Design and synthesis of 4′-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methyl)biphenyl-2-carbonitrile analogs as bacterial peptide deformylase inhibitors

Article abstract of DOI:10.1111/cbdd.12817

Herein, we report the synthesis and screening of 4′-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methyl)biphenyl-2-carbonitrile analogs 11(a–j) as bacterial peptide deformylase (PDF) enzyme inhibitors. The compounds 11b (IC₅₀ value?=?139.28?μm), 11g (IC₅₀ value?=?136.18?μm), and 11h (IC₅₀ value?=?131.65?μm) had shown good PDF inhibition activity. The compounds 11b (MIC range?=?103.36–167.26?μg/mL), 11g (MIC range?=?93.75–145.67?μg/mL), and 11h (MIC range?=?63.61–126.63?μg/mL) had also shown potent antibacterial activity when compared with standard ampicillin (MIC range?=?100.00–250.00?μg/mL). Thus, the active derivatives were not only PDF inhibitors but also efficient antibacterial agents. To gain more insight on the binding mode of the compounds with PDF enzyme, the synthesized compounds 11(a–j) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. The results suggest that this class of compounds has potential for development and use in future as antibacterial drugs.

Full text of DOI:10.1111/cbdd.12817

Received Date : 04-May-2016
Revised Date : 28-Jun-2016
Accepted Date : 02-Jul-2016
Article type : Research Letter
Design
and
synthesis
of
4'-((5-benzylidene-2,4-dioxothiazolidin-3-
yl)methyl)biphenyl-2-carbonitrile
analogs
as
bacterial
Peptide
deformylaseinhibitors
1
2
3
Firoz A. Kalam Khan , Rajendra H. Patil , Devanand B. Shinde , Jaiprakash N.
Sangshetti 1*
1
Y.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Aurangabad 431001 (M.S.),
India
2 Department of Biotechnology, Savitribai Phule Pune University, Pune 411007 (M.S.), India
3 Shivaji University, Vidyanagar, Kolhapur 416 004 (M.S.), India
*Corresponding author. Tel.: +91 240-2381129.
E-mail address: jnsangshetti@rediffmail.com (J.N. Sangshetti).
Herein, we report the synthesis and screening of 4'-((5-benzylidene-2,4-dioxothiazolidin-3-
yl)methyl)biphenyl-2-carbonitrile analogs 11(a-j) as bacterial Peptide deformylase (PDF)
enzyme inhibitors. The compounds 11b (IC50 value= 139.28 µM), 11g (IC50 value= 136.18
µM) and 11h (IC50 value= 131.65 µM) had shown good PDF inhibition activity. The
compounds 11b (MIC range= 103.36-167.26 µg/mL), 11g (MIC range= 93.75-145.67
µg/mL) and 11h (MIC range= 63.61-126.63 µg/mL) had also shown potent antibacterial
activity when compared with standard ampicillin (MIC range= 100.00-250.00 µg/mL).
Thus, the active derivatives were not only PDF inhibitors but also efficient antibacterial
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/cbdd.12817
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agents. In order to gain more insight on the binding mode of the compounds with PDF
enzyme, the synthesized compounds 11(a-j) were docked against PDF enzyme of E. coli and
compounds exhibited good binding properties. The results suggest that this class of
compounds has potential for development and use in future as antibacterial drugs.
Keywords: biphenyl, thiazolidinedione, bacterial PDF inhibition, antibacterial activity,
molecular docking study
Running title: Bacterial PDF inhibition of biphenyl-thiazolidinedione
The discovery of antibiotics and their impact on bacterial infections represents one of the great
success stories of 20th –century medicine but there is growing concern about increasing antibiotic
resistance (1).The latest antibiotic Linezolid (Zyvox TM) was approved by US-FDA in 2000,
unfortunately, already a few cases of Linezolid resistance pathogens in hospital isolates have
been reported (2).While vancomycin is an efficient therapeutic agent for most antibiotic-resistant
Gram-positive bacteria, vancomycin-resistant S. aureus was reported in U.S. in 2002 (3, 4). This
crisis has resulted in an intensive research effort to develop a new class of compounds that
exhibit novel mechanisms of antibacterial activity. Although microbial genomes have revealed
an abundance of potentially useful targets, little has so far resulted from these much-heralded
efforts (5-7). Recent reports from several laboratories have suggested that peptide deformylase
(PDF), an enzyme responsible for removing the N-terminal of formyl group from newly
synthesized polypeptides and may be suitable target for antibacterial drug discovery (8-10). PDF
is present in all bacteria and essential for bacterial survival (11). Indeed, PDF inhibitors have
been reported to act as broad-spectrum antibacterial agents (12). The fact that the PDF is
essential for producing the mature protein in bacterial cells provides a rational basis to choose it
as a potential and novel target for antibacterial agents.
