Synthesis and Bioactivity of Quinoline-3-carboxamide Derivatives

Article abstract of DOI:10.1002/jhet.3132

Twelve novel substituted 2-chloroquinoline-3-carboxamide derivatives were prepared from acetanilides using the Vilsmeier–Haack reaction, producing 2-chloro-3-carbaldehyde quinolines, followed by oxidation of the 3-carbaldehyde to the carboxylic acid and coupling this group with various anilines. The structures of the synthesized compounds were confirmed by NMR, mass spectrometry, and single crystal X-ray diffraction. The chemical shifts of H-5 and H-8 were shown to be influenced by the substituent at C-6. The substituent at C-6 was also seen to affect the chemical shift of C-5, C-7, and C-8, with C-5 and C-7 being more shielded in 5j (F substituted) in comparison with 5g (Cl substituted) and 5d (CH₃ substituted). The compounds showed weak activity in the mM range against Gram-positive and Gram-negative bacteria of which 5b, 5d, and 5f showed the best activity with minimum bactericidal concentration values for 5b being 3.79?mM against methicillin-resistant Staphylococcus aureus and 5d and 5f having minimum bactericidal concentration values of 3.77 and 1.79?mM against S.?aureus ATCC 25923, respectively.

Full text of DOI:10.1002/jhet.3132

Month 2018
Synthesis and Bioactivity of Quinoline-3-carboxamide Derivatives
*
Hogantharanni Govender, Chunderika Mocktar, and Neil A. Koorbanally
School of Chemistry and Physics and School of Health Sciences, University of KwaZulu-Natal, Private Bag X54001,
Durban 4000, South Africa
*
E-mail: koorbanally@ukzn.ac.za
Received September 23, 2017
DOI 10.1002/jhet.3132
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Twelve novel substituted 2-chloroquinoline-3-carboxamide derivatives were prepared from acetanilides
using the Vilsmeier–Haack reaction, producing 2-chloro-3-carbaldehyde quinolines, followed by oxidation
of the 3-carbaldehyde to the carboxylic acid and coupling this group with various anilines. The structures
of the synthesized compounds were confirmed by NMR, mass spectrometry, and single crystal X-ray
diffraction. The chemical shifts of H-5 and H-8 were shown to be influenced by the substituent at C-6.
The substituent at C-6 was also seen to affect the chemical shift of C-5, C-7, and C-8, with C-5 and C-7 being
more shielded in 5j (F substituted) in comparison with 5g (Cl substituted) and 5d (CH3 substituted). The
compounds showed weak activity in the mM range against Gram-positive and Gram-negative bacteria of
which 5b, 5d, and 5f showed the best activity with minimum bactericidal concentration values for 5b being
3.79 mM against methicillin-resistant Staphylococcus aureus and 5d and 5f having minimum bactericidal
concentration values of 3.77 and 1.79 mM against S. aureus ATCC 25923, respectively.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
carboxylic acids include potassium permanganate,
chromium (VI) oxide, pyridinium dichromate, pyridinium
chlorochromate, silver nitrate in basic media, via the
nitrile with phosphoryl chloride and hydroxylamine and
then conversion to the carboxylic acid with sodium
hydroxide or hydrogen peroxide with sodium chlorite and
formic acid [19,20]. This provides a further functional
group on which to build on the quinoline scaffold.
Quinolines with a carboxamide group linked to an
isoxazolyl group has been previously synthesized by first
forming butanamides with 4-amino-5-styrylisoxazoles
and β-keto esters under microwave conditions and
then forming the quinoline portion with o-amino
benzaldehydes [21]. Quinoline carboxamides were also
made in a one-pot reaction by reacting cyano acetic
acid methyl ester, 2-amino benzaldehydes, and 2-
bromobenzylamines in good yields [22]. Laquinimod, an
experimental drug used for the treatment of multiple
sclerosis, was prepared from quinoline carboxylic
acids, ethylamine, carbodiimides, thionyl chloride, and
triethylamine [23]. Carbodiimides such as 1-ethyl-3-(3-
dimethylaminopropyl) carbodiimide hydrochloride (EDC)
Quinoline derivatives have been known to have
medicinal applications such as antimalarial, antibacterial
[1,2], antifungal [3,4], antiviral [5,6], anticancer,
antitumor [7], anti-obesity [8], and anti-inflammmatory
activities [9,10]. Over the years, quinine, chloroquine,
and mefloquine were used for the effective treatment of
malaria [11]. Quinoline-3-carboxamides have been used
in clinical trials for cancer treatment and autoimmune
conditions
[12].
The
quinoline-3-carboxamide
tasquinimod was found to be effective during the early
stages of tumor development [13], while paquinimod was
used recently in clinical trials for the treatment of
systemic sclerosis [14].
Various methods such as the Doebner–von Miller,
Skraup, Vilsmeier–Haack, Combes, Friedlander, and
Knorr synthesis have been employed for the synthesis of
quinolines and their derivatives [15]. Among these, the
Vilsmeier–Haack reaction is popularly used for the
synthesis of 2-chloro-3-formyl quinolines [16–18].
Reagents used to oxidize the aldehyde further to
© 2018 Wiley Periodicals, Inc.

H. Govender, C. Mocktar, and N. A. Koorbanally
Vol 000
together with hydroxybenzotriazole (HOBt) were
commonly used reagents to couple quinoline carboxylic
acids with amines forming quinoline carboxamides
[24,25]. Besides forming carboxamides, quinoline
carboxylic acids were also used to synthesize
benzodiazepin-12-ones and benzimidazoles with o-
phenyldiamines [17].
could be seen at δC 163.5, and C-8a and C-2 adjacent to
the nitrogen of the quinoline ring could be observed at δC
146.8 and δC 145.9. C-10 adjacent to the amide nitrogen
appeared at δC 138.7 and C-4 at δC at 138.2. The other
aromatic carbon resonances were present between δC
119.5 to 131.9 and assigned based on heteronuclear
single quantum coherence and heteronuclear multiple
bond correlation correlations. For example, C-3 was
differentiated from C-4a because of HMBC correlations
from C-4a to H-6 and H-8. C-8a with HMBC
correlations to H-4, H-5, and H-7 allowed the distinction
to be made between C-2 and C-8a. H-4 was also verified
by an HMBC correlation to the carbonyl resonance at δC
163.5. The structures of the remaining derivatives were
characterized similarly, and apart from slight differences
on the quinoline ring (when a substituent was present at
C-6) and the N-phenyl ring (due to para substitution),
most resonances were similar.
We herein report on the synthesis of 12 novel quinoline-
3-carboxamide derivatives and their antibacterial activity.
RESULTS AND DISCUSSION
Chemistry. Twelve novel 2-chloro-N-phenylquinoline-
3-carboxamides were prepared, starting from anilines,
forming acetanilides, and using Vilsmeier reagents,
dimethylformamide (DMF), and phosphoryl chloride to
produce the 2-chloroquinoline-3-carbaldehyde scaffold
following the procedure in Toth et al. [26]. The Pinnick
oxidation was then used to oxidize the 3-carbaldehydes to
the carboxylic acids, which were then coupled to various
anilines to produce 2-chloro-N-phenylquinoline-3-
carboxamide derivatives in yields of 32–53%, following
the procedures in George et al. [27] and Li et al. [28]
(Fig. 1). The structures of the synthesized compounds
were elucidated by 1H, 13C, and 2D NMR, mass
spectrometry, and single crystal X-ray diffraction.
When methyl, chloro, and fluoro groups were
substituted at C-6, interesting observations were made in
1
the H NMR spectrum regarding the chemical shifts of
H-5, H-7, and H-8. With the methyl group 5d, H-8
appeared as a doublet at δH 7.94 (J = 8.6 Hz), H-5
slightly more shielded at δH 7.89 as a broad singlet, and
H-7 most shielded, overlapping with H-20/60 as a double
doublet at δH 7.75 (J = 8.8, 1.9 Hz). However, when the
methyl group was replaced by a chloro group 5g, H-5
was now the most deshielded resonance, a doublet at δH
8.28 followed by the more shielded H-8 doublet at δH
8.07 and H-7 still the most shielded appearing as a
double doublet at δH 7.94 (J = 9.0, 2.4 Hz). With fluorine
at this position (5j), the order of resonances was similar
to 5d. H-8 was the most deshielded and now a double
doublet at δH 8.13 with J = 9.4 Hz (ortho coupling) and
5.2 Hz (coupling with F). This was followed by the more
shielded H-5 at δH 7.96, now a double doublet due to
coupling with F (JH-5,F = 9.0 Hz and JH-5,H-7 = 3.0 Hz).
The H-7 resonance was still the most shielded at δH 7.85
appearing as a triplet of doublets (JH-7,H-8 = JH-7,
The 1H NMR spectrum of 5a showed two characteristic
singlets at δH 10.73 and δH 8.74 attributed to the amide
proton NH-10 and H-4 on the quinoline ring. H-5 and H-
8 appeared as two doublets at δH 8.14 and 8.04,
respectively, with J = 8.4 Hz each, and H-6 and H-7 were
observed at δH 7.92 (H-7) and δH 7.73 (H-6) as triplets of
doublets with J = 8.4 Hz for ortho coupling and 1.2 Hz
for meta coupling. The aromatic protons on the N-phenyl
ring were present as a doublet at δH 7.75 (H-20/60) and
two triplets at δH 7.39 (H-30/50) and 7.15 (H-40) with
ortho coupling of 7.6 Hz for each of the resonances. In
the 13C NMR spectrum, the amide carbonyl resonance
Figure 1. Synthetic route to 2-chloroquinoline-3-carboxamides 5a–l; (i) acetic anyhdride, acetic acid; (ii) DMF, POCl3, 82°C, reflux 24 h; (iii) NaClO2,
NaH2PO4.2H2O, butan-1-ol, r.t., 2 h; (iv) EDC, Et3N, HOBt, DMF, r.t., 24 h.
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Synthesis and Bioactivity of Quinoline-3-carboxamides
1
= 8.9 Hz and JH-7,H-5 = 3.0 Hz). Overlaid H NMR
stronger than electron donation by resonance, causing C-
6 to appear at δC 160.8 as a doublet (JC-F = 246.2 Hz).
