Design of potent fluoro-substituted chalcones as antimicrobial agents

Article abstract of DOI:10.1080/14756366.2016.1265517

Owing to ever-increasing bacterial and fungal drug resistance, we attempted to develop novel antitubercular and antimicrobial agents. For this purpose, we developed some new fluorine-substituted chalcone analogs (3, 4, 9–15, and 20–23) using a structure–a

Full text of DOI:10.1080/14756366.2016.1265517

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: http://www.tandfonline.com/loi/ienz20
Design of potent fluoro-substituted chalcones as
antimicrobial agents
Serdar Burmaoglu, Oztekin Algul, Arzu Gobek, Derya Aktas Anil, Mahmut
Ulger, Busra Gul Erturk, Engin Kaplan, Aylin Dogen & Gönül Aslan
To cite this article: Serdar Burmaoglu, Oztekin Algul, Arzu Gobek, Derya Aktas Anil, Mahmut
Ulger, Busra Gul Erturk, Engin Kaplan, Aylin Dogen & Gönül Aslan (2017) Design of potent
fluoro-substituted chalcones as antimicrobial agents, Journal of Enzyme Inhibition and
Medicinal Chemistry, 32:1, 490-495, DOI: 10.1080/14756366.2016.1265517
To link to this article: http://dx.doi.org/10.1080/14756366.2016.1265517
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2017
VOL. 32, NO. 1, 490–495
http://dx.doi.org/10.1080/14756366.2016.1265517
RESEARCH ARTICLE
Design of potent fluoro-substituted chalcones as antimicrobial agents
c
b
b
d
c
Serdar Burmaoglua,b , Oztekin Algul , Arzu Gobek , Derya Aktas Anil , Mahmut Ulger , Busra Gul Erturk ,
ꢀ
ꢀ
e
d
f
€ €
Engin Kaplan , Aylin Dogen and Gonul Aslan
b
aTercan Vocational High School, Erzincan University, Erzincan, Turkey; Department of Chemistry, Faculty of Science, Ataturk University, Erzurum,
c
d
Turkey; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mersin University, Mersin, Turkey; Department of Pharmaceutical
e
Microbiology, Faculty of Pharmacy, Mersin University, Mersin, Turkey; Advanced Technology Education, Research, and Application Center,
Mersin University, Mersin, Turkey; Department of Medical Microbiology, Faculty of Medicine, Mersin University, Mersin, Turkey
f
ABSTRACT
ARTICLE HISTORY
Received 1 August 2016
Revised 17 October 2016
Accepted 22 November 2016
Owing to ever-increasing bacterial and fungal drug resistance, we attempted to develop novel antitubercu-
lar and antimicrobial agents. For this purpose, we developed some new fluorine-substituted chalcone ana-
logs (3, 4, 9–15, and 20–23) using a structure–activity relationship approach. Target compounds were
evaluated for their antitubercular efficacy against Mycobacterium tuberculosis H37Rv and antimicrobial
activity against five common pathogenic bacterial and three common fungal strains. Three derivatives (3,
9, and 10) displayed significant antitubercular activity with IC50 values of ꢁ16,760. Compounds derived
from trimethoxy substituent scaffolds with monofluoro substitution on the B ring of the chalcone structure
exhibited superior inhibition activity compared to corresponding hydroxy analogs. In terms of antimicrobial
activity, most compounds (3, 9, 12–14, and 23) exhibited moderate to potent activity against the bacteria,
and the antifungal activities of compounds 3, 13, 15, 20, and 22 were comparable to those of reference
drugs ampicillin and fluconazole.
KEYWORDS
Chalcone; antitubercular
activity; antimicrobial
activity; SAR
Introduction
be easily synthesized via the Claisen–Schmidt reaction of aceto-
phenones and benzaldehydes under basic conditions.
