Novel Chalcone-Thiazole Hybrids as Potent Inhibitors of Drug Resistant Staphylococcus aureus

Article abstract of DOI:10.1021/acsmedchemlett.5b00169

A series of novel hybrids possessing chalcone and thiazole moieties were synthesized and evaluated for their antibacterial activities. In general this class of hybrids exhibited potency against Staphylococcus aureus, and in particular, compound 27 exhibited potent inhibitory activity with respect to other synthesized hybrids. Furthermore, the hemolytic and toxicity data demonstrated that the compound 27 was nonhemolytic and nontoxic to mammalian cells. The in vivo studies utilizing a S. aureus septicemia model demonstrated that compound 27 was as potent as vancomycin. The results of antibacterial activities underscore the potential of this scaffold that can be utilized for developing a new class of novel antibiotics.

Full text of DOI:10.1021/acsmedchemlett.5b00169

Subscriber access provided by NEW YORK UNIV
Letter
Novel chalcone-thiazole Hybrids as Potent
Inhibitors of Drug Resistant Staphylococcus Aureus
Koneni V. Sashidhara, K Bhaskara Rao, Pragati Kushwaha, Ram K Modukuri, Pratiksha
Singh, Isha Soni, Praveen K. Shukla, Sidharth Chopra, and Mukesh Pasupuleti
ACS Med. Chem. Lett., Just Accepted Manuscript • Publication Date (Web): 29 May 2015
Downloaded from http://pubs.acs.org on May 30, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Medicinal Chemistry Letters is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 7
ACS Medicinal Chemistry Letters
1
2
3
4
5
6
7
8
Novel chalcone-thiazole Hybrids as Potent Inhibitors of
Drug Resistant Staphylococcus Aureus
Koneni V. Sashidharaa,*, K. Bhaskara Raoa, Pragati Kushwahaa, Ram K. Modukuria,
9
Pratiksha Singhb, Isha Sonib, P. K. Shuklab, Sidharth Choprab and Mukesh Pasupuletib
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
b
aMedicinal & Process Chemistry Division and Division of Microbiology, CSIR−Central Drug Research
Institute (CSIR-CDRI), Sector 10, Jankipuram extension, Sitapur Road, Lucknow-226031, Uttar Pradesh,
India.
KEYWORDS: Chalcone- thiazole hybrids, Staphylococcus aureus, antibacterial activities, MIC
Abstract: A series of novel hybrids possessing chalcone and thiazole moieties were synthesized and
evaluated for their anti-bacterial activities. In general this class of hybrids exhibited potency against
Staphylococcus aureus and in particular compound 27 exhibited potent inhibitory activity with respect to
other synthesized hybrids. Furthermore, the hemolytic and toxicity data demonstrated that the compound 27
was non-hemolytic and non-toxic to mammalian cells. The in vivo studies utilizing a S. aureus septicemia
model, demonstrated that the compound 27 was as potent as vancomycin. The results of antibacterial
activities underscore the potential of this scaffold that can be utilized for developing a new class of novel
antibiotics.
Staphylococcus aureus is an opportunistic
pathogen that can cause wide spectrum of
infections, ranging from severe to potentially fatal
or invasive diseases. Recent data suggested that
the incidence of infection due to S. aureus seems
to be the highest in neonates, immune
compromised and/or hospitalized individuals
with a mortality rate as high as 50%. In USA
alone, S. aureus has been accounted for 80,461
infections and 11,285 deaths per year, indicating
the seriousness of the problem.1 Currently to treat
S. aureus infections, wide range of FDA approved
drugs are available ranging from ciprofloxacin to
oritavancin. Unfortunately, acquiring resistance to
the antibiotics by S. aureus has recently increased
the number of untreatable infections.2 Recent
strategies to develop a vaccine for S. aureus have
not been very successful as data suggested that
vaccination with bacterial cell-surface antigens
increases disease severity instead of offering
protection.3 Given this, Centers for Disease
Control, USA have listed S. aureus as
new antimicrobial agents against S. aureus,
especially strains resistant to multiple antibiotics
is an urgent and unmet medical need.
