Iodine mediated pyrazolo-quinoline derivatives as potent anti-proliferative agents

Article abstract of DOI:10.1016/j.bmcl.2018.01.023

A novel series of substituted pyrazolo-quinoline derivatives 7pa–7qg were synthesized efficiently by using molecular iodine in DMSO and further characterized based on ¹H NMR, ¹³C NMR, IR and HRMS spectral studies. All the synthesized

Full text of DOI:10.1016/j.bmcl.2018.01.023

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Iodine mediated pyrazolo-quinoline derivatives as potent
anti-proliferative agents
Suresh Kasaboina a, Venkatesh Ramineni a, Saleha Banu a, Yadagiri Bandi a, Lingaiah Nagarapu a,
,
⇑
Naresh Dumala b, Paramjit Grover b
a Organic Chemistry Division-II (C P C Division), CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India
b Toxicology Unit, Pharmacology and Toxicology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, Telangana, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of substituted pyrazolo-quinoline derivatives 7pa–7qg were synthesized efficiently by
using molecular iodine in DMSO and further characterized based on 1H NMR, 13C NMR, IR and HRMS
spectral studies. All the synthesized derivatives were screened for their in vitro cytotoxic activity against
a panel of five different cancer cell lines such as A549, HeLa, SKNSH, HepG2 and MCF7. The compounds
7pc, 7pd, and 7pj exhibited considerable to promising anti-proliferative activity with IC50 values of 3.76,
3.87 and 3.83 mM against SKNSH cancer cell line. It was revealed that the compounds 7pa and 7pg have
shown very close IC50 values of 2.43 and 6.01 mM, against A549 and MCF7 cancer cell lines respectively,
which compared to positive control of Doxorubicin. This is the first report on the synthesis and in vitro
anti-proliferative evaluation of pyrazolo-quinoline derivatives.
Received 31 October 2017
Revised 2 January 2018
Accepted 15 January 2018
Available online xxxx
Keywords:
Quinoline
Pyrazole
Anti-proliferative agents
Doxorubicin
Ó 2018 Elsevier Ltd. All rights reserved.
Cancer is a fatal disease. It is caused by changes in a cell’s DNA.
Some of these changes may be inherited from our parents (genetic
factors, 5–10%), while others may be caused by outside exposures,
which are often referred to as environmental factors (90–95%).1–3
Nitrogen-containing heterocycles have always played a major role
in the pharmaceutical and agrochemical industries because of their
potent physiological properties which have resulted in numerous
applications.4
Quinoline is a heterocyclic scaffold of paramount importance to
human race. Functionalized quinolines and their hetero-fused ana-
logs represent an important class of organic molecules. Derivatives
of this scaffold have been reported to exhibit various biological
activities, including anti-inflammatory, anticancer, anti-diabetic,
and antipsychotic effects (Fig. 1).5–11
In recent years, pyrazoles have attracted significant scientific
attention due to their special skeleton and various bioactivities
containing anti-inflammatory,12 anti-microbial,13,14 anti-convul-
sant,15 anti-depressant,16 anti-mycobacterial,17 anti-oxidant,18
anti-viral,19 insecticidal,20 and anti-tumor,21 activities. Presence
of this nucleus in multiple pharmacological agents has made it
an indispensible anchor for design and development of new phar-
macological agents.22
number of cellular lines and are employed in anti-cancer drug dis-
covery screening.23 For instance (Fig. 1), pyrrolo-[3,4-c]-pyrazole I
(Danusertib), advanced in phase II clinical trials for the treatment
of Bcr-Abl positive leukaemias, due to good pharmacokinetic prop-
erties along with general safety profiles shown in phase I.24
Keeping in view the potential biological activities of quinolines
and pyrazoles, it was perceived that if both the heterocyclic moi-
eties are synergized in a single nucleus, the new compounds
obtained were likely to possess significant biological activities. Lit-
erature survey informs that pyrazolo[4,3-c]quinolines have been
associated with various biological activities, like anti cancer, selec-
tive cyclooxygenase-2 (COX-2) inhibitors that could reduce pain
and as anti-inflammatory agents.25
In view of biological significance of quinolines and pyrazoles
and in continuation to our ongoing research activities,26 to dis-
cover and develop new anticancer agents, we herein report an effi-
cient method for the synthesis of pyrazolo-quinoline derivatives
(7pa–7qg) using molecular iodine in excellent yields. The synthe-
sized hybrids 7pa–7qg were evaluated for their in vitro anti-prolif-
erative activity against five human cancer cell lines such as A549
(lung), HeLa (cervical), SKNSH (neuroblastoma), HepG2 (hepatocel-
lular) and MCF7 (mammary gland) using a MTT method. Signifi-
cantly, the compounds 7pc, 7pd, and 7pj exhibited considerable
to promising anti-proliferative activity with IC50 values of 3.76,
3.87 and 3.83 mM against SKNSH cancer cell line. It was revealed
that the compounds 7pa and 7pg have shown very close IC50 val-
Of utmost importance, simple and condensed pyrazole deriva-
tives have often shown anti-proliferative activities towards a wide
⇑
Corresponding author.
E-mail address: nagarapu@iict.res.in (L. Nagarapu).
https://doi.org/10.1016/j.bmcl.2018.01.023
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kasaboina S., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.023

2
S. Kasaboina et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
ues of 2.43 and 6.01 mM, against A549 and MCF7 cancer cell lines
respectively (see Fig. 2).
The crucial intermediate 2-(1,3-diphenyl-1H-pyrazol-5-yl)ani-
line (5) was prepared by modifying reported methods as illustrated
in Scheme 1. Compound 327 was obtained by the condensation of
2-nitrobenzaldehyde and acetophenone in the presence of 40%
NaOH and ethanol. Subsequently, cyclized pyrazoles 428 were
achieved with phenyl hydrazine in the presence of iodine in acetic
acid. The NO2 group of the corresponding pyrazoles 4 was reduced
Table 1
A series of pyrazolo-quinoline hybrids (7pa–7qg).
Fig. 1. Biologically active drugs having quinolines and pyrazoles.
Fig. 2. Design strategy for new pyrazole fused quinoline derivatives.
Scheme 1. Synthesis of 2-(1,3-diphenyl-1H-pyrazol-5-yl)aniline. Reagents and
conditions: (i) 40% NaOH, EtOH, rt, 30 min; (ii) phenyl hydrazine, I2, AcOH, reflux,
3 h; (iii) Fe powder, Con.HCl, MeOH, reflux, 3 h.
Scheme 2. Synthesis of pyrazolo-quinoline derivatives (7pa–7qg). Reagents and
conditions: (iv) aldehydes (6a–j), I2, DMSO, 80 °C, 3 h.
Please cite this article in press as: Kasaboina S., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.023

