Synthesis and biological activity of new chalcone scaffolds as prospective antimicrobial agents

Article abstract of DOI:10.1007/s11164-020-04359-6

Chalcones are open-chain flavonoids which contains two aromatic rings are joined by 3-carbons α-, β-unsaturated carbonyl chain. The, β-unsaturated ketonic group which is liable for the antimicrobial activity of the chalcone is additionally of vast use in

Full text of DOI:10.1007/s11164-020-04359-6

Research on Chemical Intermediates (2021) 47:1625–1641
https://doi.org/10.1007/s11164-020-04359-6
Synthesis and biological activity of new chalcone scafolds
as prospective antimicrobial agents
Sangeeta Narwal1 · Sanjiv Kumar2 · Prabhakar Kumar Verma3
Received: 14 September 2020 / Accepted: 11 December 2020 / Published online: 11 January 2021
© The Author(s), under exclusive licence to Springer Nature B.V. part of Springer Nature 2021
Abstract
Chalcones are open-chain favonoids which contains two aromatic rings are joined
by 3-carbons α-, β-unsaturated carbonyl chain. The, β-unsaturated ketonic group
which is liable for the antimicrobial activity of the chalcone is additionally of vast
use in further chemical modifcation into a variety of heterocyclic compounds. A
new series of chalcone derivatives was synthesized and characterized by spectral
analysis (IR, 1H-NMR, 13C-NMR, MS and elemental analysis) and evaluated
for its in vitro antimicrobial activity against bacterial (Gram negative and Gram
positive) and fungal strains using tube dilution method. The antimicrobial screen-
ing results revealed that some compounds of the series 1 (MICpa=1.16 µM), 3
(MICbs=1.82 µM), 6 (MICan=2.09 µM), 8 (MICec and se=0.94 and 1.88 µM)
and 17 (MICsa and ca=0.91 and 1.81 µM) showed the most promising antimicro-
bial activity against both Gram-positive as well as Gram-negative bacterial and fun-
gal strains, and comparable to the standard drugs used as positive control (cefadroxil
and fuconazole).
Keywords Chalcone derivatives · Antimicrobial activity · Spectral analysis · SAR
study
Abbreviations
MIC
Minimum Inhibitory Concentration
Micro mole
Mµ
MBC
MFC
Minimum Bactericidal Concentration
Minimum Fungicidal Concentration
* Sanjiv Kumar
sanjiv.pharmsci@gmail.com
1
2
3
Department of Pharmaceutical Sciences, Indira Gandhi University, Meerpur, Rewari,
Haryana 123401, India
Department of Pharmaceutical Sciences, Chaudhary Bansi Lal University, Bhiwani,
Haryana 127021, India
Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak,
Haryana 124001, India
Vol.:(0123456789)
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S. Narwal et al.
B. subtilis
S. aureus
E. coli
Bacillus subtilis
Staphylococcus aureus
Escherichia coli
S. enterica
Salmonella enterica
P. aeruginosa Pseudomonas neruginosa
C. albicans
A.niger
IR
Candida albicans
Aspergillus niger
Infrared spectroscopy
Nuclear magnetic resonance
Dimethyl sulfoxide
NMR
DMSO
CDCl3
FT-IR
Deuterated chloroform
Fourier-transform infrared spectroscopy
Introduction
Chalcones, one of the major classes of natural products, are open-chain favanoids
in which two aromatic rings are linked by a 3-carbon α, β-unsaturated/saturated car-
bonyl system [1]. Various types of antimicrobial drugs are already present inside
the market but thanks to the arbitrary use of antimicrobial drugs often followed the
experience of resistant strains of microorganism [2]. Mutation, phenotypic change,
gene transfer and selective pressure also are signifcant causes behind antimicrobial
resistance [3]. So, there is an urgent need to discover new antimicrobial agent which
have an extensive spectrum of activity against the resistant micro-organism [4, 5].
Staphylococcus aureus and other microorganisms are the major human pathogen
cause’s mild superfcial infections to severe life-threatening invasive infections [6,
7]. An important quality for an antimicrobial drug is selective toxicity, meaning that
it selectively kills or inhibits the growth of microbial targets while causing minimal
or no harm to the host [8].
