Synthesis, antibacterial activity and docking studies of substituted quinolone thiosemicarbazones

Article abstract of DOI:10.1080/10426507.2019.1618298

Fifteen 2-quinolone thiosemicarbazone derivatives of which eleven were new, were synthesized at room temperature. The key intermediate was the quinolone carbaldehyde, from which thiosemicarbazones were formed by the reaction of thiosemicarbazides with the aldehyde moiety. The structures of the synthesized compounds were elucidated by 1D and 2D-NMR spectroscopy and mass spectrometry. The synthesized compounds showed antibacterial activity with MBCs in the range 0.80 to 36.49 mM against Staphylococcus aureus, Staphylococcus aureus Rosenbach (MRSA), Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli and Salmonella typhimurium. The best activity was seen when a larger halogen such as chlorine and bromine were substituted at C-6 on the quinolone scaffold and when a planar phenyl group was present on the thiosemicarbazone moiety. Activity was reduced when a smaller fluorine atom was present at C-6 or when a methyl group was attached to the thiosemicarbazone. This group of compounds showed a high negative binding affinity, which suggested promising antimcrobial activity. The 6-chloro derivative with a phenyl group on the thiosemicarbazone had the greatest negative binding affinity.

Full text of DOI:10.1080/10426507.2019.1618298

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Synthesis, antibacterial activity and
docking studies of substituted quinolone
thiosemicarbazones
Hogantharanni Govender, Chunderika Mocktar, Hezekiel M. Kumalo & Neil
A. Koorbanally
To cite this article: Hogantharanni Govender, Chunderika Mocktar, Hezekiel M. Kumalo &
Neil A. Koorbanally (2019): Synthesis, antibacterial activity and docking studies of substituted
quinolone thiosemicarbazones, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2019.1618298
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2019.1618298
Synthesis, antibacterial activity and docking studies of substituted quinolone
thiosemicarbazones
Hogantharanni Govendera, Chunderika Mocktarb, Hezekiel M. Kumaloc, and Neil A. Koorbanallya
b
aSchool of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa; School of Health Sciences, University of KwaZulu-
c
Natal, Durban, South Africa; Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
ABSTRACT
ARTICLE HISTORY
Received 6 January 2019
Accepted 9 May 2019
Fifteen 2-quinolone thiosemicarbazone derivatives of which eleven were new, were synthesized at
room temperature. The key intermediate was the quinolone carbaldehyde, from which thiosemi-
carbazones were formed by the reaction of thiosemicarbazides with the aldehyde moiety. The
structures of the synthesized compounds were elucidated by 1D and 2D-NMR spectroscopy and
mass spectrometry. The synthesized compounds showed antibacterial activity with MBCs in the
range 0.80 to 36.49 mM against Staphylococcus aureus, Staphylococcus aureus Rosenbach (MRSA),
Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli and Salmonella typhimurium. The
best activity was seen when a larger halogen such as chlorine and bromine were substituted at C-
6 on the quinolone scaffold and when a planar phenyl group was present on the thiosemicarba-
zone moiety. Activity was reduced when a smaller fluorine atom was present at C-6 or when a
methyl group was attached to the thiosemicarbazone. This group of compounds showed a high
negative binding affinity, which suggested promising antimcrobial activity. The 6-chloro derivative
with a phenyl group on the thiosemicarbazone had the greatest negative binding affinity.
KEYWORDS
Quinolone; thiosemicarba-
zone;
N-methylthiosemicarbazones;
phenylthiosemicarbazones;
antibacterial activity
GRAPHICAL ABSTRACT
Introduction
bacterial infections.[7,8] Other derivatives of quinoline have
also shown good antimicrobial activity.[9,10]
Quinolones are derived from hydroxyquinolines, heterocyclic
molecules containing pyridine fused to a benzene ring.
These quinolines are synthesized by a variety of methods
including the Skraup, Combes, Doebner-von Miller, Knorr
and Pfitzinger syntheses.[1] Quinolones are usually formed
by the Conrad-Limpach synthesis.[2] Fluoroquinolones in
particular are important antibiotics currently prescribed for
bacterial infections.[3] They are used in the treatment of
respiratory, gastrointestinal, gynaecologic and skin infec-
tions, and pneumonia[4,5] and act by interfering with DNA
Thiosemicarbazones belong to a class of Schiff based
ligands usually synthesized by condensing aldehydes or
ketones with thiosemicarbazide.[11] They can also be pre-
pared by first forming the imine between the aldehyde and
hydrazine and then reacting this with isothiocyanate.[12]
Thiosemicarbazone derivatives have various pharmacological
activities, including antibacterial,[13,14] antioxidant,[15] anti-
malarial,[16] antitumor,[17] antiviral,[18] anticancer,[19,20] anti-
HIV[21] and antitubercular activity.[21]
The combination of two structural scaffolds, each having
replication.[6] Drugs such as ciprofloxacin and levofloxacin pharmacological activity of their own could lead to mole-
have broad spectrum activity and are drugs of choice against cules with enhanced therapeutic effects.[22] These molecules
CONTACT Neil A. Koorbanally
Koorbanally@ukzn.ac.za
School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X54001, Durban, 4000, South Africa.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2019.1618298.