Tuberculosis, caused by Mycobacterium tuberculosis, is one of the
most important diseases worldwide. According to a 2014 report
by the WHO, incidences, prevalence, and mortality rates of tuber-
culosis have globally decreased. However, in 2014 alone, an esti-
mated 9.6 million new cases of tuberculosis and 1.5 million deaths
caused by the disease were reported1. Furthermore, the emer-
gence of multidrug-resistant and extensively drug-resistant strains
has led to a growing need for effective novel agents in the fight
against tuberculosis. Unfortunately, there are very few new drugs
being developed for this purpose2. Consequently, there is a grow-
ing need for the development of effective drugs to combat
tuberculosis.
The incidences of failure in the treatment of bacterial and fun-
gal infections have increased because of the emergence of multi-
drug-resistant strains due to misuse of antimicrobial drugs3.
Therefore, the synthesis of effective, novel antimicrobial com-
pounds has become extremely important.
In recent years, compounds containing fluorine have become
common as potential lead drugs5. It has been reported that inser-
tion of a fluorine atom into a biologically active compound results
in minimal steric change, thus maintaining interactions with
enzyme active sites, receptor recognitions sites, and other bio-
logical systems6. Furthermore, it has been indicated that the high
electronegativity of fluorine can lead to significant changes in the
physical and chemical properties of the molecule6,7. For example,
it is known that a moderate to high change in the lipophilicity of
a compound can impart it with improved antitubercular activity. It
has been established in recent literature that fluorine-substituted
compounds exhibit improved bioactivity and efficacy. Compounds
with a chalcone backbone have also been reported to exhibit anti-
microbial activity8–10
.
In this study, we performed antitubercular and antimicrobial
activity studies on eleven B-ring fluoro-substituted chalcones and
two nonsubstituted chalcones that we have previously synthesized
in an efficient, high-yielding manner11. These activity studies indi-
cated that they may be used in the treatment of tuberculosis and
other bacterial and fungal infections.
Chalcones are compounds with simple chemistry that offer
easy synthetic access to various substituted derivatives. As well as
being important constituents of various natural products, chal-
cones, also called a,b-unsaturated ketones, are important synthetic
precursors. Chalcones and their synthetic derivatives possess
extensive pharmacological properties, such as antihypertensive,
antiplatelet, antidiabetic, antineoplastic, antiangiogenic, antiretro-
viral, anti-inflammatory, antihistaminic, antioxidant, antitubercular,
Experimental
General
All reagents used were commercially available unless otherwise
antifungal, anti-invasive, and antiulcer properties4. Chalcones can specified and all solvents were distilled before use. Melting points
CONTACT Serdar Burmaoglu
sburmaoglu@erzincan.edu.tr
Tercan Vocational High School, Erzincan University, Tercan Vocational High School, Erzincan, 24800
Turkey
ꢀ
These authors contributed equally.
Supplemental data for this article can be accessed here
ß 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distri-
bution, and reproduction in any medium, provided the original work is properly cited.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
491
350
300
250
200
150
100
50
were measured with Gallenkamp melting point devices. IR Spectra:
PerkinElmer Spectrum One FT-IR spectrometer. 1H- and 13C-NMR
Spectra: Varian 400 and Bruker 400 spectrometers. Elemental ana-
lysis results were obtained on a Leco CHNS-932 instrument.
Synthesis
(E)-3-(4-Fluorophenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one (11);
0
3
4
9
10 11 12 13 14 15 20 21 22 23 INH EMB
Compounds
Figure 1. Comparative analysis of the antitubercular activity of the synthesized
compounds and the standard drugs EMB and INH.
To
a
solution of 2,4,6-trimethoxyacetophenon (1) (1 g,
Company, Sparks, MD) supplemented with 10% OADC at 37 ꢃC for
7–10 days, until a density corresponding to 10–2 to 10–4 dilutions
were obtained from McFarland standard No. 1. Then, 0.1 mL of the
diluted suspension was inoculated onto the control and the other
tubes with compounds in different concentrations. The tubes were
incubated at 37 ꢃC in a 5% CO2 atmosphere for 3 weeks. The MIC
values were defined as the lowest concentration that inhibited
more than 90% of the bacterial growth, and the results for INH and
EMB were interpreted according to the CLSI. The MIC was consid-
ered as the lowest concentration that showed no visible colonies in
all dilutions. The biological activity studies of the compounds were
performed twice. The results of these two studies were almost the
same. The IC50 values were calculated as the average activity values
for the compounds. The results are given in Figure 1.