The C-7, C-8, and C-5 resonances at δC 134.0, 127.4,
and 127.0, respectively, in 5d (CH3 at C-6) occur at
similar chemical shifts in 5 g (Cl at C-6); however, there
is a distinct difference in the C-5 and C-7 resonances in
5j (F at C-6), which appeared much more shielded at δC
112.2 and 122.4, respectively, as doublets with JC-F of
22.3 and 25.7 Hz, respectively. This indicates an increase
in electron density at these particular carbon atoms,
through electron donation by resonance from the fluorine.
These results indicate that this scaffold with fluorine at C-
F
spectra showing these resonances and their differences
are presented in Figure 2.
The different substituents at C-6 also have a noticeable
effect on the C-5, C-6, C-7, and C-8 resonances.
Interestingly, when the methyl group is present at C-6, it
resonates at δC 137.7, and when the chloro group is
substituted at C-6, this resonance is more shielded at δC
131.6, indicating that electron donation through
resonance is much stronger than the inductive effect.
However, when the highly electronegative fluoro group is
placed at this position, the inductive effect is much
1
Figure 2. Overlay of H NMR spectra showing the shifts in the H-5, H-7, and H-8 resonances as a result of substitution of H-6. [Color figure can be
viewed at wileyonlinelibrary.com]
Figure 3. Overlay of 13C NMR spectra for 5d, 5g, and 5j showing the shifts in resonances of C-5 to C-8 as a result of substitution at C-6. [Color figure can
be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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H. Govender, C. Mocktar, and N. A. Koorbanally
Vol 000
3-carbaldehydes, oxidation to the carboxylic acids and
amide coupling with anilines using EDC and HOBt.
Substitution at C-6 resulted in either upfield or downfield
shifts in the 1H NMR spectra for H-5, H-7, and H-8 and in
the 13C NMR for C-5 to C-8. All synthesized compounds
showed weak antibacterial activity with the best activity
being seen by 5b (6-H, 40-CH3), 5d (6-CH3, 40-H), and 5f
(6-CH3, 40-F). Thus, the electron donating methyl groups
either at C-6 or C-40 were shown to be responsible for the
antibacterial activity of the quinoline carboxamide scaffold.
EXPERIMENTAL
Figure 4. ORTEP diagram of 5f. [Color figure can be viewed at
wileyonlinelibrary.com]
General.
Chemical reagents and solvents were
purchased from Sigma Aldrich, via Capital Laboratories,
South Africa. Silica gel 60 (0.063–0.2 mm) was used for col-
umn chromatography. Alumina-backed silica gel 60 F254
plates (Merck, Darmstadt, Germany) was used for thin-layer
chromatography (TLC) and visualized under ultraviolet
(UV) light (254 nm). Melting points were conducted on an
Electrothermal IA 9100 Digital melting point appara-
tus (Cole-Parmer, Staffordshire, UK) and are uncorrected.
Infrared (IR) spectra were recorded on a Perkin Elmer Spec-
trum 100 instrument (PerkinElmer Inc., Waltham, MA) with
Universal ATR sampling accessory. 1H, 13C, and 2D NMR
spectra were acquired on either Bruker AvanceIII 400 or
600 MHz spectrometers (Bruker Co., Karlsruhe, Germany)
6 is ideal for nucleophilic substitution at C-6 and for
electrophilic substitution at C-5 and C-7. These distinct
differences are shown in the overlaid 13C NMR spectra
of 5d, 5g, and 5j (Fig. 3).
The crystal structure of the 4-fluorophenyl derivative 5f
was obtained to explore the three-dimensional structure of
the molecule. The molecule is essentially planar with all
bond angles close to 120° and the N-phenyl group pointing
away from the quinoline nucleus. The torsion angle for
C8-C7-N1-C1 is 8.9(3) indicating that the N-phenyl group
is slightly out of the plane of the quinoline nucleus.
Figure 4 shows an ORTEP diagram of 5f. The refinement
parameters are given in the Supporting Information.
1
at frequencies of 400.22 MHz for H and 100.63 MHz for
13C. Chemical shifts were reported as δ values (ppm) relative
to an internal standard of tetramethylsilane or to the solvent
line of DMSO-d6 (δH = 2.50, δC = 39.52). High-
resolution mass data were obtained using a Waters
Micromass LCT Premier TOF-MS instrument (Microsep
Pty Ltd., Johannesburg, South Africa). UV analyses were
conducted with a UV–VIS–NIR Shimadzu series 3600 spec-
trophotometer (Shimadzu, Tokyo, Japan) using methanol.
Antibacterial activity. The synthesized compounds 5a–
5l were screened against two Gram-positive and four
Gram-negative
strains
[Staphylococcus
aureus,
methicillin-resistant S. aureus (MRSA), Pseudomonas
aeruginosa, Klebsiella pneumoniae, Escherichia coli, and
Salmonella typhimurium] using the disc diffusion assay.
