Synthesis of novel fluorophenylpyrazole-picolinamide derivatives and determination of their anticancer activity

Article abstract of DOI:10.1080/00397911.2020.1791341

A series of fluorophenylpyrazole-picolinamide derivatives were synthesized in high yields using a cross-coupling reaction catalyzed by in situ formed palladium-N-heterocyclic carbenes (Pd-NHCs). The synthesized novel derivatives were evaluated for in vitro anticancer activity against a panel of four human tumor cell lines, HeLa (cervical), A-549 (lung), MCF-7 (breast), and IMR-32 (neuroblastoma). Four compounds, 11c, 11e, 11j, and 11k, showed growth inhibition (low μM) comparable with the standard drug cisplatin, providing a preliminary structure–activity relationship for the series. The present procedure is operationally simple and works with a wide range of substrates and may thus be useful in further compound optimization.

Full text of DOI:10.1080/00397911.2020.1791341

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis of novel fluorophenylpyrazole-
picolinamide derivatives and determination of
their anticancer activity
Shravankumar Kankala , Koteshwar Rao Rama , Chekrapani Kesari , Fredrik
Björkling , Srinivas Nerella , Prasad Gundepaka , Hanmanthu Guguloth &
Niranjan Thota
To cite this article: Shravankumar Kankala , Koteshwar Rao Rama , Chekrapani Kesari , Fredrik
Björkling , Srinivas Nerella , Prasad Gundepaka , Hanmanthu Guguloth & Niranjan Thota (2020):
Synthesis of novel fluorophenylpyrazole-picolinamide derivatives and determination of their
anticancer activity, Synthetic Communications, DOI: 10.1080/00397911.2020.1791341
To link to this article: https://doi.org/10.1080/00397911.2020.1791341
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1791341
Synthesis of novel fluorophenylpyrazole-picolinamide
derivatives and determination of their anticancer activity
Shravankumar Kankalaa , Koteshwar Rao Ramab, Chekrapani Kesarib,
c
a
, Prasad Gundepakad, Hanmanthu Gugulotha,
€
Fredrik Bjorkling , Srinivas Nerella
and Niranjan Thotac
b
aDepartment of Chemistry, Kakatiya University, Warangal, Telangana, India; Department of Chemistry,
c
Mewar University, Chittorgarh, Rajasthan, India; Department of Drug Design and Pharmacology,
d
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Centre for
Pharmaceutical Science, Institute of Science and Technology, JNTU, Hyderabad, India
ABSTRACT
ARTICLE HISTORY
Received 19 January 2020
A series of fluorophenylpyrazole-picolinamide derivatives were syn-
thesized in high yields using a cross-coupling reaction catalyzed by
in situ formed palladium-N-heterocyclic carbenes (Pd-NHCs). The syn-
thesized novel derivatives were evaluated for in vitro anticancer
activity against a panel of four human tumor cell lines, HeLa (cer-
vical), A-549 (lung), MCF-7 (breast), and IMR-32 (neuroblastoma).
Four compounds, 11c, 11e, 11j, and 11k, showed growth inhibition
(low mM) comparable with the standard drug cisplatin, providing a
preliminary structure–activity relationship for the series. The present
procedure is operationally simple and works with a wide range of
substrates and may thus be useful in further compound
optimization.
KEYWORDS
Fluorophenylpyrazole-picoli-
namide; cross-coupling;
palladium-N-heterocyclic
carbenes; anticancer activity
GRAPHICAL ABSTRACT
N
N
Cl
N
N
R
R
B O
F
O
H
N
N
N
N
F
F
NHC Precursor
R
HN
I
CN
Pd(OAc)2,NEt3,
ACN/Water, reflux 4h
F
F
F
O
N
N
11a-k
N
CN
11 examples including aliphatic and aromatic amines with good to excellent yields.
Introduction
Cancer is among the leading causes of human deaths worldwide, with ꢀ9.5 million
deaths in 2018. This very serious and potentially life-threatening illness is a heavy bur-
den for the individual patients but also for the health care system and society as a
whole. Thus, a constant search for new drugs and improved treatment modalities are
needed. Cancer is a highly complex set of diseases; some forms are today efficiently
CONTACT Shravankumar Kankala
Warangal, Telangana, India; Niranjan Thota
shravankankala@yahoo.com
Department of Chemistry, Kakatiya University,
Department of Drug Design and
thotaniranjan1@gmail.com
Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