ß 2019 Taylor & Francis Group, LLC

2
H. GOVENDER ET AL.
Scheme 1. Synthetic route to the quinoline thiosemicarbazones 5a–o.
are often referred to as ‘molecular hybrids’ and extensive produced the final quinolone thiosemicarbazone derivatives
work has recently been carried out on quinoline hybrids.[23]
Quinoline-thiosemicarbazone hybrids have been prepared by
reacting quinoline carbaldehydes with substituted thiosemi-
carbazides and have shown antibacterial,[24] antifungal,[24]
antitubercular,[25] antioxidant,[26–28] anti-inflammatory,[29]
and anticancer activity.[27,30,31]
Although similar compounds have been synthesized pre-
viously,[27,28] a range of these derivatives halogenated at C-6
have not been synthesized and investigated for their antibac-
terial activity. Similar compounds have only shown cytotoxic
and antioxidant activity.[27,28] Due to the emergence of anti-
bacterial resistance, alternatives to commonly used antibiot-
ics are needed.[32,33] Thus, a small library of quinolone
thiosemicarbazones were synthesized and tested for antibac-
terial activity in order to identify hit compounds to be used
as leads in the fight against antibacterial resistance.
5a–o[31] (Scheme 1). The yields obtained for the final com-
pounds were between 69 and 96%. The synthesized com-
pounds contained electron donating hydrogen and methyl
groups and electron withdrawing halogens at C-6 on the
quinolone scaffold and the thiosemicarbazone was varied
with methyl and phenyl groups to determine the best pos-
sible functionalities for antibacterial activity.
Of the 15 derivatives synthesized, only 5a, 5b, 5f and 5k
were previously reported.[27,28] All quinolones containing a
halogen at C-6 and two of the quinolones containing a
methyl at C-6 were new.
1
The synthesized compounds were characterized using H,
13C, 2D NMR spectroscopy and mass spectrometry. For
1
example, the H NMR spectrum of 5d, the 6-chloro deriva-
tive, showed the presence of the quinoline ring with two
doublets at dH 7.67 (2.3 Hz, H-5) and dH 7.31 (8.8 Hz, H-8)
and a double doublet at dH 7.53 (8.8, 2.3 Hz, H-7). H-4
occurred as a singlet at dH 8.70 and NH-1 occurred at dH
12.12. J3 HMBC correlations of H-8 with C-6 and C-4a
allowed both these carbon singlets to be assigned to dC
126.5 and 120.3 respectively, while H-4, H-5 and H-7 all
showed J3 HMBC correlations to C-8a at dC 137.5. The
quinolone carbonyl resonance was present at dC 178.1
The thiosemicarbazone moiety was characterized by the
H-9 (imine) proton occurring as a singlet at dH 8.25. The
NH-11 proton resonance occurred at dH 11.69 and two
broadened singlets at dH 8.35 and 8.04 were attributed to
NH-13a and NH-13b. The thiosemicarbazone carbon, C-12
Results and discussion
Chemistry
Fifteen derivatives of quinolone-thiosemicarbazone hybrids
were prepared, starting with the acetylation of anilines
(1a–e) with acetic anhydride (forming acetanilides 2a–e)
and then forming the 3-formyl-2-quinolines 3a–e using the
Vilsmeier-Haack reaction with dimethyl formamide and
phosphoryl chloride,[34] which under acidic conditions
formed the quinolines 4a–e. Reaction of the quinoline-3-car-
baldehydes with methyl or phenylhydrazides 4a–e with thio-
semicarbazide, 4-methyl- or 4-phenylthiosemicarbazide, occurred at dC160.7.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Table 2. Binding affinities for the quinolone-thiosemicarbazone hybrids
against DNA Gyrase.
Inhibitor
Binding affinity (kcal/mol)
5g
5k
5l
5n
ꢀ9.6
ꢀ11.1
ꢀ10.9
ꢀ11.3
ꢀ9.1
5o
Levofloxacin
ꢀ13.4
Figure 1. Key HMBC correlations for 5d.
in disc diffusion assays against Serratia marcescens and deri-
vatisation of the thiosemicarbazone moiety led to moderate
activity against Bacillus cereus, E. coli and S.
marcescens.[35,36]
Table 1. Antibacterial activity of the quinolone-thiosemicarbazone hybrids
(MBC in mM).
Compound
Gram positive
Gram negative
No.
R1
R2
MRSA
S.a
P.a
S.t
E.c
K.p
5g
5l
5m
5n
5o
CH3
CH3 Phenyl
Br
Cl
F
CH3
18
0.93
0.80
0.88
15
0.087
0.19
9.1
3.7
3.1
1.8
1.8
9.1
1.9
25
7.0
29
9.1
0.93
6.3
7.0
15
4.6
30
6.3
7.0
15
37
7.4
25
28
29
0.022
0.0030
Molecular docking
Phenyl
Phenyl
Phenyl
Quinolones such as ciprofloxacin bind to DNA gyrase, a
type II topoisomerase enzyme, to inhibit negative supercoil-
ing of DNA by preventing ligation of dsDNA breaks. The
structure of the DNA gyrase complex was used as a starting
point for modeling. The docking of substituted quinolone
thiosemicarbazones was carried out using the potential bind-
ing sites of the receptor DNA gyrase. The main goal was to
understand the ability of the synthesized molecules to inter-
act with the target.