4.75 mmol) in MeOH (20 mL) 4-fluorobenzaldhyde (7) (0.6 mL
7.6 mmol) and 50% KOH solution (10 mL) was added sequentially
and stirred for 15 h at room temperature. After 15 h, solvent was
evaporated; 2 M HCl solution (15 mL) was added and crude prod-
uct was extracted with DCM (3 ꢂ 20 mL). The combined extracts
were dried over Na2SO4. The solvent was removed in vacuo and
the remaining residue purified via coloumn chromatography over
silica gel using gradient elution with EtOAc and Hexanes to yield
compound 11, as a yellow solid (80% yield). Rf (EtOAc/Hexanes
30:70) ¼ 0.27; MP ¼ 122–123 ꢃC; IR (KBr, cmꢄ 1) vmax 3502, 2941,
2841, 1651, 1599; Anal. calcd for C18H18O4: C, 68.35; H, 5.42;
Found: C, 68.16; H, 5.38.
1H NMR (400 MHz, CDCl3) d 7.52–7.48 (m, 2H), 7.32 (d, 1H, B
part of AB system, J ¼ 16 Hz), 7.07–7.01 (m, 2H), 6.87 (d, 1H, A part
of AB system, J ¼ 16 Hz), 6.15 (s, 2H), 3.84 (s, 3H), 3.76 (s, 6H).
13C NMR (100 MHz, CDCl3) d 194.1, 164.0 (d, C-20, JCF
¼
Antimicrobial activity studies
249.8 Hz), 162.7, 159.1, 142.8, 131.5, 130.4 (d, C-18, JCF ¼8.4 Hz),
Antimicrobial susceptibility testing was performed by the modifica-
tion of literature methods14,15. We used the microbial strains
Staphylococcus aureus (ATCC 25925), Streptococcus pyogenes (ATCC
19615), Enterococcus faecalis (ATTC 29212), Escherichia coli (ATCC
25293), Pseudomonas aeruginosa (ATCC 27853), Candida albicans
(ATCC 10231), Candida glabrata (RSHM 40199), and Candida para-
psilosis (ATTC 22019).
The fungal and bacterial cell inoculum were prepared from a
stock culture grown in tryptic soy agar (TSA) at 28 ꢃC for 24 h, and
Mueller–Hinton agar (MHA) at 37 ꢃC for 24 h, respectively. The
microorganism suspension concentrations were adjusted according
to McFarland 0.5 turbidity tubes using sterilized saline. Stock solu-
tions of the title compounds were prepared in DMSO at 1000 mg/
mL. A modified microdilution test was applied for antimicrobial
activity, and the experiments were run in duplicate independently.
For antifungal activity testing, 100 mL Tryptic Soy Broth (TSB)
was added to each of the 11 wells. A 100 mL aliquot of the tested
chemical solution was added to the first well, and twofold dilu-
tions were prepared. Then, 5 mL of fungal suspension was added
to each tube except the last one, which acted as the control well.
For antibacterial activity testing, 100 mL Mueller–Hinton broth
(MHB) was added to each of the 11 wells. A 100 mL aliquot of the
chemical derivative solution was added to the first tube, and two-
fold dilutions were prepared. Then, 5 mL of the bacterial suspen-
129.0, 116.1 (d, C-19, JCF ¼21.7 Hz), 111.9, 90.9, 56.1, 55.7.