Natural and synthetic chalcones have been
reported to exhibit broad spectrum of
pharmacological activity.8 They are of special
interest due to their pronounced antimicrobial
activities.9, 10 On the other side, thiazole ring is
microorganism
of
serious
threat
level.
(http://www.cdc.gov/ drug resistance /threat-
report-2013/).
Regrettably, many pharmaceutical companies
have abolished their programs on new antibiotic
and
recent search for novel targets by genomic and
4,
5
discovery and development long ago
Figure 1. Designing of chalcone-thiazole hybrids
proteomic based approaches also have yielded
Given the alarming
only limited success.6,
situation of drug-resistant S. aureus, the search for
by pharmacophore hybridization.
7
1
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 2 of 7
1
2
3
4
5
6
7
8
9
norfloxacin and gentamycin as reference drugs.
The in vitro antibacterial results confirmed that
some of the chalcone-thiazole hybrids exhibited
antibacterial activity against various strains of
Staphylococcus aureus as shown in Table 1 with
compounds 22, 25 and 27 being the most potent in
the series. A pictorial representation of the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
preliminary
Structure–activity
relationships
(SARs) could be summarized as depicted in Figure
2. The presence of bulky tert butyl side chain (22,
25,27) is preferred over isopropyl and n-propyl
groups at ortho position to hydroxyl group. In the
chalcone part though both aromatic and
heteroaromatic groups are tolerated, the presence
of 4-methylphenyl group is optimum. While in
the thiazole core phenyl with dimethoxy
substitution (27) is preferred over monomethoxy
(26) and ethyl ester (23,24,31).
Figure 2. SAR of synthesized hybrids.
found to be a common structural component in a
large number of biological agents.11 Thiazoles have
also been extensively studied for their
antibacterial activities.12-15 Though in some cases
combining two pharmacophores may lead to
inactive and molecular obese compounds, the
design of hybrid molecules has generated
immense interest in medicinal chemists as it can
lead to compounds with superior efficacy while
By using human RBCs, hemolytic activity for all
the test compounds was evaluated and the results
showed that all the compounds were non-
hemolytic (Figure 3A). Among all the compounds,
22 and 27 were selected to screen in the MTT
assay as these molecules showed a lower MIC
values and no hemolytic activity (Figure 3A).
circumventing the problem of resistance.16,
17
Increasingly in literature examples of hybrid
molecules, incorporating chalcone and thiazoles
are reported as being active as antimicrobials.18
Thus keeping in view the antimicrobial potential
of chalcones and thiazoles, it was envisaged that
the synthesis and antibacterial evaluation of
hitherto novel chalcone-thiazole hybrids is worth
the attempt. Figure 1 shows the representative
structures of potent antibacterial compounds that
contain either chalcone or thiazoles and form the
basis of our designed prototype.
Scheme 1. Synthesis of chalcone-thiazole hybrids.