In the past few years, different classes of PDF inhibitor like, peptidic inhibitors, pseudopeptidic
inhibitors and non-peptidic inhibitors as antibacterial agents have been reported (13). The non
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peptidic PDF inhibitors, which are assumed to be less prone to degradation, are not much
explored (14-19). The non-peptidic inhibitors like, biaryl acid analogues were developed by
Merck Research Laboratories and evaluated as PDF inhibitor against E. coli PDF enzyme.A
representative structure for these biaryl acid analogs is shown in Figure 1. The biaryl acid
analogs are composed of a “head group” of aromatic/heterocyclic rings, a biaryl group, and an
acidic group on the biaryl B-ring. Structure-activity relationship (SAR) studies of biaryl acid
analogues revealed that substitution at the head group, biaryl group, and the nature of acidic
group all contributed to the inhibitory activity of these compounds against PDF enzyme. The
acidic group of these compounds may bind to the metal ion and instead interact with an amino
acid residue within PDF active site much like the binding of the angiotensin II receptor.The
structure of two biaryl acid compounds 1 (IC50= 3.9 μM) and 2 (IC50= 22.8 μM) are presented in
Figure 2 (20).The thiazolidinedione (TZD) scaffold has attracted significant interest of
researchers and has become an important class of heterocyclic compounds because of their utility
for miscellaneous biological activities including antimicrobial activity (21, 22). The structure of
two antibacterial compounds 3 (MIC range= 6.25-12.5 μg/mL) (23) and 4 (MIC range= 4.00-
128.00 μg/mL) (24) having TZD scaffold are presented in Figure 2. With aim to improve the
antibacterial activity of biaryl acid analogs as PDF inhibitors, we coupled the biphenyl moiety
and TZD nucleus. Based on these reports, we, therefore, decided to explore some new biphenyl
containing cyano (-CN) group as acid pharmacophore coupled with TZD scaffold for bacterial
PDF enzyme inhibition activity.
In continuous of our work on synthesis of bioactive molecules (25-29), we report the synthesis of
a novel series of 4'-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methyl)biphenyl-2-carbonitrile
analogs 11(a-j), and the study of their effects on inhibition of E. coli PDF enzyme. The various
aromatic rings with different substituent have been introduced at “head group” position of TZD
with aim to improve the overall properties of the synthesized series. The compounds were also
evaluated for antibacterial activity against Gram-negative bacteria namely, E. coli and Gram-
positive bacteria namely, B. subtilis. To explore the underlying mechanisms of PDF inhibition,
we docked synthesized compounds against E. coli PDF enzyme.
The synthetic approaches employed for synthesis of titled compounds 11(a-j) are outlined in
Scheme 1. 2,4-thiazolidinedione 7 was synthesized by refluxing commercially available starting
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materials thiourea 5 and chloracetic acid 6(30). The compounds 8(a-j) was synthesized via
Knoevenagel condensation reaction by reacting 2,4-thiazolidinedione 7 and various aromatic
aldehydes in presence of sodium acetate and acetic acid (31). The 4'-(bromomethyl)biphenyl-2-
carbonitrile 10 was synthesized from commercially available 4'-methylbiphenyl-2-carbonitrile 9
in good yield (85 %) according to published procedure (32). Further, to expand the series, the
compounds 11(a-j) were prepared by reacting the compound 10 with various synthesized
compounds 8(a-j)in N,N-dimethylformamide (DMF) using K2CO3 as catalyst (Supporting
information). The compounds 11(a-j) were obtained in good yields (74-86 %). The compounds
11(a-j) were characterized by means of IR, 1H NMR, 13C NMR and Mass Spectrometry and data
confirmed the proposed structures (Supporting information).