The chemistry of chalcone has been generated intensive scientifc interest due
to their industrial and biological application. Chalcone is natural biocides and are
eminent intermediates in the synthesis of heterocyclic moieties exhibiting diverse
biological activities. Chalcone is the core substructure of some natural compounds
and important precursor for the synthesis of various heterocyclic compounds like
pyrimidines, pyrazolines, pyrazoles, favonoids, isofavonoids [9], benzoyl coumar-
ones, deoxybenzoins, hydantoins and aurones containing benzylidene acetophenone,
having some therapeutic value, where the two aromatic rings are joined by a 3 car-
bon α, β-unsaturated carbonyl system [10]. Generally, they consist of polyhydroxy
groups in their aromatic nuclei and exist as either trans (E, 1) or cis (Z, 2) isomeric
forms (Fig. 1); whereas, trans isomer being thermodynamically more stable than
cis form [11]. Chalcones contain conjugated double bonds and a totally delocalized
π-electron system on both benzene rings. The non-toxic concentrations of all com-
pounds were determined on the HEK-293 cell line. Then, anti-proliferative activity
studies were performed at these non-toxic concentrations [1].
The radical-quenching property of these phenolic groups augment the inter-
est within the use of these compounds as food preservatives or chalcone-rich plant
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Fig. 1 Trans (E, 1) or Cis (Z, 2) isomers of chalcone
extracts as drugs [12]. Chalcones are generally known by diferent names i.e. ben-
zylidene acetophenone, phenyl styryl ketone, β-phenylacrylophenone α-phenyl-β-
benzoylethylene etc. these names are given by Kostanecki and Tambor [4]. Chal-
cones have been shown potent pharmacological profle and have received a great
deal of attention due to their relatively simple structures, ease of hydrogen atom
manipulation, simple chemistry, ease of synthesis, diversity of substituent’s and
are associated with a plethora of biological actions like antifungal, antimalarial
[13, 14], anticancer, antidiabetic, antituberculor, antioxidant, neuroprotective,
antiviral [15], anti-Alzheimer, anti-infuenza [16], anti-infammatory, anti-ulcer-
ative, gastric protectants [10], anticonvulsant, anti-infammatory, antileishmanial
[11], antiallergic, antispasmodic, fungicidal, antibacterial [5], germicidal, her-
bicidal and insecticidal, [17] immunosuppressive pharmacological activity [18].
Chemical modifcation of chalcone is one of the most universal approaches in
drug discovery with improved therapeutic efect and the wide occurrence of chal-
cone in bioactive natural products [10]. Marketed drugs of chalcone used in clini-
cal practice, selected drugs are shown in Fig. 2
Stereochemically, chalcone can exist both cis (Z) and trans (E) isomeric forms,
but the Z isomer is most unstable because of steric efect of ring A with group.
In chalcones, two aromatic nuclei are present therefore the electrophilic α,
β-unsaturated carbonyl system is in continuous conjugation. It may be the reason
for their stability, electron transfer reactions and low redox potential, more sig-
nifcant for its potent biological activities [9].
Recently, it has been reported that para-hydroxy phenyl nucleus present in
chalcone derivative (I) [19] improved the antidiabetic activity. ortho-Hydroxy
and para-methoxy substitution on phenyl ring enhanced the antimicrobial poten-
tial of the chalcone compounds (II) [20], tri-Methoxy at 2nd, 4th and 5th position
of the phenyl ring of chalcone derivatives improved the antioxidant activity (III)
[21]. Bromo group at meta-position of the phenyl nucleus of chalcone deriva-
tive (IV) [22] improved the antiviral activity. Any substitutions on chalcone and
heterocyclic derivatives (pyrimidine moiety) have shown antitubercular activity
[23]. The di- and tri-acetylbenzyl derivatives showed the good anti-neurotoxicity
activity [24]. The presence of electron releasing (-OH and -OCH3) and electron
withdrawing (-Br) functional groups on various position of phenyl ring (I, II,
III and IV) of the chalcone derivatives enhanced their biological activity [25],
from these information we have reported a design of diferent biologically active
agents (Fig. 3).
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S. Narwal et al.
Fig. 2 Marketed drugs of chalcone
Fig. 3 Literature based design of the proposed chalcone derivatives
In light of above-mentioned details, we hereby enlighten design, synthesis and eval-
uate antimicrobial activity of 3-(substituted aldehyde)-1-(4-substituted phenyl)prop-2-
en-1-one derivatives.
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Synthesis and biological activity of new chalcone scafolds…
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Experimental
All other chemicals and reagents obtained from marketable sources and these are
used without further purifcation. Confrmation of the fnal product formed in the
reaction done by thin layer chromatography technique (TLC plate), using silica gel
G as stationary phase and benzene as mobile phase. Melting points of fnal deriva-
1
tives were obtained by open capillary tube method. 13C-NMR and H-NMR of the
synthesized compounds were recorded at 150 MHz and 600 MHz, respectively on
Bruker Avance III 600 NMR spectrometer by taking suitable deuterated solvent
and the results were expressed in parts per million (δ, ppm) downfeld from internal
1
standard (tetramethylesilane). H-NMR data are given as multiplicity (s, singlet; d,
doublet; t, triplet; m, multiplet) and number of protons. An infrared (IR) spectrum
were recorded on Bruker 12,060,280, Software: OPUS 7.2.139.1294 spectrometer
in the sort of 400–4000 by making pellets with KBr using FT-IR Spectrophotometer
and the value of λ max were found in cm−1 [26]. Elemental analysis was performed
on PerkinElmer 2400 C, H and N analyzer and all synthesized chalcone derivatives
gave C, H and N analysis within 0.4% of the theoretical results. Mass spectra of
synthesized compounds were taken on Waters Micromass Q-ToF Micro instrument.
Synthetic procedure
The reaction mixture of para-substituted acetophenone (0.01 M) and subsequent
aldehyde (0.01 M) was stirred for 2–3 h in methanol (30 ml) in a round bottom fask.
NaOH solution (10 ml sodium hydroxide solution 40%) was added drop wise and
continuous stirring at room temperature. The reaction mixture was placed at room
temperature overnight and then it was poured into ice cold water after that the solu-
tion was acidifed by dilute HCl (hydrochloric acid). Then the precipitated of fnal
product was fltered, desiccated and recrystallized from ethanol (Rectifed spirit)
[27].
Antimicrobial evaluation (In Vitro)
The antimicrobial potential of the synthesized new derivatives of chalcone was
evaluated against microorganisms, i.e., Gram-positive bacterial strains (S. aureus
MTCC3160 [2, 6], B. subtilis MTCC441), Gram-negative bacterial strains (E. coli
MTCC443, S. enterica MTCC116 and P. aeruginosa MTCC3542) and fungal strains
(C. albicans MTCC227, A. niger MTCC281) using tube dilution method [28].
For the synthesized derivatives and standard drugs i.e. cefadroxil and fuconazole
stock solution (100 µg/mL in DMSO) was prepared [29]. Here, two types of broth
were used for antimicrobial study, i.e., Sabouraud dextrose broth-I.P for antifungal
study and double strength nutrient broth-I.P for antibacterial study. The synthesized
chalcone compounds and reference drugs were incubated at diferent temperature
i.e. Gram-positive and Gram-negative bacterial strains at 37 1 °C for 24 h, fungal
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S. Narwal et al.
strains- A. niger at 25 1 °C for 7 days and C. albicans at 37 1 °C for 48 h. The
antimicrobial screening result, i.e., minimum inhibitory concentration was recorded
in (MIC=µM).
Results and discussion
Chemistry
The chemistry of chalcone moiety has generated intensive scientifc interest due to
their industrial and biological application. Chalcone is natural biocides and are emi-
nent intermediates in the synthesis of heterocyclic moieties exhibiting diverse bio-
logical activities. The synthesis of allylic chalcone derivatives by Claisen–Schimdt
condensation reaction followed various steps discussed in synthetic Scheme 1.
Here, the reaction of various p-substituted acetophenone with substituted alde-
hyde in the presence of sodium hydroxide solution in methanolic solvent at room
Scheme 1 Synthetic scheme of 3–(substituted aldehyde)–1–(4–substituted phenyl) prop–2–en–1-one
derivatives (1–17)
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Synthesis and biological activity of new chalcone scafolds…
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temperature resulted in the formation of the various biologically active compounds
(1–17). The molecular structures of synthesized compounds were characterized by
physicochemical properties and spectral characteristics are presented Table 1 and
Table 2, respectively. The phenyl nucleus exhibited the C–H stretching in range of
3183–2854 cm−1. Peak range at 1390–1331 cm−1 showed the –C–N str. of the com-
pounds. Peak range 1691–1523 cm−1 indicates the presence of –C=O stretch in the
compound [30]. Here, also the appearance of –NO2 asymmetric stretches in a scale
of 1524–1253 cm–1 of the synthesized compounds. The compound having peak
range 1692–1519 cm−1 indicates the presence of –C=C– group. The compounds
1
showed the Ar-NO2 stretch (C–N str.) in the range of 854–724 cm−1. H–NMR
showed the presence of OCH3 group at 3.73 δ ppm. The presence of singlet signal
of OH group at 5.35–5.00 δ ppm and showed multiplet protons of aromatic ring
at 6.26–8.45 δ ppm [10, 31]. In addition, 2 doublet signal around at 7.39–7.59 δ
ppm confrm the presence of protons of O=CH=CH– groups. 13C–NMR δ
showed the diferent carbon signal of the compound around at 121.4 (–CH), 68.0
(–OCH), 145.0, 148.1 (phenyl), 115.8, 127.8, 130.8 (Ar–C), 157.7 (–NH–C=0),
189.7(C=O), 14.8 (–OCH2CH3) [31] and synthesized chalcone compounds gave C,
H and N analysis within. 0.4% of the theoretical values.
In vitro antimicrobial activity
The newly synthesized chalcone derivatives were evaluated for their in vitro antimi-
crobial potential against Gram–positive bacterial strains (S. aureus and B. subtilis),
Table 1 The physicochemical
Comp M. Formula
M. Wt m.pt. (˚C) Rf Value* % Yield
properties of synthesized
chalcone derivatives
1
2
3
4
5
6
7
C15H11NO4
C15H10N2O5
C18H17NO6
C15H10N2O5
C17H15NO5
C16H13NO5
C19H20N2O3
269
298
343
298
313
299
324
67–69
123–125
>200
0.58
0.31
0.53
0.68
0.63
0.51
0.56
0.61
0.41
0.42
0.45
0.62
0.39
0.38
0.62
0.47
0.35
70.97
75.08
84.68
76.69
65.49
72.56
72.56
75.08
71.45
69.32
72.59
68.34
69.56
76.45
75.00
84.72
78.78
208–210
61–63
73–75
68–70
139–141
95–97
68–70
82–84
77–79
119–121
>200
8
C15H10BrNO3 331
9
C15H10N2O5
C17H15NO5
C16H13NO4
C15H11NO4
C15H12ClNO
C18H18O5
C13H13NO4
C12H11NO3
C17H12BrNO3 358
298
313
283
269
257
314
247
217
10
11
12
13
14
15
16
17
71–73
55–57
56–58
*TLC mobile phase: Benzene
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S. Narwal et al.
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Gram–negative bacterial strains (E. coli, S. enterica and P. aeruginosa) and fungal
strains (C. albicans, A. niger) using tube dilution method.
The minimum inhibitory concentration (MIC, i.e., lowest conc. required of
test substance to fnish or abolish the bacterial/Fungal growth) values of the syn-
thesized compounds are presented in Table 3. From the results of antimicrobial
screening (Fig. 4) it has been observed that the whole synthesized compounds
showed appreciable antimicrobial activity. An active compound was found to be
active against specifc microorganisms. In case of Gram+ve bacterial strain,
compound 3 (MICbs =1.82 µM) showed signifcant antibacterial activity against
B. subtilis and compound 17 (MICsa =0.91 µM) exhibited promising antibac-
terial activity against S. aureus [32]. In case of Gram−ve bacterial strains, com-
pound 1 (MICpa =1.16 µM) showed appreciable activity against P. aeruginosa and
Table 3 Antimicrobial screening
Comp
Minimum inhibitory concentration (MIC=µM/ml)
results of the synthesized
compounds
Bacterial strains
Gram–posi-
Fungal
strains
Gram-negative
tive bacteria bacteria
S.A
B.S
E.C
P.A
S.E
C.A
A.N
1
4.64
4.64 2.32 1.16 2.32 4.64 4.64
2
16.76 4.19 1.05 2.10 4.19 8.38 2.10
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3.64
2.10
1.00
4.18
3.85
3.76
4.19
1.00
4.41
2.32
2.43
1.99
2.53
1.44
0.91
1.82 1.82 1.82 3.64 1.82 3.64
4.19 2.10 2.10 4.19 4.19 4.19
3.99 3.99 1.99 1.99 3.99 3.99
2.09 2.09 2.09 4.18 4.18 2.09
3.85 1.93 1.93 1.93 1.93 3.85
3.76 0.94 1.88 1.88 3.76 3.76
4.19 2.10 2.10 4.19 4.19 4.19
1.99 1.00 1.99 3.99 3.99 3.99
2.21 4.41 2.21 2.21 4.41 4.41
4.64 4.64 2.32 4.64 4.64 9.29
4.85 4.85 2.43 2.43 4.85 4.85
3.98 3.98 1.99 3.98 3.98 3.98
5.06 2.53 2.53 5.06 5.06 5.06
5.75 5.75 2.88 5.75 5.75 5.75
3.62 1.81 1.81 3.62 1.81 3.62
Std. Drugs
1.72a 1.72a 1.72a 1.72a 1.72a 2.04b 2.04b
DMSO
NA
NA
NA
NA
NA
NA
NA
Broth Control NG
NG
NG
NG
NG
NG
NG
Std. Drugs (+Ve Control): aCefadroxil, bFluconazole; DMSO Dime-
thyl sulfoxide; Microbial species- B.S.: Bacillus subtilis; S.A.:
Staphylococcus aureus; E.C.: Escherichia coli; C.A.: Candida
albicans; A.N.: Aspergillus niger; P.A.: Pseudomonas aeruginosa;
S.E.: Salmonella enterica; N.A: No activity; N.G: No growth
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S. Narwal et al.
Antibacterial Screening Results
18
16
14
12
10
8
S.A.
B.S.
E.C.
P.A.
S.E.
6
4
2
0
Compounds and standard drugs
Fig. 4 Antibacterial screening results
compound 8 (MICec and se =0.94 and 1.88 µM) displayed good antibacterial activity
against E. coli and S. enterica. In case of antifungal screening results (Fig. 5), Com-
pound 6 (MICan =2.09 µM) showed signifcant activity against A. niger and com-
pound 17 (MICca =1.81 µM) showed promising antifungal activity against C. albi-
cans [5]. The antimicrobial screening results were comparable to the reference drugs
(Cefadroxil and Fluconazole) used as positive control and DMSO used as negative
control [33].
Examination of MBC/MFC study
On the basis of minimum inhibitory concentration results of the synthesized deriva-
tives against diferent microbial strains, i.e., Gram-positive (S. aureus and B. sub-
tilis) [34], Gram-negative (E. coli, P. aeruginosa and S. enterica) [8] and fungal
strains.
(C. albicans and A. niger) after that we determine their MBC and MFC by Agar
and Sabouraud dextrose media, respectively, and shows results within the range of
95–97% end point reduction of the used bacterial and fungal strains (used as test)
[35, 36].
Fig. 5 Antifungal screening results
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Synthesis and biological activity of new chalcone scafolds…
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Fig. 6 Structure activity relationship study of synthesized chalcone derivatives
SAR (Structure activity relationship)
From the above mentioned antimicrobial results of the synthesized chalcone deriva-
tives, the subsequent structure activity relationship can be derived in Fig. 6.
(a) In the synthesized derivatives, the electron releasing groups, i.e., –OH and –
OCH3 are present on benzylidene portion of the synthesized compounds 1, 3
and 6 improved the antibacterial activity against P. aeruginosa, B. subtilis and
antifungal activity against A. niger.
(b) In, Compound 8, presence of electron withdrawing group (–Br) on benzylidene
portion improved the antibacterial activity against E. coli and S. enterica.
(c) Alpha–Br–cinnamaldehyde (Compound 17) improves the antimicrobial activity
against S. aureus and C. albicans.
(d) Presence the NO2, NH2 and OH substitution groups on benzylidene portion
(para–position) of acetophenone play a crucial role to improves the antibacterial
and antifungal activity against the microorganisms [37].
Conclusion
In this study, we concluded that the newly prepared chalcone compounds 1, 3, 6, 8
and 17 displayed appreciable antimicrobial activity against Gram-positive bacterial
strains (S. aureus, B. subtilis), Gram-negative bacterial strains (E. coli, S. enterica
and P. aeruginosa) and fungal strains (C. albicans, A. niger). The antimicrobial
screening results of synthesized compounds were found to be more potent than ref-
erence drugs (Cefadroxil and Fluconazole). So, the newly synthesized derivatives
may be used as lead molecules for the development of novel therapeutic agents.
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Acknowledgements Thanks to the Head, Department of Pharmaceutical Sciences, Maharshi Dayanand
University, Rohtak, for kind support and providing the necessary facilities.
Author contributions PKV - designed research work; SN - performed research work and SK- analyzed
the spectral data, biological screening results and wrote the manuscript. All authors read and approved
the fnal manuscript.
Funding Not applicable.
Data availability We have presented all our main data in the form of tables and fgures.
Compliance with ethical standards
Confict of interest The author(s) confrms that this article content has no confict of interest.
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