OH
OH
R
R1
OH
R
R
CHO
R
CHO
(i), (ii)
(iii)
7
8
9
tert-butyl
tert-butyl
tert-butyl
4- MeC6H4
4- MeOC6H4
C4H3O
CHO
1-3
10 tert-butyl
11 Isopropyl
12 Isopropyl
13 Isopropyl
14 Isopropyl
15 n-propyl
C4H3S
R
4-6
4- MeC6H4
4- MeOC6H4
C4H3O
C4H3S
C4H3O
R1
O
7-15
1,4 tert-butyl
2,5 Isopropyl
3,6 n-propyl
S
O
The synthetic routes for the preparation of the
target chalcone-thiazole hybrids are depicted in
the scheme 1. The synthesis of aromatic
dicarbaldehydes (4-6) were achieved by the Duff
formylation reaction on 2- substituted phenols
with hexamethylenetetramine (HMTA) and
trifluoroacetic acid (TFA) at 120 oC followed by
hydrolysis using 10% aqueous H2SO4.19 The
regioselective synthesis of chalcones(7-15) was
S
H2N
(iv)
Br
R2
N
H2N
NH2
R2
16-18
19-21
OH
OH
S
R2
R
CHO
R
N
S
N
(v)
H2N
N
R2
22-34
R1
O
R1
O
R
R1
R2
22 tert-butyl 4- MeC6H4
23 tert-butyl 4- MeOC6H4
COOC2H5
COOC2H5
COOC2H5
COOC2H5
C6H4OCH3
C6H4(OCH3)2
C6H4(OCH3)2
C6H4(OCH3)2
C6H4OCH3
COOC2H5
COOC2H5
COOC2H5
COOC2H5
achieved using acid catalyzed
between aromatic dicarbaldehydes
condensation
and
24 tert-butyl
25 tert-butyl
26 tert-butyl
27 tert-butyl
28 tert-butyl
29 tert-butyl
30 tert-butyl
31 Isopropyl
32 Isopropyl
33 n-propyl
34 Isopropyl
C4H3O
C4H3S
4- MeC6H4
4- MeC6H4
4- MeOC6H4
C4H3S
substituted acetophenones.20 The 2-aminothiazole
derivatives (19-21) were synthesized by the
reaction between thiourea and phenacylbromide
derivatives in presence of ethanol as solvent.
Finally, the target compounds were synthesized
via formation of the Schiff’s bases between
chalcones (7-15) and 2-aminothiazole derivatives
(19-21) in presence of ethanol. All the new
synthesized compounds were characterized using
NMR, IR and mass spectrometry (Supporting
Information).
4- MeOC6H4
4- MeC6H4
4- MeOC6H4
C4H3O
C4H3S
o
Reagents and conditions: (i) HMTA, TFA, 120 C,
o
4h; (ii) aq. H2SO4, 100 C, 2h; (iii) conc. HCl, p-
R1C6H4COCH3, 1, 4-dioxane, 80-90 oC, 2.5-3.5 h;
(iv, v) Ethanol, reflux, 3h.
Initially, we screened all the synthesized hybrids
for their antibacterial activity in vitro with
2
ACS Paragon Plus Environment

Page 3 of 7
ACS Medicinal Chemistry Letters
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Table 1. Antibacterial activity of chalcone-thiazole hybrids
Com
poun
d
Minimum inhibitory conc.(MIC) in µM
Bacteria
Fungi
1
2
3
3a
13.1
12.7
13.8
13.3
12.2
11.6
11.2
11.7
11.9
13.5
26.1
51.2
27.5
104.9
33.6
9.8
3b
3c
3.3
3.2
13.8
3.3
12.2
1.4
5.6
11.7
3.0
13.5
26.1
51.2
13.7
104.9
0.5
4
5
6
7
8
9
10
>104.9
>101.5
>110.5
>106.7
>97.9
>92.5
>89.8
>93.9
>94.9
>108.1
>104.5
>102.4
>110.0
6.5
>104.9
>101.5
>110.5
>106.7
>97.9
>92.5
>89.8
>93.9
>94.9
>108.1
>104.5
>102.4
>110.0
1.6
6.5
12.7
13.8
13.3
12.2
5.8
11.2
23.5
11.9
27.0
26.1
51.2
27.5
1.6
6.5
>104.9
>101.5
>110.5
>106.7
>97.9
>92.5
>89.8
>93.9
>94.9
>108.1
>104.5
>102.4
>110.0
3.3
>104.9
>101.5
>110.5
>106.7
>97.9
>92.5
>89.8
>93.9
>94.9
>108.1
>104.5
>102.4
>110.0
>104.9
>33.6
>156.6
0.7
>104.9
>101.5
>110.5
>106.7
>97.9
>92.5
>89.8
>93.9
>94.9
>108.1
>104.5
>102.4
>110.0
104.9
33.6
>104.9
>101.5
>110.5
>106.7
>97.9
>92.5
>89.8
>93.9
>94.9
>108.1
>104.5
>102.4
>110.0
104.9
33.6
>104.9
>101.5
>110.5
>106.7
>97.9
>92.5
>89.8
>93.9
>94.9
>108.1