Antitubercular studies
Agar proportion method: The MIC values of each synthesized com-
pound 3, 4, 9–15, 20–23 were obtained by agar dilution in dupli-
cate as recommended by the Clinical Laboratory Standards
Institute (CLSI)12,13. Positive and negative growth controls were
used in each assay. INH (Sigma I3377) and EMB (Sigma E4630) were
used as control agents. M. tuberculosis H37Rv was used as the
standard strain and was provided by Refik Saydam National Public
Health Agency, National Tuberculosis Reference Laboratory, Ankara,
Turkey. Stock solutions of the tested compounds and reference
compounds were prepared in DMSO/H2O (50%) at a concentration
of 1000 mg/mL. These solutions were then filtered through a 0.22-
mm membrane filter (Millex-GP SLGP033RS, Merck Millipore, Merck
KGaA Darmstadt, Germany). Middlebrook 7H10 agar medium (BBL,
Becton Dickinson and Company, Sparks, MD) was supplemented
with oleic acid–albumin–dextrose–catalase (OADC, BBL, Becton
Dickinson and Company, Sparks, MD). Compounds and control
agents were added to obtain an appropriate final concentration in
the medium. The final concentrations of INH and EMB were
0.2–1 mg/mL and 5–10 mg/mL, respectively. Compounds were pre-
pared at final concentrations of 5, 10, 20, 40, and 80 mg/mL. Agar
without any reference or tested compounds was used as a positive sion was added to each tube, except the last control well. A
growth control, and 3.0 mL of prepared medium was dispensed control tube containing 5 mL of the fungal and bacterial suspen-
into sterile tubes. The DMSO concentration in the final solutions sions alone without the tested compounds was also prepared. All
was not above 1% for antimycobacterial activity.
Inoculum preparation: H37Rv was
plates were incubated at 28 ꢃC (for fungi) and at 37 ꢃC (for bac-
in teria) for 24 h. After incubation, the MICs (Tables 2 and 3) were
maintained
Lowenstein–Jensen medium. A culture suspension was prepared by obtained by noting the growth inhibitions. The concentration
subculturing in Middlebrook 7H9 broth (BBL, Becton Dickinson and resulting in a 50% reduction in the optical density (OD) values was

492
S. BURMAOGLU ET AL.
compared to a reproduction control at 450 nm by spectrophoto-
Using this procedure11, base-catalyzed Claisen–Schmidt con-
metric evaluation and defined as the MIC value. Fluconazole and densation afforded chalcones 3, 9–11, and 12 in yields of
ampicillin were used as reference drugs. The results were read 80–95%. Hydrogenation of the chalcone compounds over Pd–C
visually and by measuring optical density for 24 h.
gave 4, 13, 14, and 15 in yields of 70–90%. Trihydroxy-chalcones
were synthesized using the same procedure. Before the condensa-
tion reaction, the methoxymethyl ether (MOM) group was used to
protect the hydroxyl groups. The base-catalyzed reaction was then
used to afford MOM-protected chalcones. After deprotection,
hydrogenation of 20 and 21 over Pd–C gave the target com-
pounds 22 and 23 in yields of 80% and 85%, respectively. The
general method for the synthesis of these chalcones is briefly
described in Scheme 2.
Result and discussion
Chemistry
We previously reported the synthesis of 11 B-ring fluoro-substi-
tuted and two nonsubstituted chalcone derivatives11. The general
structure of synthesized compounds is shown in Scheme 1.
Scheme 1. General structures of synthesized compounds.
OMe O
OMe O
OMe O
O
i
ii
H
MeO
OMe
MeO
OMe
MeO
OMe
1
2
3
4
OMe O
OMe O
OMe
O
iv
H
iii
F
F
F
MeO
OMe
MeO
OMe
MeO
OMe
5=2-F
6=3-F
7=4-F
9=2-F
13=2-F
10=3-F
11=4-F
1
14=3-F
15=2,5-diF
8=2,5-diF
12=2,5-diF
OH
O
OH
O
OH
O
O
H
vi
v
F
F
HO
OH
MOMO
OMOM
MOMO
OMOM
5=2-F
8=2,5-diF
18=2-F
19=2,5-diF
16
17
vii
OH
O
OH O
viii
F
F
HO
OH
HO
OH
22=2-F
23=2,5-diF
20=2-F
21=2,5-diF
Scheme 2. Preparation of non- and fluoro-substituted trimethoxy/trihydroxy chalcones. Reagents and conditions: (i) 50% KOH, MeOH, (ii) H2, Pd-C, EtOH, (iii) 50% KOH,
MeOH, (iv) H2, Pd-C, EtOH, (v) DIPEA, MOMCl, DCM, (vi) 50% KOH, MeOH, (vii) 12M HCl, EtOAc, (viii) H2, Pd-C, EtOH.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
493
Table 1. Substitution patterns and antitubercular activity of target compounds (3, 4, 9–15, and 20–23).
