph), 3.60e3.75 (m, 4 H,
d
1.11 (s, 9 H, (CH3)3C), 1.46 (s, 9 H, NHBoc), 3.60e3.95 (m, 8 H,
piperizine-CH2), 3.75e3.93 (m, 4 H, piperizine-CH2), 4.92 (d,
J ¼ 7.2 Hz, 1 H, CHNH), 5.17 (d, J ¼ 8.2 Hz, 1 H, NH), 6.60e6.64 (m, 2
H, Ar-H), 7.10e7.33 (m, 5 H, Ar-H), 7.34e7.67 (m, 3 H, Ar-H),
7.70e7.80 (m, 2 H, Ar-H), 8.09 (d, J ¼ 7.5 Hz, 1 H, Ar-H), 8.15 (d,
J ¼ 7.6 Hz, 1 H, Ar-H), 8.17e8.24 (m, 1 H, Ar-H), 8.53 (s, 1 H, Ar-H).
piperizine-CH2), 4.45 (d, J ¼ 9.5 Hz, 1 H, NHCH), 5.25e5.35 (m, 1 H,
NH), 6.23 (dd, J ¼ 5.0, 6.5 Hz, 1 H, H15), 6.73 (d, J ¼ 8.5 Hz, 1 H, H13),
7.45e7.55 (m, 2 H, H11 and H14), 7.57e7.63 (m, 1 H, H10), 7.72 (dd,
J ¼ 2.5, 9.0 Hz, 1 H, H7), 7.77 (d, J ¼ 9.0 Hz, 1 H, H8), 8.19 (d,
J ¼ 7.5 Hz, 1 H, H9), 8.21 (dd, J ¼ 1.5, 5.0 Hz, 1 H, H16), 8.45 (d,
J ¼ 7.0 Hz, 1 H, H12), 8.55 (d, J ¼ 1.5 Hz, 1 H, H5). 13C-NMR
13C-NMR (100.6 MHz, CDCl3):
d 28.2 (OC(CH3)3), 38.9 (CH2Ph), 45.1
(piperazine-CH2), 49.4 (piperazine-CH2), 53.8 (NHCH), 80.3 (OC
(CH3)3), 107.2 (Ar-C), 113.0 (Ar-C), 118.3 (Ar-C), 118.6 (Ar-C), 121.7
(Ar-C), 123.9 (Ar-C), 126.0 (Ar-C), 127.2 (Ar-C), 127.9 (Ar-C), 128.6
(Ar-C), 129.3 (Ar-C), 129.7 (Ar-C), 130.2 (Ar-C), 130.4 (Ar-C), 132.2
(Ar-C),132.5 (Ar-C),134.0 (Ar-C),135.4 (Ar-C),137.4 (Ar-C),137.6 (Ar-
C),139.8 (Ar-C),147.8 (Ar-C),147.98 (Ar-C),148.5 (Ar-C),154.9 (Ar-C),
156.4 (Ar-C), 158.5 (Ar-C), 159.7 (Ar-C), 168.9 (CaO). ESI-MS m/z of
(125.8 MHz, CDCl3): d 26.5 (CH3)3C), 28.3 (Boc), 35.0 (C(CH3)3), 45.1
(piperazine-CH2), 49.5 (piperazine-CH2), 60.8 (NHCH), 80.3
((CH3)3CO), 107.2 (C13), 113.0 (C15), 118.4 (Ar-C), 118.8 (Ar-C), 121.9
(Ar-C), 124.1 (C9), 126.2 (C5), 130.0 (C11), 130.4 (C12), 130.5 (C8),
132.4 (C10), 134.1 (C7), 137.4 (C14), 140.1 (Ar-C), 148.0 (C16), 148.1
(Ar-C), 148.7 (Ar-C), 155.5 (Ar-C), 156.5 (Ar-C), 158.5 (Ar-C), 159.8

1324
R.S. Upadhayaya et al. / European Journal of Medicinal Chemistry 46 (2011) 1306e1324
[M þ H]þ 733.40, 735.30 was obtained for a calculated mass of
C), 126.1 (C5), 127.1 (Ar-C), 127.8 (Ar-C), 130.0 (C12), 130.2 (C11),
130.5 (Ar-C),130.6 (Ar-C), 132.5 (Ar-C),134.2 (C7),140.2 (Ar-C), 141.3
(Ar-C), 143.68 (Ar-C), 143.81 (Ar-C), 148.2 (Ar-C), 148.7 (Ar-C), 156.3
(Ar-C), 156.5 (Ar-C), 158.8 (Ar-C), 169.1 (CaO). ESI-MS m/z of
[M þ H]þ 806.90, 808.80 was obtained for a calculated mass of
807.22, 809.22.