>104.5
>102.4
>110.0
104.9
33.6
>104.9
>101.5
>110.5
>106.7
>97.9
>92.5
>89.8
>93.9
>94.9
>108.1
>104.5
>102.4
>110.0
104.9
33.6
>104.9
>101.5
>110.5
>106.7
>97.9
>92.5
>89.8
>93.9
>94.9
>108.1
>104.5
>102.4
>110.0
104.9
33.6
22
23
12.7
13.8
6.7
12.2
5.8
11.2
11.7
11.9
13.5
26.1
51.2
27.5
3.3
24
25
26
27
28
29
30
31
32
33
34
Gen
22
Nor
23
Van
24
Flu
25
AmB
26
0.0
1.0
0.5
2.4
1.0
1.2
0.1
>156.6
>34.5
>54.1
>156.6
>34.5
>54.1
2.4
>156.6
>34.5
>54.1
156.6
1.4
0.1
156.6
1.4
0.3
156.6
22.1
0.3
156.6
22.1
0.5
156.6
1.4
0.0
>34.5
>54.1
>34.5 >34.5 >34.5
>54.1 >54.1 >54.1
0.0
1.E. coli (ATCC 9637), 2. P. aeruginosa (ATCC BAA-427), 3. S. aureus (ATCC 25923), 3a. S. aureus (ATCC 700699 Methicillin Resistant), 3b.
27
S. aureus (ATCC 29213), 3c. S. aureus (ATCC 33592 Methicillin & Gentamicin Resistant), 4. K. pneumonia (ATCC 27736), 5. C. albicans, 6.
28
C. neoformans, 7. S. schenckii, 8. T. mentagrophytes, 9. A. fumigates, 10. C. parapsilosis (ATCC 22019); Gen. Gentamicin, Nor.
29
Norfloxacin, Van. Vancomycin, Flu. Fluconazole; AmB, Amphotericin-B.
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Effect of chalcone-thiazole hybrids on eukaryotic cells. (A) Influence of test compounds (22-
36) on erythrocytes in the absence of human serum. Hemolytic effects of the test compounds were
investigated and the corresponding data for vancomysin and polymyxin B-sulphate are included for
comparison. RBC was incubated at 100 µg/mL and 2 % Trition X-100 was used as positive control.
Hemoglobin released was measured at 540 nm and is expressed as a percentage of Trition X-100
induced hemolysis. (B) The MTT assay (right top panel) was used to measure the viability of
Mammalian fibroblast cell line, L929 in the presence of compounds 22 and 27. In the assay, enzymes
associated with metabolic activity will modify the MTT into a dye, blue formazan which is measured at
550 nm. (C) Morphological changes on the L929 were investigated by using phase contrast microscopy.
Cells were incubated for 24 hours at 1X MIC for 24 hours and stained with Giemsa stain before
observing under the phase contrast microscope for the morphological changes.
3
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 4 of 7
1
2
3
4
5
A
B
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. Static and cidal curve with different concentrations of compound 27 (A). Compound 27 (1X and 10
X of MIC concentration) were incubated with S. aureus for 24h and at regular time points aliquot was taken
and CFU was calculated. In vivo antimicrobial activity of the compound 27 (B). BALB/C mice were initially
made neutropenic by injecting cyclophosphamide (150 mg/Kg of body weight), followed by S. aureus ATCC
29213 injection. After 3 hour of post infection, compound 27 and vancomycin at 15 mg/Kg of body weight was
injected into mice for 2 times at an interval of 3 hours between injection. After 24 hours, the mice were
sacrificed and the organs (spleen, kidney, liver) were crushed before plating them on the TH plates for CFU
determination. The data from three independent experiments were pooled and the P-value was determined
using the ANOVA on ranks by using Sigma stat software (***P<0.001 and **P<0.05).