The docking study with the assistance of lig-plot (Figures
S1–S3) indicated that compound 5g (Figure S3) showed a
similar binding mode to Ciprofloxacin, a quinolone reported
to inhibit negative supercoiling of DNA by preventing liga-
tion of dsDNA breaks. The corresponding binding affinity
for each antagonist is displayed in Table 2. The test com-
pounds showed a high –ve binding affinity and hence sug-
Levofloxacin
Ciprofloxacin
0.022 0.35 0.0216 0.00034
0.094 0.19 0.0030 0.0030
Confirmation that the thiosemicarbazone fragment was
linked to the quinolone core was indicated by the J2 HMBC
correlation of H-9 to C-3 at dC 126.1 and the J3 HMBC cor-
relation of H-9 to C-2. Important HMBC correlations are
depicted in Figure 1.
Antibacterial study
The synthesized quinolone thiosemicarbazones were tested
for their antibacterial activity against two Gram positive bac-
teria (S. aureus and methicillin resistant S. aureus (MRSA))
and four Gram negative strains (P. aeruginosa, K. pneumo-
niae, E. coli and S. typhimurium). In general, the N-phenyl
thiosemicarbazones showed better activity than the N-methyl
or unsubstituted thiosemicarbazone derivatives, with three
of the compounds, 5l (6-methyl), 5m (6-bromo) and 5n (6-
chloro) showing activity of <1 mM against MRSA, being
just one order of magnitude lower than that of levofloxacin
and comparable to ciprofloxacin, currently used antibiotics.
However, all other quinolones had MBC values with 2
orders of magnitude worse than levofloxacin and 3 orders of
magnitude worse than ciprofloxacin against the strains
gested
promising
antimicrobial
activity.
However,
improvements to these structures are still needed since none
of the quinolone derivatives had more binding affinity than
the reference ligand. Of the five compounds, 5n showed the
highest binding affinity and this structure could be used as a
starting point for modification. These results are encourag-
ing due to a number of different hydrogen interactions
observed from the different complexes. These interactions
could provide a mechanism of action for the tested com-
pounds and indicate the possibility of developing novel anti-
bacterial agents targeting an early step in peptidoglycan
tested with the exception of E. coli where the activity of the biosynthesis.
compounds were 4–5 orders of magnitude worse than levo-
floxacin (Table 1). This indicates that in order for activity to
occur, a large substituent such as chlorine, bromine or
Conclusions
methyl is essential at C-6 and a planar aromatic ring is
needed on the thiosemicarbazone portion of the molecule.
This was indicated by reduced activity when a methyl group
was present on the thiosemicarbazone (as in 5g) and when a
small fluorine atom was present at C-6 (as in 5o).
Comparing the five active compounds, 5l and 5n showed
the broadest spectrum of activity, being active at < 10 mM
against 5 of the 6 strains tested against. In the literature,
derivatives of 8-hydroxyquinoline thiosemicarbazones were
inactive against S. aureus, P. aeruginosa and Micrococcus
A series of 2-chloroquinolone-3-thiosemicarbazones (5a–o)
were easily prepared from quinolone carbaldehyde precur-
sors. Three compounds showed good activity against MRSA,
only one order of magnitude lower than levofloxacin. Better
activity was seen by those compounds with a N-phenyl
group in the thiosemicarbazide moiety and with a halogen
or methyl group at C-6 on the quinolone framework.
Although the thiosemicarbazones had moderate activity, the
results indicate that 6-methyl and 6-chloroquinolone N-phe-
nyl thiosemicarbazone moieties could be a useful scaffold to
luteus, however all were active with small zones of inhibition synthesize antibacterial compounds.

4
H. GOVENDER ET AL.
6-Methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde thio-
semicarbazone (5b) yellow solid (90% yield), mp 287–289 ꢁC,
IR tmax (cmꢀ1): 3273 (Ar-N-H), 3155, 3015 (N-H), 1651
(C ¼ O), 1531 (C ¼ N), 810 (C ¼ S); UV kmax (MeOH) nm
(log e) 223 (3.90), 245 (3.82), 351 (4.10), 388 (4.22); 1H
NMR (DMSO-d6, 400 MHz) dH 11.92 (1H, s, H-1), 11.62
(1H, s, H-11), 8.69 (1H, s, H-4), 8.29 (1H, bs, H-13a), 8.26
(1H, s, H-9), 8.07 (1H, bs, H-13b), 7.42 (1H, bs, H-5), 7.35
(1H, dd, J ¼ 8.4, 1.7 Hz, H-7), 7.22 (1H, d, J ¼ 8.4 Hz, H-8),
2.34 (3H, s, H-6a); 13C NMR (DMSO-d6, 100 MHz) dC
178.0 (C-12), 160.8 (C-2), 136.9 (C-8a), 136.8 (C-9), 134.8
(C-4), 132.3 (C-7), 131.3 (C-6), 128.8 (C-5), 125.2 (C-3),
119.1 (C-4a), 115.1 (C-8), 20.4 (C-6a).
Experimental
General
Reagents and solvents were supplied by Sigma Aldrich, via
Capital Laboratories, South Africa. Silica gel 60 (63–200 lm)
was used for column chromatography. Alumina-backed sil-
ica gel 40 F254 plates (Merck) were used for TLC and visual-
ized under a UV lamp at 254 nm. Melting points were
determined on an Electrothermal IA 9100 Digital melting
point apparatus and are uncorrected. Infrared spectra were
recorded on a Perkin Elmer Spectrum 100 instrument with
Universal ATR sampling accessory. H, 13C and 2D NMR
1
spectra were acquired on Bruker AvanceIII 400 or 600 MHz
spectrometers (Bruker Co., Karlsruhe, Germany) at frequen-
6-Bromo-2-oxo-1,2-dihydroquinoline-3-carbaldehyde thio-
semicarbazone (5c) yellow solid (69% yield), mp 281–283 ꢁC,
IR tmax (cmꢀ1): 3350 (Ar-N-H), 3214, 3146 (N-H), 1642
(C ¼ O), 1514 (C ¼ N), 821 (C ¼ S); UV kmax (MeOH) nm
cies of 400.22 MHz for H and 100.63 MHz for 13C and ref-
1
erenced to TMS. High-resolution mass spectral data was
acquired on a Waters Micromass LCT Premier TOF-MS
instrument. UV analysis was carried out on a UV-VIS-NIR
Shimadzu series 3600 spectrophotometer using methanol as
1
(log e): 245 (4.37), 352 (4.05), 389 (4.17); H NMR (DMSO-
d6, 400 MHz) dH 12.13 (1H, s, H-1), 11.70 (1H, s, H-11),
8.72 (1H, s, H-4), 8.38 (1H, bs, H-13a), 8.24 (1H, s, H-9),
8.03 (1H, bs, H-13b), 7.80 (1H, d, J ¼ 2.0 Hz, H-5), 7.66
(1H, dd, J ¼ 8.8, 2.0 Hz, H-7), 7.26 (1H, d, J ¼ 8.8 Hz, H-8);
13C NMR (DMSO-d6, 100 MHz) dC 184.1 (C-12), 160.7 (C-
2), 137.8 (C-8a), 136.1 (C-9), 133.7 (C-4), 133.3 (C-7), 130.1
(C-5), 126.5 (C-3), 120.9 (C-6), 117.3 (C-8), 113.8 (C-4a);
HRMS: (m/z) 346.9578 [M þ Na] (calculated for
C11H9N4ONaSBr, 346.9578).
1
a solvent. The Supplemental Materials contains sample H
and 13C NMR spectra for 5a–o (Figures S3–S62).
General procedure for synthesis of 2-chloroquinoline-3-
carbaldehydes (3a–e)
The different derivatives were synthesized using the method
in Toth et al.[34]
6-Chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde thio-
semicarbazone (5d) yellow solid (94% yield), mp 283–285 ꢁC,
IR tmax (cmꢀ1): 3259 (Ar-N-H), 3192, 3151 (N-H), 1645
(C ¼ O), 1519 (C ¼ N), 824 (C ¼ S); UV kmax (MeOH) nm
General procedure for the synthesis of N-methyl, N-
phenyl and thiosemicarbazone derivatives (5a–o)
1
(log e): 242 (4.43), 352 (4.08), 387 (4.20); H NMR (DMSO-
The substituted 2-chloroquinoline-3-carbaldehydes (3a–e)
(1 mmol) was heated under reflux with 70% acetic acid
(10 mL) for 4–6 h and upon cooling the product preciptated
out of solution to form (4a–e). The thiosemicarbazone
derivatives were then formed according to the method in
Bisceglie et al.[31] Substituted thiosemicarbazides, 4-methyl
d6, 400 MHz) dH 12.12 (1H, s, H-1), 11.69 (1H, s, H-11),
8.70 (1H, s, H-4), 8.35 (1H, s, H-13a), 8.25 (1H, s, H-9),
8.04 (1H, s, H-13b), 7.67 (1H, d, J ¼ 2.3 Hz, H-5), 7.54 (1H,
dd, J ¼ 8.8, 2.3 Hz, H-7), 7.32 (1H, d, J ¼ 8.8 Hz, H-8); 13C
NMR (DMSO-d6, 100 MHz) dC 178.1 (C-12), 160.7 (C-2),
137.5 (C-8a), 136.2 (C-9), 133.8 (C-4), 130.7 (C-7), 127.1
(C-5), 126.5 (C-6), 126.1 (C-3), 120.3 (C-4a), 117.1 (C-8);
HRMS: (m/z) 303.0086 [M þ Na] (calculated for
C11H9N4ONaSCl, 303.0083).
thiosemicarbazides
or
4-phenylthiosemicarbazides
(1.0 mmol) dissolved in methanol (80 mL) were added to an
equivalent amount of 4a–e (200 mg; 1.0 mmol) and the solu-
tion stirred at room temperature for 24 h. Upon completion,
the flask was placed in an ice bath, where a solid formed,
which was filtered, washed with ethanol and dried.