733.21, 735.21.
7.2.2.48. (9H-Fluoren-9-yl)methyl 2-(2-bromo-6-(4-(pyridin-2-yl)
piperazin-1-yl)-7H-indeno[2,1-c]quinolin-7-ylideneaminooxy)-2-
oxoethylcarbamate (52) Procedure A, yield 40%. Brown solid; mp
185e186 ꢀC. IRnmax (KBr, cmꢁ1) 1719.12,1776.16; 1H-NMR (600 MHz,
CDCl3):
d 3.75e3.82 (m, 4 H, piperizine-CH2), 3.85e3.92 (m, 4 H,
Acknowledgments
piperizine-CH2), 4.23 (t, J ¼ 8.4 Hz, 1 H, Fmoc-CH), 4.32e4.40 (m, 2
H, Fmoc-CH2), 4.44 (d, J ¼ 7.0 Hz, 2 H, COCH2), 5.60e5.70 (m, 1 H,
NH), 6.60e6.68 (m, 1 H, Ar-H), 6.72e6.79 (m, 1 H, Ar-H), 7.20e7.30
(m, 2 H, Ar-H), 7.35e7.41 (m, 2 H, Ar-H), 7.42e7.48 (m, 1 H, Ar-H),
7.49e7.52 (m, 1 H, Ar-H), 7.55e7.64 (m, 3 H, Ar-H), 7.66e7.80 (m, 4
H, Ar-H), 8.13 (d, J ¼ 7.5 Hz, 1 H, Ar-H), 8.22 (d, J ¼ 3.5 Hz, 1 H, Ar-H),
8.32 (d, J ¼ 7.5 Hz, 1 H, Ar-H), 8.51 (s, 1 H, Ar-H). 13C-NMR
We thank Dr. Robert Goldman, National Institute of Health, USA
for the biological screening of compounds. We thank Uppsala
University, Sweden for valuable scientific support through Prof.
Jyoti Chattopadhyaya. Generous financial support from the Euro-
pean Union (Project No. 222965, Project name: New approaches to
target Tuberculosis, Call identifier: FP7-Health-2007-B) and TCG
Life Sciences, Kolkata for funding the collaboration are also grate-
fully acknowledged.
(150.9 MHz, CDCl3):
d 42.0 (COCH2), 45.4 (piperazine-CH2), 47.1
(Fmoc-CH), 49.5 (piperazine-CH2), 67.5 (Fmoc-CH2), 107.8 (Ar-C),
113.1 (Ar-C), 118.6 (Ar-C), 119.9 (Ar-C), 120.0 (Ar-C), 121.8 (Ar-C),
124.2 (Ar-C), 125.1 (Ar-C), 126.1 (Ar-C), 127.05 (Ar-C), 127.12 (Ar-C),
127.66 (Ar-C), 127.77 (Ar-C), 129.9 (Ar-C), 130.4 (Ar-C), 130.6 (Ar-C),
132.5 (Ar-C), 134.2 (Ar-C), 140.1 (Ar-C), 141.3 (Ar-C), 143.7 (Ar-C),
148.2 (Ar-C), 148.6 (Ar-C), 156.3 (Ar-C), 156.4 (Ar-C), 158.6 (Ar-C),
167.2 (CaO). ESI-MS m/z of [M þ H]þ 765.30, 767.20 was obtained
for a calculated mass of 765.18, 767.18.
Appendix. Supplementary information
Supplementary data related to this article can be found online at
doi:10.1016/j.ejmech.2011.01.053.