The PDF enzyme was extracted from E. coli (NCIM-2931) bacteria and stabilized using 5 mM
NiCl2. The synthesized compounds 11(a-j) were tested against E. coli PDF-Ni enzyme using
spectrophotometric method (33). The IC50 values (concentration that decreased PDF by 50 %) of
synthesized compounds is presented in Table 1. The synthesized compounds 11(a-j) had shown
moderate (IC50 range= 131.65- 227.54 μM) PDF inhibition activity. Compounds 11b (IC50=
139.28μM), 11g (IC50= 136.18μM) and 11h (IC50= 131.65μM) were considered to be shown as
significantE. coli PDF-Ni enzyme inhibition activity when compared with other synthesized
compounds. Compounds 11a (IC50= 179.33 μM), 11c (IC50= 227.54 μM), 11d (IC50= 152.41
μM), 11e (IC50= 214.58 μM), 11f (IC50= 204.87μM), 11i (IC50= 172.39 μM) and11j (IC50=
176.21μM) were found to be less active against E. coli PDF-Ni enzyme when compared with
other active compounds11b, 11g and 11h.
Structure-activity studies of 4'-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methyl)biphenyl-2-
carbonitrile analogs11(a-j) revealed that head group, biaryl group and acidic group (-CN) all
contributed to inhibitory activity against bacterial PDF enzyme. The compounds 11(a-j) showed
varied PDF inhibition activity depending upon the various substituents present on phenyl ring
(head group). From the assay data summarized in Table 1, compound 11a (IC50= 179.33 μM)
with Ar= phenyl showed less PDF inhibition activity. Introduction of 4-Cl substituent on phenyl
ring 11b (IC50= 139.28 μM) led to increase in PDF inhibition activity by 1.5 fold when compared
with compound 11a. The replacement 4-Cl with 2-Cl11c (IC50= 227.54 μM) on phenyl ring led
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to decrease in PDF inhibition activity by 2 folds and gave least active compounds of the
synthesized series 11(a-j). The replacement of 4-Cl substituent with 4-F 11d (IC50= 152.41 μM)
on phenyl ring led to decrease in PDF enzyme inhibition activity. The introduction of 2,6-di-
Cl11h (IC50= 131.65 μM) led to most potent PDF inhibitors of the synthesized series 11(a-j).
Further, replacement of 4-Cl with 4-OCH3 11e (IC50= 214.58 μM) showed decrease in PDF
enzyme inhibition activity by 1.5 fold. The substitution of 2,4-di-OCH3 group on phenyl ring 11f
(IC50= 204.87 μM) led to decrease in PDF inhibition activity. The replacement of 2,4-di-OCH3
group with 2,5-di-OCH311g (IC50= 136.18 μM) and 3,4-di-OCH311i (IC50= 172.39 μM) showed
improved PDF inhibition activity by 1.5 fold when compared with compound 2,4-di-OCH311f.
The introduction of 3,4,5-trimethoxygroup on phenyl ring 11j (IC50= 176.21 μM) showed similar
PDF inhibition activity when compared with compound 11a(IC50= 179.33 μM). Thus,
compounds 11b, 11dand 11h with electron withdrawing groups (except 11c) like, halogens were
more active than compounds 11e, 11f, 11i and 11j (except 11g) with electron donating groups
like, -OCH3, on phenyl ring .