Compounds 5b–5f showed broad spectrum activity in the
disc diffusion assay having zones of inhibition greater
than 7 mm in five or more of the bacterial strains and
were subject to the broth microdilution method to
determine their minimum bactericidal concentration
(MBC) values. However, none of the compounds showed
significant antibacterial activity. The best activity was
shown by 5b (3.79 mM against MRSA), and 5d and 5f
(3.77 and 1.79 mM against S. aureus ATCC 25923,
respectively). The disc diffusion and MBC data for all
compounds are given in the Supporting Information.
Synthesis. General procedure for synthesis of para
substituted acetanilides 2.
Acetic anhydride (10 mL,
0.1 mol) and glacial acetic acid (10 mL, 0.175 mol) were
added to substituted anilines (0.1 mole), heated gently
under reflux for 1 h, and poured into ice water (200 mL),
where crystals of the acetylated product was formed. The
crystals were filtered and recrystallized with acetic
acid : water (1:2), producing the acetanilides in yields of
between 94 and 100%.
General procedure for synthesis of 2-chloroquinoline-3-
carbaldehydes 3.
Substituted 2-chloroquinoline-3-
carbaldehydes (3a–d) were prepared according to the
method in Toth et al. [26]. Briefly, dry N,N,-
dimethylformamide (DMF) (9.6 mL; 0.125 mol) was
transferred under inert conditions to a two-neck round
bottom flask, placed in an ice bath (0°C) to which
phosphoryl chloride (POCl3) (32.2 mL; 0.35 mol) was
CONCLUSION
A series of 2-chloroquinoline-3-carboxamides (5a–l)
were successfully synthesized from substituted acetanilides
using the Vilsmeier–Haack reaction, forming the quinoline
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Synthesis and Bioactivity of Quinoline-3-carboxamides
added dropwise with constant stirring. The appropriate
acetanilide (0.05 mol) was then added and heated under
reflux with a condenser fitted with a CaCl2 drying tube at
82°C for 24 h. The reaction was monitored to completion
using TLC. Upon completion, the mixture was cooled,
poured into 300 mL ice water, and stirred for 1 h at 0–
10°C. A pale yellow precipitate formed and was filtered
off, washed with 100-mL water, and dried producing 2-
chloroquinoline-3-carbaldehydes in yields ranging from
1.2, H-6), 7.39 (2H, t, J = 7.6 Hz, H-30/50), 7.15 (1H, t,
J = 7.6 Hz, H-40); 13C NMR (DMSO-d6, 100 MHz): δ
163.5 (C-9), 146.8 (C-8a), 145.9 (C-2), 138.7 (C-10),
138.2 (C-4), 132.0 (C-7), 130.7 (C-3), 128.9 (C-30/50),
128.4 (C-5), 128.0 (C-6), 127.7 (C-8), 126.1 (C-4a),
124.1 (C-40), 119.5 (C-20/60); HR-ESI(+)-MS. Anal.
Calcd for C16H11N2OClNa (M + Na)+: 304.0458.
Found: 304.0459.
2-Chloro-N-4-tolylquinoline-3-carboxamide
(5b).
43 to 74%.
Cream solid; Yield: 44%; mp 138–140°C; IR (KBr) 3238
General procedure for the oxidation of 2-chloroquinoline-3-
carbaldehydes 3 to 2-chloroquinoline-3-carboxylic acids 4.
The procedure in George et al. [27] was carried out with
modifications. The substituted 2-chloroquinoline-3-
carbaldehydes (4.68 mmol) was dissolved in n-butanol
(N─H), 1657 (C═O) cmꢀ1; UV λmax (MeOH) (log ε):
1
237 (4.31), 310 (3.47), 325 (3.32) nm; H NMR (DMSO-
d6, 400 MHz): δ 10.64 (1H, s, H-10), 8.73 (1H, s, H-4),
8.13 (1H, d, J = 8.3 Hz, H-5), 8.04 (1H, d, J = 8.3 Hz,
H-8) 7.91 (1H, td, J = 8.3, 1.2 Hz, H-7), 7.74 (1H, td,
J = 8.3, 1.2 Hz, H-6), 7.62 (2H, d, J = 8.3 Hz, H-20/60),
7.20 (2H, d, J = 8.3 Hz, H-30/50), 2.29 (3H, s, 40-CH3);
13C NMR (DMSO-d6, 100 MHz): δ 163.3 (C-9), 146.8
(C-8a), 146.0 (C-2), 138.1 (C-4), 136.2 (C-10), 133.1 (C-
40), 131.9 (C-7), 130.7 (C-3), 129.2 (C-30/50), 128.4 (C-
5), 127.9 (C-6), 127.7 (C-8), 126.1 (C-4a), 119.5 (C-20/
60), 20.5 (40-CH3); HR-ESI(+)MS. Anal. Calcd for
C17H13N2OClNa (M + Na)+: 319.0614. Found: 319.0617.
(89 mL), and
a solution of sodium dihydrogen
orthophosphate (5.56 g; 35.61 mmol) and sodium chlorite
(4.29 g; 47.47 mmol) in water (39 mL) was gradually
added and stirred for 2 h at room temperature. The
reaction was monitored to completion by TLC,
concentrated in vacuo, and diluted with water (68 mL)
and ethyl acetate (50 mL). Sodium carbonate (5 g) was
added to the mixture to separate the two layers and the
lower aqueous layer acidified with HCl to pH 4 where
the 2-chloroquinoline-3-carboxylic acids 4 precipitated as
cream-colored compounds with yields of between 54 and
2-Chloro-N-(4-fluorophenyl)quinoline-3-carboxamide
(5c).
Cream solid; Yield: 46%; mp 199–201°C; IR
72%.
(KBr) 3241 (N─H), 1669 (C═O) cmꢀ1; UV λmax
(MeOH) (log ε): 237 (3.98), 296 (3.48), 325 (3.18) nm;
1H NMR (DMSO-d6, 400 MHz): δ 10.82 (1H, s, H-10),
8.77 (1H, s, H-4), 8.17 (1H, d, J = 8.0 Hz, H-5), 8.07
(1H, d, J = 8.4 Hz, H-8), 7.95 (1H, td, J = 8.4, 1.3 Hz,
H-7), 7.76–7.80 (3H, m, H-20/60, H-6), 7.26 (2H, t,
J = 8.8 Hz, H-30/50); 13C NMR (DMSO-d6, 100 MHz): δ
163.4 (C-9), 158.4 (d, J = 240.6 Hz, C-40), 146.8 (C-8a),
145.9 (C-2), 138.2 (C-4), 135.1 (d, J = 2.3 Hz, C-10),
132.0 (C-7), 130.5 (C-3), 128.4 (C-5), 128.0 (C-6), 127.7
(C-8), 126.0 (C-4a), 121.4 (d, J = 7.9 Hz, C-20/60), 116.0
(d, J = 22.1 Hz, C-30/50); HR-ESI(ꢀ)MS. Anal. Calcd for
C16H9N2OFCl (M-H)+: 299.0387. Found: 299.0390.
General procedure for synthesis of 2-chloro-N-
phenylquinoline-3-carboxamides (5a–l).
used by Li et al. [28] for the synthesis of quinoline-3-
carboxamides was followed with modifications. EDC
(0.99 mmol) and 1-hydroxybenzotrizole (HOBt)
(0.99 mmol) were added sequentially at room temperature
The procedure
to the substituted quinoline-3-carboxylic acids
4
(0.9 mmol) dissolved in 10 mL DMF. The reaction
mixture was stirred for 30 min before adding the
appropriate substituted arlyamines (0.99 mmol) and
triethylamine (1.895 mmol) to the mixture and stirring at
room temperature for 24 h. Upon completion, the reaction
mixture was poured into ice water, where it formed a
cream-colored precipitate. This was washed with water,
dried, and purified using column chromatography on silica
gel with hexane : ethyl acetate (9:1) producing 2-chloro-N-
phenylquinoline-3-carboxamide derivatives 5a–l in yields
of between 32 and 53%.
2-Chloro-6-methyl-N-phenylquinoline-3-carboxamide
(5d).
Cream solid; Yield: 43%; mp 173–175°C, IR
(KBr) 3253 (N─H), 1660 (C═O) cmꢀ1; UV λmax
(MeOH) (log ε): 241 (4.13), 327 (3.17) nm; 1H NMR
(DMSO-d6, 400 MHz): δ 10.71 (1H, s, H-10), 8.62 (1H,
s, H-4), 7.94 (1H, d, J = 8.6 Hz, H-8), 7.89 (1H, br s, H-
5), 7.75 (1H, dd, J = 8.8, 1.9 Hz, H-7), 7.72 (2H, d,
J = 7.6 Hz, H-20/60), 7.39 (2H, t, J = 7.6 Hz, H-30/50),
7.15 (1H, t, J = 7.6 Hz, H-40), 2.54 (3H, s, 6-CH3); 13C
NMR (DMSO-d6, 100 MHz): δ 163.6 (C-9), 145.4 (C-
8a), 144.9 (C-2), 138.7 (C-10), 137.7 (C-6), 137.4 (C-4),
134.0 (C-7), 130.7 (C-3), 128.9 (C-30/50), 127.4 (C-8),
127.0 (C-5), 126.1, (C-4a), 124.1 (C-40), 119.5 (C-20/60),
2-Chloro-N-phenylquinoline-3-carboxamide
(5a).
Cream solid; Yield: 32%; mp 178–180°C; IR (KBr)
3256 (N─H), 1660 (C═O) cmꢀ1; UV λmax (MeOH) (log
ε): 237 (3.95), 309 (3.14), 325 (2.93) nm; 1H NMR
(DMSO-d6, 400 MHz): δ 10.73 (1H, s, H-10), 8.75 (1H,
s, H-4), 8.14 (1H, d, J = 8.4 Hz, H-5), 8.04 (1H, d,
J = 8.4 Hz, H-8), 7.92 (1H, td, J = 8.4, 1.2 Hz, H-7),
7.75 (2H, d, J = 7.6 Hz, H-20/60), 7.73 (1H, td, J = 8.4,
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H. Govender, C. Mocktar, and N. A. Koorbanally
Vol 000
21.1 (6-CH3); HR-ESI(+)MS. Anal. Calcd for
(N─H), 1656 (C═O) cmꢀ1; UV λmax (MeOH) (log ε):
241 (4.31), 309 (3.22); 330 (3.05) nm; H NMR (DMSO-
1
C17H13N2OClNa (M + Na)+: 319.0614. Found: 319.0616.
