Substituted 1,3-dioxoisoindoline-4-aminoquinolines coupled via amide linkers: Synthesis, antiplasmodial and cytotoxic evaluation

Article abstract of DOI:10.1016/j.bioorg.2019.04.006

Synthesis of C-5-substituted 1,3-dioxoisoindoline-4-aminoquinolines having amide group as a spacer was developed with an intent to evaluate their antiplasmodial activities. The synthesized dioxoisoindoline-aminoquinolines tethered with β-alanine as a spacer and secondary amine as substituent displayed good anti-plasmodial activities. Compound 7j, with an optimum combination of β-alanine and an ethyl chain length as linker along with diethylamine as the secondary amine counterpart at dioxoisoindoline proved to be most potent and non-cytotoxic with IC₅₀ of 0.097 μM against W2 strain of P. falciparum and a selective index of >2000.

Full text of DOI:10.1016/j.bioorg.2019.04.006

BioorganicChemistry88(2019)102912
Contents lists available at ScienceDirect
Bioorganic Chemistry
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Substituted 1,3-dioxoisoindoline-4-aminoquinolines coupled via amide
linkers: Synthesis, antiplasmodial and cytotoxic evaluation
⁎
Anu Rania, Jenny Legacb, Philip J. Rosenthalb, Vipan Kumara,
a Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India
b Department of Medicine, University of California, San Francisco, CA, USA
A R T I C L E I N F O
A B S T R A C T
Keywords:
Synthesis of C-5-substituted 1,3-dioxoisoindoline-4-aminoquinolines having amide group as a spacer was de-
veloped with an intent to evaluate their antiplasmodial activities. The synthesized dioxoisoindoline-aminoqui-
nolines tethered with β-alanine as a spacer and secondary amine as substituent displayed good anti-plasmodial
activities. Compound 7j, with an optimum combination of β-alanine and an ethyl chain length as linker along
with diethylamine as the secondary amine counterpart at dioxoisoindoline proved to be most potent and non-
cytotoxic with IC50 of 0.097 µM against W2 strain of P. falciparum and a selective index of > 2000.
1,3-Dioxoisoindoline-4-aminoquinolines
Microwave
Antiplasmodial
Cytotoxicity
Selectivity index
1. Introduction
parasites by Artemisinin while the partner drug clears the remaining
parasites [8] However, the emergence of resistance to Artemisinin in
P. falciparum, the causative organism of malaria, is the most virulent
form of the parasite responsible for a maximum number of malaria-
related deaths, worldwide [1]. According to WHO report 2018, there
was a substantial reduction in malaria burden from 2010 to 2015 with
number of cases falling from 239 million to 214 million, globally.
However, the reversed progress in countries with the highest malaria
burden has obstructed the global progress in malaria-controlling pro-
grams. The year 2017 witnessed 435,000 malaria deaths, affecting
mostly children below the age of 5 years [2,3].
the South-East Asian region has not only placed greater demand on the
partner drugs but also jeopardized their future efficacy [9].
Despite the emergence of resistance, CQ still remains the first line
treatment in countries endemic for uncomplicated P. vivax malaria [10]
and is an excellent scaffold with restricted host toxicity, affordability
and synthetic vulnerability [11]. The conjugation of 4-aminoquinoline
with biologically active pharmacophores is considered a significant
strategy which has propelled the scientific community for developing
new aminoquinoline scaffolds with better activity and low incidence of
resistance [12–15].
Several heterocyclic compounds viz. 4-aminoquinoline, 8-amino-
quinoline, acridine-dione, pyridine, quinolone-tetroxane, indole, imi-
dazolopiperazine and methoxy-thiazinoquinone derivatives have re-
cently emerged as potential antimalarials [4,5]. Among these, quinoline
is considered as one of the core heterocycles for the treatment of ma-
laria, being present in a number of antimalarial drugs as well as clinical
candidates viz. Chloroquine (CQ), Mefloquine, Amopyroquine, Amo-
diaquine, Primaquine, Pyronaridine, Isoquine, tert-butylisoquine, Fer-
roquine, Piperaquine and Tafenoquine as shown in Fig. 1 [4]. Chlor-
oquine was the main-stay in the treatment of malaria for decades,
however, the extensive use of CQ has resulted in the development of
resistance in Southeast Asia, Oceania, and South America in the late
1950s and early 1960s [6]. Since then, CQ resistance has spread to
nearly all parts of the world and paved the way for the development of
Artemisinin Combination Therapy (ACT) [7]. The primary advantage of
using ACT is the expeditious reduction in the majority of malaria
1,3-dioxoisoindolines are nitrogen-containing heterocycles with
extensive pharmacological properties including; anti-convulsant, an-
algesic, anti-inflammatory, hypolipidemic and immunomodulatory,
antiplasmodial, antitubercular and anticancer activities [16]. A series of
1,3-dioxoisoindolines functionalized with cyclic amines have shown to
possess antiplasmodial activities with the compound possessing a pi-
peridinopiperidine moiety exhibiting an IC50 of 1.16 μM [17]. Recently,
we introduced a functionalized dioxoisoindoline ring in the side chain
of 4-aminoquinoline in order to acess their anti-plasmodial activities.
The compound with a tetrabromo substituted dioxoisoindoline was a
promising candidate with an IC50 of 0.10 µM against CQ-resistance
strain (W2) of P. falciparum [18].
In view of the above and in continuation of our effort to develop
new antimalarials [19], the present manuscript encompasses the
synthesis of substituted 1,3-dioxoindoline-4-aminoquinolines having an
⁎ Corresponding author.
E-mail address: vipan_org@yahoo.com (V. Kumar).
https://doi.org/10.1016/j.bioorg.2019.04.006
Received 6 February 2019; Received in revised form 4 April 2019; Accepted 5 April 2019
Availableonline11April2019
0045-2068/©2019ElsevierInc.Allrightsreserved.

A. Rani, et al.
BioorganicChemistry88(2019)102912
Fig. 1. Structures of 4-aminoquinoline and 8-aminoquinoline based molecules under clinical trials.
amide core between the two pharmacophores along with varied sec-
ondary amines at the C-5 position of dioxoindoline ring. The inclusion
of amide-core has reported to enhance the anti-plasmodial activities
against both CQ sensitive and the resistant strains of P. falciparum [20].
doublet of quinoline ring proton at 6.50 (J = 5.4 Hz) and a multiplet of
four protons of dioxoisoindoline ring at 7.82–7.88. The presence of
signals at δ 167.2 corresponding to carbonyl carbons and 168.0 because
of amide carbonyl in the 13C NMR spectrum along with methylenes at δ
37.9, 40.7 and glycine carbon at δ 42.3, as confirmed by the 13C NMR
(DEPT) spectrum, further validated the assigned structure.
2. Results and discussion
The synthesized conjugates 6m-r were employed as precursors for
affording the conjugates 7a-r having a secondary amino functionality at
C-5 position of dioxoisoindoline ring. Thus, the microwave heating of
6m-r with various secondary amine in dry NMP at 160 °C for 5 min led
to the synthesis of 7a-r in moderate to good yields (Scheme 3). The
synthesized conjugates 7a-r were characterized using spectral and
analytical techniques. For example, the compound 7j showed a mole-
cular ion peak at 494.1902 [M+H]+ in its High-Resolution Mass
Spectrum (HRMS). The salient features of its 1H NMR spectrum in-
cluded the appearance of triplet because of two methyl at δ 1.05
(J = 7.0 Hz) and multiplet at 3.22–3.26 corresponding to methylene
protons of diethylamine, doublet at 2.37 (J = 7.3 Hz) and 3.69
(J = 7.3 Hz) because of methylene protons of dioxoisoindoline linked β-
alanine, two doublet at 6.45 (J = 5.4 Hz) and 8.35 (J = 5.0 Hz) corre-
sponding to quinoline ring protons along with two triplets at 7.29
2.1. Synthetic chemistry
For the synthesis of the desired 1,3-dioxoisoindoline-4-aminoqui-
nolines, amide coupling was attempted to connect two pharmacophores
followed by microwave heating to substitute fluoro at C-5 position with
different secondary amines.
The one-set of precursor viz. 1,3-dioxoisoindolin-2-yl based car-
boxylic acids 3a-c and 4a-b were synthesized via heating substituted
phthalic anhydrides with various amino acids in dry toluene using
triethylamine as a base for 6 h. The synthesized acids viz. 3a-c and 4a-b
were used in subsequent steps without further purification (Scheme 1).
For the synthesis of conjugates 6a-l, amide coupling of the precursors’
3a-c with 7-chloroquinoline based diamines 5 [21] was attempted
using EDC and HOBt in the presence of N,N-diisopropylethylamine
(DIEA) in dry DMF at room temperature. Similar protocol was em-
ployed for the synthesis of 6m-r having a fluoro-substtuent at C-5 po-
sition of dioxoisoindolines (Scheme 2). The structure to the synthesized
dioxoisoindoline-4-aminoquinoline based amides were assigned on the
basis of spectral data and analytical evidenced. For example, compound
6a exhibited a molecular ion peak at 409.1041 in its high resolution
mass spectrum (HRMS). The noteworthy features of its 1H NMR spec-
trum included the presence of singlet at δ 3.31 because of ethylene (NH-
CH2-CH2-NH); singlet at 4.18 because of glycine (CH2) protons, two
triplets at 7.33 (J = 5.0 Hz) and 8.45 (J = 5.6 Hz) because of eNH, a
(J = 5.4 Hz) and 8.23 (J = 5.3 Hz) because of the eNH protons. Its 13
C
NMR spectrum revealed the appearance of signals at δ 168.0 and 168.6,
corresponding to dioxoisoindoline carbonyls, a signal at 170.0 of amide
carbonyl along with methylene carbons at δ 25.4, 27.5, 34.6, 37.7,
39.7, 42.7, 44.7 40.6 and 47.4 and diethylamine carbons at δ 12.6 and
53.2, as confirmed by 13C NMR (DEPT) spectrum.
2.2. In vitro anti-plasmodial evaluation
The synthesized scaffolds were assayed against CQ-resistance and
mefloquine-sensitive W2 strain of P. falciparum and the observed ac-
tivities are given in Table 1. Evidently, most of the synthesized scaffolds
displayed good antiplasmodial activities with some of them have either
comparable or better activities than standard drug, Chloroquine (CQ).
Analyzing the activity data revealed an interesting Structure-Activity
Relationships (SARs) among the synthesized compounds with activity
showing dependence both on the nature of substituent at the dioxoin-
doline ring along with the length of alkyl chain (m, n) introduced as
linker between two pharmacophores.
Scheme 1. Synthesis of unsubstituted (3a-c) and C-5 fluoro-substituted (4a-b)
2-(1,3-dioxoisoindolin-2-yl)acetic acid/3-(1,3-dioxoisoindolin-2-yl)propanoic
acid/4-(1,3-dioxoisoindolin-2-yl)butanoic acid.
Among compounds 6a-l (R = H); the activity increases with an in-
crease in chain length as apparent from glycyl and β-alanyl linked
2

A. Rani, et al.
BioorganicChemistry88(2019)102912
Scheme 2. Synthesis of unsubstituted (6a-l) and
C-5 fluoro-substituted (6m-r) N-(2-((7-chlor-
oquinolin-4-yl)amino)alkyl)-2-(1,3-dioxoi-
soindolin-2-yl)alkylamides.
compounds 6d (n = 8, 0.24 µM) and 6h (n = 8, 0.15 µM), respectively.