The antibacterial activity was evaluated against one Gram-negative bacteria namely, E. coli
(NCIM-2256) and one Gram-positive bacteria namely, B. subtilis (NCIM-2063) using ampicillin
as standard drug. Minimum inhibitory concentration (MIC) values were determined using
standard agar method (34). Dimethyl sulfoxide was used as solvent control. MIC values of the
tested compounds are presented in Table 1. Interestingly, our results demonstrated that most
potent PDF inhibitors that is 11b (MIC range= 167.26-103.36 μg/mL), 11g(MIC range= 145.67-
93.75 μg/mL) and 11h (MIC range= 63.61-126.63 μg/mL) showed also a significantly potent
antibacterial activity against E. coli and B. subtilis when compared with standard ampicillin
(MIC range= 100.00-250.00 μg/mL). All the synthesized compounds 11(a-j) (MIC range=
63.61-251.97 μg/mL) had shown significant antibacterial activity when compared with
ampicillin (MIC range= 100.00-250.00 μg/mL). All the synthesized compounds, except 11j
(MIC= 251.97 μg/mL) had shown better antibacterial activity against B. subtiliswhen compared
with standard ampicillin(MIC= 250.00 μg/mL). The compounds 11a (MIC= 84.23 μg/mL), 11f
(MIC= 88.65 μg/mL), 11g (MIC= 93.75 μg/mL), 11h (MIC= 63.61 μg/mL), 11i (MIC= 91.29
μg/mL) and 11j (MIC= 78.55 μg/mL) had shown better antibacterial activity against E. coli
when compared with standard ampicillin(MIC= 100.00 μg/mL). Compounds 11a, 11f, 11g, 11h
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and 11i had shown broad spectrum of antibacterial activity against both Gram-positive (B.
subtilis) and Gram-negative (E. coli) bacteria when compare with standard ampicillin.
The activity data (Table 1) revealed that synthesized compounds 11(a-j) had significant
antibacterial activity. The replacement of H atom of phenyl ring of head group 11a (MIC range=
84.23-228.15 μg/mL) by 4-Cl11b resulted improved in antibacterial activity against B. subtilis
(MIC= 167.26 μg/mL) but decrease in activity againstE. coli(MIC= 103.36 μg/mL). The
replacement of 4-Cl by 2-Cl11c on phenyl ring improved the antibacterial activity against B.
subtilis (MIC= 118.38 μg/mL) by 1.5 fold and decrease in activity against E. coli (MIC= 155.45
μg/mL) by 1.5 fold. When 4-Cl11b was replaced with 4-F 11d on phenyl ring, there was increase
in antibacterial activity against B. subtilis (MIC= 96.59 μg/mL) by 1.7fold bur there was no
significant change in antibacterial activity against E. coli (MIC= 102.29 μg/mL). Introduction of
2,6-di-Cl11h (MIC range= 63.61-126.63 μg/mL) on phenyl ring led to most potent antibacterial
when compared with remaining synthesized compounds. Further, introduction of 4-OCH3 11e on
phenyl ring resulted in decrease in antibacterial activity against E. coli (MIC= 123.33 μg/mL)
and increase in activity against B. subtilis (MIC= 179.69 μg/mL) when compared with
compound 11a. The introduction of 2,4-di-OCH311f (MIC range= 88.65-165.59 μg/mL), 2,5-di-
OCH311g (MIC range= 93.75-145.67 μg/mL) and 3,4-di-OCH311i (MIC range= 91.29-206.56
μg/mL) had shown significant antibacterial activity when compared with standard ampicillin
(MIC range= 100.00-250.00 μg/mL). The introduction of 3,4,5-tri-OCH311jhad shown improved
antibacterial activity against E. coli(MIC= 78.55 μg/mL) but led to least activeagainst B.
subtilis(MIC= 251.97 μg/mL) when compared with ampicillin. The activity data suggested that
compounds 11e, 11f, 11g, 11i and 11j with electron-donating substituent like, -OCH3on phenyl
ring of head group showed better antibacterial activity against E. colithan compounds 11b, 11c
and 11d with electron-withdrawing substituent (except 11h) like,-Cl and -F group. On the other
hand, compounds 11b, 11c, 11dand 11h with electron-withdrawing substituent like, halogens
onphenyl ring of head group showed better antibacterial activity against B. subtilis than
compounds 11e, 11f, 11g, 11i and 11jwith electron-donating substituent like, -OCH3.
In order to gain more insight on the binding mode of the compounds with Peptide deformylase
(PDF), we docked the synthesized compounds 11(a-j) against crystal structure of E. coli PDF-Ni
(PDB ID: 1G2A) (35) which is obtained Protein Data Bank. The standard operating procedure
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implemented in VLife MDS 4.3 package was followed for GRIP batch docking of final
synthesized compounds against three-dimensional structures of E. coli PDF-Ni enzyme (36).
Docking calculation and hydrogen bond interactions are shown in Table 2. The interaction
energy of the compounds 11(a-j) and their PDF inhibition activity showed the corresponding
results. The active compounds 11b, 11g and 11h showed lowest interaction energy that is -61.57
kcal/mol, -63.10 kcal/mol and -70.13 kcal/mol, respectively. The docking results indicated that
thesynthesized compounds 11(a-j) held in the active pocket by combination of hydrophobic and
van der Waals interactions with the PDF enzyme. The various hydrophobic and van der Waal’s
interactions occurred between these compounds and active site of PDF enzyme include GLU41,
GLU42, GLY43, ILE44, GLY45, ILE86, GLU87, GLU88, GLY89, CYS90, LEU91, PRO94,
GLU95, ARG97, LEU125, ILE128, CYS129 and HIS132.
The docking study of most active compound 11h revealed (Figure 3) that compound is buried
deep into the active site by forming various hydrophobic and van der Waal’s interactions with
amino acid residues like, GLU41, GLY43, ILE44, GLY45, ILE86, GLU87, GLU88, GLY89,
CYS90, GLU95, LEU91, ARG97, LEU125, ILE128 and HIS132. The amino acids ILE44 (2.26
Å) and ARG97 (1.46 Å) had formed strong hydrogen bonds with oxygen of 2-C=O
(thiazolidinone nucleus) and nitrogen of CN group, respectively with compound 11h. The chloro
groups were held in active pocket by forming interactions with amino acid residues like, GLU87,
GLU88, GLY89, ILE128, CYS129 and HIS132. Thus, chloro group may be responsible for
increased in PDF inhibition activity.The docking study of least active compound 11c (Figure 3)
had shown least binding energy that is -33.07 kcal/mol. The docking study revealed that
compound 11c was held in active pocket by forming various hydrophobic and van der Waal’s
interactions with amino acid residues like, GLY43, ILE44, GLY45, LEU46, ILE86, GLU87,
GLU88, GLY89, CYS90, LEU91, ARG97, LEU125, ILE128, CYS129, HIS132, GLU133 and
HIS136. The amino acids GLY89 (2.29 Å) and ARG97 (2.24 Å) had formed strong hydrogen
bonds with oxygen of 4-C=O (thiazolidinone nucleus) and nitrogen of CN group, respectively
with compound 11c. The chloro group had formed weak van der Waal’s interactions with amino
acids GLY45 and HIS136. Due to poor binding interactions with PDF enzyme, compound 11c
may have shownthe least PDF enzyme inhibition activity among the synthesizedcompounds.
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In summary, a series of 4'-((5-benzylidene-2,4-dioxothiazolidin-3-yl)methyl)biphenyl-2-
carbonitrile analogs 11(a-j) was synthesized efficiently in good yields. The synthesized
compounds were evaluated for in vitrobacterial PDF enzyme inhibition and antibacterial
activities. The compounds 11b (IC50= 139.28 μM), 11g (IC50= 136.18 μM) and 11h (IC50=
131.65 µM) showed good PDF enzyme inhibition activity. Also, these active compounds 11b
(MIC range= 103.36-167.26 µg/mL), 11g (MIC range= 93.75-145.67 µg/mL) and 11h (MIC
range= 63.61-126.63 µg/mL) had shown potent antibacterial activity when compared with
standard ampicillin (MIC range= 100.00-250.00 µg/mL). Further, to understand the mechanism
of PDF inhibition, we docked the synthesized compounds 11(a-j) against E. coli PDF-Ni
enzyme. Molecular docking study showed good binding of these compounds to the active site of
E. coli PDF-Ni enzyme and thus had potential to inhibit PDF enzyme.These preliminary
encouraging results of biological screening of the tested compounds could offer an excellent
framework in this field that may lead to discovery of potent and novel antibacterial agent.
Acknowledgements
The author FAKK andJNS is grateful to Department of Science and Technology (DST), New
Delhi, India for Fast Track Project (SR/FT/LS119/2012). The authors are also thankful to the
Mrs. FatmaRafiqZakaria, Chairman, Maulana Azad Educational Trust and Dr. Zahid Zaheer,
Principal, Y.B. Chavan College of Pharmacy, Dr. RafiqZakaria Campus, Aurangabad 431 001
(M.S.), India for constant support and providing necessary facilities.Authors are also thankful to
SAIF, Punjab University, India for providing spectra.
Conflicts of interest
Authors have no conflicts of interest.
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Figure Legends
Figure 1. General structure of biaryl acid analogs for bacterial PDF enzyme inhibition.
Figure 2. The structures of reported of biaryl acid analogs, thiazolidinedione derivatives and
synthesized compounds 11(a-j).
Figure 3. Docking study of compounds 11c and11h with E. coli PDF-Ni (PDB ID: 1G2A).
Scheme
Scheme 1. Synthesis of titled compounds 11(a-j); Reagents: (a) H2O, Conc. HCl, Reflux for 12
h; (b) Ar-CHO, NaOAc, AcOH, Reflux; (c) NBS, H2O2, DCM, Reflux; (d) Compounds 8(a-j),
K2CO3, DMF, RT, Stir.
Table
Table 1: Bacterial PDF enzyme inhibition and antibacterial activities of synthesized compounds
11(a-j).
Table 2: Docking statistics of synthesized compounds 11(a-j) against E. coli PDF-Ni enzyme.
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Table 1: Bacterial PDF enzyme inhibition and antibacterial activities of synthesized compounds
11(a-j).
Entry
IC50 SEM (μM)
E. coli PDF-Ni
179.33 3.65
139.28 3.26
227.54 4.59
152.41 2.68
214.58 2.84
204.87 3.25
136.18 2.89
131.65 1.65
172.39 2.78
176.21 3.59
ND
MIC SEM (μg/mL)
E. coli
B. subtilis
228.15 4.89
84.23 2.58
11a
103.36 2.14 167.26 3.76
155.45 1.98 118.38 3.85
102.29 1.59 96.59 2.96
123.33 2.15 179.69 4.45
11b
11c
11d
11e
88.65 1.51
93.75 2.51
63.61 1.95
91.29 2.49
78.55 3.05
165.59 3.88
145.67 2.45
126.63 3.35
206.56 2.16
251.97 4.56
11f
11g
11h
11i
11j
Ampicillin
100.00 1.55 250.00 2.25
Experiments were performed in triplicates and compared to DMSO-treated controls; Standard
errors were all within 10% of the mean; ND: not done.
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Table 2: Docking statistics of synthesized compounds 11(a-j) against E. coli PDF-Ni enzyme.
Entry
Affinity
H-bonds
H-bonding ligand
H-binding receptor
Atom No. Residue Element
ILE44
H-bonds
(kcal/mol)
length (Å)
Element
4-O of TZD
N of CN
-45.16
-61.57
-33.07
-49.86
02
02
02
03
19
29
19
20
19
29
20
30
28
19
31
17
20
20
28
20
31
19
31
20
29
34
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
707
1543
707
2.44
1.64
2.38
2.09
2.29
2.24
2.01
2.46
2.19
2.29
2.00
2.00
2.45
1.86
1.64
2.26
1.46
2.02
1.85
1.86
2.07
2.32
11a
11b
11c
11d
ARG97
ILE44
4-O of TZD
2-O of TZD
4-O of TZD
N of CN
LEU91
GLY89
ARG97
ILE44
1436
1414
1542
707
2-O of TZD
N of CN
GLY89
GLU95
ILE44
1414
1500
707
F
-40.14
-46.03
-63.10
-70.13
-46.35
-48.82
02
02
02
02
02
03
4-O of TZD
N of CN
11e
11f
11g
11h
11i
ARG97
GLY89
GLY89
ILE44
1543
1414
1414
707
S of TZD
2-O of TZD
2-O of TZD
O of 2-OCH3
2-O of TZD
N of CN
ARG97
ILE44
1543
707
ARG97
GLY89
ARG97
LEU91
ARG97
CYC129
1546
1414
1542
1436
1543
2053
4-O of TZD
N of CN
2-O of TZD
N of CN
11j
O of 3-OCH3
TZD: 2,4-thiazolidinedione nucleus.
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This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.