These results clearly demonstrated that the tested
molecules do not have any toxicity issue at tested
(10X MIC) concentrations. In order to prove that
the test molecules are indeed non-toxic, MTT
assay was carried out to measure the toxicity of 22
and 27 against mammalian fibroblast cell line,
L929 (Figure 3B). Results showed that the tested
compounds did not show any toxicity against
L929 cells at MIC and lower concentrations. Even
though the test compounds did not have any
immediate toxic effects, we were interested to
investigate whether the molecules induced any
morphological changes over 24h (Figure 3C). L929
cells were exposed to test compounds at 1X MIC,
followed by staining and observed under the
phase contrast microscope to see any changes in
the morphology of the cells. Results demonstrated
that the test compounds have no immediate
toxicity nor induced any morphological changes.
In comparison to control, compound treated L929
cells were normal in appearance, transparent and
attached to the surface of the wells of tissue
culture plate (Figure 3C).
In order to investigate the possible in vivo efficacy
of compound 27, we injected the compound into
mice infected intraperitoneally with S. aureus
ATCC 29213. In the control group, mice injected
with bacteria developed severe signs of sepsis
whereas the treatment group mice showed
symptoms of mild to average sick behavior, but
later recovered upon second dose of injection.
Compared to the controls, treatments with
compound 27 yielded a increase in survival and
significantly lower bacterial numbers in the spleen
and liver of the animals as compared to kidney
(Figure 4B). We believe that the lower activity of
the drug in the kidney may be due to excretion of
the drug through urine or drug metabolism.21
In conclusion, we have designed and synthesized
a new class of hybrids by using pharmacophore
hybridization approach. The majority of these
hybrid compounds, especially, 27, exhibited
promising in vitro and in vivo antibacterial
activity against S. aureus. Furthermore, these
compounds were not showing the hemolytic
activity against human erythrocytes at 50μg/ml
concentration. Further studies to unravel the
mechanism of action and structural optimization
of this lead are currently underway in our
laboratory. It is intended that this study will help
to discover and develop new class of next
generation antibacterial agents.
Next, in order to determine whether the
compounds
exhibited
time-dependent
or
concentration-dependent antimicrobial activity,
compound 27 was tested at 1X and 10X MIC
against S. aureus ATCC 29213 and aliquots were
plated at regular intervals. As can be seen in
Figure 4A, the compound exhibits concentration
dependent activity with a 10 log10 reduction in cfu
in comparison to no-drug control at 24h, which is
comparable to levofloxacin. Based upon the above
results, we were of opinion that the developed
molecule could be tested in vivo conditions.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization of all
compounds together with protocols for biological
assays are available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
4
ACS Paragon Plus Environment

Page 5 of 7
ACS Medicinal Chemistry Letters
1
2
3
4
5
6
7
8
9
Corresponding Author
benzothiazole- and benzoxazoleureas. J. Med.
Chem. 1969, 12, 1016-1018.
Email:kv_sashidhara@cdri.res.in,
sashidhar123@gmail.com (Dr. Koneni V. Sashidhara)
(12) Desroy, N.; Denis, A.; Oliveira, C.;
Atamanyuk, D.; Briet, S.; Faivre, F.; LeFralliec, G.;
Bonvin, Y.; Oxoby, M.; Escaich, S.; Floquet, S.;
Drocourt, E.; Vongsouthi, V.; Durant, L.; Moreau,
F.; Verhey, T. B.; Lee, T. W.; Junop, M. S.; Gerusz,
V. Novel HldE-K Inhibitors Leading to Attenuated
Gram Negative Bacterial Virulence. J. Med. Chem.