The introduction of butyric acid, however reduced the antiplasmodial
activity except for compound 6i (n = 2); which exhibited IC50 values of
0.28 µM. Introducing a fluoro substituent at the C-5 position of diox-
oisoindolines resulted in the reduction of antiplasmodial efficacy in
case of glycine linked scaffolds (6m-o) while the activity improved
considerably with the introduction of β-alanine at shorter chain lengths
as evident by 6p (0.36 µM) and 6q (0.22 µM). Introducing different
the perspective of bioavailability [22]. The generalized antiplasmodial
structure activity relationship/cytotoxicity and plausible anti-
plasmodial mechanism of the synthesized 5-secondary amino sub-
stituted 1,3-dioxoisoindoline-4-aminoquinolines tethered via amide
bond is elucidated in Fig. 3.
In conclusion, a series of C-5 substituted 1,3-dioxoisoindoline-4-
aminoquinolines has been urbanized with the aim of studying their
structure–activity relationship against P. falciparum. Almost all of the
synthesized scaffolds exhibited promising antiplasmodial activity and
good selectivity index. The antiplasmodial activities were substantially
enhanced with introduction of secondary amine at C-5 position of di-
oxoisoindoline ring while the inclusion of amide as spacer improved
their cytotoxic profiles.
secondary
amines
(morpholine,
diethylamine,
2-hydro-
xyethylpiperazine) at C-5 of dioxoisoindoline (7a-r) substantially im-
proved the activity profiles presumably because of direct co-relation
between the basicity and activity. The increase in basicity of the com-
pound results in its better accumulation inside the acidic food vacuole
of the parasite. Among the glycine tethered hybrids having a secondary
amine at the C-5 position (7a-c, 7g-l, 7m-o), the reduction in activity
was observed even at longer alkyl chain lengths except for 7n and 7o
having 2-hydroxyethylpiperazine, which exhibited IC50 values of 0.86
and 0.46 µM, respectively. The presence of alanine between the diox-
oisoindoline core and amide linkage among hybrids, 7d-f, 7j-l and 7p-r
improved the antiplasmodial activities in general with few of the con-
jugates exhibiting comparable or better activity profiles than the stan-
dard drug CQ. Cytotoxic studies of all the synthesized compounds were
also carried out on mammalian Vero cells so as to confirm whether the
observed activities were because of their inherent anti-plasmodial ef-
ficacy or cytotoxicity (Table 1). Analyzing the cytotoxicity of the syn-
thesized conjugates revealed that most of the compounds were found to
be non-cytotoxic (Table 1).
3. Experimental section
3.1. General
All starting materials and reagents were purchased from Sigma-
Aldrich and Merck. Thin-layer chromatography was performed on a
film of silica gel that contained a fluorescent indicator F254 supported
on an aluminum sheet (Merck). Veego Precision Digital Melting Point
apparatus (MP-D) was used for the determination of melting points
which are uncorrected. 1H NMR spectra were recorded in deuterated
chloroform (CDCl3) using Bruker 500 (500 MHz) and Jeol 400
(400 MHz) spectrometers while TMS is used as internal standard.
Comparing the activity and cytotoxicity profiles of the presently
synthesized compounds with our previous report [18], the introduction
of an amide linkage although did not improve the antiplasmodial ac-
tivity but resulted in the reduction of the cytotoxicity as evident by
compound I and 6h (Fig. 2). Among fluoro substituted dioxoisoindo-
line-4-aminoquionolines, the introduction of amide core resulted in an
improvement in antiplasmodial activity as apparent on comparing II
and 6q. The replacement of fluoro with secondary amine resulted in
substantial improvement in both activity as well as cytotoxicity as
shown by compound 7j.
Microwave
reactions
were
performed
in
a
Biotage®
Initiator + instrument using sealed 2–5 mL process vials. Reaction
times refer to irradiation time at the target temperature, not the total
irradiation time. The temperature was measured with an IR sensor.
Chemical shift values are specified as parts per million (ppm) downfield
from TMS while coupling constant (J) values are in Hertz. Patterns of
Splitting are designated as s: singlet, d: doublet, t: triplet, dd: double
doublet, m: multiplet, ddd: doublet of a doublet of a doublet, and br:
broad peak. 13C NMR spectra were recorded on Bruker 125 MHz and
Jeol 100 MHz spectrometers in DMSO-d6. Elemental analyses were
performed on Heraus CHN-O-Rapid Elemental Analyzer. High-
Resolution Mass Spectra (HRMS) were recorded on a Bruker-micrOTOF-
Q II spectrometer using ESI as the ion source.
The ClogP value of chloroquine is reported to be 5.06 while the
calculated ClogP values of the promising compounds were found to be
3.20, 4.10, and 3.15 respectively. Further, the protonation of secondary
amino group of the synthesized compound is feasible under physiolo-
gical condition. The ClogP values of protonated 7d, 7j and 7q were
calculated to be 0.04, 0.35 and −0.01 which are quite appropriate from
Scheme 3. Synthesis of C-5 amine substituted 1,3-dioxoisoindolines linked with 4-aminoquinolines via amide spacer 7a-r.
3

A. Rani, et al.
BioorganicChemistry88(2019)102912
Table 1
In vitro antiplasmodial activity of synthesized compounds (6a-r, 7a-r) against CQ resistant W2 strains of P. falciparum with cytotoxicity evaluation on mammalian
Vero cells and their Selectivity index.
Code
R
m
n
% Yield
IC50 (µM)
SD
IC50 (µM) (cytotoxicity)
SI
ClogPa
6a
6b
6c
6d
6e
6f
H
1
1
1
1
2
2
2
2
3
3
3
3
1
1
1
2
2
2
1
1
1
2
2
2
1
1
1
2
2
2
1
1
1
2
2
2
2
4
6
8
2
4
6
8
2
4
6
8
2
4
6
2
4
6
2
4
6
2
4
6
2
4
6
2
4
6
2
4
6
2
4
6
82
81
85
76
81
77
79
70
83
74
76
78
82
85
84
81
76
77
76
79
81
76
82
78
79
78
79
70
72
68
75
83
75
71
68
65
5.65
3.66
3.35
0.24
0.30
0.41
0.29
0.15
0.28
0.84
1.57
0.58
1.99
1.05
1.49
0.36
0.22
0.66
3.21
1.28
1.78
0.13
0.22
0.64
1.14
1.17
1.22
0.097
0.26
0.53
1.04
0.86
0.46
0.28
0.14
0.18
0.23
0.6
> 245
> 229.2
247.7
–
3.00
3.54
4.55
5.57
3.27
3.81
4.83
5.84
3.54
4.09
5.10
6.11
2.17
2.71
3.72
2.44
2.98
3.99
2.93
3.47
4.48
3.20
3.74
4.75
3.83
4.38
5.38
4.10
4.65
5.66
2.34
2.88
3.89
2.61
3.15
4.16
5.00
H
0.03
0.1
–
H
73.94
H
0.04
0.01
0.01
0.02
0.03
0.02
0.03
0.6
> 203.1
> 236.9
> 222.1
87.5
–
H
–
H
–
6g
6h
6i
H
301.7
H
> 197.5
> 229.2
> 215.4
> 203.1
101.7
–
H
–
6j
H
–
6k
6l
H
–
H
0.07
0.8
175.3
6m
6n
6o
6p
6q
6r
5-F
> 234.7
> 220.2
> 207.4
93.16
–
5-F
0.01
0.1
–
5-F
–
5-F
0.02
0.004
0.2
258.7
5-F
109.8
499.0
5-F
57.2
86.66
7a
7b
7c
7d
7e
7f
5-Morpholinyl
0.9
> 202.7
> 191.8
20.16
–
5-Morpholinyl
0.1
–
5-Morpholinyl
0.8
11.3
5-Morpholinyl
0.003
0.004
0.02
0.3
26.46
203.5
5-Morpholinyl
135.5
615.9
5-Morpholinyl
> 177.5
44.41
–
7g
7h
7i
5-(diethylamino)
5-(diethylamino)
5-(diethylamino)
5-(diethylamino)
5-(diethylamino)
5-(diethylamino)
5-(2-(piperazin-1-yl)ethan-1-ol)
5-(2-(piperazin-1-yl)ethan-1-ol)
5-(2-(piperazin-1-yl)ethan-1-ol)
5-(2-(piperazin-1-yl)ethan-1-ol)
5-(2-(piperazin-1-yl)ethan-1-ol)
5-(2-(piperazin-1-yl)ethan-1-ol)
38.9
0.05
0.03
46.88
40.0
> 186.8
202.7
–
7j
0.006
2089
7k
7l
0.01
0.004
0.004
0.2
84.41
324.6
> 182
> 186.5
> 177.2
> 168.8
ND
–
7m
7n
7o
7p
7q
7r
–
–
0.07
0.05
0.01
0.006
0.07
–
–
168.8
1205.7
–
> 164.9
CQ
a
ClogP calculated from molinspiration.
Fig. 2. Comparison of activity/cytotoxicity of 6h, 6q, 7j with previously reported scaffolds I and II.
4

A. Rani, et al.
BioorganicChemistry88(2019)102912
63.23; H, 4.85; N, 12.82. found: C, 63.35; H, 4.79; N,12.88.
Weak bases assist in
drug
via
accmulation
pH
trapping
Amide
the
core reduces
cytotoxicity
3.2.3. N-(6-((7-chloroquinolin-4-yl)amino)hexyl)-2-(1,3-dioxoisoindolin-
2-yl)acetamide (6c)
White solid; mp 110–111 °C; 1H NMR (400 MHz, DMSO-d6) δ
1.32–1.41 (m, 6H, 3x-CH2-); 1.57–1.64 (m, 2H, eCH2e); 3.00–3.05 (m,
2H, eCH2e); 3.20–3.25 (m, 2H, eCH2e); 4.13 (s, 2H, eCH2e); 6.44 (d,
J = 5.6 Hz, 1H, Ar-H); 7.38–7.42 (m, 2H, Ar-H + NH-exchangeable
with D2O); 7.74 (d, J = 2.2 Hz, 1H, Ar-H); 7.80–7.86 (m, 4H, Ar-H);
8.16 (t, J = 5.6 Hz, 1H, NH-exchangeable with D2O); 8.25 (d,
J = 9.0 Hz, 1H, Ar-H); 8.34 (d, J = 5.5 Hz, 1H, Ar-H); 13C NMR
(100 MHz, DMSO-d6) δ 26.5, 26.7, 28.2, 29.4, 39.1, 40.6, 42.9, 99.1,
117.8, 123.6, 124.7, 127.8, 132.3, 134.2, 135.0, 148.8, 150.9, 151.7,
166.3, 168.1. HRMS Calcd for C25H25ClN4O3 [M+H]+ 465.1649 found
465.1629. Anal Calcd (%): C, 64.58; H, 5.42; N, 12.05. found: C, 64.67;
H, 5.49; N, 12.13.
O
N
N
O
4-aminoquinoline
N
N
N
require for π−π
n
m
H
H
stacking
O
with heme
Cl
n=2&4
m=2,
(for good anti-plasmodial activities)
Fig. 3. Structure Activity Relationship (SAR) of 4-aminoquinoline based mo-
lecules.
