Design, Synthesis, and Biological and In Silico Study of Fluorine-Containing Quinoline Hybrid Thiosemicarbazide Analogues

Article abstract of DOI:10.1002/jhet.3617

A novel series of fluorine-containing quinoline hybrid thiosemicarbazide analogues (8a–8l) were synthesized and tested for their biological activities. The antibacterial results demonstrated that compounds 8d and 8l [minimal inhibitory concentration (MIC) 62.5?μg/mL] were shown to have higher biological activity than ampicillin against Escherichia coli. Compound 8b (MIC 25?μg/mL) was shown to have the highest activity than was ampicillin against Staphylococcus aureus. The antifungal results demonstrated that compound 8j (MIC 100?μg/mL) has shown good activity. Most of the targeted compounds have shown potent antimalarial activity. Compounds 8d (0.19?μg/mL), 8g (0.30?μg/mL), 8h (0.36?μg/mL), 8k (0.10?μg/mL), 8l (0.28?μg/mL), 8k (0.10?μg/mL), and 8l (0.28?μg/mL) have notable activity than does the reference drug quinine. Compounds 8d (0.27?μg/mL), 8g (0.30?μg/mL), and 8k (0.17?μg/mL) have shown excellent activity against chloroquine-resistant strain. The MTT assay performed on peripheral blood lymphocyte cultures showed a high percentage of lymphocyte viability [8d (99.64), 8g (99.46), 8h (98.83), and 8k (99.51)] at a maximum dose (10?μg/mL), depicting no cytotoxicity of these compounds on human lymphocytes in vitro. A molecular docking study was performed on Pf-DHFR-TS inhibitor. A molecular dynamics study has shown compound 8g to have better affinity with protein. ADME-Tox and pharmacophore study of synthesized compounds suggested prediction of active site.

Full text of DOI:10.1002/jhet.3617

Month 2019
Design, Synthesis, and Biological and In Silico Study of Fluorine-Con-
taining Quinoline Hybrid Thiosemicarbazide Analogues
Dhaval B. Patel,a Kinjal D. Patel,a Neelam P. Prajapati,a Krupa R. Patel,a Dhanji P. Rajani,b Smita D. Rajani,b
c
c
a
*
Naumita S. Shah, Devendra D. Zala, and Hitesh D. Patel
aDepartment of Chemistry, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
bMircrocare Laboratory and Tuberculosis Research Center, Surat, Gujarat, India
cDepartment of Zoology, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
*E-mail: drhiteshpatel1@gmail.com
Received August 7, 2018
DOI 10.1002/jhet.3617
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A novel series of fluorine-containing quinoline hybrid thiosemicarbazide analogues (8a–8l) were synthe-
sized and tested for their biological activities. The antibacterial results demonstrated that compounds 8d and
8l [minimal inhibitory concentration (MIC) 62.5 μg/mL] were shown to have higher biological activity than
ampicillin against Escherichia coli. Compound 8b (MIC 25 μg/mL) was shown to have the highest activity
than was ampicillin against Staphylococcus aureus. The antifungal results demonstrated that compound
8j (MIC 100 μg/mL) has shown good activity. Most of the targeted compounds have shown potent antima-
larial activity. Compounds 8d (0.19 μg/mL), 8g (0.30 μg/mL), 8h (0.36 μg/mL), 8k (0.10 μg/mL), 8l
(0.28 μg/mL), 8k (0.10 μg/mL), and 8l (0.28 μg/mL) have notable activity than does the reference drug qui-
nine. Compounds 8d (0.27 μg/mL), 8g (0.30 μg/mL), and 8k (0.17 μg/mL) have shown excellent activity
against chloroquine-resistant strain. The MTT assay performed on peripheral blood lymphocyte cultures
showed a high percentage of lymphocyte viability [8d (99.64), 8g (99.46), 8h (98.83), and 8k (99.51)] at
a maximum dose (10 μg/mL), depicting no cytotoxicity of these compounds on human lymphocytes in vitro.
A molecular docking study was performed on Pf-DHFR-TS inhibitor. A molecular dynamics study has
shown compound 8g to have better affinity with protein. ADME-Tox and pharmacophore study of synthe-
sized compounds suggested prediction of active site.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
diverse diseases [4]. Worldwide, 28% agrochemicals and
20–25% of approved drugs contain at least one fluorine
atom to enhance the action against diseases [6,7].
Therefore, the discovery of new molecules with fluorine
groups is very much important in the medicinal chemistry
for the potent activity against the diseases, but it is a
challenging task in the medicinal chemistry to discover a
potency in molecule [8].
Quinoline derivatives are largely used in the
pharmaceutical chemistry owing to the wide range of
applications. Quinoline derivatives possess various
biological activities such as antiviral [9], anticancer
[10,11], antibacterial [12], antifungal [10], anti-obesity
[13], anti-inflammatory [14,15], antimalarial [16,17],
antituberculosis [18,19], hypnotic [20], antischizophrenic
The insertion of fluorine-containing groups in
the molecules can be as profound as a strong electron-
withdrawing effect, with improvement of metabolic
stability, bioactivity, and lipophilicity [1–3]. In
the
comparison
of
non-fluorinated
analogues,
organofluorinated analogues are mainly important in the
medicinal chemistry owing to the changes in the
chemical–physical properties of the organic molecules in
which these atoms are bounded. Fluorine-containing
organic molecules have changed their electrostatic
interaction, pKa value, and molecular stability; and
absorption of membranes increased simultaneously with
lipophilicity [4,5]. In fact, many fluorinated drugs with
improve efficiency are recently used for treatment of
[21],
anti-protozoal
[22],
anti-cholesterol
[23],
© 2019 Wiley Periodicals, Inc.

D. B. Patel, K. D. Patel, N. P. Prajapati, K. R. Patel, D. P. Rajani, S. D. Rajani,
N. S. Shah, D. D. Zala, and H. D. Patel
Vol 000
anthelmintic [24], and analgesic activities [25], and
these activities were demonstrated in drug molecules,
which are shown in Figure 1. At present, a wide range of
microorganism such as fungi, viruses, and bacteria are
becoming resistant against drugs that are used to treat
infectious diseases. These infectious diseases have been
resistant against various drugs such as methicillin,
vancomycin, fluconazole, chloroquine, and isoniazid
[26–30]. Thus, design, development, and structure
modification existing drugs are necessary with highly
selective potency on specific strains. Molecular
hybridization concept was used for designing target
molecules (Fig. 1). In silico studies like molecular
docking [31], ADME-Tox [32,33], pharmacophore [34],
and molecular dynamics[35] have suggested potent
hypothetical prediction of the new molecule.
In continuation of our research, we have designed
quinoline hybrid thiosemicarbazide analogues for their
in vitro biological. Our previous work on quinoline
hybrid thiosemicarbazide analogues demonstrated
promising antimalarial analogues as compared with the
standard chloroquine [36]. In the present study, we have
tried to develop new fluorinated analogues as potent
molecules against diseases. Synthesized fluorinated
molecules (8a–8l) were tested in various biological
strains to check their potency as antibacterial, antifungal,
antimalarial, and antituberculosis. Furthermore, they
were screened against chloroquine-resistant Plasmodium
molecular docking, molecular dynamics, ADME-Tox,
and pharmacophore for their prediction of active agents.
RESULT AND DISCUSSION
Chemistry. Initially, the hybrid molecules 8a–8l were
synthesized via one-pot reaction between aldehyde,
pyruvic acid, and aniline with catalytic amount of
trifluoroacetic acid under the reflux condition using the
protocols as outlined in Scheme 1. These compounds
were subsequently treated with con. H2SO4 with ethanol
under reflux condition for the ethyl ester of compound;
obtained products were directly used as starting
materials to form hydrazide via ethanolic condensation
reaction with hydrazine hydrate [36]. Previously
synthesized hydrazides and various isothiocyanates were
added in the ethanol under reflux condition to afford
final products in good yield (Scheme 1) (Table 1,
entries 1 to 12). Here, we have observed that final step
of reaction carried out without taking glacial acetic
acid, with the reaction taking longer time and affording
lower yield. We have also checked this reaction under
the microwave irradiation condition, but we could not
obtain higher yield in this study. Final products were
characterized by various spectroscopic techniques such
as electrospray ionization–mass spectrometry (ESI–MS),
1H-NMR, 13C-NMR, and Fourier transform infrared
(FTIR). The spectroscopic data are given in the
Supporting Information.
falciparum,
for
the
better
understanding
of
mechanism of action of title molecules. We have studied
Figure 1. Molecular hybridization strategy of target molecules. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Design, Synthesis, Biological and In-Silico Study of Fluorine Containing Quino-
line Hybrid Thiosemicarbazide Analogues
Scheme 1. Synthetic strategies for fluorinated quinoline hybrid thiosemicarbazide analogues (8a-8l) [Color figure can be viewed at wileyonlinelibrary.
com]
Pharmacology results. In vitro antibacterial and
antifungal activity.
demonstrated that analogues 8j (MIC 100 μg/mL) and 8f,
8g, and 8k (MIC 250 μg/mL) were more potent than
griseofulvin but have very poor activity than does
nystatin in the Candida albicans strain. Moreover,
analogues 8a–8l have shown less activity against
Aspergillus niger and Aspergillus clavatus strains. The
graphical representation of antibacterial and antifungal
activities is shown in Figure 2. The antifungal and
antibacterial activities suggested that synthesized
molecules were found to be biologically active.