d6, 600 MHz): δ 10.66 (1H, s, H-10), 8.68 (1H, s, H-4),
8.26 (1H, d, J = 2.5 Hz, H-5), 8.06 (1H, d, J = 9.0 Hz,
H-8), 7.92 (1H, dd, J = 9.0, 2.5 Hz, H-7), 7.59 (2H, d,
J = 8.3 Hz, H-20/60), 7.19 (2H, d, J = 8.3 Hz, H-30/50),
2.29 (3H, s, 40-CH3); 13C NMR (DMSO-d6, 100 MHz): δ
163.5 (C-9), 147.0 (C-2), 145.8 (C-8a), 137.8 (C-4),
136.6 (C-10), 133.8 (C-40), 132.80 (C-7), 132.79 (C-3),
132.2 (C-4a), 130.4 (C-8), 129.8 (C-30/50), 127.55 (C-5),
127.46 (C-6), 120.1 (C-20/60); 21.0 (40-CH3); HR-ESI(ꢀ)
MS. Anal. Calcd for C17H11N2OCl2 (M-H)+: 329.0248.
Found: 329.0247.
2-Chloro-6-methyl-N-4-tolylquinoline-3-carboxamide
(5e).
Cream solid; Yield: 38%; mp 224–226°C, IR
(KBr) 3244 (N─H), 1656 (C═O) cmꢀ1; UV λmax
(MeOH) (log ε): 240 (4.42), 311 (3.86), 328 (3.82) nm;
1H NMR (DMSO-d6, 400 MHz): δ 10.62 (1H, s, H-10),
8.60 (1H, s, H-4), 7.93 (1H, d, J = 8.6 Hz, H-8), 7.89
(1H, s, H-5), 7.75 (1H, dd, J = 8.6, 1.8 Hz, H-7), 7.61
(2H, d, J = 8.4 Hz, H-20/60), 7.19 (2H, d, J = 8.4 Hz, H-
30/50), 2.53 (3H, s, 6-CH3), 2.29 (3H, s, 40-CH3); 13C
NMR (DMSO-d6, 100 MHz): δ 163.4 (C-9), 145.4 (C-
8a), 145.0 (C-2), 137.7 (C-6), 137.3 (C-4), 136.3 (C-10),
133.9 (C-7), 133.0 (C-40), 130.8 (C-3), 129.2 (C-30/50),
127.4 (C-8), 127.0 (C-5), 126.1 (C-4a), 119.5 (C-20/60),
21.1 (6-CH3), 20.5 (4’-CH3); HR-ESI(+)MS. Anal. Calcd
for C18H15N2OClNa (M + Na)+: 310.0771. Found:
310.0770.
2,6-dichloro-N-(4-fluorophenyl)quinoline-3-carboxamide
(5i).
Cream solid; Yield: 44%; mp 167–169°C; IR
(KBr) 3229 (N─H), 1656 (C═O) cmꢀ1; UV λmax
(MeOH) (log ε): 236 (4.18), 280 (3.64); 330 (3.22) nm;
1H NMR (DMSO-d6, 400 MHz): δ 10.84 (1H, s, H-10),
8.72 (1H, s, H-4), 8.27 (1H, d, J = 2.4 Hz, H-5), 8.07
(1H, d, J = 9.0 Hz, H-8), 7.93 (1H, dd, J = 9.0, 2.4 Hz,
H-7), 7.74 (2H, dd, J = 8.9, 5.0 Hz, H-20/60), 7.24 (2H, t,
J = 8.9 Hz, H-30/50); 13C NMR (DMSO-d6, 100 MHz): δ
163.7 (C-9), 159.1 (d, J = 239.5 Hz, C-40), 146.9 (C-2),
145.8 (C-8a), 137.9 (C-4), 135.4 (C-10), 133.0 (C-7),
132.9 (C-4a), 131.9 (C-3), 130.4 (C-8), 127.6 (C-5),
127.4 (C-6), 122.0 (d, J = 7.8 Hz, C-20/60), 116.1 (d,
J = 22.2 Hz, C-30/50); HR-ESI(ꢀ)MS. Anal. Calcd for
C16H9N2OCl2F (M-H)+: 332.9998. Found: 333.0006.
2-Chloro-N-(4-fluorophenyl)-6-methylquinoline-3-
carboxamide (5f).
Cream solid; Yield: 53%; mp 196–
198°C; IR (KBr) 3244(N─H), 1658 (C═O) cmꢀ1; UV
λmax (MeOH) (log ε): 241 (4.44), 327 (3.40) nm; 1H
NMR (DMSO-d6, 400 MHz): δ 10.78 (1H, s, H-10), 8.61
(1H, s, H-4), 7.93 (1H, d, J = 8.6 Hz, H-8), 7.88 (1H, br
s, H-5), 7.74 (2H, d, J = 8.8 Hz, H-20/60), 7.72–7.74 (1H,
m, H-7), 7.23 (2H, t, J = 8.8 Hz, H-30/50), 2.53 (3H, s, 6-
CH3); 13C NMR (DMSO-d6, 100 MHz): δ 163.6 (C-9),
158.4 (C-40), 145.4 (C-8a), 144.9 (C-2), 137.8 (C-6),
137.4 (C-4), 135.1 (C-10), 134.0 (C-7), 130.4 (C-3),
127.4 (C-8), 127.0 (C-5), 126.0 (C-4a), 121.4 (d,
J = 7.9 Hz, C-20/60), 116.0 (d, J = 22.2 Hz, C-30/50), 21.1
(6-CH3); HR-ESI(ꢀ)MS. Anal. Calcd for C17H12N2OF
(M-Cl)+: 279.0934. Found: 279.0945.