6-Fluoro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde thio-
semicarbazone (5e) yellow solid (94% yield), mp 284–286 ꢁC,
IR tmax (cmꢀ1): 3273 (Ar-N-H), 3144, 3048 (N-H), 1642
(C ¼ O), 1527 (C ¼ N), 806 (C ¼ S); UV kmax (MeOH) nm
2-Oxo-1,2-dihydroquinoline-3-carbaldehyde thiosemicarba-
zone (5a) yellow solid (74% yield), mp 296–298 ꢁC, IR tmax
(cmꢀ1): 3369 (Ar-N-H), 3267, 3148 (N-H), 1642 (C ¼ O),
1519 (C ¼ N), 824 (C ¼ S); UV kmax (MeOH) nm (log e) 242
1
(log e): 223 (4.21), 351 (3.76), 387 (3.89); H NMR (DMSO-
d6, 400 MHz) dH 12.07 (1H, s, H-1), 11.69 (1H, s, H-11),
8.72 (1H, s, H-4), 8.35 (1H, bs, H-13a), 8.26 (1H, s, H-9),
8.05 (1H, bs, H-13b), 7.45-7.39 (2H, m, H-5, H-7), 7.34 (1H,
dd, J ¼ 8.6, 4.8 Hz, H-8); 13C NMR (DMSO-d6, 100 MHz) dC
178.0 (C-12), 160.5 (C-2), 157.0 (d, J ¼ 237.3 Hz, C-6), 136.2
(C-9), 136.2 (C-8a), 133.9 (C-4), 126.4 (C-3), 119.7 (d,
J ¼ 8.9 Hz, C-4a), 118.9 (d, J ¼ 24.5 Hz, C-7), 116.9 (d,
J ¼ 8.5 Hz, C-8), 112.6 (d, J ¼ 22.4 Hz, C-5); HRMS: (m/z)
1
(4.11), 382 (4.15); H NMR (DMSO-d6, 400 MHz) dH 11.99
(1H, s, H-1), 11.63 (1H, s, H-11), 8.74 (1H, s, H-4), 8.27
(2H, bs, H-9, H-13a), 8.09 (1H, bs, H-13b), 7.65 (1H, dd,
J ¼ 8.4, 1.0 Hz, H-5), 7.51 (1H, td, J ¼ 8.4, 1.4 Hz, H-6), 7.31
(1H, d, J ¼ 8.2 Hz, H-8), 7.31 (1H, td, J ¼ 8.2, 1.0 Hz, H-7);
13C NMR (DMSO-d6, 100 MHz) dC 178.0 (C-12), 160.9 (C-
2), 138.8 (C-8a), 136.8 (C-9), 135.1 (C-4), 130.9 (C-6), 128.5
(C-5), 125.2 (C-3), 122.4 (C-7), 119.2 (C-4a), 115.1 (C-8);
HRMS: (m/z) 269.0475 [M þ Na] (calculated for
C11H10N4ONaS, 269.0473).
287.0380
C11H9N4OFNaS, 287.0379).
[M þ Na]
(calculated
for
2-Oxo-1,2-dihydroquinoline-3-carbaldehyde N-methylthio-
semicarbazone (5f) yellow solid (78% yield), mp 285–287 ꢁC,

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
IR tmax (cmꢀ1) 3341 (Ar-N-H), 3156 (N-H), 1641 (C ¼ O), 297–299 ꢁC, IR tmax (cmꢀ1): 3399 (Ar-N-H), 3172 (N-H),
1526 (C ¼ N), 809 (C ¼ S), UV kmax (MeOH) nm (log e): 1663 (C ¼ O), 1501 (C ¼ N), 825 (C ¼ S); UV kmax (MeOH)
1
233 (4.30), 385 (4.06); H NMR (DMSO-d6, 400 MHz) dH nm (log e): 229 (4.31), 280 (4.37); 1H NMR (DMSO-d6,
12.02 (1H, s, H-1), 11.69 (1H, s, H-11), 8.67 (1H, s, H-4), 400 MHz) dH 12.09 (1H, s, H-1), 11.74 (1H, s, H-11), 8.62
8.59 (1H, q, J ¼ 4.5 Hz, H-13), 8.28 (1H, s, H-9), 7.66 (1H, (1H, s, H-4), 8.58 (1H, q, J ¼ 4.5 Hz, H-13), 8.27 (1H, s, H-
d, J ¼ 7.6 Hz, H-5), 7.52 (1H, td, J ¼ 8.2, 0.9 Hz, H-7), 7.32 9), 7.44 (1H, d, J ¼ 8.6 Hz, H-5), 7.43 (1H, td, J ¼ 8.6, 2.8 Hz,
(1H, d, J ¼ 8.2 Hz, H-8) , 7.23 (1H, t, J ¼ 7.6, Hz, H-6), 3.05 H-7), 7.34 (1H, dd, J ¼ 8.6, 4.8 Hz, H-8), 3.05 (3H, d,
(3H, d, J ¼ 4.5 Hz, H-14); 13C NMR (DMSO-d6, 100 MHz) J ¼ 4.5 Hz, H-14); 13C NMR (DMSO-d6, 100 MHz) dC 177.8
dC 177.7 (C-12), 160.9 (C-2), 138.8 (C-8a), 136.3 (C-9), (C-12), 160.6 (C-2), 157.1 (d, J ¼ 237.2 Hz, C-6), 135.9 (C-
134.6 (C-4), 130.9 (C-6), 128.4 (C-7), 125.5 (C-3), 122.4 (C- 9), 135.6 (C-8a), 133.7 (d, J ¼ 3.8 Hz, C-4), 126.7 (C-3),
5), 119.1 (C-4a), 115.2 (C-8), 30.8 (C-14); HRMS: (m/z) 119.7 (d, J ¼ 8.9 Hz, C-4a), 118.9 (d, J ¼ 24.6 Hz, C-5), 117.1
283.0632
C12H12N4ONaS, 283.0630).
6-Methyl-2-oxo-1,2-dihydroquinoline-3-carbaldeyde
methylthiosemicarbazone (5g) yellow solid (88% yield), mp
[M þ Na];
(calculated
for (d, J ¼ 8.5 Hz, C-8), 112.7 (d, J ¼ 22.4 Hz, C-7), 30.8 (C-14);
HRMS: (m/z) 301.0529 [M þ Na] (calculated for
N-
C12H11N4OFNaS, 301.0535).
2-Oxo-1,2-dihydroquinoline-3-carbaldehyde N-phenylthio-
340–342 ꢁC, IR tmax (cmꢀ1): 3342 (Ar-N-H), 3245, 3161 (N- semicarbazone (5k) yellow solid (94%), mp 331–333 ꢁC, IR
H), 1648 (C ¼ O), 1518 (C ¼ N), 838 (C ¼ S); UV kmax tmax (cmꢀ1): 3306 (Ar-N-H), 3164 (N-H), 1650 (C ¼ O), 1529
(MeOH) nm (log e): 245 (4.36), 390 (4.22); 1H NMR (C ¼ N), 815 (C ¼ S); UV kmax (MeOH) nm (log e): 238
1
(DMSO-d6, 400 MHz) dH 11.94 (1H, s, H-1), 11.68 (1H, s, (4.36), 388 (4.36); H NMR (DMSO-d6, 400 MHz) dH 12.04
H-11), 8.61 (1H, s, H-4), 8.57 (1H, q, J ¼ 4.6 Hz, H-13), 8.27 (2H, s, H-1/H-11), 10.16 (1H, s, H-13), 8.87 (1H, s, H-4), 8.40
(1H, s, H-9), 7.43 (1H, bs, H-5), 7.35 (1H, dd, J ¼ 8.4, (1H, s, H-9), 7.68 (1H, d, J ¼ 7.7 Hz, H-8), 7.58 (2H, d,
1.7 Hz, H-7), 7.23 (1H, d, J ¼ 8.4 Hz, H-8), 3.05 (3H, d, J ¼ 7.6 Hz, H-2’/6’), 7.53 (1H, td, J ¼ 7.7, 1.2 Hz, H-7), 7.39
J ¼ 4.6 Hz, H-14), 2.35 (3H, s, H-6a); 13C NMR (DMSO-d6, (2H, t, J ¼ 7.6 Hz, H-3’/5’), 7.33 (1H, d, J ¼ 8.2 Hz, H-5), 7.20-
100 MHz) dC 177.7 (C-12), 160.8 (C-2), 136.9 (C-8a), 136.4 7.25 (2H, m, H-4’, H-6); 13C NMR (DMSO-d6, 100 MHz) d
(C-9), 134.4 (C-4), 132.3 (C-7), 131.3 (C-6), 127.7 (C-5), 176.0 (C-12), 160.9 (C-2), 138.98 (C-8a), 138.96 (C-1’), 137.5
125.4 (C-3), 119.1 (C-4a), 115.1 (C-8), 30.8 (C-14), 20.4 (C- (C-9), 135.5 (C-4), 131.1 (C-7), 128.5 (C-5), 128.1 (C-3’/5’),
6a); HRMS: (m/z) 297.0785 [M þ Na] (calculated for 126.1 (C-2’/6’), 125.5 (C-4’), 125.1 (C-3), 122.4 (C-6), 119.1
C13H14N4ONaS, 297.0786).
6-Bromo-2-oxo-1,2-dihydroquinoline-3-carbaldehyde
methylthiosemicarbazone (5h) yellow solid (72% yield), mp
(C-4a), 115.2 (C-8); HRMS: (m/z) 345.0777 [M þ Na] (calcu-
N- lated for C17H14N4ONaS, 345.0786).
6-Methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde
N-
332–334 ꢁC, IR tmax (cmꢀ1): 3379 (Ar-N-H), 3300, 3148 (N- phenylthiosemicarbazone (5l) yellow solid (96% yield), mp
H), 1652 (C ¼ O), 1519 (C ¼ N), 816 (C ¼ S); UV kmax 344–346 ꢁC; IR tmax (cmꢀ1): 3312 (Ar-N-H), 3140 (N-H),
(MeOH) nm (log e): 247 (4.44), 392 (4.20); 1H NMR 1651 (C ¼ O), 1530 (C ¼ N), 823 (C ¼ S); UV kmax (MeOH)
(DMSO-d6, 400 MHz) dH 12.15 (1H, s, H-1), 11.76 (1H, s, nm (log e): 246 (4.31), 357 (4.15), 393 (4.26); 1H NMR
H-11), 8.63 (1H, s, H-4), 8.55 (1H, q, J ¼ 4.6 Hz, H-13), 8.25 (DMSO-d6, 400 MHz) dH 12.03 (1H, s, H-1), 11.97 (1H, s,
(1H, s, H-9), 7.83 (1H, d, J ¼ 2.2 Hz, H-5), 7.67 (1H, dd, H-11), 10.14 (1H, s, H-13), 8.80 (1H, s, H-4), 8.40 (1H, s,
J ¼ 8.8, 2.2 Hz, H-7), 7.27 (1H, d, J ¼ 8.8 Hz, H-8), 3.05 (3H, H-9), 7.58 (2H, d, J ¼ 7.7 Hz, H-2’/6’), 7.46 (1H, bs, H-5),
d, J ¼ 4.6 Hz, H-14); 13C NMR (DMSO-d6, 100 MHz) dC 7.35-7.41 (3H, m, H-3’/4’/5’); 7.21-7.25 (2H, m, H-7, H-8),
177.8 (C-12), 160.7 (C-2), 137.8 (C-8a), 135.7 (C-9), 133.3 2.34 (3H, s, H-6a); 13C NMR (DMSO-d6, 100 MHz) dC
176.0 (C-12), 160.9 (C-2), 138.9 (C-1’), 137.6 (C-9), 137.1
(C-8a), 135.3 (C-4), 132.4 (C-7), 131.3 (C-6), 128.1 (C-3’/5’),
127.9 (C-5), 125.9 (C-2’/6’), 125.5 (C-4’), 125.0 (C-3), 119.1
N- (C-4a), 115.1 (C-8), 20.4 (C-6a); HRMS: (m/z) 359.0943
(C-7), 133.2 (C-4), 130.1 (C-5), 126.7 (C-3), 120.8 (C-6),
117.4 (C-8), 113.8 (C-4a), 30.8 (C-14); HRMS: (m/z)
336.9761 [M-H] (calculated for C12H10N4OSBr, 336.9759).