Moreover, quinoline hybrid thiosemicarbazides act as
The biological results are
summarized in Table 2. The synthesized molecules (8a–
8l) were evaluated for their in vitro antibacterial activity
against the selected Gram-positive and Gram-negative
bacteria. The analysis efforts suggested that analogues
(8a–8l) indicate potency against selected microorganism.
Compounds 8d and 8l [minimal inhibitory concentration
(MIC) 62.5 μg/mL] were more potent than ampicillin
(MIC 100 μg/mL), and analogues 8b, 8g, and 8j (MIC
100 μg/mL) have equivalent activity against Escherichia
coli. Analogues 8b (MIC 25 μg/mL), 8a and 8d (MIC
100 μg/mL), and 8g (MIC 62.5 μg/mL) were highly
potent than was ampicillin (MIC 250 μg/mL) against
Staphylococcus aureus. Analogue 8b was shown to have
higher activity than were chloramphenicol and
ciprofloxacin. In addition, analogues 8d (MIC
100 μg/mL) and 8j and 8l (MIC 100 μg/mL) were shown
to have good activity against Streptococcus pyogenes
than does ampicillin (Table 2) but were half as effective
were chloramphenicol (MIC 50 μg/mL) and ciprofloxacin
(MIC 50 μg/mL). Moreover, analogues 8c, 8e, 8f, 8i, and
8j (MIC 250 μg/mL) and 8h (MIC 125 μg/mL) were
shown to have good activity against S. aureus. On the
other hand, analogues 8a, 8b, 8g, and 8h (MIC
125 μg/mL) were shown to have less potency against
S. pyogenes than does ampicillin. The antifungal results
more powerful antimicrobial agents.
In vitro antimalarial activity and structure–activity
relation.
The
synthesized
analogues
8a–8l
were investigated for their antimalarial activity and
chloroquine resistance against P. falciparum by
measuring MIC value (Table 2). Compounds 8d
(0.19 μg/mL) with –CF3 and –F groups; 8g (0.17 μg/mL)
with –F and –Cl groups; 8h (0.36 μg/mL) with –CF3, –F,
Cl, and Br groups; 8k (0.10 μg/mL) with –F, –NO2
group; and 8l (0.28 μg/mL) with –CF3, –F, and OCH3
groups have remarkable activity against reference drug
quinine (0.268 μg/mL). Remaining analogues 8a
(1.21 μg/mL) with –CF3 and –F groups; 8b (1.93 μg/mL)
with –CF3 and –F groups; 8c (2.01 μg/mL) with –CF3
group; 8e (0.67 μg/mL) with –F, –Br group; 8f (1.20 μg/
mL) with –CF3, –Cl, and –Br groups; 8i (1.08 μg/mL)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. B. Patel, K. D. Patel, N. P. Prajapati, K. R. Patel, D. P. Rajani, S. D. Rajani,
N. S. Shah, D. D. Zala, and H. D. Patel
Vol 000
Table 1
Synthesized fluorinated quinoline hybrid thiosemicarbazide molecules (8a-8l).
Entry
1
Code no.
R1
R2
R3
Product
Yield (%)a
8a
4-CF3
6-CF3
74
2
8b
2-Cl
8-CF3
68
3
8c
3,5-di CF3
7-CF3
58
4
8d
2,6-di F
6-CF3
78
5
8e
4-F
6-Br
50
6
8f
4-CF3
7-CF3–6-Br
61
(Continues)
Journal of Heterocyclic Chemistry
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Month 2019
Design, Synthesis, Biological and In-Silico Study of Fluorine Containing Quino-
line Hybrid Thiosemicarbazide Analogues
Table 1
(Continued)
Entry
7
Code no.
R1
R2
R3
Product
Yield (%)a
65
8g
2,4-di F
7-Cl–6-F
8
8h
2-Br
8-Cl–6-CF3
70
9
8i
4-F
8-Cl–6-CF3
58
10
8j
H
10-Cl–6-CF3
60
11
8k
2,4-di F
6-F
75
12
8l
4-CF3
6-F
68
aPurified yield.
with –CF3, –F, and –Cl group; and 8j (0.72 μg/mL) with –
CF3, –Cl, and –CH3 groups have shown poor potency than
do reference drugs quinine (0.268 μg/mL) and chloroquine
(0.020 μg/mL). The graphical result of antimalarial activity
is shown in Figure 2. As per the study, we have found that
analogues having electron-withdrawing functional group
such as single tri-fluoro, fluoro, and chloro showed high
activity, and also analogue having electron- donating
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. B. Patel, K. D. Patel, N. P. Prajapati, K. R. Patel, D. P. Rajani, S. D. Rajani,
N. S. Shah, D. D. Zala, and H. D. Patel
Vol 000
Table 2
In vitro biological activity of compounds (8a–8l) in MIC (μg/mL).
Antibacterial
Gram-negative
organismd
Gram-positive
organisme
Antifungala
Antimalarialb
Anti-TBc
Entry
Product code
Ec
250
Pa
Sa
Sp
Ca
An
Ac
Pf
H37Rv
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
250
250
125
250
125
100
125
500
125
62.5
125
100
NT
50
100
25
125
125
250
50
>1000
>1000
500
1000
1000
250
250
>1000
500
100
250
500
NT
NT
NT
100
500
NT
NT
NT
NT
200
250
>1000
>1000
>1000
500
>1000
>1000
1000
1000
500
500
NT
NT
NT
100
100
NT
NT
1000
1000
>1000
>1000
>1000
500
>1000
>1000
1000
>1000
500
500
NT
NT
NT
100
100
NT
NT
1.21
1.93
2.01
0.19
0.67
1.20
0.17
0.36
1.08
0.72
0.10
0.28
NT
NT
NT
NT
NT
NT
NT
0.26
0.02
100
50
100
125
62.5
250
250
100
500
250
100
250
62.5
100
50
250
100
250
250
62.5
125
250
250
500
500
250
50
250
62.5
100
250
100
100
250
62.5
50
500
250
125
125
250
100
250
100
100
50
9
10
11
12
13
14
15
16
17
18
19
20
21
8j
8k
8l
50
Ampf
Camf
Ciprof
Nyf
Grisf
INHf
RMPf
Quinf
CQf
NT
NT
NT
NT
NT
0.20
1.00
NT
NT
25
25
50
50
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT, not tested.
aValues expressed in μg/mL. Candida albicans MTCC 227 (Ca), Aspergillus niger MTCC 282 (An), Aspergillus clavatus MTCC 1323 (Ac).
bAntimalarial screening using Plasmodium falciparum strain; values expressed in IC50 μg/mL.
cAntituberculosis screening using H37Rv strain; values expressed in μg/mL.
dValues expressed in μg/mL. Escherichia coli MTCC 443 (Ec) and Pseudomonas aeruginosa MTCC 1688 (Pa).
eValues expressed in μg/mL. Staphylococcus aureus MTCC 96 (Sa) and Streptococcus pyogenes MTCC 442 (Sp).
fReference drugs ampicillin, chloramphenicol, ciprofloxacin, nystatin, griseofulvin, isoniazid, rifampicin, quinine, and chloroquine.
Figure 2. Graphical representation of biological activity. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Design, Synthesis, Biological and In-Silico Study of Fluorine Containing Quino-
line Hybrid Thiosemicarbazide Analogues
groups such as substituted methyl and methoxy showed
remarkable antimalarial potency.
other groups at the quinoline ring at the sixth position
such as –Br have shown less biological activity.