References
7.2.2.49. (9H-Fluoren-9-yl)methyl 1-(2-bromo-6-(4-(pyridin-2-yl)
piperazin-1-yl)-7H-indeno[2,1-c]quinolin-7-ylideneaminooxy)-4-
methyl-1-oxopentan-2-ylcarbamate (53) Procedure A, yield
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34%. Brown solid; mp 125e126 ꢀC. IRn
(KBr, cmꢁ1) 1774.12; 1H-
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NMR (400 MHz, CDCl3):
H, CHCH2CH), 3.60e3.40 (m,
d
0.92e1.10 (m, 6 H, CH3), 1.72e1.82 (m, 3
H, piperizine-CH2), 4.23 (t,
8
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J ¼ 6.72 Hz,1 H, ArCHCH2), 4.40e4.50 (m, 2 H, ArCHCH2), 4.70e4.83
(m, 1 H, CHNH), 5.32 (d, J ¼ 8.8 Hz, 1 H, NHCH), 6.61 (t, J ¼ 6.0 Hz, 1
H, Ar-H), 6.73 (d, J ¼ 8.5 Hz,1 H, Ar-H), 7.26e7.34 (m, 2 H, Ar-H), 7.38
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3 H, Ar-H), 7.69e7.85 (m, 4 H, Ar-H), 8.16e8.27 (m, 2 H, Ar-H), 8.41
(d, J ¼ 7.6 Hz, 1 H, Ar-H), 8.55 (s, 1 H, Ar-H). 13C-NMR (100.6 MHz,
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45.1 (piperazine-CH2), 47.1 (Ar-CH), 49.4 (piperazine-CH2), 51.5,
67.2 (OCH2), 107.2 (Ar-C), 113.1 (Ar-C), 118.4 (Ar-C), 118.6 (Ar-C),
119.9 (Ar-C), 121.7 (Ar-C), 124.1 (Ar-C), 125.0 (Ar-C), 126.0 (Ar-C),
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for a calculated mass of 821.24, 823.24.
7.2.2.50. (9H-Fluoren-9-yl)methyl 1-(2-bromo-6-(4-(pyridin-2-yl)
piperazin-1-yl)-7H-indeno[2,1-c]quinolin-7-ylideneaminooxy)-3-
methyl-1-oxobutan-2-ylcarbamate (54) Procedure A, yield
70%. Brown solid; mp 127e128 ꢀC. IRnmax (KBr, cmꢁ1) 1772.28; 1H-
NMR (600 MHz, CDCl3):
d
1.06 (d, J ¼ 6.6 Hz, 3 H, CH3), 1.11 (d,
J ¼ 6.6 Hz, 3 H, CH3), 2.27e2.35 (m, 1 H, CH(CH3)2), 3.60e3.98 (m, 8
H, piperazine-CH2), 4.21e4.27 (m, 1 H, Fmoc-CH), 4.40e4.56 (m, 2
H, Fmoc-CH2), 4.64 (dd, J ¼ 6.0, 9.0 Hz, 1 H, NCH), 5.45 (d, J ¼ 9.0 Hz,
1 H, NH), 6.61e6.66 (m, 1 H, H15), 6.74 (d, J ¼ 8.4 Hz, 1 H, H13),
7.26e7.33 (m, 2 H, Ar-H), 7.36e7.41 (m, 2 H, Ar-H), 7.47e7.52 (m, 2
H, H11 and H14), 7.58e7.62 (m, 3 H, Ar-H), 7.72 (dd, J ¼ 1.8, 9.0 Hz, 1
H, H7), 7.77 (d, J ¼ 9.0 Hz,1 H, Ar-H), 8.18 (d, J ¼ 7.8 Hz,1 H, H9), 8.22
(d, J ¼ 4.2 Hz, 1 H, H16), 8.40 (d, J ¼ 7.8 Hz, 1 H, H12), 8.54 (d,
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J ¼ 1.8 Hz, 1 H, H5). 13C-NMR (150.9 MHz, CDCl3):
d 17.9 (CH3), 19.2
(CH3), 31.7 (CH(CH3)2), 45.3 (piperazine-CH2), 47.2 (Fmoc-CH), 49.5
(piperazine-CH2), 58.4 (NCH), 67.3 (Fmoc-CH2), 113.0 (C15), 118.5
(Ar-C), 118.7 (Ar-C), 120.0 (Ar-C), 121.9 (Ar-C), 124.2 (C9), 125.1 (Ar-
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