2
S. KANKALA ET AL.
Figure 1. Some representative examples of active pharmaceutical ingredients containing a pyra-
zole group.
treated, such as testicular cancer, while others only have very limited treatment options,
in particular in their advanced stages. There are several common hallmarks of cancer
including sustained proliferative signaling, unlimited replicative potential, and activation
of invasion and metastasis some of which may serve as therapeutic targets.[1]
In this article, we describe the synthesis and assessment of anticancer activity of a
novel series of fluorophenylpyrazole-picolinamide derivatives. N, O, and S-hetero-
cycles are structural units present in many drugs covering most therapeutic areas.[2]
Among them the pyrazole group have been extensively used as scaffold for drug
compounds (Figure 1).[3] For example, pyrazole containing derivatives have been
found to posess potent anticancer activity by the inhibition of the cyclin-dependent
kinases (CDKs).[4] Thus, an efficient synthesis of these is most desired. Previously
we have reported the synthesis of isoxazole-indole,[5] and isoxazole-mercaptobenzimi-
dazole,[6] derivatives, providing compounds with a combined anti-inflammatory and
analgesic activity.
The combination of pyridine amides and pyrazole unit in one structure have been
shown to provide synergistic effect in drug action and tunable structure–activity rela-
tionship (SAR). Recenlty researchers from Pfizer Inc, USA reported that pyrazole-
pyridine derivatives provide potent inhibitors of Casein kinase 1 (CK1).[7] Inspired by
this and in continuation of our research work in the fields of (i) N-heterocyclic carbene
complexes (NHCs),[5,8] (ii) natural product based hybrid compounds,[9–11] and (iii) anti-
cancer hybrid compounds[12–14] herein we report, a facile synthesis of new series of pyr-
azole-picolinamide derivatives, which to our knowledge have not previously been
synthesized.
Compounds were designed and prepared through the combination of primary amines
(aliphatic and aromatic), and fluorophenylpyrazole-picolinic acid. The straight forward

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SYNTHETIC COMMUNICATIONSV
3
Scheme 1. Synthesis of Pyrazole-boran ester 6. Reagents and conditions: (a) DMFDMA, DMF, 100 ꢁC,
22 h, yield (87%); (b) Hydrazine, aq. EtOH, 12 h, RT, yield (64%); (c) CH3I, Cs2CO3, DMF, 4 h, RT, yield
(82%); (d) NBS, DCM, 4 h, RT, yield (85%); (e) Isopropoxyboronic acid pinacol ester, n-BuLi, THF,
ꢂ78 ꢁC, 1 h, yield (60%).
synthesis was accomplished by Suziki cross-coupling of readily obtained starting materi-
als using in situ formed palladium-N-heterocyclic carbenes (Pd-NHCs). The prepared
compounds were assessed in vitro for anticancer activity.
Results and discussion
The fluorophenylpyrazole-boran ester 6 and 3-fluoro-4-iodopicolinonitrile (7) are key
intermediates for the preparation of fluorophenylpyrazole-picolinic acid 9. The synthesis
of target intermediate pyrazole-boran ester 6 was prepared in five-steps in good yields
(Scheme 1).[15,16] Synthesis started with the condensation of 4-fluoroacetopheneone (1)
with N,N-dimethylformamide dimethyl acetal (DMF-DMA) to afford corresponding
enaminone 2. Further, enaminone 2 was treated with hydrazine to yield 4-fluorophenyl-
pyrazole (3). Then, the pyrazole compound 3 was N-alkylated using methyl iodide in
the presence of cesium carbonate to furnish compound 4 followed by aromatic bromi-
nation using NBS in DCM to afford the brominated compound 5. In the last step the
Pyrazole-boran ester 6 was formed from 5 using isopropoxyboronic acid pinacol ester
in the presence of butyllithium.
4-Fluorophenylpyrazole-picolinic acid (9) was coupled to primary amines (10a–k) to
obtain fluorophenylpyrazole-picolinamide compounds (11a–k). The carboxylic acid fluo-
rophenylpyrazole-picolinic acid (9) was obtained in a two-step synthesis (Scheme 2).
In the first step, the fluorophenylpyrazole-cyanopyridine (8) was obtained by Suziki
cross-coupling of fluorophenylpyazole-boran ester (6) with 3-fluoro-4-iodo-cyanopyri-
dine (7) using a catalytic system consisting of 1:2 Pd(OAc)2 þ Im-Cl, and slightly excess
of base (Et3N).
Initially the homogeneous Pd(II)-catalyzed Suziki-coupling between fluorophenylpya-
zole-boran ester (6) and 3-fluoro-4-iodo-cyanopyridine (7) was investigated as a model
reaction using four different sets of catalytic conditions (Table 1, entries 1–4). These
experiments were set to assess the influence of N-heterocyclic carbene (NHC) ligand