Molecular docking study also suggested that the highly
electronegative group at the C-6 position of the quinoline
ring has the best binding. Indeed, as seen from Figure 4
a–c, with compounds that formed H-bond with the
quinoline ring and thiosemicarbazide linkage, it is proven
that quinoline core with –CF3 and –F groups at the sixth
position and thiosemicarbazide linkage are necessary to
improve the protein interaction as well as the biological
activity. The structure–activity relationship, which
emerged from the screening data as shown in Table 2,
demonstrated that thiosemicarbazide linkage at the phenyl
ring without any group with –CF3 at the seventh (8c)
position of the quinoline ring showed moderate activity,
but with –CF3 at the sixth (8d) position of the quinoline
ring, it showed high activity. The compounds with
thiosemicarbazide linkage at the phenyl ring with 3,5-di
Cl (8g), 2,6-di F (8h), and 4-NO2 (8k) have a vital role
in biological activity. Also, other groups with
thiosemicarbazide linkage at the phenyl ring with 2,4-di F
(8a), 3-Cl (8f), 4-methyl (8j), and 3-methoxy (8l) showed
moderate activity against P. falciparum.
The substitution pattern of the hybridized quinoline ring
and thiosemicarbazides linkage at different positions was
observed to have an effect on the biological activity.
Compounds attached with high electro-negative
substituents such as –CF3 (8d, 8h) and –F (8g, 8k) at the
sixth position of the quinoline ring led to an increase in
the malarial activity. The trifluoromethyl (–CF3) at the
seventh and eight positions of the quinoline ring was
found to be less active. In contrast, compounds bearing
Table 3
Drug resistance study of analogues (8a–8l) against Plasmodium
falciparum and MTT assay peripheral blood lymphocytes culture.
Chloroquine-
resistant
MTT assayb
Code
no.
Plasmodium
Entry
falciparuma
0.1c
1.0c
10.0c
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
Control
Quinine
2.09
3.08
4.17
0.27
0.99
2.60
0.30
0.63
2.02
1.32
0.17
0.57
—
—
—
—
99.76
—
—
99.57
99.51
—
—
99.71
—
—
—
—
99.67
—
—
99.51
99.04
—
—
99.70
—
—
—
—
99.64
—
—
99.46
98.83
—
—
99.51
—
Antituberculosis activity.
All synthesized molecules
were tested against the Mycobacterium tuberculosis
H37Rv using microplate Alamar Blue method as listed in
Table 2. This methodology is nontoxic when using a
thermally stable reagents and shows good correlation
with proportional and BACTEC radiometric method. In
this series, we have observed compounds 8b and 8k
(MIC 50 μg/mL) to be highly active, which have a –F
group with core moiety. We have also observed that
introducing di-CF3, Cl, and Br (8c, 8f, 8i) groups in the
moiety reduces the potency of molecules, which indicates
9
10
11
12
13
14
100
99.61
100
99.42
100
99.24
—
aChloroquine-resistant Plasmodium falciparum strain.
bCytotoxicity study (% cell viability) on human peripheral blood lym-
phocyte culture.
cIn μg/mL.
Figure 3. Percent cell viability of peripheral blood lymphocytes by MTT assay. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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D. B. Patel, K. D. Patel, N. P. Prajapati, K. R. Patel, D. P. Rajani, S. D. Rajani,
N. S. Shah, D. D. Zala, and H. D. Patel
Vol 000
the relevance of fluorine atom for the activity in the moiety.
Analogues 8c, 8f, and 8i (250 μg/mL), 8a, 8e, 8g, and 8h,
(100 μg/mL) and 8d and 8j (62.5 μg/mL) have shown less
activity against M. tuberculosis. The graphical
representation of antituberculosis activity is shown in
Figure 2.
MTT assay. Selected molecules (8d, 8g, 8h, and 8k)
were evaluated for their cytotoxicity by MTT assay in
peripheral human blood lymphocyte cultures.
A
cytotoxicity study was carried out by three different
concentrations of molecules (0.1, 1, and 10 μg/mL), and
the results are shown in Table 3 and Figure 3. According
to the result, it was depicted that in a range of 0.1 to
10 μg/mL concentration, none of the synthesized
fluorinated quinoline hybrid thiosemicarbazide analogues
showed cytotoxicity, and the results were comparable
with those of quinine and control (Table 3 and Fig. 3).
Molecular docking method. A molecular docking study
was performed on Schrödinger suite program, Glide
version 4.5 [37]. This software was operated under the
Linux system on Intel 2.8 MHz processor with 8 GB
RAM. LigPrep-v2.1 tool was used for ligand preparation
via grid base method with energy minimization. Protein
Preparation Wizard v-11.4 tool was used for the protein
preparation, which was downloaded by Protein Data
Bank with X-ray crystallographic structure. The
downloaded proteins were prepared via the following
steps: removal of ligand molecules from the active site,
optimization of hydrogen bonding, removal of cofactors,
removal water molecules, and energy minimization. With
the use of default setting of molecular docking software,
prepared ligands were docked into the active site of
protein. The final GlideScore collected as a term of
scoring function.
Automated docking setup.
Molecular docking was
performed by using default settings of Maestro v-11.4.
Selected proteins 1J3K [38], 3QG2 [39], and 3QGT[40]
were auto-downloaded via software under the specific
organism P. falciparum. The expression system of E. coli
was performed under systematic steps, as follows: default
setting and flexible space of ligands were validated by
comparison of biological activity, and GlideScore,
docking parameter, and best docked ligands were fit into
the cavities with lower energy score. Subsequently, small
molecule compounds with respect to low-energy
molecules were docked using the same parameters. The
Linux system was used for the molecular docking study
using Schrödinger Glide. The Glide tool was used for
searching favorable cavity interaction for the ligand and
protein using grid-based method.
Figure 4. (A) Molecular docking interaction of 8d and 8g in protein
1J3K. (B) Molecular docking interaction of 8g and 8h in protein 3QG2.
(C) Molecular docking interaction of 8d and 8k in protein 3QGT.
[Color figure can be viewed at wileyonlinelibrary.com]
Molecular docking study.
Docked poses with low
binding energy, hydrogen bond, and non-covalent
interaction such as π–π interaction and π–cation
interaction were recorded and validated (Fig. 4a–c). The
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Month 2019
Design, Synthesis, Biological and In-Silico Study of Fluorine Containing Quino-
line Hybrid Thiosemicarbazide Analogues
mechanistic value signifies that the newly synthesized
fluorinated quinoline hybrid thiosemicarbazide analogues
exhibited an auspicious selectivity towards Pf-DHFR-TS
proteins. As depicted in Figure 4a and b, expected
binding free energy for PDB: 1J3K was found between
À7.52 and À10.13 kcal/mol; for PDB: 3QG2, between
À6.60 and À9.72 kcal/mol; and for PDB: 3QGT,
between À4.70 and À8.64 kcal/mol. In these cases,
compounds 8d and 8g; compounds 8d, 8g, and 8h;
compounds 8d and 8k have shown the least binding
energy in PDB: 1J3K, 3QG2, and 3QGT, respectively.
While in the comparison in 1J3K, excluding 8d and 8g
(À10.13 and À10.44 kcal/mol), compounds 8d, 8g, and
8h (À9.057, À9.38, and À9.02 kcal/mol) in 3QG2 and
compounds 8d and 8k (À7.55, À7.86 kcal/mol) in 3QGT
have shown remarkable performance (Table 4). From the
molecular docking study, we have identified four
compounds (8d, 8g, 8h, and 8k) with the least energy
score as potent molecules among all derivatives (8a–8l)
(Table 4).
Figure 4a describes the interaction details of compounds
8d and 8g with PDB: 1J3K; compound 8d has shown two
H-bond interactions (ALA 16, 1.76 Å, ASN 108, 2.31 Å to
the quinoline ring, SER 111, 1.94 Å, VAL 103, 2.35 Å to
2° –NH) and one halogen bond (LEU 46, 2.64); compound
8g exhibited two H-bond interactions (ASN 108, 1.93 Å to
2° –NH, LEU 164 to C═S, 2.71 Å) and one halogen bond
(MET 55, 3.05 Å) (Table 5). Figure 4b describes the
interaction details of compounds 8g and 8h with PDB:
3QG2; compound 8g showed one H-bond interaction
(SER 111, 2.23 Å to the quinoline ring), one π-bond with
PHE 58, and one halogen bond (CYS 50, 3.08 Å, ARG
122, 2.08 Å); compound 8h showed two H-bond
interactions (LEU 40, 2.39 Å to 2° –NH, VAL 15,
2.29 Å to phenyl) (Table 5). Figure 4c describes the
interaction details of compounds 8d and 8k with PDB:
3GQT; compound 8d showed four H-bond interactions
(ALA 16, 2.35 Å to the quinoline ring, CYS 15, 1.65 Å
to 2° –NH, PHE 58, 2.52 Å to phenyl, PHE 116, 2.49 Å
to phenyl) and one π-bond with PHE 116; compound 8k
showed three H-bond interactions (GLY 44, 2.36 Å to
the quinoline ring, GLY 166, 2.03 Å to C═O, TRY 170,
2.21 Å to 2° –NH) and one π-bond with PHE 58
(Table 5). Generally, H-bonds expedite the solubility of
molecules, and non-covalent interaction such as cation–π
interaction involves the positive charge of a cation
converted to the electrons in a π-system of a compound.