3.2. General procedure for the synthesis of amide-linked substituted 1,3-
dioxoisoindoline-4-aminoquinolines (6a-r, 7a-r)
3.2.4. N-(8-((7-chloroquinolin-4-yl)amino)octyl)-2-(1,3-dioxoisoindolin-
2-yl)acetamide (6d)
Synthesis of C-5 substituted 2-(1,3-dioxoisoindolin-2-yl)acetic acid/
3-(1,3-dioxoisoindolin-2-yl)propanoic acid/4-(1,3-dioxoisoindolin-2-yl)
butanoic acid (3a-c, 4a-b):
White solid; mp 101–102 °C; 1H NMR (500 MHz, DMSO-d6) δ
1.22–1.41 (m, 12H, 6x-CH2-); 3.03–3.07 (m, 2H, eCH2e); 3.22–3.26
(m, 2H, eCH2e); 4.17 (s, 2H, eCH2e); 6.45 (d, J = 5.3 Hz, 1H, Ar-H);
7.29 (t, J = 5.3 Hz, 1H, NH-exchangeable with D2O); 7.43 (dd, J = 2.3,
8.9 Hz, 1H, Ar-H); 7.77 (d, J = 2.3 Hz, 1H, Ar-H); 7.84–7.90 (m, 4H, Ar-
H); 8.18 (t, J = 5.6 Hz, 1H, NH-exchangeable with D2O); 8.27 (d,
J = 9.0 Hz, 1H, Ar-H); 8.38 (d, J = 5.4 Hz, 1H, Ar-H); 13C NMR
(125 MHz, DMSO-d6) δ 26.4, 26.6, 28.2, 28.4, 29.3, 29.6, 37.8, 40.6,
42.8, 99.2, 117.9, 123.4, 124.3, 127.9, 132.1, 134.2, 135.2, 148.7,
150.6, 151.4, 166.1, 168.0. HRMS Calcd for C27H29ClN4O3 [M+H]+
493.1962 found 493.1956. Anal Calcd (%): C, 65.78; H, 5.93; N, 11.36;
found: C, 65.65; H, 5.99; N, 11.41.
Substituted Phthalic anhydrides (1 mmol), amino acids (1.2 mmol)
and triethylamine (Et3N) (1.2 mmol) were mixed in toluene and the
reaction mixture was refluxed for 6 h. The progress of the reaction was
monitored by thin layer chromatography (TLC). Toluene was evapo-
rated under reduced pressure and the solid residue was stirred with 1 N-
HCl in ice-cold water. The resulted white powder was filtered, dried and
used for subsequent step without any purification.
Synthesis of C-5 substituted N-(2-((7-chloroquinolin-4-yl)amino)
alkyl)-2-(1,3-dioxoisoindolin-2-yl)alkylamides (6a-r):
1.0 mmol of (1,3-dioxoisoindolin-2-yl) acid, N-ethyl-N-dimethyla-
minopropyl carbodiimide (EDC) (1.1 mmol), hydroxybenzotriazole
(HOBt) (1.2 mmol) and N,N-Diisopropylethylamine (2.0 mmol) were
mixed in minimum DMF and the obtained mixture was stirred for
5 min. Then, 4-aminoquinoline-diamines (1.0 mmol) was added to the
reaction mixture and the stirring was continued for 5 h. The reaction
end was proved by thin layer chromatography (TLC). Then, DMF was
evaporated using rotary evaporator and cold water (20 mL) was added,
and solid precipitates obtained were filtered and washed with cold
water. The crude product was recrystallized in absolute ethanol.
3.2.5. N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-3-(1,3-dioxoisoindolin-
2-yl)propanamide (6e)
White solid; mp 182–183 °C; 1H NMR (400 MHz, DMSO-d6) δ 2.42
(t, J = 7.2 Hz, 2H, eCH2e); 2.25–2.30 (m, 4H, 2x-CH2-); 3.75 (t,
J = 7.4 Hz, 2H, eCH2e); 6.56 (d, J = 5.8 Hz, 1H, Ar-H); 7.45 (dd,
J = 2.0, 9.0 Hz, 1H, Ar-H); 7.70–7.74 (m, 4H, Ar-H); 7.79 (d,
J = 2.3 Hz, 1H, Ar-H); 7.93 (t, J = 5.6 Hz, 1H, NH-exchangeable with
D2O); 8.17 (d, J = 9.1 Hz, 1H, Ar-H); 8.29 (t, J = 5.4 Hz, 1H, NH-ex-
changeable with D2O); 8.40 (t, J = 5.8 Hz, 1H, Ar-H); 13C NMR
(100 MHz, DMSO-d6) δ 34.6, 34.9, 37.6, 42.9, 99.0, 117.2, 123.4,
124.8, 125.4, 126.7, 132.0, 134.7, 135.3, 146.2, 149.6, 152.2, 168.1,
170.9. HRMS Calcd for C22H19ClN4O3 [M]+ 423.1179 found 423.1161.
Anal Calcd (%): C, 62.49; H, 4.53; N, 13.25; found: C, 62.51; H, 4.45; N,
13.17.
3.2.1. N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-2-(1,3-dioxoisoindolin-
2-yl)acetamide (6a)
White solid; mp 189–190 °C; 1H NMR (400 MHz, DMSO-d6) δ 3.31
(s, 4H, 2x-CH2-); 4.18 (s, 2H, eCH2e); 6.50 (d, J = 5.4 Hz, 1H, Ar-H);
7.33 (t, J = 5.0 Hz, 1H, NH-exchangeable with D2O); 7.38 (dd, J = 1.8,
9.0 Hz, 1H, Ar-H); 7.74 (d, J = 2.0 Hz, 1H, Ar-H); 7.82–7.88 (m, 4H, Ar-
H); 8.11 (d, J = 9.0 Hz, 1H, Ar-H); 8.36 (d, J = 5.0 Hz, 1H, Ar-H); 8.45
(t, J = 5.6 Hz, 1H, NH-exchangeable with D2O); 13C NMR (100 MHz,
DMSO-d6) δ 37.9, 40.7, 42.3, 99.1, 117.9, 123.7, 124.4, 124.6, 128.0,
132.2, 133.9, 135.1, 149.5, 150.5, 152.4, 167.2, 168.0. HRMS Calcd for
3.2.6. N-(4-((7-chloroquinolin-4-yl)amino)butyl)-3-(1,3-dioxoisoindolin-
2-yl)propanamide (6f)
White solid; mp 172–173 °C; 1H NMR (400 MHz, DMSO-d6) δ
1.23–1.33 (m, 4H, 2x-CH2-); 2.41 (t, J = 7.1 Hz, 2H, eCH2e);
3.05–3.14 (m, 2H, eCH2e); 3.22–3.27 (m, 2H, eCH2e); 3.73 (t,
J = 7.2 Hz, 2H, eCH2e); 6.45 (d, J = 5.4 Hz, 1H, Ar-H); 7.32 (t,
J = 5.2 Hz, 1H, NH-exchangeable with D2O); 7.43 (dd, J = 2.2, 8.9 Hz,
1H, Ar-H); 7.74 (d, J = 2.2 Hz, 1H, Ar-H); 7.83–7.91 (m, 4H, Ar-H);
8.19–8.28 (m, 2H, Ar-H + NH-exchangeable with D2O); 8.38 (d,
J = 5.3 Hz, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 25.4, 27.1,
34.6, 38.2, 40.8, 42.2, 99.2, 117.5, 123.6, 124.3, 124.8, 128.3 132.5,
133.7, 135.2, 149.6, 150.2, 152.6, 168.1, 170.8. HRMS Calcd for
C
21H17ClN4O3 [M+H]+ 409.1023 found 409.1041. Anal Calcd (%): C,
61.69; H, 4.19; N, 13.70. found: C, 61.54; H, 4.27; N,13.62
3.2.2. N-(4-((7-chloroquinolin-4-yl)amino)butyl)-2-(1,3-dioxoisoindolin-
2-yl)acetamide (6b)
White solid; mp 129–130 °C; 1H NMR (400 MHz, DMSO-d6) δ
0.96–1.29 (m, 4H, 2x-CH2-); 3.08–3.15 (m, 2H, eCH2e); 3.25–3.29 (m,
2H, eCH2e); 4.16 (s, 2H, eCH2e); 6.46 (d, J = 5.5 Hz, 1H, Ar-H); 7.33
(t, J = 5.2 Hz, 1H, NH-exchangeable with D2O); 7.42 (dd, J = 2.4,
9.0 Hz, 1H, Ar-H); 7.76 (d, J = 2.3 Hz, 1H, Ar-H); 7.83–7.90 (m, 4H, Ar-
H); 8.20–8.30 (m, 2H, Ar-H + NH-exchangeable with D2O); 8.37 (d,
J = 5.4 Hz, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 25.4, 27.2,
37.2, 40.2, 42.1, 99.2, 117.8, 123.7, 124.3, 124.7, 128.1, 132.2, 133.8,
135.2, 149.4, 150.4, 152.5, 167.0, 168.1. HRMS Calcd for
C
24H23ClN4O3 [M+H]+ 451.1492 found 451.1466. Anal Calcd (%): C,
63.93; H, 5.14; N, 12.43; found: C, 63.81; H, 5.08; N, 12.38.
3.2.7. N-(6-((7-chloroquinolin-4-yl)amino)hexyl)-3-(1,3-dioxoisoindolin-
2-yl)propanamide (6g)
White solid; mp 122–123 °C; 1H NMR (400 MHz, DMSO-d6)
1.29–1.40 (m, 6H, 3x-CH2-); 1.55–1.63 (m, 2H, eCH2e); 2.40 (t,
C
23H21ClN4O3 [M+H]+ 437.1336 found 437.1323. Anal Calcd (%): C,
5

A. Rani, et al.
BioorganicChemistry88(2019)102912
J = 7.2 Hz, 2H, eCH2e); 3.01–3.07 (m, 2H, eCH2e); 3.21–3.27 (m,
2H, eCH2e); 3.72 (t, J = 7.2 Hz, 2H, eCH2e); 6.44 (d, J = 5.3 Hz, 1H,
Ar-H); 7.30 (t, J = 5.2 Hz, 1H, NH-exchangeable with D2O); 7.42 (dd,
J = 2.2, 9.0 Hz, 1H, Ar-H); 7.73 (d, J = 2.1 Hz, 1H, Ar-H); 7.83–7.92
(m, 4H, Ar-H); 8.20–8.29 (m, 2H, Ar-H + NH-exchangeable with D2O);
8.35 (d, J = 5.2 Hz, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 26.4,
26.7, 28.3, 29.1, 34.6, 39.4, 40.8, 42.2, 99.1, 117.7, 123.6, 124.2,
124.8, 128.4 132.4, 133.7, 135.1, 149.5, 150.1, 152.3, 168.1, 170.7.
HRMS Calcd for C26H27ClN4O3 [M+H]+ 479.1805 found 479.1814.
Anal Calcd (%): C, 65.20; H, 5.68; N, 11.70; found: C, 65.13; H, 5.51; N,
11.61.
1H, Ar-H); 7.81–7.86 (m, 4H, Ar-H); 8.28 (d, J = 9.0 Hz, 1H, Ar-H);
8.38 (t, J = 5.5 Hz, 1H, NH-exchangeable with D2O); 13C NMR
(125 MHz, DMSO-d6) δ 24.5, 26.4, 26.9, 28.2, 29.7, 33.5, 38.4, 40.4,
43.5, 99.2, 115.6, 119.3, 123.5, 126.4, 127.2, 132.0, 134.9, 138.5,
138.9, 143.3, 156.2, 168.1, 172.2. HRMS Calcd for C27H29ClN4O3 [M
+H]+ 493.1962 found 4931951. Anal Calcd (%): C, 65.78; H, 5.93; N,
11.36; found: C, 65.65; H, 5.82; N, 11.44.