4
S. KANKALA ET AL.
Scheme 2. Synthesis of fluorophenylpyrazole-picolinic acid 9. Reagents and conditions: (a) 1,3-
Bis(2,4,6-trimesitylphenyl)imidazolium chloride, Pd(OAc)2, Triethylamine, ACN/H2O (7:3), TBAB, Reflux,
4 h yield (96%); (b) aq.KOH, Reflux, 16 h yield (85%).
Table 1. Optimization of reaction condition for the Pd-NHC-catalyzed suziki cross couplinga.
Entry
Catalyst
Base
Reaction time (h)
Yield (%)b
1
2
3
4
5
6
7
8
Pd(OAc)2
PdCl2
Pd(OAc)2/Im-Cl
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Cs2CO3
NaOAc
K2CO3
14
16
6
6
4
4
12
5
4
4
43
52
82
79
96
88
40
90
92
88
PdCl2/Im-Cl
Pd(OAc)2/Im-Cl/TBAB
PdCl2/Im-Cl/TBAB
PdCl2/TBAB
Pd(OAc)2/Im-Cl/TBAB
Pd(OAc)2/Im-Cl/TBAB
Pd(OAc)2/Im-Cl/TBAB
9
10
aAll products were characterized 1H/13C NMR and mass spectral analysis.
bGC yields.
Figure 2. NHC precursor investigated in this work.
(Figure 2), phase transfer catalyst (PTC (TBAB ¼ Tetra-n-butylammonium bromide))
and the influence of the base in accelerating the Suziki coupling reaction. For prepar-
ation of compound 8 (Table 1).
As a further improvement, addition of a TBAB produced a maximum 96% yield in
short reaction time of ꢀ4 h with the combination of Pd(OAc)2 þ NHC ligand precursor

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Scheme 3. Synthesis of pyrazole-picolinamides 11a–k. Reagents and conditions: (a) EDCl, HOBt,
DIPEA, DMF, 6 h, RT.
(1,3-Bis(2,4,6-trimesitylphenyl)imidazolium chloride) þ Et3N (Table 1, entry 5).
Replacement of Pd(OAc)2 by PdCl2, did not improve the yield of 8 (Table 1, entry 6).
In this transformation, no Pd-black was observed. The role of a PTC to form and stabil-
ize the metal nanoparticles including PdNPs is previously described.[17,18]
Overall the Pd(II)/NHC/PTC/Et3N catalytic system provided better yields (Table 1,
entry 5) than those without NHC ligand. The effect of PTC was by self, not significant
(Table 1, entry 7). Furthermore, an exchange of base to Cs2CO3, NaOAc, or K2CO3
from Et3N did not improve the yield of 8 (Table 1, entries 8–10). This system proved
to be more efficient for the Suziki coupling of 6 with 7 than ligand-free Pd(II).
Compound 8 was then converted into the fluorophenylpyrazole-picolinic acid (9)
intermediate by alkali hydrolysis (aq. KOH) (Scheme 2). Thereafter, compound 9 was
subjected to amide coupling with primary amines 10a–k in the presence of ehtyl(dime-
thylaminopropyl)carbodiimide (EDCl), hydroxybenzatriazole (HOBt) and diisopropyle-
thylamine (DIPEA) as coupling reagents to afford pure pyrazole-picolinamide 11a-k in
high yields (Scheme 3).
The synthesized fluorophenylpyrazole-picolinamide (11a–k) compounds were charac-
1
terized by H/13C NMR, mass spectroscopy and elemental analysis.

6
S. KANKALA ET AL.
Table 2. In vitro cytotoxic activity of Pyrazole-picolinamide hybrids (11a–k) on human cancer cell
linesa (IC50 mM/mL)b.
Entry
Compound
HeLa
A549
MCF-7
IMR-32
1
2
3
4
5
6
7
8
11a
11b
11c
11d
11e
11f
11g
11h
11i
10.43 0.21
8.62 0.021
4.25 0.55
10.74 0.41
4.88 0.01
22.42 0.12
8.92 0.01
22.58 0.24
18.59 0.11
5.60 0.07
4.62 0.18
25.15 0.22
4.98 0.21
11.22 0.04
10.04 0.02
3.44 0.01
10.21 0.07
4.01 0.26
24.31 0.06
12.38 0.22
24.82 0.22
26.01 0.14
3.89 0.24
3.62 0.12
28.04 0.001
3.55 0.007
1.72 0.04
1.35 0.002
2.63 0.016
1.88 0.004
2.89 0.002
4.10 0.018
1.55 0.003
3.82 0.022
5.42 0.001
3.43 0.07
2.06 0.04
15.26 0.12
1.56 0.005
20.56 0.01
18.58 0.19
8.99 0.38
20.68 0.26
13.22 0.21
56.24 0.65
20.74 0.71
52.17 0.12
54.01 0.22
11.87 0.10
9.26 0.05
66.41 0.11
9.23 1.21
9
10
11
12
13
11j
11k
9
Cisplatin
aData represent mean values SEM. Cytotoxicity as IC50 for each cell line, is the concentration of compound which
reduced by 50% the optical density of treated cell with respect to untreated cells using the MTT assay.
bData represent as mean SEM values of these independent determinations.
Biological studies: antiproliferative activity
Many pyrazole containing molecules have shown biological activity toward several drug
targets in the past (Figure 1). However, pyrazole-picolinamides have not been synthe-
sized and studied. The new compounds 11a–k were investigated for their anticancer
activity in human cancer cell lines in comparison with the standard drug cisplatin. The
cell lines used were (i) HeLa (cervical), (ii) A-549 (Lung), (iii) MCF-7 (Breast) and (iv)
IMR-32 (neuroblastoma). The cytotoxic activity (IC50) were determined in vitro using a
MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay as previ-
ously reported.[19]
The IC50 values presented in Table 2 indicate that all the 11 fluorophenylpyrazole-pico-
linamide hybrids (11a–k) possess growth inhibitory activity against all the four human
cancer cell lines tested with activities comparable to cisplatin. In particular, some of the
compounds (11c, 11e, 11j, and 11k) were slightly more potent than cisplatin against
the HeLa (cervical), A-549 (Lung) and IMR-32 (neuroblastoma) cell lines. In respect to
the structure–activity relationship, for this set of compounds only limited conclusions can
be made. In comparison with starting compound 9 all new derivatives showed a increased
antiproliferative activity. This suggests an improved drug–target interaction. Since the
drug target is not known, further conclusions regarding stereochemical or electronic
properties needed to obtain improved activity will only be speculative.
However, the synthetic options for modification of the most potent compounds are
vast, which could lead to further amplification of the cytotoxic activity. As discussed
above, compounds 11c, 11e, 11j, and 11k with F-aryl substituent on amide linker
showed the highest antiproliferative activity (Table 2, entries 3, 5, 10, and 11) particu-
larly against the four cancer cell lines (HeLa, A-549, MCF-7, and IMR-32). However, in
the case of breast cancer cell line MCF-7 the cytotoxic activity of 11c was less than cis-
platin (Entry 3). Compound 11k, with a ꢂ2-Br-4-F-C6H4 substituent (Entry 11), was
also more active than cisplatin in all the cell lines except the MCF-7.
Compounds 11f, 11h, and 11i (entries 6, 8, and 9) with a simple cyclohexyl/phenyl
substituent (i.e. without heteroatom substituent) on amide linkers showed moderate

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SYNTHETIC COMMUNICATIONSV
7
inhibitory activity against all the cell lines. These findings may guide further modifica-
tions with respect to cancer cell selectivety and potency.
Experimental
General
All chemicals or reagents were purchased from standard commercial suppliers and
treated with standard methods before use. Solvents were dried and deoxygenated by
heating at reflux and storing over sodium. The reactions were monitored by thin layer
chromatography (TLC) on pre-coated silica GF254 plates. Melting points were deter-
1
mined on a XT4MP apparatus (Taike Corp., Beijing, China), and are uncorrected. H
and 13C NMR spectra were obtained with a Bruker MHz spectra were recorded on a
Brucker 400 NMR (for 1H), 100 NMR (for 13C) spectrometer with DMSO-d6 and
CDCl3 as the solvent.
General procedure for the synthesis of compound (9)
4-Fluorophenylpyazole-boran ester (6) (1 mmol), 3-fluoro-4-iodopicolinonitrile (7)
(1 mmol), Pd(OAc)2 (0.25 mmol%), NHC-precursor (0.5 mmol%), Triethylamine
(2 mmol) and TBAB were suspended in acetonitrile and water (7:3). The mixture was
stirred at 80 ꢁC for 4 h under inert atmosphere. After the reaction, aqueous-ACN was
removed in a rotavapor and the residue was extracted with cold ether (5 ꢃ 15 ml). The
combined ether layers were washed with brine, dried (anhydrous Na2SO4) and evaporated
under reduced pressure to afford a crude product which was subjected to column chroma-
tography (silica gel, 60–120 mesh, eluent; n-hexane/EtOAc, 8:2 gradient) to afford pure
nitrile compound (8). Further subjected to hydrolysis by using 10% KOH solution and
then refluxed for 16 h, at which point it cleared and TLC analysis indicated complete con-
sumption of the compound 8. The reaction mixture was neutralized with acetic acid and
cooled in ice, and the precipitate was collected by filtration. After being washed with cold
water (2 ꢃ 25 mL), the precipitate was dried under vacuum to afford a pure product (9).
General procedure for the synthesis of title compounds (11a–k)
4-fluorophenylpyrazole-picolinic acid (9), amine (10a–k) (1 eq), EDCl (1.1 eq), HOBt
(1.1 eq) and DIPEA (2.5 eq) were suspended in DMF. The reaction mixture was stirred
at room temperature for 6 h. After completion of the reaction added water and
extracted with ethylacetate. The combined organic layers were washed with brine, dried
(anhydrous Na2SO4) and evaporated under reduced pressure to afford a crude product
which was subjected to column chromatography (silica gel, 60–120 mesh, eluent;
n-hexane/EtOAc, 8:2 gradient) to afford pure title compounds (11a–k).
Spectral data of the compounds 8, 9, and 11a
3-Fluoro-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)picolinonitrile (8)
1
Tan yellow solid: mp 124–126 ꢁC; H NMR (400 MHz, CDCl3): d 4.03 (s, 3H), 7.06–7.10
(t, 2H), 7.26–7.29 (t, 1H), 7.38–7.42 (m, 2H), 7.85–7.86 (d, 1H), 8.27–8.28 (d, 1H) ppm.