These properties are normally useful in the medicinal
chemistry for the drug designing. Molecular docking
analysis suggested that ligands were only interacted with
key amino acid such as ALA 16, ASN 108, SER 111,
VAL 103, LEU 164, LEU 40, VAL 15, ALA 16, CYS
15, PHE 58, PHE 166, GLY 44, GLY 166, and TRY 170.
Figure 4a–c indicate the cavity fitting mode of the selected
molecules into the proteins. However, compounds 8d, 8g,
8h, and 8k exhibited high malarial activity with the least
binding energy score than did the reference.
ADME-Tox study.
After the synthesizing targeted
compounds 8a–8l, we carried out ADME-Tox study by
using isoniazid and chloroquine as references for the
drug-likeness properties. QikProp tool was used in
Maestro 11.4 to find nontoxic heat molecules subjected to
ADMET factors [41], and their allowable range limit is
listed in Table 6. Schrödinger QikProp tool having
Table 4
Molecular docking score of fluorinated quinoline hybrid thiosemicarbazide compounds (8a–8l).
PDB: 1J3Ka PDB: 3QG2a
PDB: 3QGTa
GlideScore
Entry
Code no.
GlideScore
H-bond
GlideScore
H-bond
H-bond
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
À8.417
À7.774
À8.654
À10.131
À9.312
À8.375
À10.445
À7.999
À8.223
À9.034
À7.546
À7.52
À0.638
0
À1.33
À0.7
À0.604
0
À0.7
À0.655
0
À8.981
À9.429
À6.607
À9.057
À9.189
À8.105
À9.385
À9.026
À8.855
À8.883
À8.128
À9.728
À6.326
À3.907
À5.155
À5.18
0
À4.708
À5.048
À7.977
À7.552
À5.577
À7.809
À8.642
À7.692
À7.528
À7.413
À7.862
À7.782
À7.276
À4.266
À5.558
À3.542
À1.18
À0.671
À0.089
0
0
0
À0.7
0
À0.7
À0.663
0
0
À0.7
À0.545
À0.7
0
0
9
À0.502
0
10
11
12
13
14
15
16
8j
8k
8i
À0.31
0
0
À1.167
À0.615
À1.008
À0.884
À0.7
À0.7
0
À1.232
À0.547
À0.611
À0.093
0
Ciprb
INHb
Quinb
CQb
À7.568
À4.634
À6.911
À3.688
À1.23
À1.205
À0.7
À0.463
aOrganism: Plasmodium falciparum.
bReference drugs ciprofloxacin, isoniazid, quinine, and chloroquine.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. B. Patel, K. D. Patel, N. P. Prajapati, K. R. Patel, D. P. Rajani, S. D. Rajani,
N. S. Shah, D. D. Zala, and H. D. Patel
Vol 000
Table 5
Various ligand protein interactions.
H-bond
Halogen bond
Amino acidb
π–π
interaction
Salt
bridge
Code
Protein
1J3K
Atoma
Amino acidb
BLc
1.76
BLc
2.64
8d
Quinoline-H
ALA 16
ASN 108
SER 111
VAL 103
ASN 108
LEU 164
SER 111
ARG 122
40
—
—
LEU 46
2.31
1.94
2.35
1.93
2.71
2.23
2.54
2.39
2.29
2.35
1.65
2.52
2.49
2.36
2.01
2.21
2o NH
2o NH
8g
8g
8h
8d
2o NH
C═S
—
PHE 58
—
—
—
—
—
MET 55
3.05
3QG2
3QGT
Quinoline-H
Ph-H
CYS 50
ARG 122
3.08
2.03
—
—
—
2o NH
—
—
—
—
—
—
—
Ph-H
45
Quinoline-H
ALA 16
CYS 15
PHE 58
PHE 116
GLY 44
GLY 166
TRY 170
PHE 116
2o NH
—
Ph-H
—
Ph-H
—
8k
Quinoline-H
C═O
PHE 58
—
—
2o NH
aBounded atom of ligand.
bInteractive group or atom of the amino acid.
cBond length.
Table 6
Calculated ADME-Tox properties.
Code
no.
PSA (70–
200 Å)
QPPCaco (<25 poor,
>500 great)
QPlogB B
(À1.5 to À3.0)
QPlogPo/w
QPlogS
(>À4)
PHOA (<25% poor,
>80% high)
Entry
(<5)
QPlogHERRG
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
375.975
284.463
430.615
237.964
261.773
428.671
343.42
373.322
279.602
258.338
206.694
234.685
42.892
1855.728
2748.116
1736.889
1723.085
2087.213
1860.797
1897.233
2602.537
1235.548
1922.289
590.623
0.451
0.365
0.529
0.133
0.293
0.439
0.488
0.532
À0.246
0.241
À0.387
À0.062
0.211
0.483
6.874
6.848
7.522
5.755
5.706
8.008
6.159
7.487
6.434
6.15
À8.851
À9.006
À9.775
À7.141
À6.935
À11.186
À7.248
À10.047
À9.235
À7.477
À5.867
À9.02
100
100
100
92.651
93.851
100
95.766
100
100
95.815
100
100
100
À6.151
À7.302
À6.244
À6.027
À5.707
À7.494
À4.932
À7.257
À6.701
À5.71
9
10
11
12
13
14
8k
8l
4.603
6.435
5.21
À5.245
À7.529
À5.45
1869.104
821.804
1702.53
Quina
CQa
À3.3
71.946
4.61
À4.474
3
À6.263
PSA, polar surface area; QPPCaco, caco-2-cell permeability; QPlogBB, blood partition coefficient; QPlogPo/w, partition coefficient; QPlogS, solubility
aqua; PHOA, percentage human oral absorption.
aQuinine and chloroquine as reference drugs.
Jorgensen’s method was used to generate descriptor and
pharmacophore properties [42]. Compounds 8d, 8g, 8h,
and 8k showed good drug-likeness properties, which are
active among the target compounds. Compound 8k
showed ADME-Tox properties between the given range;
also, MTT assay suggested that this compound was
nontoxic for the blood cell. The polar surface area values
of evaluated analogues were found in the range of
206.694–430.615 Å, which show good bioavailability of
the analogues [43]. Caco-2 cell permeability (QPPCaco)
for the evaluated analogues indicate good intestinal
absorption. The aqua solubility parameter (QPlogS) of
tested entities was found in the permissible range
(À5.867 to À11.186). The blood/brain partition
coefficient (QPlogBB) molecules were found to have an
acceptable range between À0.387 and 0.532. Moreover,
descriptors like octanol/water partition coefficient
(QPlogPo/w), percentage human oral absorption, and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Design, Synthesis, Biological and In-Silico Study of Fluorine Containing Quino-
line Hybrid Thiosemicarbazide Analogues
QPlogHERG showed results in the acceptable range. This
study may help in prediction of toxicity of molecules and
drug-likeness properties of synthesized molecules
(QikProp tool 2.1) [44].
was built by system builder with the aid of OPLS 2005
force field by predefined TIP3P solvation of orthorhombic
solvation boundary with box volume (8924) A3 that is
later followed by ion neutralization with addition of
sodium. This system was later minimized with 2000
iterations with convergence criterion of 1 kcal/mol/Å. The
minimized explicit solvation complex of ligand–receptor
complex is simulated for 10 ns using NPT ensemble at
300 K and 1.01325 bar with default set of relaxation
before simulation.
Molecular dynamics method.
The explicit molecular
dynamics study of the ligand–receptor compounds of the
identified lead against the native ligand in the receptor was
carried out using Desmond [44]. The best docked ligand
was selected for the molecular dynamics simulation. First,
the 8g ligand–receptor complex aqueous solvation system
Figure 5. Molecular dynamics simulation diagram of ligand 8g. (A) Ligand properties, (B) protein–ligand RMSD, (C) ligand torsion profile, (D) 2D li-
gand–protein contacts, (E) protein–ligand contacts, (F) protein RMSF, and (G) ligand RMSF. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. B. Patel, K. D. Patel, N. P. Prajapati, K. R. Patel, D. P. Rajani, S. D. Rajani,
N. S. Shah, D. D. Zala, and H. D. Patel
Vol 000
Figure 5. Continued.