S. Kasaboina et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
Table 2
(IC50/mM) values of the tested compounds against five human cancer cell lines.
Sample Code
IC50 (in mMol)
A549
HeLa
SKNSH
HepG2
MCF7
7pa
7pb
7pc
7pd
7pe
7pf
7pg
7ph
7pi
7pj
7qh
7qb
7qa
7qf
7qg
2.43 0.52
8.45 0.6
8.3 1.26
4.54 1.02
5.54 0.69
3.76 1.31
3.87 0.91
5.54 1.7
5.47 0.35
7.13 1.36
5.99 0.46
5.24 1.25
3.83 0.24
5.24 1.26
5.39 2.08
5.02 1.91
6.65 2.1
26.02 2.43
30.28 1.6
42.79 3.41
19.28 1.2
24.42 1.35
20.67 0.69
180.02 3.92
14.57 2.31
35.02 3.52
30.36 1.32
18.62 1.75
18.78 1.6
32.74 2.1
10.83 1.41
83.89 2.64
6.11 0.96
19.62 1.13
122.78 3.56
10.37 0.62
20.28 1.2
18.37 2.04
38.029 4.06
6.01 0.32
12.31 1.4
42.35 3.45
13.98 0.63
32.63 1.92
15.37 0.98
24.15 0.83
11.12 0.42
77.78 2.41
7.86 0.12
5.29 1.08
11.95 2.4
6.49 1.31
11.78 2.16
9.52 0.95
81.2 5.32
14.33 2.7
23.42 3.41
4.89 0.68
24.62 0.94
7.81 0.52
7.38 1.41
5.62 0.95
5.24 1.06
1.81 0.015
41.14 3.2
15.57 1.23
8.102 0.62
8.79 1.03
5.96 0.71
4.92 0.63
9.34 4.23
8.81 1.12
16.52 1.41
25.76 5.32
56.75 2.1
8.093 0.91
8.17 0.67
0.223 0.031
11.46 2.94
2.42 0.56
Doxorubicin
using iron powder with conc. HCl and methanol at reflux temper-
ature for 3 h, to get the crucial intermediates29 5p (78%) and 5q
(75%) yields respectively which were confirmed by 1H NMR, 13C
NMR, IR and HRMS spectral analysis.
7pc, 7pd & 7pj have shown potent activity with IC50 values of
3.76 mM, 3.87 mM and 3.83 mM against SKNSH cell line respectively.
The biological assessment results against A549 cell line indi-
cated that the analogue 7pa exhibited good anti-proliferative
activity against this particular cell line. When the activities of com-
pounds 7pa and 7qa were compared, the analogue 7pa with bromo
phenyl group incorporated at the 3rd position of pyrazole moiety
contributed promising anti-proliferative activity with 2.43 mM.
The compounds 7pg and 7ph also showed considerable anti-prolif-
erative activities with IC50 values of 5.96 and 4.92 mM respectively,
against this particular cell line.
The compound 7pj bearing furan attached to quinoline ring
showed significant activity of 4.89 mM, against Hela. The com-
pounds 7pa–7qf showed considerable activity against SKNSH
ranging from 3.76 to 7.13 mM respectively, with Doxorubicin IC50
2.42 mM. The compound 7pg exhibited potent anti-cancer activity
among all the tested compounds expressed by the IC50 value of
6.01 mM against MCF7 cancer cell line with Doxorubicin IC50
7.86 mM. This compound could be referred as a lead compound
and it could have a high biological profile more than the reference
compound against MCF7 cancer cell line.
The desired pyrazolo-quinoline derivatives 7pa–7qg were
achieved by condensation of 2-(1,3-diphenyl-1H-pyrazol-5-yl)ani-
line (5) with various aldehydes 6a–j in the presence of molecular
iodine with dimethyl sulfoxide at 80 °C for 3 h in excellent yields
(80–93%) and which were confirmed by 1H NMR, 13C NMR, IR
and HRMS spectral analysis (Scheme 2 and Table 2). The formation
of compound 7pa was evident from the HRMS spectrum with the
appearance of [M+H]+ peak at m/z 490.09101, suggesting the
molecular formula of C29H21N3Br. A singlet observed in the 1H
NMR spectrum at d 6.79 ppm in intermediate 5 was not found in
the final derivatives. The IR spectrum also revealed the absence
of stretching vibrations of the amine group (3345 cmÀ1) (see
Table 1).
The in vitro anti-proliferative activity of the targeted com-
pounds 7pa–7qg with human cancer cell lines such as A549, HeLa,
SKNSH, HepG2 and MCF7 summarized in Table 2. Based on Table 2,
the synthesized compounds 7pa–7qg showed moderate to signifi-
cant activity30 with IC50 values ranging from 2.43 to 180.02 mM.
The effect of various substituent’s attached to 1H-pyrazolo[4,3-c]
quinoline 7 was examined. In particular, the compounds 7pa &
7ph showed promising anti-proliferative activity with IC50 values
of 2.43 mM and 4.92 mM against A549 cell lines. The compounds
Moreover we noticed that there was a significant change in
their activities due to the changes in position of the substitutions
on the phenyl ring attached to quinoline and have influenced the
potency of anti-proliferative activities against all the five cancer
cell lines (Table 2).
Plausible mechanism
Ph
N
Ph
Ph
Ph
N
O
N
N
N
N
N
N
Ph
+
Ph
Ph
I2 DM
/ SO
H
NH2
-
H+
+
+
H
/
Ph
N
N
N
N
Ph
Ph
x
n
a o
id ti
O
[
]
I2 DM
/
SO
N
H
N
Please cite this article in press as: Kasaboina S., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.01.023

4
S. Kasaboina et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
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