2-Chloro-6-fluoro-N-phenylquinoline-3-carboxamide
(5j).
Cream solid; Yield: 42%; mp 187–189°C; IR
(KBr) 3242 (N─H), 1655 (C═O) cmꢀ1; UV λmax
(MeOH) (log ε): 237 (4.20), 309 (3.32); 325 (3.32) nm;
1H NMR (DMSO-d6, 600 MHz): δ 10.76 (1H, s, H-10),
8.71 (1H, s, H-4), 8.13 (1H, dd, J = 9.4, 5.2 Hz, H-8),
7.96 (1H, dd, J = 9.0, 3.0 Hz, H-5), 7.85 (1H, td, J = 8.9,
3.0 Hz, H-7), 7.73 (2H, d, J = 7.6 Hz, H-20/60), 7.41 (2H,
t, J = 7.6 Hz, H-30/50), 7.18 (1H, t, J = 7.6 Hz, H-40); 13C
NMR (DMSO-d6, 100 MHz): δ 163.8 (C-9), 160.8 (d,
J = 246.2 Hz, C-6), 146.0 (d, J = 2.8 Hz, C-2), 144.5 (C-
8a), 139.1 (C-10), 138.1 (C-4), 131.9 (C-3), 131.2 (d,
J = 9.1 Hz, C-8), 129.4 (C-30/50), 127.5 (d, J = 10.8 Hz,
C-4a), 124.7 (C-40), 122.4 (d, J = 25.7 Hz, C-7), 120.1
(C-20/60); 112.2 (d, J = 22.3 Hz, C-5); HR-ESI(ꢀ)MS.
Anal. Calcd for C16H9N2OClF (M-H)+: 299.0387. Found:
299.0392.
2,6-Dichloro-N-phenylquinoline-3-carboxamide (5g).
Cream solid; Yield: 33%; mp 156–158°C; IR (KBr) 3244
(N─H), 1660 (C═O) cmꢀ1; UV λmax (MeOH) (log ε):
1
240 (4.41), 309 (3.28); 330 (3.19) nm; H NMR (DMSO-
d6, 400 MHz): δ 10.77 (1H, s, H-10), 8.71 (1H, s, H-4),
8.28 (1H, d, J = 2.4 Hz, H-5), 8.07 (1H, d, J = 9.0 Hz,
H-8), 7.94 (1H, dd, J = 9.0, 2.4 Hz, H-7), 7.72 (2H, d,
J = 7.5 Hz, H-20/60), 7.39 (2H, t, J = 7.5 Hz, H-30/50),
7.16 (1H, t, J = 7.5 Hz, H-40); 13C NMR (DMSO-d6,
100 MHz): δ 163.2 (C-9), 146.5 (C-2), 145.3 (C-8a),
138.6 (C-10), 137.3 (C-4), 132.4 (C-7), 132.3 (C-3),
131.6 (C-6), 129.9 (C-8), 128.9 (C-30/50), 127.0 (C-5),
126.9 (C-4a), 124.2 (C-40), 119.5 (C-20/60); HR-ESI(ꢀ)
MS. Anal. Calcd for C16H9N2OCl2 (M-H)+: 315.0092.
Found: 315.0098.
2-Chloro-6-fluoro-N-4-tolylquinoline-3-carboxamide
(5k).
Cream solid; Yield: 51%; mp 195–197°C; IR
(KBr) 3233 (N─H), 1655 (C═O) cmꢀ1; UV λmax (MeOH)
1
(log ε): 237 (4.47), 311 (3.65), 325 (3.64) nm; H NMR
2,6-dichloro-N-4-tolylquinoline-3-carboxamide (5h).
Cream solid; Yield: 35%; mp 189–191°C; IR (KBr) 3236
(DMSO-d6, 400 MHz): δ 10.67 (1H, s, H-10), 8.69 (1H, s,
H-4), 8.12 (1H, dd, J = 9.3, 5.3 Hz, H-8), 7.95 (1H, dd,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis and Bioactivity of Quinoline-3-carboxamides
J = 9.0, 2.9 Hz, H-5), 7.83 (1H, td, J = 9.0, 2.9 Hz, H-7),
7.60 (2H, d, J = 8.3 Hz, H-20/60), 7.19 (2H, d, J = 8.3 Hz,
H-30/50), 2.29 (3H, s, 40-CH3); 13C NMR (DMSO-d6,
100 MHz): δ 163.1 (C-9), 160.2 (d, J = 245.8 Hz, C-6),
145.5 (d, J = 2.8 Hz, C-2), 144.0 (C-8a), 137.5 (d,
J = 5.2 Hz, C-4), 136.1 (C-10), 133.2 (C-40), 131.4 (C-3),
130.7 (d, J = 9.5 Hz, C-8), 129.3 (C-30/50), 127.0 (d,
J = 10.8 Hz, C-4a), 121.8 (d, J = 26.0 Hz, C-7), 119.6 (d,
J = 14.1 Hz, C-20/60); 111.7 (d, J = 22.4 Hz, C-5), 20.5 (C-
4’a); HR-ESI(ꢀ)MS. Anal. Calcd for C17H11N2OClF (M-
H)+: 314.0544. Found: 314.0544.