3.2.12. N-(8-((7-chloroquinolin-4-yl)amino)octyl)-4-(1,3-dioxoisoindolin-
2-yl)butanamide (6l)
White solid; mp 152–153 °C; 1H NMR (500 MHz, DMSO-d6) δ
1.20–1.39 (m, 12H, 6x-CH2-); 1.75–1.84 (m, 2H, eCH2e); 2.07–2.11
(m, 2H, eCH2e); 3.02–3.06 (m, 2H, eCH2e); 3.20–3.25 (m, 2H,
eCH2e); 3.54 (t, J = 7.2 Hz, 2H, eCH2e); 6.44 (d, J = 5.2 Hz, 1H, Ar-
H); 7.28 (t, J = 5.3 Hz, 1H, NH-exchangeable with D2O); 7.44 (dd,
J = 2.2, 8.9 Hz, 1H, Ar-H); 7.75 (d, J = 2.3 Hz, 1H, Ar-H); 7.83–7.90
(m, 4H, Ar-H); 8.19 (d, J = 5.4 Hz, 1H, Ar-H); 8.27 (d, J = 8.9 Hz, 1H,
Ar-H); 8.40 (t, J = 5.3 Hz, 1H, NH-exchangeable with D2O); 13C NMR
(125 MHz, DMSO-d6) δ 24.5, 26.4, 26.7, 28.1, 28.5, 29.4, 29.8, 33.3,
37.8, 40.5, 43.4, 99.1, 115.9, 119.34, 123.4, 126.6, 127.2, 132.1,
134.6, 138.7, 138.8, 143.3, 156.3, 168.2, 172.6. HRMS Calcd for
3.2.8. N-(8-((7-chloroquinolin-4-yl)amino)octyl)-3-(1,3-dioxoisoindolin-
2-yl)propanamide (6h)
White solid; mp 85–86 °C; 1H NMR (400 MHz, DMSO-d6) 1.20–1.40
(m, 12H, 6x-CH2-); 2.41 (t, J = 7.1 Hz, 2H, eCH2e); 3.02–3.07 (m, 2H,
eCH2e); 3.21–3.26 (m, 2H, eCH2e); 3.71 (t, J = 7.2 Hz, 2H, eCH2e);
6.43 (d, J = 5.3 Hz, 1H, Ar-H); 7.31 (t, J = 5.4 Hz, 1H, NH-exchange-
able with D2O); 7.41 (dd, J = 2.1, 9.0 Hz, 1H, Ar-H); 7.75 (d,
J = 2.0 Hz, 1H, Ar-H); 7.85–7.94 (m, 4H, Ar-H); 8.20–8.30 (m, 2H, Ar-
H + NH-exchangeable with D2O); 8.34 (d, J = 5.3 Hz, 1H, Ar-H); 13C
NMR (100 MHz, DMSO-d6) δ 26.2, 26.6, 28.2, 28.5, 29.1, 29.5, 34.6,
37.8, 40.5, 42.2, 99.2, 117.5, 123.8, 124.2, 124.9, 128.5 132.4, 133.9,
135.0, 149.5, 150.0, 152.5, 168.3, 170.9. HRMS Calcd for
C
29H33ClN4O3 [M+H]+ 521.2275 found 521.2258. Anal Calcd (%): C,
66.85; H, 6.38; N, 10.75; found: C, 66.79; H, 6.49; N, 10.61.
C
28H31ClN4O3 [M+H]+ 507.2118 found 507.2129. Anal Calcd (%): C,
3.2.13. N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-2-(5-fluoro-1,3-
dioxoisoindolin-2-yl)acetamide (6m)
66.33; H, 6.16; N, 11.05; found: C, 66.44; H, 6.26; N, 11.17.
White solid; mp 192–193 °C; 1H NMR (DMSO‑d6, 500 MHz): 3.31 (s,
4H, 2x-CH2-); 4.17 (s, 2H, eCH2e); 6.51 (d, J = 5.5 Hz, 1H, Ar-H);
7.37–7.42 (m, 2H, Ar-H + NH-exchangeable with D2O); 7.64–7.69 (m,
1H, Ar-H); 7.75 (d, J = 2.2 Hz, 1H, Ar-H); 7.77–7.80 (m, 1H, Ar-H);
7.93–7.96 (m, 1H, Ar-H); 8.13 (d, J = 9.0 Hz, Ar-H); 8.37 (d,
J = 5.5 Hz, Ar-H); 8.45 (t, J = 5.6 Hz, 1H, NH-exchangeable with D2O);
13C NMR (125 MHz, DMSO-d6) δ 36.7, 41.3, 42.5, 99.1, 111.3 (d,
J = 22.9 Hz), 117.8, 121.5 (d, J = 23.7 Hz), 124.8, 125.1, 126.7 (d,
J = 9.6 Hz), 127.9, 128.5 (d, J = 1.9 Hz), 133.4, 135.1 (d, J = 9.4 Hz),
149.7, 150.6, 152.5, 166.2 (d, J = 252.3 Hz), 166.7 (d, J = 2.3 Hz),
167.3, 169.7. HRMS Calcd for C21H16ClFN4O3 [M+H]+ 427.0929
found 427.0935. Anal Calcd (%): C, 59.09; H, 3.78; N, 13.13; found: C,
59.22; H, 3.68; N, 13.33.
3.2.9. N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-4-(1,3-dioxoisoindolin-
2-yl)butanamide (6i)
White solid; mp 177–178 °C; 1H NMR (500 MHz, DMSO-d6) δ
1.77–1.83 (m, 2H, eCH2e); 2.12 (t, J = 7.5 Hz, 2H, eCH2e); 3.32 (t,
J = 6.0 Hz, 2H, eCH2e); 3.52–3.57 (m, 4H, 2x-CH2-); 6.89 (d,
J = 7.1 Hz, 1H, Ar-H); 7.77 (dd, J = 2.2, 9.1 Hz, 1H, Ar-H); 7.81–7.86
(m, 4H, Ar-H); 8.00 (d, J = 2.1 Hz, 1H, Ar-H); 8.16 (t, J = 5.3 Hz, 1H,
NH-exchangeable with D2O); 8.53–8.57 (m, 2H, Ar-H); 9.54 (t,
J = 5.9 Hz, 1H, NH-exchangeable with D2O); 13C NMR (125 MHz,
DMSO-d6) δ 24.3, 33.1, 37.5, 37.6, 43.2, 98.9, 115.9, 119.4, 123.4,
126.1, 127.3, 132.0, 134.8, 138.4, 138.9, 143.3, 156.1, 168.3, 172.6.
HRMS Calcd for C23H21ClN4O3 [M+H]+ 437.1336 found 437.1321.
Anal Calcd (%): C, 63.23; H, 4.85; N, 12.82; found: C, 63.44; H, 4.89; N,
12.77.
3.2.14. N-(4-((7-chloroquinolin-4-yl)amino)butyl)-2-(5-fluoro-1,3-
dioxoisoindolin-2-yl)acetamide (6n)
3.2.10. N-(4-((7-chloroquinolin-4-yl)amino)butyl)-4-(1,3-
White solid; mp 140–141 °C; 1H NMR (DMSO-d6, 500 MHz):
1.50–1.56 (m, 2H, eCH2e); 1.62–1.68 (m, 2H, eCH2e); 3.11–3.15 (m,
2H, eCH2e); 3.27–3.31 (m, 2H, eCH2e); 4.18 (s, 2H, eCH2e); 6.50 (d,
J = 5.6 Hz, 1H, Ar-H); 7.45–7.47 (m, 2H, Ar-H + NH-exchangeable
with D2O); 7.68–7.72 (m, 1H, Ar-H); 7.78 (d, J = 2.3 Hz, 1H, Ar-H);
7.81–7.83 (m, 1H, Ar-H); 7.97–7.99 (m, 1H, Ar-H); 8.25 (t, J = 5.7 Hz,
NH-exchangeable with D2O); 8.29 (d, J = 9.0 Hz, Ar-H); 8.39 (d,
J = 5.5 Hz, 1H, Ar-H); 13C NMR (125 MHz, DMSO-d6) δ 25.7, 26.8,
35,2, 39.3, 42.9, 99.0, 111.7 (d, J = 23.3 Hz), 117.7, 121.5 (d,
J = 23.4 Hz), 124.4, 124.8, 126.6 (d, J = 9.6 Hz), 127.9, 128.3 (d,
J = 1.8 Hz), 133.9, 135.2 (d, J = 9.4 Hz), 149.1, 150.4, 152.2, 166.1
(d, J = 251.6 Hz), 166.9 (d, J = 2.3 Hz), 167.4, 169.8. HRMS Calcd for
dioxoisoindolin-2-yl)butanamide (6j)
White solid; mp 145–146 °C; 1H NMR (500 MHz, DMSO-d6) δ
1.22–1.34 (m, 4H, 2x-CH2-); 1.76–1.83 (m, 2H, eCH2e); 2.11 (t,
J = 7.1 Hz, 2H, eCH2e); 3.08–3.15 (m, 2H, eCH2e); 3.25–3.29 (m,
2H, eCH2e); 3.56 (t, J = 7.2 Hz, 2H, eCH2e); 6.85 (d, J = 7.1 Hz, 1H,
Ar-H); 7.76 (dd, J = 2.0, 9.0 Hz, 1H, Ar-H); 7.80–7.86 (m, 4H, Ar-H);
8.01 (d, J = 2.1 Hz, 1H, Ar-H); 8.14 (t, J = 5.4 Hz, 1H, NH-exchange-
able with D2O); 8.54–8.59 (m, 2H, Ar-H); 8.85 (t, J = 5.5 Hz, 1H, NH-
exchangeable with D2O); 13C NMR (125 MHz, DMSO-d6) δ 24.4, 25.3,
27.5, 33.4, 37.6, 40.9, 43.2, 99.1, 115.7, 119.3, 123.4, 126.4, 127.3,
132.1, 134.8, 138.5, 138.8, 143.4, 156.1, 168.2, 172.4. HRMS Calcd for
C
25H25ClN4O3 [M+H]+ 465.1649 found 465.1633. Anal Calcd (%): C,
C
23H20ClFN4O3 [M+H]+ 455.1242 found 455.1265. Anal Calcd (%):
64.58; H, 5.42; N, 12.05; found: C, 64.41; H, 5.31; N, 12.19.
C, 60.73; H, 4.43; N, 12.32; found: C, 60.59; H, 4.38; N, 12.21.
3.2.11. N-(6-((7-chloroquinolin-4-yl)amino)hexyl)-4-(1,3-
3.2.15. N-(6-((7-chloroquinolin-4-yl)amino)hexyl)-2-(5-fluoro-1,3-
dioxoisoindolin-2-yl)acetamide (6o)
dioxoisoindolin-2-yl)butanamide (6k)
White solid; mp 158–159 °C; 1H NMR (500 MHz, DMSO-d6) δ
1.18–1.25 (m, 2H, eCH2e); 1.27–1.40 (m, 4H, 2x-CH2-); 1.61–1.67 (m,
2H, eCH2e); 1.78–1.85 (m, 2H, eCH2e); 2.06–2.10 (m, 2H, eCH2e);
2.91–2.99 (m, 2H, eCH2e); 3.23–3.27 (m, 2H, eCH2e); 3.57 (t,
J = 7.1 Hz, 2H, eCH2e); 6.46 (d, J = 5.4 Hz, 1H, Ar-H); 7.32 (t,
J = 5.55 Hz, 1H, NH-exchangeable with D2O); 7.44 (dd, J = 2.1,
8.9 Hz, 1H, Ar-H); 7.71 (d, J = 5.5 Hz, 1H, Ar-H); 7.76 (d, J = 2.3 Hz,
White solid; mp 131–132 °C; 1H NMR (DMSO-d6, 400 MHz):
1.36–1.44 (m, 4H, 2x-CH2-); 1.54–1.62 (m, 4H, 2x-CH2-); 3.01–3.07
(m, 2H, eCH2e); 3.22–3.25 (m, 2H, eCH2e); 4.17 (s, 2H, eCH2e);
6.39 (d, J = 5.3 Hz, 1H, Ar-H); 7.30 (t, J = 5.4 Hz, NH-exchangeable
with D2O); 7.35 (dd, J = 2.1, 9.0 Hz, 1H, Ar-H); 7.54–7.59 (m, 1H, Ar-
H); 7.69–7.74 (m, 2H, Ar-H); 7.88–7.90 (m, 1H, Ar-H); 7.96 (t,
J = 5.5 Hz, NH-exchangeable with D2O); 8.22 (d, J = 9.0 Hz, Ar-H);
6

A. Rani, et al.
BioorganicChemistry88(2019)102912
8.31 (d, J = 5.4 Hz, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 26.5,
26.9, 28.5, 29.6, 39.5, 40.9, 42.5, 99.1, 111.4 (d, J = 23.7 Hz), 117.7,
121.9 (d, J = 23.7 Hz), 124.9, 125.4, 126.5 (d, J = 9.7 Hz), 127.8,
128.2 (d, J = 1.9 Hz), 133.7, 135.1 (d, J = 9.7 Hz), 149.6, 150.7,
152.3, 166.0 (d, J = 252.3 Hz), 166.8 (d, J = 2.4 Hz), 167.2, 169.6.