OR
O
OR
O
OR
R1
R1
R1
RO
OR
RO
OR
RO
OR
C
D
E
R= H or Me
R1= F
R= H or Me
R1= H or F
R= Me
R1= F
Compound
Main structure
R
R1
cLog pa
3
4
9
C
D
C
C
C
C
E
E
E
C
C
E
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
2-F
3-F
4-F
2,5-di F
2-F
3-F
2,5-di F
2-F
2,5-di F
2-F
3.21
3.23
3.36
3.36
3.36
3.52
4.74
4.74
4.90
2.57
2.73
2.59
2.75
10
11
12
13
14
15
20
21
22
23
H
H
H
E
2,5-di F
acLog p value of the synthesized compounds calculated using ChemBioDrawUltra 12.0.3.
All compounds except 11 were previously synthesized by our modification of the above-mentioned drug molecules (3, 9, and
group11. We report here the synthesis of compound 11 and its
10) using a structure–activity relationship (SAR) approach could be
a promising strategy for the identification of new leads toward the
development of potent antitubercular agents.
structural details.
Modification of compound 3 (the methoxy derivative with non
fluoro substituent) for activity modulation was made through
preparation of compounds with fluoro substituents on the B ring
only (9, 10, 11, and 12), and with hydroxyl substituents on the A
ring and fluoro substituents on the B ring (20 and 21). Versions of
these compounds with semisaturated or saturated linkers were
also prepared (4, 13–15, 22, and 23). The synthesized compounds
were fully characterized with common spectroscopy techniques.
To evaluate the potential of the basic pharmacophore of chal-
cone, 3 was evaluated for its antimicrobial efficacy against the
Mycobacterium tuberculosis H37Rv strain and several other bacteria
and fungi. The different functional groups carry on aromatic rings
of chalcones are responsible for their antimicrobial activities. The
details of the substitution patterns in the target compounds are
presented in Table 1.
Antimicrobial studies
Antibacterial studies
The antibacterial activities of the target compounds (3, 4, 9–15,
and 20–23) against the five common pathogenic bacterial strains
S. aureus, S. pyogenes, E. faecalis, E. coli, and P. aeruginosa is shown
in Table 2. The experiments were performed using the microdilu-
tion method with reference to the MIC values of the compounds.
The well-known commercial antibiotic ampicillin was used as the
standard drug during the assay.
Compounds 3 and 4 show significant activity against almost all
the bacterial strains, and compound 23 is the most active com-
pound against S. aureus. Interestingly, all the compounds derived
from trimethoxy-substituted chalcone scaffolds exhibit significant
inhibition activities against all the tested strains, while the other
compounds exhibit moderate and low activity.
Antitubercular studies
All the target compounds (3, 4, 9–15, and 23) were screened
against M. tuberculosis H37Rv using the agar proportion method.
Isoniazid (INH) and ethambutol (EMB) were used as the positive
drug standards for the assay. The in vitro antimycobacterial activity
in terms of the minimum inhibitory concentration (MIC) values of
the target compounds and the standard drugs are shown in
Figure 1. The three derivatives 3, 9, and 10 show significant activ-
ities, with IC50 values ꢁ16,760, and compounds 11 and 12 exhibit
moderate activities with IC50 values ꢁ31.63. The remaining eight
compounds 4, 13–15, 20–22, and 23 exhibit very low activity.
The compounds derived from trimethoxy and non- or monofluoro-
substituted chalcone scaffolds exhibit superior inhibition activity
to their hydroxyl- and difluoro-substituted analogs. This observa-
tion clearly indicates that the trimethoxy A ring and fluoro groups
Antifungal studies
Compounds 3, 4, 9–15, and 20–23 were evaluated for antifungal
activity against the C. albicans, C. glabrata, and C. parapsilosis fun-
gal strains. The MIC values obtained for the compounds are given
in Table 3. Fluconazole was used as the reference for inhibitory
activity against fungi. The antifungal activities of all the com-
pounds are comparable to that of fluconazole.
Compounds 3, 13, 15, 20, and 21 are the most active com-
pounds, with compounds 3 and 20 exhibiting excellent activity
against C. albicans at MICs of 15.62 mg/mL. Compounds 3, 13, 15,
and 21 exhibit very good activity against C. glabrata at an MIC of
31.25 mg/mL, while the other compounds (9–13, 20, 22, and 23)
on the B ring enhance the inhibition activity of the molecules. exhibit moderated inhibition with MICs of 62.5 and 125 mg/mL, as
compared to the standard fluconazole (31.25 mg/mL).
Furthermore, these results suggest that further structural

494
S. BURMAOGLU ET AL.
Compounds 13, 15, and 21 exhibit the highest activity against antifungal activity increases. Furthermore, the use of semi-satu-
P. parapsilosis, with MICs of 31.25 mg/mL, whereas all other com-
pounds exhibit low inhibitory activity compared to that of flucon-
azole, with MICs of 62.5 mg/mL. Compound 21, the hydroxyl and
difluoro-substituted chalcone analog, exhibits the highest activity.
rated linker compounds appears to improve activity against all
targets.
Conclusions
Recently, chalcone-like compounds, such as licochalcone A, which
are present in Glycyrrhiza inflata, and 24 and 25, present in Piper
sanctum, have been reported to exhibit potent antitubercular
activity against Mycobacterium tuberculosis, with MICs of 7.1, 32,
SAR
The SAR of compounds 3, 4, 9–15, and 20–23 was explored using
the data presented in Tables 1–3, and reveals that the presence of
three methoxy groups on the A ring of the chalcone increases
antitubercular activity and that activity decreases in the presence
of hydroxyl groups on the A ring. Chalcone and saturated chal-
cone compounds exhibit more pronounced antibacterial activity.
More specifically, compounds with fluoro substituents in pos-
ition 2 and/or position 5 of the B ring in the chalcone structure
exhibit significantly increased potency against the microbial
strains. The influence of Log p on the antifungal activity of the
compounds appears to be important: as Log p increases, the
and 4.0 mg/mL, respectively (Figure 2)16,17
.
In this study, based on the recent literature data, we designed
and tested a series of 2,4,6-trimethoxy or hydroxyl and non/mono-
or difluoro-substituted chalcone derivatives in order to improve
the antitubercular and antimicrobial activity of previously synthe-
sized chalcones and to gain an understanding of their SAR in
the context of anti-M. tuberculosis and antimicrobial activities
(Tables 1–3).
The synthetic route for chalcone derivatives (3, 4, 9–15, and
20–23) is represented in Scheme 1. The 13 chalcone derivatives
were prepared via two steps. The compounds tested for antituber-
cular activity were divided into two series; series A comprised tri-
methoxy-substituted compounds 3, 4, 9–15 derived from the
parent structure 3 with fluoro substituents in position 2–5 of the B
ring, and series B contained three hydroxyl substituents on the A
ring and a mono- or difluoro-substituted B ring (20–23).
Preliminary studies revealed that compounds (3, 9, 10) exhib-
ited the greatest antitubercular activity with IC50 values ꢁ16,760,
which are comparable to the antitubercular drugs INH and EMB
used as controls.
Modification of compound 3 for activity modulation was made
by introducing fluorine atoms or saturation. These compounds
were found to be either far less active than 3 or inactive. It is
widely known that molecular flexibility plays an important role in
drug–protein interactions. However, we found that the conforma-
tionally restricted chalcones were more active than the other chal-
cones. This modification was made in such a way that the total
lipophilic nature of the compounds was similar (The Log p values
for compounds are shown in Table 1). We also attempted to
assess the importance of the structure of the chalcone compounds
Table 2. MICs of compounds 3, 4, 9–15, and 20–23 and the standard ampicillin
against the selected bacterial strains.
Minimal inhibitory concentration, MIC (lg/mL)
Compounds
S. aureus
S. pyogenes
E. faecalis
E. coli
P. aeruginosa
3
4
9
10
11
12
13
14
15
20
21
22
31.25
62.5
62.5
125
62.5
15.6
62.5
62.5
125
125
62.5
125
7.8
31.25
31.25
62.5
62.5
62.5
62.5
62.5
62.5
125
125
125
125
62.5
-
31.25
62.5
31.25
125
62.5
31.25
31.25
31.25
62.5
125
31.25
31.25
62.5
125
62.5
31.25
62.5
125
125
125
62.5
31.25
62.5
125
125
125
125
125
3.9
62.5
62.5
62.5
125
125
125
125
125
31.25
125
125
125
62.5
23
Ampicillin
-
–: All tested concentrations are active.
Table 3. MICs of compounds 3, 4, 9–15, 20–23 and the standard fluconazole
against selected fungi.
Minimal inhibitory concentration, MIC (lg/mL)
Compounds
C. albicans
C. glabrata
C. parapsilosis to their effectiveness as antimicrobial agents.
The synthesized compounds were also evaluated for their in
3
4
9
10
11
12
13
14
15
20
21
22
15.62
62.5
250
125
62.5
125
125
125
62.5
15.62
125
31.25
250
-
31.25
62.5
250
62.5
62.5
125
31.25
125
31.25
62.5
125
31.25
125
62.5
62.5
62.5
62.5
62.5
62.5
31.25
62.5
31.25
62.5
62.5
31.25
62.5
-
vitro antimicrobial activity against several bacterial and fungal
strains. The tested compounds were inactive against bacteria and
fungi, and they did not exhibit significant antibacterial and anti-
fungal activities, except against S. aureus, in comparison to ampi-
cillin and fluconazole. However, the chalcone analogs exhibited
considerable antimicrobial activity. Interestingly, compounds 3 and
4 exhibited wider activity than the other compounds. Compounds
3, 20, and 11, 23 exhibited higher antibacterial and antifungal
activity against S. aureus and C. albicans, respectively.
23
In conclusion, assessment of the biological activity of these
molecules indicated that conformationally restricted chalcones are
superior to their straight chain analogs, possibly due to molecular
Fluconazole
31.25
–: All tested concentrations are active.
Figure 2. Some natural anti-tubercular agents.

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
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flexibility, and may be good leads for the future development of
antitubercular drugs.
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discovery. Org. Biomol. Chem 2016;14:8398–427.
8. Prasad YR, Rao AL, Rambabu R. Synthesis and antimicrobial
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Acknowledgements
9. Lopez SN, Castelli MV, Zacchino SA, et al. In vitro antifungal
evaluation and structure–activity relationships of a new ser-
ies of chalcone derivatives and synthetic analogues, with
inhibitory properties against polymers of the fungal cell wall.
Bioorg Med Chem 2001;9:1999–2013.
We thank the Scientific and Technological Research Council of
Turkey (TUBITAK, Grant Number: 114Z554) and Erzincan University
(Grant Number: FEN-A-300614-0098) provide financial support.
Disclosure statement
10. Patel BB, Baviskar SB, Khadabadi S, Shiradkar SM. Design and
synthesis of some novel chalcones as potent antimicrobial
agent. Asian J Res Chem 2008;1:67–9.
11. Burmaoglu S, Algul O, Anıl DA, et al. Synthesis and anti-pro-
liferative activity of fluoro-substituted chalcones. Bioorg Med
Chem Lett 2016;26:3172–6.
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
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