8
S. KANKALA ET AL.
13C NMR (100 MHz, CDCl3): 39.31, 108.64, 113.13, 115.91, 123.24, 127.38, 128.40,
130.10, 130.67, 132.73, 146.49, 149.49, 156.77, 159.44, 161.60, 164.07 ppm. MS (ESI), m/
z ¼ 297.094 [M þ H]þ. EA calcd (%) for C16H10F2N4 (296.087): calcd. C 64.86, H 3.40,
N 18.91; found. C 64.82, H 3.36, N 18.87.
3-Fluoro-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)picolinic acid (9)
1
Yellow solid: mp 130–131 ꢁC; H NMR (400 MHz, DMSO-d6): d 3.95 (s, 3H), 7.18–7.25
(t, 2H), 7.39–7.49 (m, 3H), 8.18–8.19 (d, 1H), 8.36–8.38 (d, 1H), 13.53 (bs, 1H) ppm.
13C NMR (100 MHz, DMSO-d6): 109.41, 115.64, 127.69, 129.55, 130.73, 133.49, 138.91,
144.98, 147.84, 153.42, 156.06, 160.66, 163.10, 164.47 ppm. MS (ESI), m/z ¼ 316.089
[M þ H]þ. EA calcd (%) for C16H11F2N3O2 (315.082): calcd. C 60.95, H 3.52, N 13.33;
found. C 60.91, H 3.48, N 13.29.
N-(1-(cyclohex-1-en-1-ylmethyl)piperidin-4-yl)-3-fluoro-4-(3-(4-fluorophenyl)-1-
methyl-1H-pyrazol-4-yl)picolinamide (11a)
1
Yellow solid: mp 182–184 ꢁC; H NMR (400 MHz, DMSO-d6): d 1.53–1.58 (m, 5H),
1.91–2.19 (m, 9H), 2.89–3.35 (m, 3H), 4.18–4.22 (s, 3H), 5.84 (s, 1H), 7.18–7.22 (m,
2H), 7.29–7.51 (m, 4H), 8.19 (s, 1H), 8.32–8.33 (d, 1H), 8.72 (s, 1H), 9.70–10.9 (br s,
1H) ppm. 13C NMR (100 MHz, DMSO-d6): 21.90, 22.48, 25.26, 27.55, 109.94, 115.89,
116.11, 127.45, 129.90, 130.01, 130.08, 131.07, 131.20, 133.98, 141.59, 144.69, 148.29,
153.19, 155.83, 161.14, 162.97, 163.57 ppm. MS (ESI), m/z ¼ 492.256 [M þ H]þ. EA calcd
(%) for C28H31F2N5O (491.250): calcd. C 68.41, H 6.36, N 14.25; found. C 68.38, H
6.32, N 14.21.
Conclusions
In conclusion, a facile and simple catalytic method for the synthesis of fluorophenylpyr-
azole-picolinamide derivatives in high yields was developed using a cross-coupling reac-
tion catalyzed by palladium-N-heterocyclic carbenes (Pd-NHCs). The proposed method
represents a cost-effective, eco-friendly, and practical/scalable process for synthesis of
fluorophenylpyrazole-picolinamide. The conditions applied and the results obtained in
our work for the synthesis of pyrazole-picolinamides which is believed to be an
improvement to other reported procedures. Pyrazole-picolinamide derivatives were eval-
uated for in vitro anticancer activity against a panel of four human tumor cell lines, i.e.
HeLa (cervical), A-549 (Lung), MCF-7 (Breast) and IMR-32 (neuroblastoma), and fea-
tures important for the structure-activity relationship (SAR) demonstrated. The deriva-
tives with an electron-withdrawing group, i.e. F- & NO2-aryl substituent displayed
higher activity than the compounds containing electron-donating groups, i.e. CH3- and
aliphatic/aromatic N-heterocycle and without heteroatom substituents. The compounds
11c, 11e, 11j, and 11k with F-aryl substituent on amide linker showed the highest anti-
proliferative activity which compared well with the standard drug cisplatin.

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SYNTHETIC COMMUNICATIONSV
9
The broad spectrum of anticancer activity displayed by these pyrazole-picolinamides
provide a valuable starting point for further optimization and biological studies in vitro
and in vivo.
Experimental procedures, Spectral data of compounds 9 and 11a–k. Supplementary
data associated with this article can be found, in the online version.
Acknowledgments
Dr. S. Kankala is thankful to CSIR, New Delhi for the award of Research Associate.
Disclosure statement
No potential conflict of interest was reported by the author(s).
ORCID
Shravankumar Kankala
http://orcid.org/0000-0002-1398-7620
Srinivas Nerella
http://orcid.org/0000-0003-3750-8206
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