Molecular dynamics simulation was performed to find
the best equilibrium conformation. The best docked
ligand 8g was selected for the analysis in molecular
dynamics simulation study. The analysis result of
simulation is shown in Figure 5 (A to G). The various
energies, hydrogen bonds, and Van der Waals forces
have been notified with various levels. According to the
interaction and forces, 8g ligand fluctuated at some level,
yielding a root-mean-square deviation (RMSD) value of
1.8 Å.
in co-crystal and leading bound complex for the
understanding of movement of the flap upon the ligand
binding (Fig. 5B). Co-crystal inhibitor was shown to
have two H-bond interactions with residues such as
LEU 164 and ASN 108. Hydrophobic interaction
pattern was shown to have a more stable complex with
catalytic residues such as ALA 16, LEU 46, MET 55,
PHE 58, ILE 112, PRO 113, PHE 116, and LEU 119.
These interactions were identified to have stable lead
compared with a co-crystal inhibitor. The analysis result
of simulation is shown in Figure 5 (A–G). The various
energies, hydrogen bonds, and Van der Waals forces
have been notified with various levels.
Molecular dynamics study.
The molecular dynamics
study was performed to determine the binding site of
inhibitor; simulation was carried out with best molecular
docking ligand 8g with protein 1J3K. The RMSD value
of protein backbone increased its value from 0.7 to
2.8 Å with respect to starting position. The tendency of
binding pocket residues RMSD copes well with the
ligand movement. Molecular dynamics simulations
assisted to have good coordinates for the structure
variation and molecular docking study to search for the
best cavity in the protein. Here, 8g inhibitor was shown
to have inhibitor-bound and opened catalytic active site
with PHE 58, ASN 108, and LEU 164. Molecular
dynamics simulation was shown to have catalytic,
termino-lateral regions and flap of ligand 8g shown to
have flexibility during the simulations at 25 ns
(Fig. 5A). Simulation graphs, protein–ligand interaction,
ligand properties, Root Mean Square Fluctuation
(RMSF), and tortions and are shown in Figure 5.
Moreover, ligand 8g gives the best equilibrium
conformation in the molecular dynamics simulation. The
interactive distance between the Cα atoms of active site
and flapping during 25-ns simulation has been analyzed
Pharmacophore.
In this study, we have used Phase
(Schrödinger 2017-4)[45–47] to generate pharmacophore
for the P. falciparum inhibitor. The pharmacophore model
generated 12 molecules as active molecules. Compounds
8d, 8g, 8h, and 8k with the highest IC50 value in the
antimalarial study proved to be the most active in this
series, as compared with the reference drug chloroquine.
This quinoline content could be considered as a useful
block for the future development to obtain a more potent
antimalarial agent. Default interaction features such an
acceptor (A), donor (D), hydrophobic (H), positive
ionizable (P), negative ionizable (N), and ring aromatic
(R) were used for generating a favorable pharmacophore
model.
A
flexible alignment pharmacophore was
generated on the basis of experimental data. The best
pharmacophore model consists of five features: two
hydrogen bond acceptors (A) and three aromatic ring (R)
with the highest survival score (5.263) (Fig. 6). This
model was mapped onto the antimalarial molecules and
compared with nonactive compounds.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Design, Synthesis, Biological and In-Silico Study of Fluorine Containing Quino-
line Hybrid Thiosemicarbazide Analogues
Figure 6. Pharmacophore study. [Color figure can be viewed at wileyonlinelibrary.com]
EXPERIMENTAL
All chemicals and solvents
were purchased from local suppliers; isothiocyanates
were purchased from Sigma-Aldrich (Sigma-Aldrich
Corp., S. Louis, MO) and were of analytical grade. The
reaction progress was checked by using silica gel 60
F254 aluminum sheet, under visualization of ultraviolet
light. Synthesized products were characterized by their
analytical techniques. Melting points were recorded on an
completion of reaction, the reaction mixture was poured
into ice water. Solid precipitates are filtered and washed
with ice water; further, these precipitates were
recrystallized by methanol to afford higher yield.
Materials and methods.
Synthesis of ethyl substituted quinoline-4-carboxylate
[36]. In 50-mL RBF, substituted quinoline-4-carboxylic
acid (1.0 mmol) and conc. H2SO4 (1.0 mL) in 10 mL
ethanol are put in reflux condition for 24 h. The reaction
continuity was monitored by TLC using hexane:ethyl
acetate as a solvent system; after completion of reaction,
the reaction mixture was poured into ice water. Solid
precipitates were collected and purified by column
chromatography to afford the products in good yield (90%).
OptiMelt MPA 100; FTIR were recorded on
PerkinElmer FT-IR 377 using solid potassium bromide
pallets in cmÀ1 1H-NMR spectra were recorded on a
a
.
Bruker AV 400 MHz (Bruker Corp., Billerica, MA)
using DMSO-d6 as a solvent; 13C-NMR spectra were
recorded on a Bruker AV 100 MHz using DMSO-d6 as a
solvent. ESI–MS were recorded on Advion Expression
CMS, USA (ethyl acetate as mobile phase).
Synthesis
carbohydrazide[36].
of
2-(2-chlorophenyl)quinoline-4-
In 25-mL RBF, ethyl substituted
quinoline-4-carboxylate (1.0 mmol) and hydrazine
hydrate (80%) were dissolved in a flask of ethanol. This
reaction mixture was refluxed for 3 h. The reaction was
monitored by TLC using hexane:ethyl acetate (50%) as a
solvent system; after completion of reaction, the reaction
mixture was poured into ice water. The precipitates were
collected and recrystallized by methanol to afford the
products in high yield (98%).
Synthesis
of
substituted
quinoline-4-carboxylic
acid[36,48].
In 50-mL RBF, aromatic aldehyde
(1.0 mmol) and pyruvic acid (1.0 mmol) in ethanol
(10 mL) were refluxed for 10 min; the solution of
aromatic aniline containing 10 mL ethanol (1.0 mmol)
and catalytic amount of trifluoroacetic acid (0.2 mL) was
added in the solution and refluxed for 3 h. The reaction
was monitored by thin-layer chromatography (TLC)
using hexane:ethyl acetate as a solvent system; after
General method for the preparation of substituted
quinoline hybrid-N-substituted hydrazinecarbothioamide
(8a–8l).
In 25-mL RBF, a mixture of substituted
quinoline-4-carbohydrazide (1.0 mmol) and various
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. B. Patel, K. D. Patel, N. P. Prajapati, K. R. Patel, D. P. Rajani, S. D. Rajani,
N. S. Shah, D. D. Zala, and H. D. Patel
Vol 000
isothiocyanates (1.0 mmol) in ethanol (10 mL) in the
presence of glacial acetic acid (0.5 mL) was refluxed for
3–4 h at 80°C. The reaction was monitored by TLC using
chloroform:methanol (10%) as a solvent system; after
completion of reaction, the reaction mixture was poured
into ice water. The final crude products were collected
and recrystallized by ethanol to afford pure compounds.
All final compounds were confirmed by ESI–MS, 1H-
NMR, 13C-NMR, and FT-IR.
protocols. P. falciparum strain was supplemented with
1% D-glucose, 25-mM HEPES, 0.23% bicarbonate, and
inactivated human serum. The culture was store in 37°C
temperature for the 24 h. Then, in the 5% D-sorbitol
treatment, the asynchronous P. falciparum was
synchronized. The primary stage of the parasitemia of
0.9–1.4% was at 4% hematocrit in total volume of
200 μL of the 25-mM HEPES. The slides were observed
to have ring-stage Plasmodium into schizonts and
trophozoites in the presence of the various
concentrations. of ring-stage agents. The calculated
results were described in terms of MIC (IC50) with
reference to chloroquine and quinine (Table 2).
In vitro biological assay. Antimicrobial assay.
The
antimicrobial study was performed via reported
method[49]; the results are described in Table 2. This
work has been completed by Microcare Laboratory and
Tuberculosis Research Center, Surat, as per reported
method. Mueller Hinton Broth and Sabouraud broth were
used as nutrient media to grow bacteria. The inoculum
size for the test trains was adjusted to 106 colony-
forming units per milliliter by comparing turbidity. Serial
dilutions were prepared for primary and secondary
screening. Control tube containing no antibiotic was
immediately subcultured by spreading a loopful evenly
over a quarter plate of medium suitable for the test
organism and was incubated overnight at 37°C for
bacteria or 22°C for fungi. The minimum inhibition
control of organism was read to check the accuracy of the
drug concentrations. The lowest concentration inhibition
growth of the organism was recorded as the minimum
inhibition concentration. Each test compound was diluted,
obtaining 2000 μg/mL concentration, as stock solution.