HRMS Calcd for C25H24ClFN4O3 [M+H]+ 483.1555 found 483.1561.
Anal Calcd (%): C, 62.18; H, 5.01; N, 11.60; found: C, 62.33; H, 5.12; N,
11.51.
amino)alkyl)-2-(1,3-dioxoisoindolin-2-yl)alkylamide 6m-l (1.0 mmol)
in 0.5 mL of NMP (N-Methylpyrrolidin-2-one) and secondary amines
(1.2 mmol). After sealing with a PTFE cap, the vessel was heated to 160
0C for 5 min in the microwave reactor and the completion was ascer-
tained using TLC. After completion, the contents were poured in water
(20 mL) resulting in the precipitation of the desired product. The yellow
product obtained was filtered and re-crystallized using absolute
ethanol.
3.2.16. N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-3-(5-fluoro-1,3-
dioxoisoindolin-2-yl)propanamide (6p)
3.2.19. N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-2-(5-morpholino-1,3-
dioxoisoindolin-2-yl)acetamide (7a)
White solid; mp 183–184 °C; 1H NMR (DMSO-d6, 400 MHz): 2.40 (t,
J = 7.2 Hz, 2H, eCH2e); 3.00–3.09 (m, 4H, 2x-CH2-); 3.73 (t,
J = 7.1 Hz, 2H, eCH2e); 6.41 (d, J = 5.3 Hz, 1H, Ar-H); 7.29 (t,
J = 5.5 Hz, NH-exchangeable with D2O); 7.41 (dd, J = 2.1, 9.0 Hz, 1H,
Ar-H); 7.56–7.62 (m, 1H, Ar-H); 7.70–7.74 (m, 2H, Ar-H); 7.84–7.88
(m, 1H, Ar-H); 7.99 (t, J = 5.4 Hz, NH-exchangeable with D2O); 8.22
(d, J = 9.1 Hz, Ar-H); 8.35 (d, J = 5.5 Hz, 1H, Ar-H); 13C NMR
Yellow solid; mp 216–217 °C; 1H NMR (500 MHz, DMSO-d6) δ
3.30–3.32 (m, 6H, 3x-CH2-); 3.59–3.63 (m, 2H, eCH2e); 3.74–3.76 (m,
4H, 2x-CH2-); 4.12 (s, 2H, eCH2e); 6.90 (d, J = 7.1 Hz, 1H, Ar-H); 7.25
(dd, J = 2.3, 8.5 Hz, 1H, Ar-H); 7.32 (d, J = 2.2 Hz, 1H, Ar-H); 7.66 (d,
J = 8.4 Hz, 1H, Ar-H); 7.77 (dd, J = 2.0, 9.0 Hz, 1H, Ar-H); 8.05 (d,
J = 2.1 Hz, 1H, Ar-H); 8.55–8.57 (m, 3H, Ar-H); 9.55 (t, J = 5.9 Hz, 1H,
NH-exchangeable with D2O); 13C NMR (125 MHz, DMSO-d6) δ 39.1,
42.7, 47.6, 48.8, 66.5, 99.1, 108.3, 117.8, 118.1, 120.2, 124.5, 124.6,
125.1, 127.9, 133.5, 134.6, 149.4, 150.5, 152.3, 155.7, 166.4, 167.7,
168.4, 174.1. HRMS Calcd for C25H24ClN5O4 [M+H]+ 494.1550 found
494.1564. Anal Calcd (%): C, 60.79; H, 4.90; N, 14.18; found: C, 60.83;
H, 4.79; N, 14.31.
(100 MHz, DMSO-d6)
δ 34.5, 37.9, 40.8, 42.4, 99.2, 111.3 (d,
J = 23.2 Hz), 117.5, 121.2 (d, J = 23.4 Hz), 124.4, 124.8, 126.5 (d,
J = 9.5 Hz), 127.8, 128.2 (d, J = 1.8 Hz), 133.7, 135.0 (d, J = 9.5 Hz),
149.6, 150.3, 152.2, 166.1 (d, J = 251.9 Hz), 166.5 (d, J = 2.3 Hz),
167.1, 169.9. HRMS Calcd for C27H29ClN4O3 [M]+ 492.1928 found
4921941. HRMS Calcd for C22H18ClFN4O3 [M+H]+ 441.1085 found
441.1097. Anal Calcd (%): C, 59.94; H, 4.12; N, 12.71; found: C, 59.77;
H, 4.41; N, 12.59.
3.2.20. N-(4-((7-chloroquinolin-4-yl)amino)butyl)-2-(5-morpholino-1,3-
dioxoisoindolin-2-yl)acetamide (7b)
Yellow solid; mp 174–175 °C; 1H NMR (500 MHz, DMSO-d6) δ
1.51–1.56 (m, 2H, eCH2e); 1.63–1.69 (m, 2H, eCH2e); 3.07–3.011
(m, 2H, eCH2e); 3.25–3.28 (m, 2H, eCH2e); 3.39–3.42 (m, 4H, 2x-
CH2-); 3.70–3.74 (m, 4H, 2x-CH2-); 4.15 (s, 2H, eCH2e); 6.46 (d,
J = 5.3 Hz, 1H, Ar-H); 7.25 (dd, J = 2.2, 8.7 Hz, 1H, Ar-H); 7.28 (t,
J = 5.4 Hz, 1H, NH-exchangeable with D2O); 7.31 (d, J = 2.2 Hz, 1H,
Ar-H); 7.45 (dd, J = 2.0, 9.0 Hz, 1H, Ar-H); 7.68 (d, J = 8.8 Hz, 1H, Ar-
H); 7.79 (d, J = 2.1 Hz, 1H, Ar-H); 8.16 (t, J = 5.5 Hz, 1H, NH-ex-
changeable with D2O); 8.27 (d, J = 9.0 Hz, 1H, Ar-H); 8.39 (d,
J = 5.3 Hz, 1H, Ar-H); 13C NMR (125 MHz, DMSO-d6) δ 25.4, 27.6,
37.9, 40.6, 42.7, 47.4, 66.3, 99.1, 108.5, 117.7, 118.2, 120.3, 124.5,
124.7, 125.2, 127.7, 133.9, 134.5, 149.6, 150.5, 152.7, 155.6, 166.4,
3.2.17. N-(4-((7-chloroquinolin-4-yl)amino)butyl)-3-(5-fluoro-1,3-
dioxoisoindolin-2-yl)propanamide (6q)
White solid; mp 177–178 °C; 1H NMR (DMSO-d6, 400 MHz):
1.38–1.45 (m, 2H, eCH2e); 1.51–1.58 (m, 2H, eCH2e); 2.38 (t,
J = 7.2 Hz, 2H, eCH2e); 2.98–3.03 (m, 2H, eCH2e); 3.15–3.20 (m,
2H, eCH2e); 3.72 (t, J = 7.3 Hz, 2H, eCH2e); 6.39 (d, J = 5.4 Hz, 1H,
Ar-H); 7.28 (t, J = 5.4 Hz, NH-exchangeable with D2O); 7.39 (dd,
J = 2.3, 9.1 Hz, 1H, Ar-H); 7.54–7.59 (m, 1H, Ar-H); 7.69–7.72 (m, 2H,
Ar-H); 7.85–7.88 (m, 1H, Ar-H); 7.98 (t, J = 5.5 Hz, NH-exchangeable
with D2O); 8.21 (d, J = 9.0 Hz, Ar-H); 8.33 (d, J = 5.4 Hz, 1H, Ar-H);
13C NMR (100 MHz, DMSO-d6) δ 25.6, 27.1, 34.4, 35.1, 38.6, 42.5,
99.1, 111.4 (d, J = 23.5 Hz), 117.9, 121.5 (d, J = 23.5 Hz), 124.5,
124.6, 126.2 (d, J = 9.6 Hz), 127.8, 128.3 (d, J = 1.7 Hz), 133.9, 135.1
(d, J = 9.5 Hz), 149.4, 150.6, 152.3, 166.2 (d, J = 251.7 Hz), 166.8 (d,
J = 2.4 Hz), 167.2, 169.8. HRMS Calcd for C24H22ClFN4O3 [M+H]+
469.1398 found 469.1387. Anal Calcd (%): C, 61.47; H, 4.73; N, 11.95;
found: C, 61.55; H, 4.88; N, 11.87.
167.9, 168.2, 174.1. HRMS Calcd for
C
27H28ClN5O4 [M+H]+
522.1863 found 522.1878. Anal Calcd (%): C, 62.13; H, 5.41; N, 13.42;
found: C, 62.31; H, 5.33; N, 13.53.
3.2.21. N-(6-((7-chloroquinolin-4-yl)amino)hexyl)-2-(5-morpholino-1,3-
dioxoisoindolin-2-yl)acetamide (7c)
Yellow solid; mp 160–161 °C; 1H NMR (500 MHz, DMSO-d6) δ
1.30–1.45 (m, 6H, 3x-CH2-); 1.64–1.67 (m, 2H, eCH2e); 3.04–3.09 (m,
2H, eCH2e); 3.23–3.27 (m, 2H, eCH2e); 3.36–3.39 (m, 4H, 2x-CH2-);
3.72–3.75 (m, 4H, 2x-CH2-); 4.12 (s, 2H, eCH2e); 6.45 (d, J = 5.4 Hz,
1H, Ar-H); 7.22 (dd, J = 2.4, 8.6 Hz, 1H, Ar-H); 7.27 (t, J = 5.5 Hz, 1H,
NH-exchangeable with D2O); 7.32 (d, J = 2.3 Hz, 1H, Ar-H); 7.42 (dd,
J = 2.3, 8.9 Hz, 1H, Ar-H); 7.66 (d, J = 8.6 Hz, 1H, Ar-H); 7.77 (d,
J = 2.2 Hz, 1H, Ar-H); 8.15 (t, J = 5.6 Hz, 1H, NH-exchangeable with
D2O); 8.26 (d, J = 9.0 Hz, 1H, Ar-H); 8.38 (d, J = 5.4 Hz, 1H, Ar-H);
13C NMR (125 MHz, DMSO-d6) δ 26.4, 26.7, 28.1, 29.4, 39.0, 42.7,
47.5, 48.9, 66.2, 99.0, 108.2, 117.9, 118.0, 120.1, 124.4, 124.5, 125.0,
127.9, 133.7, 134.7, 149.5, 150.5, 152.4, 155.7, 166.5, 167.8, 168.3,
3.2.18. N-(6-((7-chloroquinolin-4-yl)amino)hexyl)-3-(5-fluoro-1,3-
dioxoisoindolin-2-yl)propanamide (6r)
White solid; mp 138–139 °C; 1H NMR (DMSO-d6, 400 MHz):
1.32–1.39 (m, 6H, 3x-CH2-); 1.54–1.63 (m, 2H, eCH2e); 2.39 (t,
J = 7.1 Hz, 2H, eCH2e); 3.00–3.05 (m, 2H, eCH2e); 3.19–3.24 (m,
2H, eCH2e); 3.71 (t, J = 7.2 Hz, 2H, eCH2e); 6.38 (d, J = 5.3 Hz, 1H,
Ar-H); 7.29 (t, J = 5.4 Hz, NH-exchangeable with D2O); 7.37 (dd,
J = 2.2, 9.0 Hz, 1H, Ar-H); 7.53–7.59 (m, 1H, Ar-H); 7.68–7.73 (m, 2H,
Ar-H); 7.86–7.89 (m, 1H, Ar-H); 7.95 (t, J = 5.4 Hz, NH-exchangeable
with D2O); 8.20 (d, J = 9.1 Hz, Ar-H); 8.32 (d, J = 5.3 Hz, 1H, Ar-H);
13C NMR (100 MHz, DMSO-d6) δ 26.7, 26.9, 28.3, 29.5, 34.1, 39.3,
40.7, 42.4, 99.0, 111.5 (d, J = 23.4 Hz), 117.5, 121.8 (d, J = 23.7 Hz),
124.8, 125.3, 126.1 (d, J = 9.7 Hz), 127.9, 128.2 (d, J = 1.9 Hz),
133.8, 135.0 (d, J = 9.7 Hz), 149.5, 150.5, 152.2, 166.1 (d,
J = 251.6 Hz), 166.9 (d, J = 2.5 Hz), 167.3, 169.7. HRMS Calcd for
174.2. HRMS Calcd for
C
29H32ClN5O4 [M+H]+ 550.2176 found
550.2188. Anal Calcd (%): C, 63.32; H, 5.86; N, 12.73; found: C, 63.51;
H, 5.65; N, 12.68.
C
26H26ClFN4O3 [M+H]+ 497.1711 found 497.1723. Anal Calcd (%):
3.2.22. N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-3-(5-morpholino-1,3-
dioxoisoindolin-2-yl)propanamide (7d)
C, 62.84; H, 5.27; N, 11.27; found: C, 62.77; H, 5.33; N, 11.16.
General procedure for synthesis of C-5 secondary amine sub-
stituted N-(2-((7-chloroquinolin-4-yl)amino)alkyl)-2-(1,3-dioxoi-
soindolin-2-yl)alkylamides (7a-r): In a microwave reaction vial was
added a solution of C-5 fluoro substituted N-(7-chloroquinolin-4-yl)
Yellow solid; mp 208–209 °C; 1H NMR (400 MHz, DMSO-d6) δ 2.38
(t, J = 7.3 Hz, 2H, eCH2e); 3.20–3.28 (m, 8H, 4x-CH2-); 3.67–3.73 (m,
6H, 3x-CH2-); 6.44 (d, J = 5.6 Hz, 1H, Ar-H); 7.06 (dd, J = 2.3, 8.4 Hz,
1H, Ar-H); 7.16 (d, J = 2.2 Hz, 1H, Ar-H); 7.25 (t, J = 5.1 Hz, 1H, N-H-
7

A. Rani, et al.
BioorganicChemistry88(2019)102912
exchangeable with D2O); 7.36 (dd, J = 2.3, 9.0 Hz, 1H, Ar-H); 7.50 (d,
J = 8.6 Hz, 1H, Ar-H); 7.73 (d, J = 2.3 Hz, 1H, Ar-H); 8.02 (d,
J = 9.0 Hz, 1H, Ar-H); 8.24 (t, J = 5.5 Hz, 1H, N-H-exchangeable with
D2O); 8.35 (d, J = 5.1 Hz, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ
34.7, 34.8, 37.7, 42.8, 47.4, 66.2, 99.0, 108.0, 117.7, 117.8, 119.9,
124.2, 124.5, 124.7, 127.9, 133.8, 134.4, 149.4, 150.4, 152.3, 155.5,
168.0, 168.3, 170.9. HRMS Calcd for C26H26ClN5O4 [M+H]+
508.1707 found 508.1716. Anal Calcd (%): C, 61.48; H, 5.16; N, 13.79;
found: C, 61.55; H, 5.26; N, 13.88.
1H, Ar-H); 6.92 (d, J = 8.7 Hz, 1H, Ar-H); 6.99 (s, 1H, Ar-H), 7.44–7.50
(m, 2H, Ar-H + NH-exchangeable with D2O); 7.59 (d, J = 8.5 Hz, 1H,
Ar-H); 7.78 (s, 1H, Ar-H), 8.18 (t, J = 5.2 Hz, 1H, NH-exchangeable
with D2O); 8.29 (d, J = 9.0 Hz, 1H, Ar-H); 8.39 (d, J = 5.7 Hz, 1H, Ar-
H); 13C NMR (100 MHz, DMSO-d6) δ 12.5, 25.5, 27.1, 38.8, 41.5, 42.5,
44.8, 99.1, 105.2, 114.8, 116.3, 117.7, 124.5, 124.6, 125.4, 127.1,
127.4, 134.2, 135.3, 150.9, 151.6, 152.3, 166.7, 167.9, 168.6 HRMS
Calcd for C27H30ClN5O3 [M+H]+ 508.2071 found 508.2079. Anal
Calcd (%): C, 63.84; H, 5.95; N, 13.79; found: C, 63.72; H, 5.80; N,
13.66.
3.2.23. N-(4-((7-chloroquinolin-4-yl)amino)butyl)-3-(5-morpholino-1,3-
dioxoisoindolin-2-yl)propanamide (7e)
3.2.27. N-(6-((7-chloroquinolin-4-yl)amino)hexyl)-2-(5-(diethylamino)-
1,3-dioxoisoindolin-2-yl)acetamide (7i)
Yellow solid; mp 158–159 °C; 1H NMR (400 MHz, DMSO-d6) δ
1.52–1.57 (m, 2H, eCH2e); 1.61–1.67 (m, 2H, eCH2e); 2.36 (t,
J = 7.1 Hz, 2H, eCH2e); 3.19–3.28 (m, 8H, 4x-CH2-); 3.65–3.71 (m,
6H, 3x-CH2-); 6.42 (d, J = 5.4 Hz, 1H, Ar-H); 7.04 (dd, J = 2.2, 8.7 Hz,
1H, Ar-H); 7.14 (d, J = 2.2 Hz, 1H, Ar-H); 7.23 (t, J = 5.3 Hz, 1H, N-H-
exchangeable with D2O); 7.32 (dd, J = 2.2, 8.9 Hz, 1H, Ar-H); 7.51 (d,
J = 8.7 Hz, 1H, Ar-H); 7.71 (d, J = 2.2 Hz, 1H, Ar-H); 8.01 (d,
J = 9.0 Hz, 1H, Ar-H); 8.25 (t, J = 5.4 Hz, 1H, N-H-exchangeable with
D2O); 8.33 (d, J = 5.2 Hz, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ
25.5, 27.4, 34.6, 34.9, 37.9, 42.9, 47.7, 66.1, 99.1, 108.2, 117.5, 117.9,
119.4, 124.1, 124.6, 124.8, 127.7, 133.6, 134.2, 149.1, 150.2, 152.1,
155.6, 168.1, 168.2, 170.7. HRMS Calcd for C28H30ClN5O4 [M+H]+
536.2020 found 536.2009. Anal Calcd (%): C, 62.74; H, 5.64; N, 13.07;
found: C, 62.87; H, 5.55; N, 13.20.
Yellow solid; mp 158–159 °C; 1H NMR (400 MHz, DMSO-d6) δ 1.12
(t, 6H, 2x-CH3); 1.32–1.44 (m, 6H, 3x-CH2-); 1.63–1.67 (m, 2H,
eCH2e); 3.07–3.10 (m, 2H, eCH2e); 3.25–3.30 (m, 2H, 2x-CH2-);
3.37–3.41 (m, 4H, 2x-CH2-); 4.11 (s, 2H, eCH2e); 6.50 (d, J = 5.4 Hz,
1H, Ar-H); 6.90 (dd, J = 2.2, 8.8 Hz, 1H, Ar-H); 6.98 (d, J = 2.3 Hz, 1H,
Ar-H), 7.43–7.50 (m, 2H, Ar-H + NH-exchangeable with D2O); 7.54 (d,
J = 8.6 Hz, 1H, Ar-H); 7.75 (d J = 2.2 Hz 1H, Ar-H), 8.20 (t,
J = 5.3 Hz, 1H, NH-exchangeable with D2O); 8.27 (d, J = 9.0 Hz, 1H,
Ar-H); 8.37 (d, J = 5.4 Hz, 1H, Ar-H);13C NMR (100 MHz, DMSO-d6) δ
12.4, 26.3, 26.9, 28.2, 29.5, 39.2, 41.3, 42.9, 44.6, 99.2, 105.1, 114.8,
116.3, 117.6, 124.7, 124.9, 125.4, 127.3, 127.7, 134.3, 135.3, 150.8,
151.6, 152.4, 166.6, 167.8, 168.7 HRMS Calcd for C29H34ClN5O3 [M
+H]+ 536.2384 found 536.2371. Anal Calcd (%): C, 64.98; H, 6.39; N,
13.06; found: C, 64.80; H, 6.49; N, 13.18.
3.2.24. N-(6-((7-chloroquinolin-4-yl)amino)hexyl)-3-(5-morpholino-1,3-
dioxoisoindolin-2-yl)propanamide (7f)
3.2.28. N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-3-(5-(diethylamino)-
1,3-dioxoisoindolin-2-yl)propanamide (7j)
Yellow solid; mp 126–127 °C; 1H NMR (400 MHz, DMSO-d6) δ
1.31–1.46 (m, 6H, 3x-CH2-); 1.53–1.56 (m, 2H, eCH2e); 2.35 (t,
J = 7.1 Hz, 2H, eCH2e); 3.05–3.09 (m, 2H, eCH2e); 3.23–3.27 (m,
2H, eCH2e); 3.35–3.39 (m, 4H, 2x-CH2-); 3.66–3.73 (m, 6H, 3x-CH2-);
6.41 (d, J = 5.3 Hz, 1H, Ar-H); 7.03 (dd, J = 2.1, 8.6 Hz, 1H, Ar-H);
7.15 (d, J = 2.1 Hz, 1H, Ar-H); 7.25 (t, J = 5.2 Hz, 1H, N-H-ex-
changeable with D2O); 7.33 (dd, J = 2.0, 8.9 Hz, 1H, Ar-H); 7.53 (d,
J = 8.8 Hz, 1H, Ar-H); 7.73 (d, J = 2.1 Hz, 1H, Ar-H); 8.03 (d,
J = 9.0 Hz, 1H, Ar-H); 8.26 (t, J = 5.3 Hz, 1H, N-H-exchangeable with
D2O); 8.34 (d, J = 5.3 Hz, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ
26.5, 26.9, 28.1, 29.5, 34.6, 38.2, 40.1, 42.8, 47.6, 66.2, 99.2, 108.1,
117.6, 117.8, 119.3, 124.2, 124.7, 124.8, 127.6, 133.7, 134.1, 149.3,
150.1, 152.4, 155.5, 168.1, 168.3, 170.5 HRMS Calcd for C30H34ClN5O4
[M+H]+ 564.2333 found 564.2326. Anal Calcd (%): C, 63.88; H, 6.08;
N, 12.42; found: C, 63.97; H, 6.19; N, 12.33.
Yellow solid; mp 189–190 °C; 1H NMR (400 MHz, DMSO-d6) δ 1.05
(t, J = 7.0 Hz, 6H, 2x-CH3); 2.37 (t, J = 7.3 Hz, 2H, –CH2); 3.22–3.26
(m, 4H, 2x-CH2-); 3.38–3.42 (m, 4H, 2x-CH2-); 3.69 (t, J = 7.3 Hz, 2H,
–CH3); 6.45 (d, J = 5.4 Hz, 1H, Ar-H); 6.76 (dd, J = 2.6, 8.8 Hz, 1H, Ar-
H); 6.85 (d, J = 2.6 Hz, 1H, Ar-H), 7.29 (t, J = 5.2 Hz, 1H, NH-ex-
changeable with D2O); 7.37 (dd, J = 2.2, 9.0 Hz, 1H, Ar-H); 7.44 (d,
J = 8.6 Hz, 1H, Ar-H); 7.73 (d, J = 2.4 Hz 1H, Ar-H), 8.05 (d,
J = 9.0 Hz, 1H, Ar-H); 8.23 (t, J = 5.3 Hz, 1H, NH-exchangeable with
D2O); 8.35 (d, J = 5.0 Hz, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ
12.6, 34.6, 37.7, 41.1, 42.7, 44.8, 99.0, 105.0, 114.6, 116.2, 117.8,
124.3, 124.5, 124.6, 125.2, 127.8, 133.9, 135.0, 149.3, 150.5, 152.2,
168.1, 168.6, 170.9 HRMS Calcd for C26H28ClN5O3 [M+H]+ 494.1914
found 494.1902. Anal Calcd (%): C, 63.22; H, 5.71; N, 14.18; found: C,
63.32; H, 5.66; N, 14.27.
3.2.25. N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-2-(5-(diethylamino)-
1,3-dioxoisoindolin-2-yl)acetamide (7g)
3.2.29. N-(4-((7-chloroquinolin-4-yl)amino)butyl)-3-(5-(diethylamino)-
1,3-dioxoisoindolin-2-yl)propanamide (7k)
Yellow solid; mp 197–198 °C; 1H NMR (400 MHz, DMSO-d6) δ 1.10
(t, 6H, 2x-CH3); 3.22–3.27 (m, 4H, 2x-CH2-); 3.36–3.41 (m, 4H, 2x-
CH2-); 4.11 (s, 2H, eCH2e); 6.52 (d, J = 5.5 Hz, 1H, Ar-H); 6.91 (d,
J = 8.8 Hz, 1H, Ar-H); 6.97 (s, 1H, Ar-H), 7.46–7.50 (m, 2H, Ar-H, NH-
exchangeable with D2O); 7.56 (d, J = 8.6 Hz, 1H, Ar-H); 7.77 (s, 1H,
Ar-H), 8.16 (t, J = 5.2 Hz, 1H, NH-exchangeable with D2O); 8.28 (d,
J = 8.9 Hz, 1H, Ar-H); 8.38 (d, J = 5.6 Hz, 1H, Ar-H); 13C NMR
(100 MHz, DMSO-d6) δ 12.4, 37.6, 40.8, 42.6, 44.7, 99.0, 105.3, 114.7,
116.2, 117.8, 124.4, 124.6, 125.5, 127.2, 127.7, 134.1, 135.5, 150.7,
151.7, 152.2, 166.6, 167.6, 168.9 HRMS Calcd for C25H26ClN5O3 [M
+H]+ 480.1758 found 480.1743. Anal Calcd (%): C, 62.56; H, 5.46; N,
14.59; found: C, 62.65; H, 5.39; N, 14.67.
Yellow solid; mp 161–162 °C; 1H NMR (400 MHz, DMSO-d6) δ 1.04
(t, J = 7.1 Hz, 6H, 2x-CH3); 1.52–1.57 (m, 2H, eCH2e); 1.60–1.67 (m,
2H, eCH2e); 2.35 (t, J = 7.2 Hz, 2H, –CH3); 3.11–3.15 (m, 2H,
eCH2e); 3.25–3.30 (m, 2H, eCH2e); 3.37–3.41 (m, 4H, 2x-CH2-); 3.67
(t, J = 7.2 Hz, 2H, –CH3); 6.43 (d, J = 5.3 Hz, 1H, Ar-H); 6.77 (dd,
J = 2.4, 8.7 Hz, 1H, Ar-H); 6.84 (d, J = 2.4 Hz, 1H, Ar-H), 7.26 (t,
J = 5.4 Hz, 1H, NH-exchangeable with D2O); 7.37 (dd, J = 2.1, 9.0 Hz,
1H, Ar-H); 7.45 (d, J = 8.7 Hz, 1H, Ar-H); 7.75 (d, J = 2.2 Hz 1H, Ar-
H), 8.07 (d, J = 9.0 Hz, 1H, Ar-H); 8.25 (t, J = 5.3 Hz, 1H, NH-ex-
changeable with D2O); 8.36 (d, J = 5.2 Hz, 1H, Ar-H); 13C NMR
(100 MHz, DMSO-d6) δ 12.6, 25.4, 27.5, 34.6, 37.7, 39.7, 42.7, 44.7,
99.1, 105.2, 114.3, 116.1, 117.8, 124.2, 124.5, 124.7, 125.4, 127.9,
133.7, 135.1, 149.3, 150.6, 152.4, 168.1, 168.5, 170.7 HRMS Calcd for
3.2.26. N-(4-((7-chloroquinolin-4-yl)amino)butyl)-2-(5-(diethylamino)-
1,3-dioxoisoindolin-2-yl)acetamide (7h)
C
28H32ClN5O3 [M+H]+ 522.2227 found 522.2239. Anal Calcd (%): C,
64.42; H, 6.18; N, 13.42; found: C, 64.36; H, 6.27; N, 13.39.
Yellow solid; mp 173–174 °C; 1H NMR (400 MHz, DMSO-d6) δ 1.13
(t, 6H, 2x-CH3); 1.50–1.57 (m, 2H, eCH2e); 1.62–1.68 (m, 2H,
eCH2e); 3.10–3.14 (m, 2H, eCH2e); 3.27–3.31 (m, 2H, 2x-CH2-);
3.39–3.43 (m, 4H, 2x-CH2-); 4.10 (s, 2H, eCH2e); 6.51 (d, J = 5.6 Hz,
3.2.30. N-(6-((7-chloroquinolin-4-yl)amino)hexyl)-3-(5-(diethylamino)-
1,3-dioxoisoindolin-2-yl)propanamide (7l)
Yellow solid; mp 142–143 °C; 1H NMR (400 MHz, DMSO-d6) δ 1.08
8

A. Rani, et al.
BioorganicChemistry88(2019)102912
(t, J = 7.3 Hz, 6H, 2x-CH3); 1.35–1.45 (m, 6H, 3x-CH2-); 1.61–1.66 (m,
2H, eCH2e); 2.37 (t, J = 7.2 Hz, 2H, –CH3); 3.10–3.14 (m, 2H,
eCH2e); 3.24–3.30 (m, 2H, eCH2e); 3.36–3.41 (m, 4H, 2x-CH2-); 3.68
(t, J = 7.2 Hz, 2H, –CH3); 6.42 (d, J = 5.2 Hz, 1H, Ar-H); 6.75 (dd,
J = 2.2, 8.6 Hz, 1H, Ar-H); 6.85 (d, J = 2.4 Hz, 1H, Ar-H), 7.26 (t,
J = 5.3 Hz, 1H, NH-exchangeable with D2O); 7.37 (dd, J = 2.0, 9.0 Hz,
1H, Ar-H); 7.47 (d, J = 8.7 Hz, 1H, Ar-H); 7.77 (d, J = 2.2 Hz 1H, Ar-
H), 8.06 (d, J = 9.0 Hz, 1H, Ar-H); 8.26 (t, J = 5.3 Hz, 1H, NH-ex-
changeable with D2O); 8.38 (d, J = 5.2 Hz, 1H, Ar-H); 13C NMR
(100 MHz, DMSO-d6) δ 12.6, 26.4, 26.9, 28.5, 29.8, 34.6, 39.5, 41.1,
42.7, 44.5, 99.1, 105.3, 114.4, 116.1, 117.9, 124.2, 124.6, 124.8,
125.4, 127.8, 133.8, 135.2, 149.4, 150.7, 152.5, 168.1, 168.7, 170.6
HRMS Calcd for C30H36ClN5O3 [M+H]+ 550.2540 found 550.2521.
Anal Calcd (%): C, 65.50; H, 6.60; N, 12.73; found: C, 65.55; H, 6.52; N,
12.65.
26.1, 26.8, 28.1, 29.4, 39.5, 42.9, 47.5, 49.1, 53.5, 59.1, 60.4, 99.0,
108.1, 117.9, 118.1, 119.3, 124.5, 124.8, 125.1, 127.9, 133.7, 134.6,
149.3, 150.6, 152.1, 155.7, 166.6, 167.7, 168.2 HRMS Calcd for
C31H37ClN6O4 [M+H]+ 593.2598 found 593.2604. Anal Calcd (%): C,
62.78; H, 6.29; N, 14.17; found: C, 62.70; H, 6.33; N, 14.24.
3.2.34. N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-3-(5-(4-(2-
hydroxyethyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)propanamide (7p)
Yellow solid; mp 211–212 °C; 1H NMR (500 MHz, DMSO-d6) δ
2.42–2.45 (m, 4H, 2x-CH2-); 2.53 (t, J = 5.1 Hz, 4H, 2x-CH2-);
3.26–3.31 (m, 4H, 2x-CH2-); 3.33–3.35 (m, 4H, 2x-CH2-); 3.52–3.55
(m, 2H, eCH2e); 3.76 (t, J = 7.1 Hz, 2H, eCH2e); 4.47 (s, 1H, OH);
6.49 (d, J = 5.4 Hz, 1H, Ar-H); 7.11 (dd, J = 2.3, 8.5 Hz, 1H, Ar-H);
7.19 (d, J = 2.3 Hz, 1H, Ar-H); 7.28 (t, J = 5.2 Hz, 1H, NH-exchange-
able with D2O); 7.40 (dd, J = 2.2, 9.0 Hz, 1H, Ar-H); 7.53 (d,
J = 8.4 Hz, 1H, Ar-H); 7.77 (d, J = 2.3 Hz, 1H, Ar-H); 8.08 (d,
J = 8.9 Hz, 1H, Ar-H); 8.25 (t, J = 5.4 Hz, 1H, NH-exchangeable with
D2O); 8.39 (d, J = 5.4 Hz, 1H, Ar-H); 13C NMR (125 MHz, DMSO-d6) δ
34.7, 34.8, 37.7, 42.7, 47.2, 53.2, 59.0, 60.5, 99.0, 107.9, 117.7, 117.8,
119.2, 124.2, 124.5, 124.8, 127.9, 133.8, 134.5, 149.4, 150.4, 152.3,
153.3, 168.0, 168.4, 170.9. HRMS Calcd for C28H31ClN6O4 [M+H]+
551.2129 found 551.2141. Anal Calcd (%): C, 61.03; H, 5.67; N, 15.25;
found: C, 61.17; H, 5.78; N, 15.16.
3.2.31. N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-2-(5-(4-(2-
hydroxyethyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)acetamide (7m)
Yellow solid; mp 218–219 °C; 1H NMR (500 MHz, DMSO-d6) δ 2.45
(t, J = 6.1 Hz, 2H, eCH2e); 2.54 (t, J = 4.8 Hz, 4H, 2x-CH2-);
3.11–3.15 (m, 2H, eCH2e); 3.26–3.29 (m, 2H, eCH2e); 3.42 (t,
J = 4.5 Hz, 4H, 2x-CH2-); 3.53 (t, J = 6.1 Hz, 2H, eCH2e); 4.10 (s, 2H,
eCH2e); 4.48 (s, 1H, eOH); 6.47 (d, J = 5.4 Hz, 1H, Ar-H); 7.21 (dd,
J = 1.5, 8.6 Hz, 1H, Ar-H); 7.30 (d, J = 1.4 Hz, 1H, Ar-H); 7.35 (t,
J = 5.6 Hz, 1H, NH-exchangeable with D2O); 7.45 (dd, J = 2.1, 9.0 Hz,
1H, Ar-H); 7.66 (d, J = 8.6 Hz, 1H, Ar-H); 7.78 (d, J = 2.0 Hz, 1H, Ar-
H); 8.18 (t, J = 5.7 Hz, 1H, NH-exchangeable with D2O); 8.29 (d,
J = 9.0 Hz, 1H, Ar-H); 8.39 (d, J = 5.4 Hz, 1H, Ar-H); 13C NMR
(125 MHz, DMSO-d6) δ 38.7, 42.4, 47.5, 49.1, 53.3, 59.1, 60.6, 99.0,
108.1, 117.3, 117.8, 119.4, 124.3, 124.6, 125.1, 127.9, 133.7, 134.7,
149.5, 150.6, 152.2, 155.5, 166.7, 167.8, 168.2 HRMS Calcd for
3.2.35. N-(4-((7-chloroquinolin-4-yl)amino)butyl)-3-(5-(4-(2-
hydroxyethyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)propanamide (7q)
Yellow solid; mp 162–163 °C; 1H NMR (500 MHz, DMSO-d6) δ
1.50–1.55 (m, 2H, eCH2e); 1.62–1.68 (m, 2H, eCH2e); 2.41–2.47 (m,
4H, 2x-CH2-); 2.55 (t, J = 5.0 Hz, 4H, 2x-CH2-); 3.13–3.16 (m, 2H,
eCH2e); 3.27–3.31 (m, 2H, eCH2e); 3.41 (t, J = 4.5 Hz, 4H, 2x-CH2-);
3.54 (t, J = 6.1 Hz, 2H, eCH2e); 3.75 (t, J = 7.1 Hz, 2H, eCH2e); 4.48
(s, 1H, OH); 6.47 (d, J = 5.5 Hz, 1H, Ar-H); 7.10 (dd, J = 2.2, 8.6 Hz,
1H, Ar-H); 7.18 (d, J = 2.2 Hz, 1H, Ar-H); 7.27 (t, J = 5.3 Hz, 1H, NH-
exchangeable with D2O); 7.41 (dd, J = 2.1, 9.0 Hz, 1H, Ar-H); 7.52 (d,
J = 8.5 Hz, 1H, Ar-H); 7.78 (d, J = 2.2 Hz, 1H, Ar-H); 8.05 (d,
J = 9.0 Hz, 1H, Ar-H); 8.27 (t, J = 5.4 Hz, 1H, NH-exchangeable with
D2O); 8.40 (d, J = 5.3 Hz, 1H, Ar-H); 13C NMR (125 MHz, DMSO-d6) δ
25.4, 27.9, 34.6, 37.9, 39.1, 42.7, 47.8, 53.1, 59.1, 60.6, 99.1, 107.8,
117.4, 117.9, 119.1, 124.3, 124.5, 124.9, 127.8, 133.9, 134.6, 149.6,
150.3, 152.5, 153.5, 168.1, 168.7, 170.6. HRMS Calcd for
C
27H29ClN6O4 [M+H]+ 537.1972 found 537.1961. Anal Calcd (%): C,
60.39; H, 5.44; N, 15.65; found: C, 60.49; H, 5.38; N, 15.77.
3.2.32. N-(4-((7-chloroquinolin-4-yl)amino)butyl)-2-(5-(4-(2-
hydroxyethyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)acetamide (7n)
Yellow solid; mp 151–152 °C; 1H NMR (500 MHz, DMSO-d6) δ
1.50–1.55 (m, 2H, eCH2e); 1.62–1.68 (m, 2H, eCH2e); 2.44 (t,
J = 6.1 Hz 2H, eCH2e); 2.55 (t, J = 4.9 Hz, 4H, 2x-CH2-); 3.10–3.14
(m, 2H, eCH2e); 3.25–3.29 (m, 2H, eCH2e); 3.41 (t, J = 4.5 Hz, 4H,
2x-CH2-); 3.54 (t, J = 6.1 Hz, 2H, eCH2e); 4.11 (s, 2H, eCH2e); 4.49
(s, 1H, eOH); 6.48 (d, J = 5.5 Hz, 1H, Ar-H); 7.22 (dd, J = 1.5, 8.5 Hz,
1H, Ar-H); 7.31 (d, J = 1.4 Hz, 1H, Ar-H); 7.34 (t, J = 5.6 Hz, 1H, NH-
exchangeable with D2O); 7.43 (dd, J = 2.2, 9.0 Hz, 1H, Ar-H); 7.65 (d,
J = 8.5 Hz, 1H, Ar-H); 7.77 (d, J = 2.0 Hz, 1H, Ar-H); 8.19 (t,
J = 5.7 Hz, 1H, NH-exchangeable with D2O); 8.27 (d, J = 9.0 Hz, 1H,
Ar-H); 8.38 (d, J = 5.4 Hz, 1H, Ar-H); 13C NMR (125 MHz, DMSO-d6) δ
25.5, 27.1, 38.8, 42.5, 47.3, 49.0, 53.2, 59.0, 60.5, 99.1, 108.2, 117.8,
117.9, 119.4, 124.4, 124.5, 125.0, 127.8, 133.8, 134.7, 149.4, 150.5,
152.2, 155.5, 166.6, 167.8, 168.3 HRMS Calcd for C29H33ClN6O4 [M
+H]+ 565.2285 found 565.2268. Anal Calcd (%): C, 61.64; H, 5.89; N,
14.87; found: C, 61.58; H, 5.79; N, 14.79.
C
30H35ClN6O4 [M+H]+ 579.2442 found 579.2457. Anal Calcd (%): C,
62.22; H, 6.09; N, 14.51; found: C, 62.32; H, 6.19; N, 14.43.
3.2.36. N-(6-((7-chloroquinolin-4-yl)amino)hexyl)-3-(5-(4-(2-
hydroxyethyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)propanamide (7r)
Yellow solid; mp 102–103 °C; 1H NMR (500 MHz, DMSO-d6) δ
1.32–1.44 (m, 6H, 3x-CH2-); 1.63–1.68 (m, 2H, eCH2e); 2.42–2.48 (m,
4H, 2x-CH2-); 2.54 (t, J = 5.0 Hz, 4H, 2x-CH2-); 3.11–3.15 (m, 2H,
eCH2e); 3.24–3.30 (m, 2H, eCH2e); 3.43 (t, J = 4.8 Hz, 4H, 2x-CH2-);
3.57 (t, J = 6.1 Hz, 2H, eCH2e); 3.75 (t, J = 7.1 Hz, 2H, eCH2e); 4.47
(s, 1H, OH); 6.45 (d, J = 5.4 Hz, 1H, Ar-H); 7.09 (dd, J = 2.1, 8.7 Hz,
1H, Ar-H); 7.16 (d, J = 2.1 Hz, 1H, Ar-H); 7.28 (t, J = 5.1 Hz, 1H, NH-
exchangeable with D2O); 7.40 (dd, J = 2.0, 9.0 Hz, 1H, Ar-H); 7.51 (d,
J = 8.4 Hz, 1H, Ar-H); 7.79 (d, J = 2.1 Hz, 1H, Ar-H); 8.07 (d,
J = 9.0 Hz, 1H, Ar-H); 8.29 (t, J = 5.5 Hz, 1H, NH-exchangeable with
D2O); 8.41 (d, J = 5.3 Hz, 1H, Ar-H); 13C NMR (125 MHz, DMSO-d6) δ
26.3, 26.9, 28.4, 29.6, 34.5, 39.7, 42.8, 47.4, 49.3, 53.7, 59.3, 60.6,
99.0, 107.7, 117.5, 117.9, 119.3, 124.4, 124.8, 124.8, 127.9, 133.8,
134.7, 149.5, 150.5, 152.8, 153.8, 168.2, 168.9, 170.5. HRMS Calcd for
3.2.33. N-(6-((7-chloroquinolin-4-yl)amino)hexyl)-2-(5-(4-(2-
hydroxyethyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)acetamide (7o)
Yellow solid; mp 118–119 °C; 1H NMR (500 MHz, DMSO-d6) δ
1.31–1.45 (m, 6H, 3x-CH2-); 1.62–1.67 (m, 2H, eCH2e); 2.46 (t,
J = 6.2 Hz, 2H, eCH2e); 2.54 (t, J = 4.8 Hz, 4H, 2x-CH2-); 3.07–3.11
(m, 2H, eCH2e); 3.20–3.27 (m, 2H, eCH2e); 3.40 (t, J = 4.7 Hz, 4H,
2x-CH2-); 3.55 (t, J = 6.2 Hz, 2H, eCH2e); 4.10 (s, 2H, eCH2e); 4.48
(s, 1H, eOH); 6.47 (d, J = 5.4 Hz, 1H, Ar-H); 7.20 (dd, J = 1.6, 8.6 Hz,
1H, Ar-H); 7.30 (d, J = 1.5 Hz, 1H, Ar-H); 7.34 (t, J = 5.5 Hz, 1H, NH-
exchangeable with D2O); 7.44 (dd, J = 2.1, 9.0 Hz, 1H, Ar-H); 7.64 (d,
J = 8.4 Hz, 1H, Ar-H); 7.75 (d, J = 2.0 Hz, 1H, Ar-H); 8.16 (t,
J = 5.5 Hz, 1H, NH-exchangeable with D2O); 8.25 (d, J = 9.0 Hz, 1H,
Ar-H); 8.36 (d, J = 5.3 Hz, 1H, Ar-H); 13C NMR (125 MHz, DMSO-d6) δ
C
32H39ClN6O4 [M+H]+ 607.2755 found 607.2769. Anal Calcd (%): C,
63.30; H, 6.47; N, 13.84; found: C, 63.21; H, 6.33; N, 13.79.
3.3. Methods for assessment of the antiplasmodial activity of test
compounds
The W2 strain of P. falciparum was cultured in RPMI-1640 medium
9

A. Rani, et al.
BioorganicChemistry88(2019)102912
with 0.5% Albumax I (Gibco) following the standard procedures and
using 5%
Appendix A. Supplementary material
stage, micrDo-wsoerlbl ictuolltutoressywnecrheroinncizuebaptaerdaswitieths. dTiffoeirneinttiactoenactentthreatiroinngs
of the compounds for 48 h. The compounds were added from DMSO
stocks keeping 0.1% as the maximum concentration of DMSO. Controls
lacking inhibitors included 0.1% DMSO. The culture medium was re-
moved after 48 h when control cultures had developed new rings which
were further incubated at RT for 48 h at pH 7.4 with 1% formaldehyde
in PBS. Fixed parasites were then shifted to 0.1% Triton X-100 in PBS
containing 1 nM YOYO-1 dye (Molecular Probes). Using Cell Quest
software (Beckton Dickinson), parasitemia was determined from dot
plots (forward scatter vs. fluorescence) acquired on a FACSort flow
cytometer. The determination of IC50 values for growth inhibition was
done from plots of percent control parasitemia over inhibitor con-
centration with Prism 5.0 program, (GraphPad Software), with data
from duplicate experiments fitted by non-linear regression [23].
Scanned 1H and 13C NMR spectra of few representative compounds
viz. 6a, 6c, 6e, 6i, 6n, 6q, 7a, 7c, 7d, 7j, 7n and 7p are provided in the
electronic supplementary information. Supplementary data to this ar-
ticle can be found online at https://doi.org/10.1016/j.bioorg.2019.04.
006.
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Conflict of interest
The authors have declared no conflict of interest.
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