6-Chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde
methylthiosemicarbazone (5i) yellow solid (78% yield), mp [M þ Na] (calculated for C18H16N4ONaS, 359.0943).
324–326 ꢁC, IR tmax (cmꢀ1): 3373 (Ar-N-H), 3165 (N-H),
6-Bromo-2-oxo-1,2-dihydroquinoline-3-carbaldehyde
N-
phenylthiosemicarbazone (5m) yellow solid (82% yield), mp
1647 (C ¼ O), 1520 (C ¼ N), 818 (C ¼ S); UV kmax (MeOH)
339–341 ꢁC; IR tmax (cmꢀ1): 3323 (Ar-N-H), 3141 (N-H),
nm (log e): 245 (4.41), 390 (4.29); 1H NMR (DMSO-d6,
400 MHz) dH 12.15 (1H, s, H-1), 11.76 (1H, s, H-11), 8.63 1647 (C ¼ O), 1526 (C ¼ N), 815 (C ¼ S); UV kmax (MeOH)
(1H, s, H-4), 8.56 (1H, q, J ¼ 4.6 Hz, H-13), 8.25 (1H, s, H- nm (log e): 220 (4.37), 247 (4.36), 393 (4.21); 1H NMR
(DMSO-d6, 400 MHz) dH 12.17 (1H, s, H-1), 12.11 (1H, s,
9), 7.69 (1H, d, J ¼ 2.3 Hz, H-5) , 7.56 (1H, dd, J ¼ 8.8,
H-11), 10.10 (1H, s, H-13), 8.81 (1H, s, H-4), 8.37 (1H, s,
2.3 Hz, H-7), 7.33 (1H, d, J ¼ 8.8 Hz, H-8), 3.05 (3H, d,
J ¼ 4.6 Hz, H-14); 13C NMR (DMSO-d6, 100 MHz) dC 177.8
(C-12), 160.7 (C-2), 137.5 (C-8a), 135.8 (C-9), 133.4 (C-4),
130.6 (C-7), 127.0 (C-5), 126.8 (C-6), 126.1 (C-3), 120.3 (C-
4a), 117.1 (C-8), 30.8 (C-14); HRMS: (m/z) 293.0273 [M-H]
(calculated for C12H10N4OSCl, 293.0264).
H-9), 7.85 (1H, d, J ¼ 2.2 Hz, H-5), 7.67 (1H, dd, J ¼ 8.8,
2.2 Hz, H-7), 7.59 (2H, d, J ¼ 7.6 Hz, H-2’/6’), 7.40 (2H, t,
J ¼ 7.6 Hz, H-3’/5’), 7.35 (1H, d, J ¼ 8.8 Hz, H-8), 7.24 (1H,
t, J ¼ 7.6 Hz, H-4’); 13C NMR (DMSO-d6, 100 MHz) dC
176.1 (C-12), 160.7 (C-2), 138.8 (C-1’), 137.6 (C-8a), 136.8
N- (C-9), 134.1 (C-4), 133.4 (C-7), 130.2 (C-5), 128.2 (C-3’/5’),
6-Fluoro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde
methylthiosemicarbazone (5j) yellow solid (79% yield), mp 126.3 (C-3), 125.9 (C-2’/6’), 125.5 (C-4’), 120.8 (C-6), 117.4

6
H. GOVENDER ET AL.
(C-8), 113.8 (C-4a); HRMS: (m/z) 422.9888 [M þ Na] (calcu- plates were examined for activity, which was indicated by
lated for C17H13N4ONaSBr, 422.9891).
zones of inhibition around the area where the sample was
6-Chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde
N- placed. Those compounds that showed broad spectrum
phenylthiosemicarbazone (5n) yellow solid (86% yield), mp activity were selected for the MBC assay.
325–327 ꢁC; IR tmax (cmꢀ1): 3315 (Ar-N-H), 3146 (N-H),
1650 (C ¼ O), 1527 (C ¼ N), 819 (C ¼ S); UV kmax (MeOH)
nm (log e): 230 (4.17), 245 (4.25), 393 (4.12); 1H NMR
(DMSO-d6, 400 MHz) dH 12.17 (1H, s, H-1), 12.10 (1H, s,
H-11), 10.11 (1H, s, H-13), 8.81 (1H, s, H-4), 8.37 (1H, s,
H-9), 7.71 (1H, d, J ¼ 2.4 Hz, H-5), 7.60 (2H, d, J ¼ 7.6 Hz,
H-2’/6’), 7.56 (1H, dd, J ¼ 8.8, 2.4 Hz, H-7), 7.40 (2H, t,
J ¼ 7.6 Hz, H-3’/5’), 7.34 (1H, d, J ¼ 8.8 Hz, H-8), 7.24 (1H,
t, J ¼ 7.6 Hz, H-4’); 13C NMR (DMSO-d6, 100 MHz) dC
176.1 (C-12), 160.7 (C-2), 138.9 (C-1’), 137.6 (C-8a), 136.9
(C-9), 134.2 (C-4), 130.8 (C-7), 128.2 (C-3’/5’), 127.2 (C-5),
126.4 (C-3), 126.1 (C-4a), 125.9 (C-2’/6’), 125.5 (C-4’), 120.3
(C-6), 117.1 (C-8); HRMS: (m/z) 379.0394 [M þ Na] (calcu-
lated for C17H13N4ONaSCl, 379.0396).
The MBCs were determined in triplicate using a modifi-
cation of the Broth Dilution Method.[38] A 10 mg sample of
the test compounds was dissolved in 1 mL DMSO and seri-
ally diluted in triplicate. Mueller-Hinton agar plates were
lawn inoculated with the different bacterial strains, which
were prepared as described above. A 5 mL sample of each
dilution of the selected compounds was spotted onto the
Mueller-Hinton agar plates and incubated for 24 h at 37 ꢁC.
The experiment was conducted in triplicate and averaged.
The MBC was the lowest concentration that showed a zone
of inhibition around the area where the sample was placed.
Molecular docking
6-Fluoro-2-oxo-1,2-dihydroquinoline-3-carbaldehdye
N-
The crystal structure (PDB ID: 2XCT) of the DNA gyrase
complex was taken from the Protein from the RSCB Protein
Data Bank.[39] The missing residues were added using a
graphical user interface tool of molecular modeling,
Chimera[40] and a ligand interaction map was generated
using the web version of Pose View. The docking calcula-
phenylthiosemicarbazone (5o) yellow solid (90% yield), mp
296–298 ꢁC, IR tmax (cmꢀ1): 3312 (Ar-N-H), 3156 (N-H),
1650 (C ¼ O), 1531 (C ¼ N), 826 (C ¼ S); UV kmax (MeOH)
nm (log e): 223 (4.42), 351 (4.45), 387 (4.46); 1H NMR
(DMSO-d6, 400 MHz) dH 12.12 (1H, s, H-1), 12.09 (1H, s,
H-11), 10.14 (1H, s, H-13), 8.81 (1H, s, H-4), 8.39 (1H, s, tions were performed using Autodock Vina.[41] During
H-9), 7.58 (2H, d, J ¼ 7.6 Hz, H-2’/6’), 7.34-7.46 (5H, m, H- docking, Geister partial chargers were assigned and the
5, H-7, H-8, H-3’/5’), 7.23 (1H, t, J ¼ 7.6, Hz, H-4’); 13C Autodock atom types were defined using the Autodock
Graphical user interface supplied by MGL tools.[42] The
NMR (DMSO-d6, 100 MHz) d 176.1 (C-12), 160.6 (C-2),
docked conformations were generated using the Lamarckian
157.1 (d, J ¼ 237.4 Hz, C-6), 138.9 (C-1’), 137.0 (C-9), 135.7
Genetic Algorithm, considered to be one of the best docking
(C-8a), 134.5 (d, J ¼ 3.4 Hz, C-4), 128.1 (C-3’/5’), 126.4 (C-
methods available.[43,44] The files were converted into the
3), 125.9 (C-2’/6’), 125.5 (C-4’), 119.7 (d, J ¼ 8.9 Hz, C-4a),
pdbqt format required for docking using Raccoon software.
The gridbox was defined using Autodock Vina with the grid
119.2 (d, J ¼ 24.7 Hz, C-7), 117.1 (d, J ¼ 8.1 Hz, C-8), 112.8
(d, J ¼ 22.4 Hz, C-5); HRMS: (m/z) 363.0686 [M þ Na] (cal-
parameters being X ¼ 40, Y ¼ 36 and Z ¼ 24 for the dimen-
culated for C17H13N4OFNaS, 363.0692).
sions and X ¼ 54.750, Y ¼ 39.250 and Z ¼ ꢀ19.389 for the
center grid box and the reports for each calculation were in
Antibacterial activity
(kcal/mol). This technique has been validated in previ-
ous studies.[45]
The thiosemicarbazone derivatives were tested for antibac-
terial activity against two Gram positive strains, S. aureus
ATCC 25923 (S.a), and S. aureus Rosenbach ATCC BAA-
1683 (methicillin resistant S. aureus, MRSA) and four Gram
negative bacterial strains (P. aeruginosa ATCC 27853 (P.a),
K. pneumoniae ATCC 31488 (K.p), E. coli ATCC 25922 (E.c)
Acknowledgements
NK thanks the National Research Foundation South Africa for a
Competitive Grant for Rated Researchers (Grant No. 118534) and
Incentive Funding for Rated Researchers (Grant No. 114817).
and S. typhimurium ATCC 14026 (S.t)). The compounds
were first subject to a preliminary screen using the disc dif-
fusion assay[37] and based on their activity, selected com-
ORCID
pounds were chosen to determine their minimum
bactericidal concentration (MBC).
Neil A. Koorbanally
http://orcid.org/0000-0002-6214-4021
The different bacterial strains were grown in Nutrient
Broth (Biolab, South Africa) at 37 ꢁC in a shaking incubator
at 115 rpm for 18 h. The bacteria were diluted with sterile
distilled water to achieve a final concentration equivalent to
a 0.5 McFarland’s standard using a McFarland’s densitom-
eter. Mueller-Hinton agar plates (Biolab, South Africa) were
lawn inoculated with the bacteria using a throat swab. A
5 mL sample of each compound (10 mg mLꢀ1 in DMSO) was
placed onto the Mueller-Hinton plates in triplicate and incu-
bated at 37 ꢁC for 18 h. After the incubation period, the
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