In the primary screening, 125, 250, 500, and 1000 μg/mL
concentrations of the test compounds were taken. The
active synthesized compounds found in this primary
screening were further tested in a second dilution set
against all organisms. The drugs found to be active in the
primary screening were similarly diluted to obtain 5.25,
12.5, 25, 62.5, 50, and 100 μg/mL concentrations. The
highest dilution showing at least 99% inhibition was
taken as the minimum inhibition concentrations. The
synthesized quinoline hybrid thiosemicarbazides (8a–8l)
were examined for antimicrobial activity against two
Gram-positive bacterial strains such as S. aureus MTCC
96 and S. pyogenes MTCC 142, two Gram-negative
bacterial strains such as E. coli MTCC 443 and
Pseudomonas aeruginosa MTCC 8, and three fungal
strains such as A. clavatus MTCC 1323, C. albicans
MTCC 227, and A. niger MTCC 282. Antibacterial
standard drugs such as ciprofloxacin, chloramphenicol,
and ampicillin and antifungal standard drugs such as
griseofulvin and nystatin were used as control, respectively
In vitro antituberculosis assay.
The antituberculosis
activity was performed on H37Rv strain by already
known method [40]; results are described in Table 2. The
assay was determined by Lowenstein Jensen agar method
in terms of minimum inhibition concentration against
M. tuberculosis H37Rv strain. The primary screening
250, 500, and 1000 μg/mL and secondary screening
3.125, 6.250, 12.5, 25, 50, 100, and 200 μg/mL doses of
compounds were tested via Lowenstein Jensen agar
method; then, it was treated by inspissation method.
Culture of M. tuberculosis H37Rv was grown on
Lowenstein Jensen medium by harvesting in 0.85%
saline in bijou bottles. The stock solution of the tested
compound was prepared in dimethyl sulfoxide solution.
Then, these tubes were incubated at 37°C for 24 h,
followed by streaking of M. tuberculosis H37Rv. These
tubes were also further incubated at 37°C for the growth
of bacilli under observation at 12, 22, and 28 days’
incubation. Tubes containing compounds were compared
with control tubes in which medium alone was incubated
with M. tuberculosis H37Rv. The concentration at which
no development of colonies occurred was taken as the
minimum inhibition concentration of the compounds with
reference to rifampicin as standard drug (Table 2).
MTT assay. Selected analogues (8d, 8g, 8h, and 8k)
were solubilized in mixture of culture-grade dimethyl
sulfoxide (DMSO) (HiMedia: TC185). Different
concentrations of 0.1, 1.0, and 10.0 μg/mL with final
concentration of <0.5% DMSO of analogues were tested
separately three times for the cytotoxicity study for 24-h
exposure
using
3-(4,5-dimethylthiazole-2-yl)-2,5-
diphenyltetrazolium bromide MTT assay on human
(n = 3) peripheral blood lymphocyte cells [51]. This
method is based on the reduction of the yellow
tetrazolium salt MTT by mitochondrial dehydrogenase
enzyme of metabolically active cells into dark blue
crystals, which is largely impermeable to cell membrane,
thus resulting in its accumulation within healthy cells.
The amount of formazan produced is directly
proportional to the number of viable cells. Lymphocytes
were separated by using HiSep (HiMedia: LSM 1077-
(Table 2).
In vitro antimalarial assay. The malarial activity was
performed on the P. falciparum strain by reported
method; [50] the result is mentioned in Table 2. In vitro
antimalarial activity was performed using microassay
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Design, Synthesis, Biological and In-Silico Study of Fluorine Containing Quino-
line Hybrid Thiosemicarbazide Analogues
LS001) and were cultured in 2.0-mL micro-centrifuge tube
using 1.5 mL of RPMI 1640 culture media (HiMedia:
AL028A) supplemented with 10% fetal bovine serum
(HiMedia: RM1112). After 24 h of treatment, the culture
medium was replaced with fresh serum-free culture
media, and 0.02-mL MTT (5 mg/mL, HiMedia:
RM1131) was added in each micro centrifuge tube
(MCT). After 4 h of incubation with MTT, media were
removed, and the resulting purple formazan was
solubilized in 1.0 mL of DMSO. The optical density was
(s, 2H, –NH–C═O, –NH–C═S), 10.85 (s, 1H, Ar–NH–
C═S); 13C-NMR (δ ppm, 100 MHz, DMSO-d6): 121.04,
123.29, 125.37, 125.65, 126.46, 127.53, 127.75, 128.26,
129.44, 129.99, 130.36, 130.68, 131.36, 131.68, 138.63,
139.07, 139.70, 147.65, 156.40, 166.14. Elemental Anal.
Calcd for C26H15F9N4OS: C 51.83, H 2.51, N 9.30, O
2.66, S 5.32. Found: C 51.80, H 2.50, N 9.35, O 2.64, S
5.25.
2-(2-(2,6-Difluorophenyl)-6-(trifluoromethyl)quinoline-4-
carbonyl)-N-phenylhydrazinecarbothioamide (8d).
Dark
yellow solid. ESI–MS; m/z: 502.09 (M)+, 500.90 (M-2);
IRνmax (KBr) cmÀ1: 1149 (C–F), 1479 (C═N), 1678
(C═O), 2931 (CH-str), 3209 (CH-str), 3548 (–NH),
3670 (–NH); 1H-NMR (δ ppm, 400 MHz, DMSO-d6,
J = Hz): δ 7.77–7.46 (m, 3H), 7.93–7.86 (m, 4H), 8.14
(s, 2H), 8.21–8.16 (d, J = 20, 2H), 8.35 (s, 1H), 9.75
(s, 1H, –NH–C═O), 10.14 (s, 1H, –NH–C═S), 10.93 (s,
1H, Ar–NH–C═S); 13C-NMR (δ ppm, 100 MHz,
DMSO-d6): 121.13, 123.24, 125.57, 127.51, 127.75,
128.85, 129.45, 129.97, 130.35, 130.67, 131.37, 131.64,
132.47, 132.81, 135.99, 138.72, 147.62, 156.47.
Elemental Anal. Calcd for C24H15F5N4OS: C 57.37, H
3.01, N 11.15, O 3.18, S 6.38. Found: C 57.40, H 3.00,
read
at
570
nm
using
Epoch
microplate
spectrophotometer (Epoch, Biotech, USA). The percent
viability was analyzed using a given formula.
Spectral
Data. N-(2,4-Difluorophenyl)-2-(6-
(trifluromethyl)-2-(4-(trifluoromethyl)phenyl)quinoline-4-
carbonyl)hydrazinecarbothioamide (8a). Dark yellow solid.
ESI–MS; m/z: 568.93 (M-2), 569.92 (M + 1)+; IRνmax
(KBr) cmÀ1: 1132 (C–F), 1475.93 (C═N), 1668 (C═O),
3120 (CH-str), 3179 (CH-str), 3243 (CH-str), 3568 (–
NH), 3651 (–NH); 1H-NMR (δ ppm, 400 MHz,
DMSO-d6, J = Hz): δ 7.43 (s, 2H), 7.78–7.55 (m, 5H),
7.90–7.87 (t, J = 6, 1H), 8.20–8.14 (t, J = 20, 2H), 8.35
(s, 1H), 9.84 (s, 1H, –NH–C═O), 10.15 (s, 1H, –NH–
C═S), 10.94 (s, 1H, Ar–NH–C═S); 13C-NMR (δ ppm,
100 MHz, DMSO-d6): 121.10, 123.22, 125.55, 127.52,
127.77, 128.76, 129.45, 129.96, 130.36, 130.68, 131.36,
131.64, 138.73, 139.42, 147.61, 156.46. Elemental Anal.
Calcd for C25H14F8N4OS: C 52.64, H 2.47, N 9.82, O
2.80, S 5.62. Found: C 52.60, H 2.44, N 9.76, N 9.76, O
N 11.17, O 3.20, S 6.40.
2-(6-Bromo-2-(4-fluorophenyl)quinoline-4-carbonyl)-N-(2,4-
difluorophenyl)hydrazinecarbothioamide (8e). White solid.
ESI–MS; m/z: 557.93 (M)+, 558.92 (M + 1)+; IRνmax
(KBr) cmÀ1: 555 (C-Br), 1153 (C–F), 1480 (C═N), 1678
(C═O), 3030 (CH-str), 3058 (CH-str), 3195 (CH-str),
1
3570 (–NH), 3644 (–NH); H-NMR (δ ppm, 400 MHz,
2.67, S 5.57.
DMSO-d6, J = Hz): δ 7.69–7.56 (m, 3H), 7.85–7.71 (m,
2H), 7.90–7.86 (t, J = 8, 1H), 8.13–8.10 (t, J = 6, 2H),
8.21–8.13 (d, J = 16, 2H), 8.23 (s, 1H), 9.46 (s, 2H, –
NH–C═O, –NH–C═S), 10.58 (s, 1H, Ar–NH–C═S);
13C-NMR (δ ppm, 100 MHz, DMSO-d6): 120.35, 120.93,
123.25, 125.38, 125.61, 127.51, 127.70, 129.41, 129.97,
130.31, 130.66, 131.38, 131.65, 138.69, 147.59, 156.42,
166.28. Elemental Anal. Calcd for C23H14BrF3N4OS: C
51.99, H 2.66, N 10.54, O 3.01, S 6.03. Found: C 51.97,
2-(2-(2-Chlorophenyl)-8-(trifluoromethyl)quinoline-4-
carbonyl)-N-(2,6-difluorophenyl)hydrazinecarbothioamide
(8b). Dark yellow solid. ESI–MS; m/z: 536 (M)+, 553.7
(M + 1)+; IRνmax (KBr) cmÀ1: 1148 (C–F), 1481 (C═N),
1662 (C═O), 3062 (CH-str), 3166 (CH-str), 3279 (CH-
str), 3567 (–NH), 3650 (–NH); 1H-NMR (δ ppm,
400 MHz, DMSO-d6, J = Hz): δ 7.18–7.14 (t, J = 8, 1H),
7.69–7.54 (t, 2H), 7.84–7.72 (m, 3H), 7.90–7.87 (t, J = 6,
2H), 8.16–8.14 (d, J = 8, 2H), 8.39 (s, 1H), 9.91 (s, 1H,
–NH–C═O), 10.05 (s, 1H, –NH–C═S), 10.86 (s, 1H, Ar–
NH–C═S); 13C-NMR (δ ppm, 100 MHz, DMSO-d6):
120.97, 123.27, 125.63, 127.54, 127.77, 129.45, 129.99,
130.36, 130.70, 131.35, 131.69, 138.61, 140.63, 147.67,
156.37. Elemental Anal. Calcd for C24H14ClF5N4OS: C
53.69, H 2.63, N 10.44, O 2.98, S 5.97. Found: C 53.72,
H 2.60, N 10.60, O 3.07, S 6.08.
2-(6-Bromo-7-(trifluoromethyl)-2-(4-(trifluoromethyl)
quinoline-4-carbonyl)-N-(3-chlorophenyl)
hydrazinecarbothioamide (8f). White solid. ESI–MS; m/z:
647.82 (M)+, 645.97 (M-1); IRνmax (KBr) cmÀ1: 561 (C-
Br), 763 (C–Cl), 1137 (C–F), 1492 (C═N), 1665 (C═O),
2846 (CH-str), 2944 (CH-str), 3055 (CH-str), 3565
(–NH), 3670 (–NH); 1H-NMR (δ ppm, 400 MHz,
DMSO-d6, J = Hz): δ 7.56–7.24 (m, 2H), 7.61–7.57 (t,
J = 8, 2H), 7.78–7.66 (t, 4H), 7.91–7.87 (t, J = 8, 1H),
8.16–8.14 (t, J = 4, 2H), 8.40 (s, 1H), 10.09–9.97 (s, 2H,
–NH–C═O, –NH–C═S), 10.88 (s, 1H, Ar–NH–C═S);
13C-NMR (δ ppm, 100 MHz, DMSO-d6): 120.98, 123.26,
125.62, 127.54, 127.78, 129.46, 129.88, 130.00, 130.37,
130.70, 131.34, 131.69, 138.60, 140.69, 147.67, 156.37.
Elemental Anal. Calcd for C25H14BrClF6N4OS: C 46.35,
H 2.36, N 10.45, O 2.90, S 5.99.
2-(2-(3,5-Bis(trifluoromethyl)phenyl)-7-(trifluoromethyl)
quinoline-4-carbonyl)-N-phenylhydrazinecarbothioamide
(8c).
Dark yellow solid. ESI–MS; m/z: 602.08 (M)+,
603.10 (M + 1)+; IRνmax (KBr) cmÀ1: 1124 (C–F), 1477
(C═N), 1679 (C═O), 3069 (CH-str), 3164 (CH-str), 3276
(CH-str), 3570 (–NH), 3659 (–NH); 1H-NMR (δ ppm,
400 MHz, DMSO-d6, J = Hz): δ 7.21–7.18 (t, J = 6, 1H),
7.68–7.35 (m, 3H), 7.77–7.72 (m, 3H), 7.90–7.87 (t,
J = 6, 2H), 8.17–8.15 (d, J = 8, 2H), 8.17 (s, 1H), 9.92
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. B. Patel, K. D. Patel, N. P. Prajapati, K. R. Patel, D. P. Rajani, S. D. Rajani,
N. S. Shah, D. D. Zala, and H. D. Patel
Vol 000
H 2.18, N 8.65, O 2.47, S 4.95. Found: C 46.30, H 2.15, N
8.70, O 2.45, S 4.94.
2-(7-Chloro-2-(2,4-difluorophenyl)-6-fluoroquinoline-4-
carbonyl)-N-(3,5-dichlorophenyl)hydrazinecarbothioamide
(8g). White solid. ESI–MS; m/z: 557.93 (M)+, 558.92
(KBr) cmÀ1: 755 (C–Cl), 1188 (C–F), 1478 (C═N), 1659
(C═O), 3052 (CH-str), 3156 (CH-str), 3335 (CH-str),
3566 (–NH), 3654 (–NH); H-NMR (δ ppm, 400 MHz,
1
DMSO-d6, J = Hz): δ 2.29 (s, 3H), 7.23–7.15 (t, J = 16,
2H), 7.31 (s, 2H), 7.56–7.51 (m, 2H), 7.76–7.61 (m, 2H),
7.90–7.86 (t, J = 8, 1H), 8.20–8.15 (d, J = 20, 2H), 8.39
(s, 1H), 9.484 (s, 2H, –NH–C═S, –NH–C═O), 10.80 (s,
1H, Ar–NH–C═S); 13C-NMR (δ ppm, 100 MHz,
DMSO-d6): 20.54, 121.01, 123.30, 125.66, 127.52,
127.71, 128.70, 129.42, 129.98, 130.32, 130.67, 131.35,
131.68, 136.49, 138.65, 147.63, 156.39. Elemental Anal.
Calcd for C25H18ClF3N4OS: C 58.31, H 3.52, N 10.88, S
(M + 1)+; IRνmax (KBr) cmÀ1: 756 (C–Cl), 1184 (C–F),
1437 (C═N), 1659 (C═O), 3112 (CH-str), 3192 (CH-str),
3285 (CH-str), 3584 (–NH), 3618 (–NH); 1H-NMR (δ
ppm, 400 MHz, DMSO-d6, J = Hz): δ 7.55–7.46 (t,
J = 20, 2H), 7.65–7.55 (d, J = 40, 2H), 7.90–7.66 (m,
1H), 8.16–8.14 (t, J = 8, 1H), 8.35 (s, 1H), 9.75 (s, 1H,
–NH–C═S), 10.13 (s, 1H, –NH–C═O), 10.92 (s, 1H, Ar–
NH–C═S); 13C-NMR (δ ppm, 100 MHz, DMSO-d6):
121.09, 123.23, 125.57 127.51, 127.75, 128.85, 129.45,
129.96, 130.34, 130.67, 131.35, 131.64, 138.68, 147.62.
Elemental Anal. Calcd for C23H12Cl3F3N4OS: C 49.70, H
2.18, N 10.08, O 2.88, S 5.77. Found: C 49.68, H 2.14,
6.23. Found: C 58.28, H 3.49, N 10.90, S 6.25.
2-(2-(2,4-Difluorophenyl)-6-fluoroquinoline-4-carbonyl)-N-
(4-nitrophenyl)hydrazinecarbothioamide (8k).
Pale yellow
solid. ESI–MS; m/z: 497.45 (M)+, 498.74 (M + 1)+;
IRνmax (KBr) cmÀ1: 753 (C–Cl), 1157 (C–F), 1478
(C═N), 1661 (C═O), 3062 (CH-str), 3164 (CH-str), 3362
(CH-str), 3646 (–NH), 3666 (–NH); 1H-NMR (δ ppm,
400 MHz, DMSO-d6, J = Hz): δ 7.57–7.49 (t, J = 16,
3H), 7.77–7.75 (m, 3H), 8.01–7.88 (m, 3H), 8.19–8.16
(d, J = 12, 1H), 8.49–8.47 (d, J = 8, 1H), 11.48 (s, 1H,
–NH–C═O), 11.85 (s, 1H, –NH–C═S), 12.39 (s, 1H, Ar–
NH–C═S); 13C-NMR (δ ppm, 100 MHz, DMSO-d6):
120.96, 123.22, 125.48, 127.59, 127.89, 128.43, 128.74,
129.48, 130.04, 130.49, 130.76, 131.27, 131.79, 131.96,
133.12, 138.42, 139.81, 147.69, 156.23, 164.24, 167.61.
Elemental Anal. Calcd for C23H14F3N5O3S: C 55.60, H
2.80, N 14.10, S 6.40. Found: C 55.53, H 2.84, N 14.08,
N 10.04, O 2.78, S 5.70.
2-(2-(2-Bromophenyl)-8-chloro-6-(trifluoromethyl)
quinoline-4-carbonyl)-N-(2,6-difluorophenyl)
hydrazinecarbothioamide (8h). White solid. ESI–MS; m/z:
615.80 (M)+, 613.96 (M-2); IRνmax (KBr) cmÀ1: 575
(C-Br), 756 (C–Cl), 1182 (C–F), 1466 (C═N), 1671
(C═O), 3059 (CH-str), 3196 (CH-str), 3397 (CH-str),
1
3547 (–NH), 3641 (–NH); H-NMR (δ ppm, 400 MHz,
DMSO-d6, J = Hz): δ 7.40–7.33 (t, J = 14, 2H), 7.57–
7.52 (m, 2H), 7.79–7.72 (m, 2H), 7.90–7.80 (t, 2H),
8.18–8.03 (t, 2H), 9.97 (s, 1H, –NH–C═S), 10.10 (s, 1H,
–NH–C═O), 10.92 (s, 1H, Ar–NH–C═S); 13C-NMR (δ
ppm, 100 MHz, DMSO-d6): 119.34, 121.85, 125.38,
126.49, 127.53, 128.06, 128.29, 128.63, 129.35, 129.74,
129.91, 130.18, 130.27, 130.63, 131.15, 131.36, 131.62,
131.75, 131.83, 134.36, 138.61, 147.66, 148.38.
Elemental Anal. Calcd for C24H13BrClF5N4OS: C 46.81,
H 2.13, N 9.10, O 2.60, S 5.21. Found: C 46.84, H 2.10,
S 6.45.
2-(6-Fluoro-2-(4-(trifluoromethyl)phenyl)quinoline-4-
carbonyl)-N-(3-methoxyphenyl)hydrazinecarbothioamide
(8l).
White solid. ESI–MS; m/z: 514.49 (M)+, 515.38
(M + 1)+; IRνmax (KBr) cmÀ1: 757 (C–Cl), 1162 (C–F),
1482 (C═N), 1668 (C═O), 3100 (CH-str), 3172 (CH-str),
3265 (CH-str), 3642 (–NH), 3682 (–NH); 1H-NMR (δ
ppm, 400 MHz, DMSO-d6, J = Hz): δ 3.75 (s, 3H, –C,
H3), 6.94–6.92 (d, J = 8, 2H), 7.55–7.30 (t, 2H), 7.55–
7.30 (t, 2H), 7.65 (s, 2H), 7.88–7.86 (d, J = 8, 1H), 8.15–
8.13 (d, J = 8, 2H), 8.39 (s, 1H), 9.81 (s, 2H, –NH–C═O,
–NH–C═O), 10.79 (s, 1H, Ar–NH–C═S); 13C-NMR (δ
ppm, 100 MHz, DMSO-d6): 55.20, 113.44, 121.03,
123.31, 125.67, 127.51, 127.70, 129.42, 129.97, 130.31,
130.66, 131.36, 131.67, 131.88, 138.67, 147.63, 156.41,
156.92. Elemental Anal. Calcd for C25H18F4N4O2S: C
58.36, H 3.53, N 10.89, S, 6.23. Found: C 58.40, H 3.50,
N 10.87, S 6.26.
N 9.04, O 2.70, S 5.17.
N-Butyl-2-(8-chloro-2-(4-fluorophenyl)-6-(trifluoromethyl)
quinoline-4-carbonyl)hydrazinecarbothioamide (8i). Cream
solid. ESI–MS; m/z: 498.92 (M)+, 499.90 (M + 1)+;
IRνmax (KBr) cmÀ1: 769 (C–Cl), 1168 (C–F), 1438
(C═N), 1677 (C═O), 3064 (CH-str), 3163 (CH-str), 3274
(CH-str), 3351 (–NH), 3661 (–NH); 1H-NMR (δ ppm,
400 MHz, DMSO-d6, J = Hz): δ 0.91–0.87 (t, 3H, –CH3),
7.57–7.54 (t, J = 6, 1H), 7.75–7.65 (m, 1H), 7.89–7.86 (t,
J = 6, 1H), 8.19–8.09 (t, J = 20, 3H), 8.34 (s, 1H), 9.44 (s,
1H, –NH–C═S), 10.30 (s, 1H, –NH–C═O), 10.57 (s, 1H,
Ar–NH–C═S); 13C-NMR (δ ppm, 100 MHz, DMSO-d6):
0.08, 13.79, 19.42, 120.94, 123.28, 125.64, 127.51,
127.67, 129.40, 129.98, 130.31, 130.67, 131.38, 131.66,
138.67, 147.61, 156.39, 166.24. Elemental Anal. Calcd for
C22H19ClF4N4OS: C 52.96, H 3.84, N 11.23, S 6.23.
Found: C 52.94, H 3.80, N 11.19, S 6.46.
CONCLUSION
In the summary, a novel series of fluorine-containing
quinoline hybrid thiosemicarbazide analogues (8a–8l)
by modern medicinal chemistry have led to the discovery
2-(8-Chloro-2-phenyl-6-(trifluoromethyl)quinoline-4-
carbonyl)-N-(p-tolyl)hydrazinecarbothioamide (8j).
White
solid. ESI–MS; m/z: 514.95 (M)+, 514.07 (M-1); IRνmax
of
a
large number of effective drugs. We have
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Design, Synthesis, Biological and In-Silico Study of Fluorine Containing Quino-
line Hybrid Thiosemicarbazide Analogues
[11] Sun, J.; Zhu, H.; Yang, Z. M.; Zhu, H. L. Eur J Med Chem
2013, 60, 23.
synthesized novel fluorine-containing quinoline hybrid
thiosemicarbazide analogues and screened for their
in vitro study in antibacterial, antifungal, antimalarial,
and antituberculosis strains. Analogues were active
against antimalarial P. falciparum strain; among
them, analogues 8d, 8g, 8h, 8k, and 8l have shown
remarkable activity than has reference drug quinine.
Analogues 8d and 8l displayed higher activity than did
ampicillin against E. coli strain. Moreover, analogues 8b,
8g, and 8j displayed equivalent activity against E. coli
strain. Analogues 8a, 8b, 8d, and 8g exhibited
more potency than did ampicillin against S. aureus stain.
The antifungal result has shown that analogues 8j, 8f, 8g,
and 8k displayed more potency than did griseofulvin
in the C. albicans strain. Analogues 8a–8l showed
poor activity against H37Rv of antituberculosis.
Furthermore, analogues 8d, 8g, and 8k have shown
excellent activity against the chloroquine-resistant
P. falciparum strains. A cytotoxicity study by MTT assay
demonstrated that analogues 8d, 8g, 8h, and 8k
are nontoxic in human peripheral blood lymphocytes
culture; this study was supported by the ADME-Tox.
For development of new antimalarial analogues, we
have carried out molecular docking, ADME-Tox,
molecular dynamics, and pharmacophore studies.
Biological activity and molecular docking study were
correlated for the potent molecules. This study suggested
the active binding site of analogues to give a best
mechanism in the in silico side. Then, the most active
molecule 8g was used for the molecular dynamics study.
Here, this article concluded that analogues 8d, 8g, and 8k
represented a promising lead for the new development of
antimalarial therapeutics.
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N. S. Shah, D. D. Zala, and H. D. Patel
Vol 000
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet