Synthesis and characterization of some novel aryl and heteroaryl chalcone derivatives of 3-(3,4,5-trimethoxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde for assessing their potentials as anticancer agents

Article abstract of DOI:10.1134/S1070363217090225

In the present study, a novel series of nine derivatives of 1-phenyl-3-(3,4,5-trimethoxyphenyl)-1H-pyrazole substituted chalcones 6a–6i were synthesized with an aim to assess their anticancer activities. The chalcone derivatives were synthesized by the Cl

Full text of DOI:10.1134/S1070363217090225

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ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 9, pp. 2056–2066. © Pleiades Publishing, Ltd., 2017.
Synthesis and Characterization of Some Novel Aryl
and Heteroaryl Chalcone Derivatives of
3-(3,4,5-Trimethoxyphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde
for Assessing Their Potentials as Anticancer Agents1
Ch. Krishna Prasada,b* and P. V. S. Machirajuc
a Department of Chemistry, Jawaharlal Nehru Technological University, Kakinada, A.P., 533003 India
b Escientia Bio Pharma Pvt Ltd, ICICI Knowledge Park, Shameerpet, Turkapalli Village, Hyderabad, Telangana, 500078 India
c Department of Chemistry, Pragati Engineering College, Surampalem, A.P., 533437 India
*e-mail: drpvsm.res@gmail.com
Received May 22, 2017
Abstract—In the present study, a novel series of nine derivatives of 1-phenyl-3-(3,4,5-trimethoxyphenyl)-1H-
pyrazole substituted chalcones 6a–6i were synthesized with an aim to assess their anticancer activities. The
chalcone derivatives were synthesized by the Claisen condensation of 1-phenyl-3-(3,4,5-trimethoxyphenyl)-1H-
pyrazole-4-carbaldehyde 4 with various aryl and heteroaryl acetophenones 5a–5i by treatment with alcoholic
sodium hydroxide in methanol at reflux temperature in good to excellent yields. The newly synthesized
derivatives were well characterized by IR, NMR, and HRMS spectroscopic techniques. The title compounds
were evaluated for in vitro antibacterial activity against a panel of gram-positive and gram-negative bacteria
and screened for anticancer activity employing EGFR lung protein based on in silico molecular docking
studies. The study results showed IC50 value ranging between 39–94 μg/mL compared to the standard
Camptothecin with an IC50 value of 47 μg/mL which indicates the anticancer potential of the majority of the
synthesized compounds.
Keywords: chalcone, pyrazole, antibacterial, anticancer, molecular docking
DOI: 10.1134/S1070363217090225
INTRODUCTION
activity through inhibition of various targets such as
epidermal growth factor (EGF), tumor growth factor
(TGF), fibroblast growth factor (FGF), telomerase and
different kinases that are significant for the manage-
ment of cancer [8–10]. Substituted pyrazole derivatives
play essential role in biologically active compounds
and are known to possess drug like properties (Fig. 1).
Important biological activities were reported for some
substituted pyrazoles and their derivatives, including
antibacterial, antifungal, antitumor, analgesic, anti-
pyretic, anti-inflammatory, antioxidant and anticancer
activities [11–14]. Trimethoxy substituted pyrazoles
(Fig. 2) also exhibit different pharmacological acti-
vities like anticancer [7, 15], antiproliferative, anti-
tubulin [16] and antimicrobial [17].
Chalcones have attracted close attention due to their
synthetic and biological applications. Chalcones are
important starting materials for the synthesis of various
heterocyclic derivatives and possess diverse
pharmacological activities such as anticancer [1], anti-
HIV [2], antituberculosis [3], antiinflammatory [4],
and anti-microbial [5] activities. The Claisen–Schmidt
condensation between arylmethylketone and aryl
aldehyde in the presence of alcoholic alkali was the
most convenient method for the synthesis of chalcones
[6] and the reactive α,β-unsaturated keto group is
responsible for their biological activity. Pyrazole
containing molecules are known to possess various
biological activities, excellent drug-like properties
(Fig. 1) and high oral bioavailability [7]. Some
pyrazole derivatives are known to exhibit anticancer
Keeping in mind various pharmacological activities
of pyrazole and chalcone motif, the authors designed
and synthesised a series of nine novel 1-phenyl-3-
(3,4,5-trimethoxyphenyl)-1H-pyrazole substituted aryl
1 The text was submitted by the authors in English.
2056

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SYNTHESIS AND CHARACTERIZATION OF SOME NOVEL ARYL
2057
NH2
N
O S O
H
N
N
N
N
N
O
O
N
N
N
N
N
N
O
N
F
F
F
Difenamizole
Epirizole
Celecoxib
Fezolamine
OH
H2N
NH
N
HO
N
N
N
O
O
O
O
HOOC
N
HO
N
OH
Cl
Isolan
Lonazolac
O
Pyrazofurin
Cl
N
HN
NH
Cl
HO
O
NH2
Cl
N
N
O
N
O
N
N
Cl
N
NH
N
N
Rimonabant
Tepoxalin
Zoniporide
Fig. 1. Drugs containing pyrazole moiety.
and heteroaryl chalcones 6a–6i for evaluation of their
antibacterial and anticancer activities.
acetophenone 1 was treated with phenyl hydrazine 2 in
the presence of acetic acid and methanol. Refluxing for
3h led to the acetophenone phenylhydrazone derivative
3 in 96% yield. In the second step the intermediate 3
was treated with Vilsmeier–Haack reagent (DMF–
POCl3) at –10°C to room temperature for 1.5 h to
afford 1-phenyl-3-(3,4,5-trimethoxyphenyl)-1H-pyrazole
carboxaldehyde 4. The obtained aldehyde 4 underwent
the Claisen–Schmidt reaction with various aryl and
heteroaryl substituted acetophenones 5a–5i in the
RESULTS AND DISCUSSION
The synthetic approach to compounds 6a–6i
(Scheme 1) involved easily accessible 1-phenyl-3-
(3,4,5-trimethoxyphenyl)-1H-pyrazole carboxaldehyde
4 and was based on the reported earlier procedure [18].
In the first step of the reaction 3,4,5-trimethoxy
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017

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2058
KRISHNA PRASAD, MACHIRAJU
O
O
O
O
O
O
O
N
O
N
N
O
NH
N
N
O
N
N
OH
a
b
Anticancer
O
O
NH2
O
S
N
N
O
O
N
O
N
N
H
N
H3C
N
O
O
c
d
Antiproliferative and
antitubulin activity
Antimicrobial
Fig. 2. Trimethoxy substituted pyrazoles possessing various biological activities.
presence of alcoholic alkali to afford the title com-
pounds 6a–6i in 62–85% yield.
strains E. coli, S. aureus, and bacillus and all other
compounds showed no activity. Compounds 6b, 6h
demonstrated lower activity against gram negative
bacteria E. coli and all other compounds were
determined to be inactive (Table 1).
The structures of newly synthesized compounds
6a–6i were characterized by IR, 1H, and 13C NMR, and
HRMS spectral analysis.
Cytotoxic activity. Compounds 6a–6i were screened
for their in vitro cytotoxic potential against human
lung carcinoma (A549) cell line using the MTT assay
(Table 2). The product 6c demonstrated the highest
potential among all synthesised compounds at micro-
molar concentration. It was evident that the com-
pounds containing 3,4,5-trimethoxy phenyl 6c, phenyl
6a, benzimidazole 7, and 3-pyridyl 6d substituted
chalcone derivatives exhibited pronounced anticancer
activity.
Biological evaluation. Antibacterial activity.
Chalcone derivatives 6a–6i were screened for their
antibacterial activity (zone of inhibition) against
Escherichia coli (MTCC 2692), Pseudomonas
aeruginosa (MTCC 2453) as gram negative and
Staphylococcus aureus (MTCC 902) and Bacillus
subtilis (MTCC 441) as gram positive bacterial strains
using the cup plate method [19, 20]. Antibacterial
activity of the synthesised compounds was compared
with standard drugs ampicillin and streptomycin at
concentrations 10, 20, and 30 µL (Table 1). According
to the test data it was evident that the compounds 6b
and 6d showed moderate activity against bacterial
Molecular docking. The common H-bonding
interactions were estimated between all docked
compounds and LYS347, LYS356 and GLU354. The
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SYNTHESIS AND CHARACTERIZATION OF SOME NOVEL ARYL
2059
Scheme 1. Synthetic route for the preparation of pyrazole substituted aryl and heteroaryl chalcones 6a–6i.
H2N
NH
O
N
O
O
O
O
O
2
O
DMF/POCl3, from −10°C to
O
O
CHO
room temperature, 1.5 h
AcOH, MeOH, reflux, 3 h
96%
50%
N
N
HN
O
NaOH, MeOH,
reflux, 3-4 h
3
4
1
62−85%
O
O
N
O
O
R
5a−5i
O
R
N
6a−6i
OMe
Cl
OMe
OMe
(a),
(f),
R =
(e),
(b),
(c),
(h),
(d),
N
N
N
Cl
(g),
N
N
(i).
S
N
N
H-bonding interactions with other surrounding residues
in the hydrophobic binding pocket were also considered.
Strong H-bonding interactions between the methoxyl
oxygen (O23) of compound 6c with the hydrogen atom
of LYS356, carbonyl oxygen (O2) with hydrogen
atoms of LYS356 and LYS347 and benzopyrone
hydrogen with hydrogen atom of LYS347 were
observed (Fig. 3a). Benzopyrone oxygen of compound
6a was likely to interact with hydrogen atoms of
GLU354 and oxygen (O23) with LYS347 (Fig. 3b).
subjected to ADMET studies using mol inspiration
server (Table 3).
The data indicated that the drug likeness score was
good. The analytical data of the compounds also
confirmed the nonmutagenic and nontoxic nature
except the products 6b and 6i.
EXPERIMENTAL
All chemicals were purchased from Alfa Aesar.
Melting points were determined (uncorrected) in open
glass capillaries on a Stuart SMP30 apparatus. IR spectra
(KBr pellets) were recorded on a Shimadzu FTIR
Adsorption, digestion, metabolism, excretion and
toxicity (ADMET) studies. The compounds were
1
8400S spectrophotometer. H NMR (400 MHz) and
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 9 2017