and serially diluted five times in Eppendorf tubes using
Mueller–Hinton broth (Johannesburg, South Africa) to
achieve concentrations of between 312.5 μg/mL to
10 mg/mL such that each Eppendorf tube contained
180 μL of the broth diluted compound. To each
Eppendorf, 20 μL of the bacterial strains (at a concentra-
tion equivalent to 0.5 McFarland Standard) was then
added and incubated for 24 h at 37°C. Thereafter,
10 μL of each concentration was spotted onto Mueller–
Hinton agar plates and incubated at 37°C to determine
the MBC. The MBC was determined as the lowest
concentration of the compound that showed no bacterial
growth after incubation. Levofloxacin was used as a stan-
dard antibiotic. Experiments were conducted in triplicate
and an average of the readings taken.
2-Chloro-6-fluoro-N-(4-fluorophenyl)quinoline-3-
carboxamide (5l).
Cream solid; Yield: 35%; mp 183–
185°C; IR (KBr) 3236 (N─H), 1660 (C═O) cmꢀ1; UV
λmax (MeOH) (log ε): 236 (4.45), 310 (3.62), 330 (3.46)
X-ray crystallography.
Crystallographic data are
1
nm; H NMR (DMSO-d6, 600 MHz): δ 10.81 (1H, s, H-
included in the Supporting Information and have been
deposited with the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB21EZ, UK.
Copies of the data can be obtained free of charge on
quoting the depository number CCDC-1575908 (Fax:
+44-1223-336-033; E-mail: deposit@ccdc.cam.ac.uk,
http://www.ccdc.cam.ac.uk).
10), 8.71 (1H, s, H-4), 8.13 (1H, dd, J = 9.0, 5.2 Hz, H-
8), 7.95 (1H, dd, J = 9.0, 2.8 Hz, H-5) 7.84 (1H, td,
J = 9.0, 2.8 Hz, H-7), 7.74 (2H, dd, J = 9.0, 4.8 Hz, H-
20/60), 7.24 (2H, t, J = 9.0 Hz, H-30/50); 13C NMR
(DMSO-d6, 100 MHz):
δ 163.7 (C-9), 162.5 (d,
J = 237.2 Hz, C-40), 160.8 (d, J = 274.0 Hz, C-6), 146.0
(C-2), 144.6 (C-8a), 138.2 (C-4), 135.5 (C-10), 131.3 (C-
8), 127.5 (d, J = 9.9 Hz, C-4a), 122.4 (d, J = 25.4 Hz, C-
7) 122.0 (d, J = 7.7 Hz, C-20/60); 116.5 (d, J = 22.2 Hz,
C-30/50), 112.2 (d, J = 22.8 Hz, C-5); HR-ESI(ꢀ)MS.
Anal. Calcd for C16H8N2OClF2 (M-H)+: 317.0293.
Found: 317.0285.
Acknowledgments. The authors wish to acknowledge the
University of KwaZulu-Natal for funding, Ms. Caryl Janse van
Rensburg for assistance with HRMS, Mr. Sizwe Zamisa for
assistance with X-ray crystallography, and Dr. Kaalin Gopaul
and Dr. Suhas Shintre for advice in the laboratory.
Antibacterial activity.
The quinoline-3-carboxamides
were screened for antibacterial activity against two Gram-
positive bacteria, S. aureus ATCC 25923 and methicillin
resistant S. aureus Rosenbach ATCC BAA-1683 (MRSA)
and four Gram-negative bacterial strains, P. aeruginosa
ATCC 27853, K. pneumoniae ATCC 31488, E. coli
ATCC 25922, and S. typhimurium ATCC 14026 (S.t).
The compounds were initially screened using the disc
diffusion method. Briefly, bacterial strains were grown in
nutrient broth (Biolab, South Africa) for 18 h at 37°C
and diluted with sterile distilled water to achieve a final
concentration equivalent to a 0.5 McFarland standard.
Mueller–Hinton agar plates (Biolab, South Africa) were
lawn inoculated with the different strains of bacteria. Discs
were impregnated with 10 μL of each sample (10 mg/mL
in DMSO), placed onto Mueller–Hinton plates, and incu-
bated for 18 h at 37°C. Compounds displaying antibacte-
rial activity by showing a zone of inhibition were further
subject to the broth microdilution method to determine
their MBC. The selected compounds 5d–f were active
against MRSA and 5b–c active against Salmonella. Exper-
iments were performed in triplicate and an average of the
readings taken.
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Additional Supporting Information may be found online
in the supporting information tab for this article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet