A novel templates of piperazinyl-1,2-dihydroquinoline-3-carboxylates: Synthesis, anti-microbial evaluation and molecular docking studies

Article abstract of DOI:10.1016/j.bmcl.2018.03.007

A series of piperazinyl-1,2-dihydroquinoline carboxylates were synthesized by the reaction of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylates with various piperazines and their structures were confirmed by ¹H NMR, ¹³C NMR, IR and mass spectral analysis. All the synthesized compounds were screened for their in vitro antimicrobial activities. Further, the in silico molecular docking studies of the active compounds was performed to explore the binding interactions between piperazinyl-1,2-dihydroquinoline carboxylate derivatives and the active site of the Staphylococcus aureus (CrtM) dehydrosqualene synthase (PDB ID: 2ZCQ). The docking studies revealed that the synthesized derivatives showed high binding energies and strong H-bond interactions with the dehydrosqualene synthase validating the observed antimicrobial activity data. Based on antimicrobial activity and docking studies, the compounds 9b and 10c were identified as promising antimicrobial lead molecules. This study might provide insights to identify new drug candidates that target the S. aureus virulence factor, dehydrosqualene synthase.

Full text of DOI:10.1016/j.bmcl.2018.03.007

Accepted Manuscript
A novel templates of piperazinyl-1,2-dihydroquinoline-3-carboxylates: Synthe-
sis, anti-microbial evaluation and molecular docking studies
Saleha Banu, Rajitha Bollu, Mohammad Naseema, P. Mary Gomedhika,
Lingaiah Nagarapu, K. Sirisha, C. Ganesh Kumar, Shravan Kumar Gunda
PII:
S0960-894X(18)30182-3
https://doi.org/10.1016/j.bmcl.2018.03.007
BMCL 25661
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 December 2017
20 February 2018
2 March 2018
Please cite this article as: Banu, S., Bollu, R., Naseema, M., Mary Gomedhika, P., Nagarapu, L., Sirisha, K., Kumar,
C.G., Gunda, S.K., A novel templates of piperazinyl-1,2-dihydroquinoline-3-carboxylates: Synthesis, anti-microbial
evaluation and molecular docking studies, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/
10.1016/j.bmcl.2018.03.007
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
A novel templates of piperazinyl-1,2-dihydroquinoline-3-carboxylates: Synthesis, anti-
microbial evaluation and molecular docking studies
Saleha Banua, Rajitha Bollua, Mohammad Naseemaa, P. Mary Gomedhikaa, Lingaiah Nagarapua*, K.
Sirishab,c, C. Ganesh Kumarb,c, Shravan Kumar Gundad
aOrganic Chemistry Division II (CPC), CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, Telangana, India
bMedicinal Chemistry and Biotechnology Division (MCB), CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500
007, India
cAcademy of Scientific and Innovative Research (AcSIR), New Delhi, India
d Bioinformatics Division, PGRRCDE, Osmania University, Hyderabad 500007, India
Fax: + 91 40 27193382; Tel: +91 40 27191509; E-mail: lnagarapuiict@yahoo.com/nagarapu@iict.res.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
A series of piperazinyl-1,2-dihydroquinoline carboxylates were synthesized by the
reaction of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylates with
1
various piperazines and their structures were confirmed by H NMR, 13C NMR, IR and
Accepted
Available online
mass spectral analysis. All the synthesized compounds were screened for their in vitro
antimicrobial activities. Further, the in silico molecular docking studies of the active
compounds was performed to explore the binding interactions between piperazinyl-1,2-
dihydroquinoline carboxylate derivatives and the active site of the Staphylococcus aureus
(CrtM) dehydrosqualene synthase (PDB ID: 2ZCQ). The docking studies revealed that the
synthesized derivatives showed high binding energies and strong H-bond interactions with
the dehydrosqualene synthase validating the observed antimicrobial activity data. Based
on antimicrobial activity and docking studies, the compounds 9b and 10c were identified
as promising antimicrobial lead molecules. This study might provide insights to identify
new drug candidates that target the S. aureus virulence factor, dehydrosqualene synthase.
Keywords:
1, 2-dihydroquinoline,
piperazines,
Antimicrobial activity,
Molecular docking,
Dehydrosqualene synthase.
2017 Elsevier Ltd. All rights reserved.
N-heterocyclic compounds remain an attractive topic
activities and/or multiple pharmacological targets and/or one part
can counterbalance the side effects caused by another part.10
Modifications in the basic structure of quinolones11 have
increased their antibacterial spectrum and potency, as well as
improving bioavailability, making quinolones useful agents for
the treatment of urinary, systemic and respiratory tract infections.
Obviously, this strategy represents an encouraging approach on
the development of new agents with potential therapeutic
application.12-18
from both fundamental organic chemistry and medicinal
chemistry point of view. Among all heterocycles, the synthesis of
quinolones has received much attention from medicinal chemists
due to a wide variety of pharmacological properties attributed to
this compound class itself. They have been reported to show
typical antibacterial activity, and also displayed a typical diverse
biological profiles such as anti-tumor, anti-tubercular, anti-HIV,
antibacterial, anti-malarial activities, and the biological properties
continue to expand1-4 as shown in Fig.1. The majority of
quinolones in clinical use are fluoroquinolones which are one of
the most useful and versatile antibacterial agents, where several
candidates are already in clinical use such as Ciprofloxacin,
Norfloxacin and Ofloxacin.5 They have emerged as one of the
dominant classes of chemotherapeutic drugs for the treatment of
various bacterial infections in both community and hospital
settings.6 However, since these compounds became available for
clinical
use,
resistance
among
Methicillin-
resistant Staphylococcus aureus has been observed in different
parts of the world.7-9 Molecular hybridization, which is based on
the incorporation of two or more pharmacophores into a single
molecule, may provide novel candidates having complimentary
Fig.1. Representative examples of biologically active quinolone-
based compounds

As a part of our efforts to develop new biologically active
molecules,19 we describe the synthesis and antimicrobial
evaluation of quinolones bearing piperazines at C-4 position as
shown in Scheme 1. All the derivatives were further screened for
in vitro antimicrobial activities. In this context, we herein report
the synthesis of piperazine linked 1,2-dihydroquinoline
carboxylate hybrids in good to excellent yields as depicted in Fig.
3.
Fig. 2. Design strategy for ethyl-2-oxo-4-(piperazin-1-yl)-1,2-
dihydroquinoline-3-carboxylate hybrids.
Synthesis of intermediates and target compounds was
accomplished according to the steps illustrated in Scheme 1. The
first synthetic step involved N-alkylation of isatoic anhydride
with iodoalkanes to obtain the corresponding N-alkyl isatoic
anhydrides 2 and 3. Condensation of diethyl malonate and N-
alkyl isatoic anhydrides in the presence of sodium hydride in dry
dimethylformamide led to compounds 4 and 5 in good yields
(78%-72%).20 The corresponding 4 and 5 were further converted
into chloro derivatives using phosphoryl chloride under thermal
condition for 3h under inert atmosphere.21 (Scheme 1).
o
Reagents and conditions: i) RI, NaH, dry DMF, 0 C-RT, 5 h ii)
Diethyl malonate, NaH, dry DMF, 120 oC, reflux, 16 h, iii)
POCl3, reflux, 3h.
Scheme 1. Synthesis of ethyl-2-oxo-4-(piperazin-1-yl)-1,2-
dihydroquinoline-3-carboxylate hybrids 9a-j and 10a-j.
All the synthesized compounds (9a-j and 10a-j) were
characterized by using H NMR, 13C NMR, HR-Mass and IR
1
Fig. 3: Newly synthesized ethyl-2-oxo-4-(piperazin-1-yl)-1,2-
dihydroquinoline-3-carboxylatederivatives 9a-j and 10a-j.
spectroscopic methods. Spectral data of all synthesized
compounds were in good agreement with the proposed structures.
In 1H NMR spectra, the characteristic triplet signals appeared for
piperazine protons at δ 3.10-3.85 ppm. The structures for all
these compounds were further confirmed by HRMS analysis. For
instance, 9a displayed a molecular ion peak at m/z 392.19687
[M+H]+ suggesting the molecular formula of C23H25N3O3.
Additionally, the IR spectra for the target compounds
9a-j and 10a-j exhibited characteristic absorption bands at 1635-
1648 cm-1, 1080-1360 cm-1 and 2924-2982 cm-1 which
corresponded to C=O, C-N and C-H3 respectively.
The synthesized hybrids 9a-j and 10a-j were evaluated for
their in vitro antimicrobial activity against Gram positive
bacterial strains such as Bacillus subtilis MTCC 121,
Staphylococcus aureus MTCC 96, Staphylococcus aureus MLS-
16 MTCC 2940, Micrococcus luteus MTCC 2470, Gram-
negative bacterial strains such as Escherichia coli MTCC 739,
Klebsiella planticola MTCC 530, Pseudomonas aeruginosa
MTCC 2453 and a fungal strain Candida albicans MTCC 3017,
and the results to this regard are tabulated in Table 1.
Ciprofloxacin and Miconazole were used as standard controls for
the bacterial and fungal strains, respectively. The compounds 9b
and 10c exhibited promising and broad spectrum antimicrobial
activity against all the test pathogens except for Klebsiella
planticola MTCC 530 and Pseudomonas aeruginosa MTCC
2453 with MIC values ranging from 3.9 to 7.8 µg/mL. Further,
the compounds 9b and 10c exhibited a MIC value of 3.9 µg/mL
against Candida albicans MTCC 3017 which was found to be
lower than that of the standard drug Miconazole (MIC value 7.8
µg/mL). Hence, from a structure-activity relationship (SAR)
perspective, it was observed that the synthesized compounds 9b
and 10c having 2-F and 4-F substituents respectively, attached to
the dihydroquinoline scaffold exhibited electron withdrawing
properties which plausibly may be contributing to the

antibacterial and anti-Candida activities. Further, the compounds
9c, 9d, 9h, 10b, 10d, 10e and 10h exhibited a MIC value of 3.9
µg/mL against Staphylococcus aureus MTCC 96. While, the
compounds 9c, 9f and 10f exhibited antifungal activity against
Candida albicans MTCC 3017 with MIC value of 7.8 µg/mL.
From the above data, it can be inferred that the substituents
attached to the phenyl ring of piperazines, exhibiting strong
electron donating and/or electron withdrawing properties may
have contributed to the antibacterial and anti-Candida activities.
Furthermore, all the synthesized compounds were also evaluated
for the minimum bactericidal concentration (MBC) and the
results to this regard are tabulated in Table 2. In this case too, the
compounds 9b and 10c were found to be promising and exhibited
broad spectrum of antimicrobial activity except for Pseudomonas
aeruginosa MTCC 2453.
Arg265 with binding energies of -7.04 Kcal/mol, -6.62 Kcal/mol
and -6.55 Kcal/mol, respectively. Further, in case of compounds
10b and 10h, there are no hydrogen bond interactions, but these
two compounds are showing binding energy and <DELTA>G on
the basis of Hydrophobic and Van der Walls interactions.
Dehydrosqualene synthase (CrtM) of Staphylococcus
aureus is involved in the synthesis of golden carotenoid pigment
staphyloxanthin.22 This pigment functions as a virulence factor in
S. aureus and also acts as an antioxidant which protects the S.
aureus against oxidative stress due to host immune defense by
reactive oxygen species and neutrophils and enables its survival
within the host cell.23-25 In the search for the next generation of
antibiotics, recent efforts have targeted virulence rather than
essential gene functions as an antimicrobial target.26 A team of
investigators, including structural biologists, chemists, and
microbiologists, discovered recently that inhibition of the S.
aureus dehydrosqualene synthase reduced the bacterial survival
during infections, offering a proof-of-principle for such a
virulence-targeted approach.22-26 Considering the above facts,
molecular docking studies were accomplished to explore the
binding interactions between the lead compounds and the active
site of Staphylococcus aureus dehydrosqualene synthase (PDB
ID: 2ZCQ).
9b
9c
9d
9h
Molecular docking is the most extensively used method for
the calculation of protein-ligand interactions. AutoDock ver. 4.2
uses binding free energy assessment to assign the best binding
conformation. Docking of all the lead compounds into the
binding site of the dehydrosqualene synthase protein and
estimating the binding affinity of the complex is a significant part
of the structure based drug design process. The structural
interactions between PDB with 9 inhibitors were docked
separately. Docking studies are commonly performed for
predicting binding modes to proteins and their binding energies
of ligands. X,Y,Z coordinates of PDB were selected by using
SPDBV. Binding energy and <DELTA>G bind value exists on
the basis of Hydrogen bond, Hydrophobic and Van der Wall
interactions.
10c
10d
Experimental activities and predicted values by
Lamarckian Genetic Algorithm dockings of the 9 compounds are
summarized in Table 3. The synthesized compounds selected for
molecular docking have some collective structural features. All
the lead compounds showed good binding energy and also
exhibited interactions and better lower free energy values,
indicating more thermodynamically favored interaction. The
compounds 9b and 9c exhibited binding energies of -6.96
Kcal/mol and -8.05 Kcal/mol, respectively, with two interacting
Arg265. Compound 9d interacted with Arg52 with binding
energy of -6.42 Kcal/mol and 9h interacted with Arg171 and two
Arg265 with binding energy of -7.21 Kcal/mol. Compound 10c
interacted with two Arg265, 10d interacted with the magnesium
(Mg) ion, MG453 and 10e interacted with Tyr183 and two
10e
Fig.4. Docking of all the lead compounds with active site of
Staphylococcus aureus dehydrosqualene synthase (PDB ID:
2ZCQ).

Table 1
Antimicrobial activity of the synthesized ethyl -2-oxo-4-(piperazin-1-yl)-1,2-dihydroquinoline-3-carboxylate hybrids 9a-j and 10a-j
Minimum inhibitory concentration (µg/mL)
Bacillus
subtilis
MTCC
121
Staphylo Staphylo
Microco Klebsiella
Escheric
Pseudo
monas
aerugin
osa
MTCC
2453
Candida
albicans
MTCC
3017
coccus
aureus
MTCC
96
coccus
aureus
MLS-16
MTCC
2940
ccus
planticola hia coli
Test compounds
luteus
MTCC
2470
MTCC
530
MTCC
739
9a
9b
9c
9d
-
3.9
-
-
-
3.9
3.9
3.9
-
-
7.8
-
-
-
-
3.9
-
-
-
-
-
-
-
3.9
-
-
-
-
-
-
-
-
3.9
7.8
-
9e
-
-
-
-
-
9f
-
-
-
-
-
-
-
7.8
9g
-
-
-
-
-
-
-
-
9h
9i
-
-
3.9
-
-
-
-
-
-
-
-
-
-
-
-
-
9j
10a
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
10b
10c
10d
10e
10f
10g
-
3.9
-
-
7.8
-
3.9
3.9
3.9
3.9
-
-
3.9
-
-
-
-
3.9
-
7.8
-
-
7.8
3.9
-
-
-
-
3.9
-
-
7.8
-
-
-
-
-
-
-
-
3.9
-
-
7.8
-
-
-
-
10h
10i
10j
-
-
-
-
3.9
-
-
-
0.9
-
-
-
-
-
-
7.8
-
0.9
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
7.8
-
Miconazole (Standard)
Ciprofloxacin (Standard)
Table 2
0.9
0.9
0.9
0.9
0.9
Minimum Bactericidal / Fungicidal Concentration (MBC / MFC) of the synthesized compounds 9a-j and 10a-j
Minimum bactericidal / fungicidal concentration (µg/mL)
Bacillus
subtilis
MTCC
121
Staphyloc Staphyloc
Microco Klebsiella Escheric Pseudomon Candida
occus
aureus
MTCC
96
occus
ccus
planticola hia coli
as
albicans
MTCC
3017
Test compounds
aureus
MLS-16
MTCC
2940
luteus
MTCC
2470
MTCC
530
MTCC
739
aeruginosa
MTCC
2453
9a
9b
9c
9d
-
7.8
-
-
-
7.8
7.8
7.8
-
-
-
7.8
-
-
-
-
-
-
-
7.8
-
-
-
-
-
-
-
-
7.8
15.6
-
15.6
-
-
9e
-
-
-
-
-
-
9f
-
-
-
-
-
-
-
15.6
9g
-
-
-
-
-
-
-
-
9h
9i
-
-
7.8
-
-
-
-
-
-
-
-
-
-
-
-
-
9j
-
-
-
-
-
-
-
-
10a
-
-
-
-
-
-
-
-
10b
10c
10d
10e
-
7.8
-
-
7.8
7.8
7.8
7.8
-
-
7.8
-
-
-
-
7.8
-
15.6
-
7.8
7.8
-
-
-
-
7.8
-
-
-
-
-
-
-
7.8
-
-
10f
15.6
15.6
-
15.6
10g
10h
10i
-
-
-
-
7.8
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
10j
-
-
0.9
-
-
0.9
-
-
0.9
15.6
-
0.9
-
-
0.9
-
-
0.9
-
-
0.9
-
7.8
-
Miconazole (Standard)
Ciprofloxacin
(Standard)

Table 3
Molecular docking studies of all lead compounds with the active site of Staphylococcus aureus dehydrosqualene synthase (PDB ID:
2ZCQ)
Test compounds
Interacting amino acids
Binding energy, ΔG (Kcal/Mol)
Dissociation constant (kI) (µM)
9b
9c
Arg265(2)
Arg265(2)
Arg52
-6.96
-8.05
-6.42
-7.21
-6.93
-7.04
-6.62
-6.55
-6.41
7.87
1.26
9d
19.82
5.19
9h
Arg265(2), Arg171
-
10b
10c
10d
10e
10h
8.33
Arg265(2)
Mg453
6.89
14.05
15.71
20.16
Tyr183, Arg265(2)
-
In conclusion, we have synthesized a series of novel
piperazinyl-1,2-dihydroquinoline carboxylates (9a-j and 10a-j
11. Hu YQ, Zhang S , Xu Z , Lv ZS , Liu ML. Eur. J. Med.
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and their structures were characterized by corresponding
spectral analyses. All the synthesized compounds have been
investigated for their antimicrobial activity. The antimicrobial
results indicated that compounds 9b and 10c were promising
and exhibited broad spectrum antimicrobial activity. Molecular
docking studies with Staphylococcus aureus dehydrosqualene
synthase (CrtM) revealed that the synthesized derivatives
showed high binding energies and strong H-bond interactions
with the dehydrosqualene synthase validating the observed
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,
,
,
,
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The authors gratefully acknowledge the financial support
through the project: DST-SERB/EEQ/095/2017 and the
University grant commission (UGC), New Delhi for the award
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.
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Supplementary Information
Experimental section and copies of the 1H NMR, 13C NMR
HRMS and IR spectra for some of the important compounds

Graphical Abstract
A novel templates of piperazinyl-1,2-dihydroquinoline-
Leave this area blank for abstract info.
3-carboxylates: Synthesis, anti-microbial evaluation and
molecular docking studies
Saleha Banua, Rajitha Bollua, Mohammad Naseemaa, P. Mary Gomedhikaa, Lingaiah Nagarapua*, K. Sirishab,c, C.
Ganesh Kumarb,c, Shravan Kumar Gundad
A series of piperizinyl-1, 2-dihydroquinoline carboxylates have been synthesized in good to excellent yields and
screened for their in vitro antimicrobial activities. Compounds 9b and 10c were identified as promising leads showing
good antimicrobial profile.
Research Highlights
 A series of piperazinyl-1,2-dihydroquinoline-3-carboxylates were synthesized.
 Screened for their in vitro antimicrobial activities.
 9b and 10c were shown significant.
 in silico study active with Staphylococcus aureus dehydrosqualene synthase.