2013, 56, 1418-1430.
(13) Mohammad, H.; Mayhoub, A. S.; Ghafoor, A.;
Soofi, M.; Alajlouni, R. A.; Cushman, M.; Seleem,
M. N. Discovery and Characterization of Potent
Thiazoles versus Methicillin- and Vancomycin-
Resistant Staphylococcus aureus. J. Med. Chem.
2014, 57, 1609-1615.
Tel.: +91 9919317940; Fax: +91-522-2623405.
ACKNOWLEDGMENT
KBR and RKM are thankful to CSIR, New Delhi, PK
for UGC, IS for ICMR fellowships. We thank to SAIF
division, CSIR-CDRI for the analytical facilities and
A.Lal for technical assistance. This is CSIR-CDRI
communication number 8996.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
(1) Antibiotic resistance threats in the United
States.
Available
from:
http://www.cdc.gov/drugresistance/threat-report-
2013/pdf/ar-threats-2013-508.pdf In Centers for
Disease Control and Prevention (CDC). Atlanta:
CDC, 2013.
(2) Chugh, T. D. Emerging and re-emerging
bacterial diseases in India. J. Biosci. 2008, 33, 549-
555.
(3) Spaulding, A. R.; Salgado-Pabon, W.;
Merriman, J. A.; Stach, C. S.; Ji, Y.; Gillman, A. N.;
Peterson, M. L.; Schlievert, P. M. Vaccination
Against Staphylococcus aureus Pneumonia. J.
Infect. Dis. 2013, 209, 1955-1962.
(4) Donadio, S.; Maffioli, S.; Monciardini, P.;
Sosio, M.; Jabes, D. Antibiotic discovery in the
twenty-first century: current trends and future
perspectives. J. Antibiot (Tokyo). 2010, 63, 423-
430.
(5) Livermore, D. M. The need for new antibiotics.
Clin. Microbiol. Infect. 2004, 10 Suppl 4, 1-9.
(6) Brotz-Oesterhelt, H.; Sass, P. Postgenomic
strategies in antibacterial drug discovery. Future
Microbiol. 2010, 5, 1553-1579.
(7) Fournier, P. E.; Raoult, D. Prospects for the
Future Using Genomics and Proteomics in
Clinical Microbiology. Annu. Rev. Microbiol. 2011,
65, 169-188.
(14) Khalaf, A. I.; Waigh, R. D.; Drummond, A. J.;
Pringle, B.; McGroarty, I.; Skellern, G. G.;
Suckling, C. J. Distamycin analogues with
enhanced
lipophilicity:
Synthesis
and
antimicrobial activity. J. Med. Chem. 2004, 47,
2133-2156.
(15) LaMarche, M. J.; Leeds, J. A.; Amaral, A.;
Brewer, J. T.; Bushell, S. M.; Deng, G. J.; Dewhurst,
J. M.; Ding, J.; Dzink-Fox, J.; Gamber, G.; Jain, A.;
Lee, K.; Lee, L.; Lister, T.; McKenney, D.; Mullin,
S.; Osborne, C.; Palestrant, D.; Patane, M. A.;
Rann, E. M.; Sachdeva, M.; Shao, J.; Tiamfook, S.;
Trzasko, A.; Whitehead, L.; Yifru, A.; Yu, D. H.;
Yan, W. L.; Zhu, Q. M. Discovery of LFF571: An
Investigational Agent for Clostridium difficile
Infection. J. Med. Chem. 2012, 55, 2376-2387.
(16) Marco-Contelles, J.; Soriano, E. The Medicinal
Chemistry of Hybrid-Based Drugs Targeting
Multiple Sites of Action. Curr. Top. Med. Chem.
2011, 11, 2714-2715.
(17) Viegas-Junior, C.; Danuello, A.; Bolzani, V. D.;
Barreir, E. J.; Fraga, C. A. M. Molecular
hybridization: A useful tool in the design of new
drug prototypes. Curr. Med. Chem. 2007, 14, 1829-
1852.
(18) Liaras, K.; Geronikaki, A.; Glamoclija, J.; Ciric,
A.; Sokovic, M. Thiazole-based chalcones as
potent antimicrobial agents. Synthesis and
biological evaluation. Bioorg. Med. Chem. 2011, 19,
3135-3140.
(19) Sashidhara, K. V.; Kumar, M.; Khedgikar, V.;
Kushwaha, P.; Modukuri, R. K.; Kumar, A.;
Gautam, J.; Singh, D.; Sridhar, B.; Trivedi, R.
Discovery of Coumarin-Dihydropyridine Hybrids
as Bone Anabolic Agents. J. Med. Chem. 2013, 56,
109-122.
(20) Sashidhara, K. V.; Kumar, A.; Kumar, M.;
Sarkar, J.; Sinha, S. Synthesis and in vitro
evaluation of novel coumarin-chalcone hybrids as
potential anticancer agents. Bioorg. Med. Chem.
Lett. 2010, 20, 7205-7211.
(8) Nowakowska, Z. A review of anti-infective and
anti-inflammatory chalcones. Eur. J. Med. Chem.
2007, 42, 125-137.
(9) de Carvalho Tavares, L.; Johann, S.; Maria de
Almeida Alves, T.; Guerra, J. C.; Maria de Souza-
Fagundes, E.; Cisalpino, P. S.; Bortoluzzi, A. J.;
Caramori, G. F.; de Mattos Piccoli, R.; Braibante,
H. T.; Braibante, M. E.; Pizzolatti, M. G.
Quinolinyl and quinolinyl N-oxide chalcones:
synthesis, antifungal and cytotoxic activities. Eur.
J. Med. Chem. 2011, 46, 4448-4456.
(10) Nielsen, S. F.; Larsen, M.; Boesen, T.;
Schonning, K.; Kromann, H. Cationic chalcone
antibiotics. Design, synthesis, and mechanism of
action. J. Med. Chem. 2005, 48, 2667-2677.
(11) Paget, C. J.; Kisner, K.; Stone, R. L.; DeLong, D.
(21) Lohr, J. W.; Willsky, G. R.; Acara, M. A. Renal
drug metabolism. Pharmacol. Rev. 1998, 50, 107-
141.
C.
Immunosuppressive and antiviral activity of
Heterocyclic
substituted
ureas.
II.
5
ACS Paragon Plus Environment

ACS Medicinal Chemistry Letters
Page 6 of 7
1
2
3
4
5
6
7
8
For Table of Contents Use Only
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Novel chalcone-thiazole Hybrids as Potent Inhibitors of
Drug Resistant Staphylococcus Aureus
Koneni V. Sashidhara*, K. Bhaskara Rao, Pragati Kushwaha, Ram K. Modukuri,
Pratiksha Singh, Isha Soni, P. K. Shukla, Sidharth Chopra and Mukesh Pasupuleti
Table of Contents
6
ACS Paragon Plus Environment

Page 7 of 7
ACS Medicinal Chemistry Letters
1
2
3
4
For Table of Contents Use Only
5
6
7
Novel chalcone-thiazole Hybrids as Potent Inhibitors of
Drug Resistant Staphylococcus Aureus
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Koneni V. Sashidhara*, K. Bhaskara Rao, Pragati Kushwaha, Ram K. Modukuri, Pratiksha
Singh, Isha Soni, P. K. Shukla, Sidharth Chopra and Mukesh Pasupuleti
Table of Contents
O
OH
S
O
N
N
O
om oun
d 2
p
7
C
.
=
on
e
c
n an
en am c n res s an
i i i t
a ococcus aureus
p y
h l
MI 5 8 µM
M thi illi
d
t
t
t
C
G
S
ATC 33592
C
(
)
1
ACS Paragon Plus Environment