4-Aminoquinoline-β-lactam conjugates: Synthesis, antimalarial, and antitubercular evaluation

Article abstract of DOI:10.1111/cbdd.12225

A library of quinoline-β-lactam-based hybrids was synthesized and tested for their antimalarial and antitubercular activities. The present antimalarial data showed the dependence of activity on the nature of linker, N-1 substituent of the β-lactam ring as well as the length of alkyl chain. Most of the compounds are not as efficient as chloroquine in inhibiting the culture growth of Plasmodium falciparum W2 strain. Nevertheless, the synthesized hybrids showed better antitubercular activities (up to five times) compared with cephalexin (up to three times) and ethionamide. Thirty four 4-aminoquinoline-β-lactam conjugates have been synthesized and evaluated for their antimalarial and anti-TB profiles.

Full text of DOI:10.1111/cbdd.12225

Chem Biol Drug Des 2014; 83: 191–197
Research Article
4-Aminoquinoline-b-Lactam Conjugates: Synthesis,
Antimalarial, and Antitubercular Evaluation
Raghu Raj1, Christophe Biot2,3, Severine
ꢀ
4,5
opment of resistance to the potent and inexpensive chloro-
quine (CQ), which has a long history in the treatment of
malaria (1,2). A significant number of antimalarial drugs
such as the antifolate combination of pyrimethamine and
sulfadoxine, as well as artemisinin combination therapies,
have been considered as the most important drugs for the
treatment of malaria. However, these drug regimens are
steadily losing their efficacy by the emergence of parasites
with reduced vulnerability to these drug combinations (3).
The development of drug resistance for the common anti-
malarials has encouraged considerable research efforts in
the development of new drugs using different approaches
(4,5), of which the molecular hybridization approach (6,7) is
quite an appealing strategy. The advantage of using molec-
ular hybridization is to activate different targets by a single
molecule, thereby increasing therapeutic efficacy as well as
bioavailability (8). The strategy is particularly interesting in
the case of bioactive compounds with high toxicity or phar-
macokinetic and pharmacodynamic restrictions. Although
there are no examples of antimalarial dual drugs in clinical
use, a number of active molecules have been identified
using this approach, viz. highly active antimalarial trioxaqu-
ines developed by covalently linking a 1,2,4-trioxane motif
to a 4-aminoquinoline moiety via an appropriate spacer (9).
4
ꢁ
Carrere-Kremer , Laurent Kremer
,
Yann Guerardel2,3, Jiri Gut6, Philip J. Rosenthal6
and Vipan Kumar1,*
ꢀ
1Department of Chemistry, Guru Nanak Dev University,
Amritsar, 143005, India
2
ꢀ
Unite de Glycobiologie Structurale et Fonctionnelle,
Universite Lille 1, F-59650, Villeneuve d’Ascq, France
ꢀ
3CNRS, UMR 8576, F-59650, Villeneuve d’Ascq, France
4Laboratoire de Dynamique des Interactions Membranaires
ꢀ
Normales et Pathologiques, UMR 5235 CNRS, Universite
Montpellier 2, Place Eugene Bataillon, 34095, Montpellier
Cedex 05, France
INSERM, DIMNP, Place Eugene Bataillon, 34095,
ꢁ
5
ꢁ
Montpellier Cedex 05, France
6Department of Medicine, University of California,
San Francisco, CA, 94143, USA
*Corresponding author: Vipan Kumar,
vipan_org@yahoo.com
A library of quinoline-b-lactam-based hybrids was syn-
thesized and tested for their antimalarial and antituber-
cular activities. The present antimalarial data showed
the dependence of activity on the nature of linker, N-1
substituent of the b-lactam ring as well as the length
of alkyl chain. Most of the compounds are not as effi-
cient as chloroquine in inhibiting the culture growth of
Plasmodium falciparum W2 strain. Nevertheless, the
synthesized hybrids showed better antitubercular
activities (up to five times) compared with cephalexin
(up to three times) and ethionamide.
Apart from its well-coveted role as an antimalarial agent,
quinoline nucleus has received recent attention because of
its antitubercular potential, which can be deduced from
the diarylquinoline TMC 207 (ex R207910). The compound
has shown bactericidal effect against dormant tubercle
bacilli with activity against drug-sensitive and drug-resis-
tant Mycobacterium tuberculosis (10,11). The drug is spe-
cifically approved for the treatment of multidrug-resistant
tuberculosis with minimal inhibitory concentration (MIC) of
0.06 lg/mL and functions by inhibiting ATP synthase sub-
unit C, an energy source for the bacterium (12). In a recent
report, Zuazo and coworkers have disclosed the antituber-
cular potential of a series of tripartite hybrids based on
pharmacophores 7-chloroquinoline (CQ), ethylenediamine
as a spacer, and phenylurea as a thiourea bioisostere (13).
From the observed structure–activity relationship (SAR), it
was concluded that the presence of a hetero-aryl group at
the 4th position of the quinoline core showed optimal
activity against M. tuberculosis (14).
Key words: 4-aminoquinoline-b-lactam conjugates, antimalarial
evaluation, antitubercular evaluation, molecular hybridization,
structure–activity relationship
Received 11 July 2013 and accepted for publication 22
August 2013
Malaria is a devastating infectious, parasitic disease esti-
mated to have affected more than 216 million people and
roughly 655 000 deaths worldwide in 2010 and continues
to be a causative factor to the high mortality rate in tropi-
cal and subtropical countries.a The disease remains a major
issue in health control, mostly among children and pregnant
women with the majority of the cases, and approximately
90% of the malaria deaths occurring in sub-Saharan Africa.
A major problem associated with this disease is the devel-
A heterocyclic system gifted with marked biological activi-
ties is the b-lactam nucleus. Interest in this class has led to
ª 2013 John Wiley & Sons A/S. doi: 10.1111/cbdd.12225
191

Raj et al.
the development of classical (e.g. penicillins and cephalo-
sporins) and non-classical (e.g. carbapenams and mono-
bactams) substrates (15–17). Current interest in this family
is focused on the synthesis and modification of the b-lac-
tam ring to obtain compounds with diverse pharmacological
potential (18). b-lactams target bacterial transpeptidases,
termed ‘penicillin binding proteins (PBPs)’, which are
responsible for the introduction of interpeptide cross-links
into bacterial peptidoglycan, thereby controlling rigidity of
the bacterial cell wall (19). b-lactams have not been widely
used for the treatment of M. tuberculosis or any other
mycobacterial infection. A major obstacle is the presence in
mycobacteria of a highly active b-lactamase (20,21). A
report on the successful use of the b-lactam meropenem
with the b-lactamase inhibitor clavulanic acid against both
replicating and non-replicating XDR-TB strains has gener-
ated hope of repurposing this class of agents for the treat-
ment of XDR-TB patients (22,23).
recorded in deuterochloroform and dimethylsulfoxide-d6
with a Jeol 300 (300 MHz) spectrometer using TMS as an
internal standard. Chemical shift values are expressed as
parts per million downfield from TMS, and J values are in
hertz. Splitting patterns are indicated as s, singlet; d, dou-
blet; t, triplet; m, multiplet; dd, double doublet; ddd, dou-
blet of a doublet of a doublet; and br, broad peak. 13C
NMR spectra were recorded on Jeol 300 (75 MHz) and
BRUKER AVANCE II (400 MHz) spectrometers in deutero-
chloroform and dimethylsulfoxide using TMS as internal
standard. High-resolution mass spectra were recorded on
Bruker-micrOTOF-Q II spectrometer.
General procedure for the synthesis of 4-
aminoquinoline-b-lactam conjugates (5a–5n)
To the stirred solution of 4 (1 mmol) in 10 mL dry DMF,
K2CO3 (3 mmol) was added at room temperature. The
reaction mixture was stirred for 15 min followed by the
addition of mesylated product 3. The reaction mixture was
then stirred at 85 °C for 12 h, and progress of the reaction
was monitored by TLC. On completion, water (15 mL) was
added to the reaction mixture, and extraction was per-
formed using ethyl acetate (2 9 50 mL). Combined
organic layers were dried over anhydrous sodium sulfate
and concentrated under reduced pressure to result in a
crude product, which was purified through column chro-
matography using chloroform/methanol (95:5) mixture.
In continuation with our endeavor for the synthesis of novel
molecular frameworks with biological potential (24–28), we
report herein a facile and convenient synthesis of 4-amino-
quinoline-b-lactam conjugates tethered via alkyl chain link-
ers as well as through amide functionality as depicted in
Figure 1 along with their antimalarial and antitubercular
evaluation.
Experimental Section
Materials and methods
General procedure for the synthesis of amide-
tethered b-lactam-4-aminoquinoline hybrids
(7a–7t)
To a solution of 3-amino-azetidin-2-one, 4 (1 mmol) in dry
DMF, 4-aminoquinoline-based acids, 6 (1 mmol), Et3N
Melting points were determined by open capillary using a
Veego Precision Digital Melting Point apparatus (MP-D)
and are uncorrected. IR spectra were recorded on a Shi-
madzu D-8001 spectrophotometer. 1H NMR spectra were
O
R
O
N
HN
N
OH
OMs
n
n
HN
NH2
Cl
Cl
N
R
O
R
O
N
N
O
H
N
N
H
N
H
N
n
N
H
n
N
Cl
Cl
Figure 1: General structure of target 4-aminoquinoline-b-lactam hybrids.
192
Chem Biol Drug Des 2014; 83: 191–197

4-Aminoquinoline-b-Lactam Conjugates
Drug susceptibility testing
(1.5 mmol), HOBt (1.2 mmol), and DCC (1.1 mmol) were
added, and the reaction mixture was stirred overnight at
room temperature. Aq. Na2CO3 was added into the reac-
tion mixture, and pH of the aqueous layer was adjusted
to 6.5–9.0 and extracted with ethyl acetate (EtOAC). The
organic layer was separated and dried over Na2SO4. The
solvent was evaporated affording crude product, which
was purified by column chromatography on silica gel with
eluent CHCl3/MeOH (95:5) resulting in the desired prod-
uct 7.
The susceptibility of M. tuberculosis to the various
compounds was determined as reported previously (32).
In brief, Middlebrook 7H10 solid medium containing
oleic-albumin-dextrose-catalase enrichment (OADC) and
20 lg/mL of pantothenic acid was supplemented with
increasing concentrations of the chemical analogues.
Serial 10-fold dilutions of each actively growing culture
were plated and incubated at 37 °C for 2–3 weeks. The
MIC was defined as the minimum concentration required
to inhibit 99% of the growth.
Biological evaluations
Result and Discussions
Methods for the assessment of antimalarial
activity of test compounds
Chemistry
The W2 strain of P. falciparum was cultured in RPMI-1640
medium with 10% human serum, following standard meth-
ods, and parasites were synchronized with 5% D-sorbitol
(29). Beginning at the ring stage, microwell cultures were
incubated with different concentrations of compounds for
48 h. The compounds were added from DMSO stocks;
the maximum concentration of DMSO used was 0.1%.
Controls without inhibitors included 0.1% DMSO. After
48 h, when control cultures had progressed to new rings,
the culture medium was removed, and cultures were incu-
bated for 48 h with 1% formaldehyde in PBS, pH 7.4, at
room temperature. Fixed parasites were then transferred
to 0.1% Triton X-100 in PBS containing 1 nM YOYO-1 dye
(molecular probes). Parasitemia was determined from dot
plots (forward scatter versus fluorescence) acquired on a
FACSort flow cytometer using CellQuest software (Beckton
Dickinson, San Jose, CA, USA). IC50 values for growth
inhibition were determined from plots of percent control
parasitemia over inhibitor concentration using the Prism
3.0 program (GraphPad Software, San Diego, CA, USA),
with data from duplicate experiments fitted by nonlinear
regression (30).
Methanesulfonic acid 2-(7-chloro-quinolin-4-ylamino)-ethyl/
propyl esters 3, required for the synthesis of the desired
hybrids 5, were prepared by initially reacting 4,7-dichloro-
quinoline 1 with ethanolamine or 1-propanol amine at
120 °C for 12 h, followed by mesylation at 0 °C in dry
CHCl3 for 2–3 h (Scheme 1). The target scaffolds 5 were
synthesized by initial stirring of 3-amino-2-azetidinones 4,
prepared via Staudinger reaction of substituted 1-aza-
dienes with azidoketene generated in situ from azidoacetic
acid and p-toluene sulfonyl chloride in the presence of tri-
ethylamine followed by reduction using Zn/NH4Cl protocol
(33), with K2CO3 in dry DMF at room temperature for
15 min., followed by the addition of mesylated product 3
(Scheme 2). The reaction mixture was stirred at 85 °C for
12 h, and the progress of reactions was monitored using
TLC. On completion, the solvent was evaporated under
reduced pressure, and the crude product obtained was
purified by column chromatography using a chloroform/
methanol (95:5) mixture. The structures of synthesized
hybrids were assigned on the basis of spectral data and
analytical evidence, with the cis-stereochemical relation-
ship between H3 and H4 confirmed on the basis of the
coupling constant J = 5.4 Hz.
In vitro antitubercular activity
For the synthesis of conjugates 7, the synthetic approach
involved an initial preparation of 4-aminoquinoline amino
acids 6 by refluxing of 4,7-dichloroquinoline 1 with corre-
sponding amino acids in phenol for 18 h (Scheme 3), fol-
lowed by acidic workup and extraction using ethyl acetate
(34). Synthesis of desired hybrids 7 was carried out via
Bacterial strains and growth conditions
Mycobacterium tuberculosis mc27000, an unmarked ver-
sion (31) of mc26030, was grown at 37°C in Sauton’s
medium supplemented with 20 lg/mL of pantothenic acid.
OH
OMs
Cl
HN
N
Cl
N
HN
N
n
n
OH
Et3N, 120 0C
MsCl
Et3N, 0 0C
H2N
n
Cl
Cl
1
2
3
n = 1,2
Scheme 1: Synthesis of 4-aminoquinoline-based mesylated products 3a–3b.
Chem Biol Drug Des 2014; 83: 191–197
193

Raj et al.
H
N
R
O
OMs
n
HN
N
n
HN
N
K2CO3, Dry DMF
85 0C, 10–12 h
N
+
NH2
O
R
Cl
N
Cl
5
3
4
R = C6H11, C7H13, p-C6H4-CH3, i-Bu,
p-C6H4-F, n-Bu, C6H5
n = 1, 2
Scheme 2: Synthesis of 4-aminoquinoline-b-lactam hybrids linked through non-ionizable covalent linker 5a–5n.
O
OH
Cl
N
HN
n
n
H2N
COOH
Phenol, reflux
18 h
Cl
Cl
N
6
1
n = 0, 1, 2, 4
Scheme 3: Synthesis of 4-aminoquinoline amino acids 6a–6d.
O
R
O
O
N
R
O
HN
OH
n
N
HN
N
N
n
HOBt, DCC, Et3N
Dry CHCl3, rt, 10 h
H
+
NH2
Cl
N
Cl
7
4
6
R = C6H11, C7H13, p-C6H4-CH3, i-Bu, p-C6H4-F
n = 0,1,2,4
Scheme 4: Synthesis of amide-tethered 4-aminoquinoline-b-lactam conjugates 7a–7t.
DCC-mediated coupling of the precursors 4 and 6 in the
P. falciparum (Table 1). Analysis of activity data in case of
presence of HOBt in dry DMF as shown in Scheme 4.
alkyl chain-tethered conjugates 5a–5n revealed an inter-
esting structure–activity relationship (SAR), with association
between activity and the length of the alkyl chain as well
as the substituent at N-1 of the b-lactam ring. Compounds
having an ethyl linker as spacer showed better activity pro-
files than those with a propyl linker irrespective of the sub-
stituent on the N-1 of b-lactam ring, except in the case of
5k and 5m. In the case of conjugates with ethyl spacers
(5a, 5c, 5e, 5g, 5i, 5k, 5 m), the test compounds with
N-aryl substituents on the b-lactam ring (5a, 5c, 5e) showed
better activities compared with counterparts with N-alkyl
substituents. In the case of conjugates tethered via a
propyl linker (5b, 5d, 5f, 5h, 5j, 5l, 5n), the scaffolds 5h
and 5j, with N-cycloalkyl substituents (cyclohexyl and
cycloheptyl), exhibited better activity compared with N-aryl
substituted compounds. The compound 5c, with an
optimum combination of aryl (p-fluorophenyl) substituent
at N-1 of the b-lactam ring and an ethyl linker, exhibited
the best activity of the test compounds, with an IC50 of
59.6 nM.
The structures of synthesized hybrids were assigned on
the basis of spectral data and analytical evidence, the
details of which have been provided in the Appendix S1,
while the salient features are discussed here. The com-
pound, for example, 7a showed a molecular ion peak
[M + H]+ at 497.1660, along with the characteristic peaks
1
1
in H and 13C NMR spectra. The H NMR spectrum exhib-
ited the presence of a singlet at d 2.21 corresponding to
methyl protons along with a triplet at d 3.96 corresponding
to methylene protons and the characteristic quinoline ring
protons. The presence of the required number of carbons
in the 13C NMR spectrum along with the two characteristic
peaks at d 160.0 and 169.6 corresponding to b-lactam
ring carbonyl and amide carbonyl, respectively, further cor-
roborated the assigned structure.
In vitro antimalarial activity and antitubercular
evaluation
The synthesized hybrids were evaluated for their
antimalarial profiles against the CQ-resistant W2 strain of
Analyzing the antimalarial activity among conjugates 7a–
7t showed an overall loss of antimalarial profile with the
194
Chem Biol Drug Des 2014; 83: 191–197

4-Aminoquinoline-b-Lactam Conjugates
Table 1: Antimalarial and antitubercular activity results of test compounds
Plasmodium falciparum
Mycobacterium tuberculosis
mc27000 strain
MIC (lg/mL)
W2 (CQ-R) strain
IC50 (nM)
Code
R
n
5a
5b
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-F
p-C6H4-F
C6H5
C6H5
C6H11
C6H11
C7H13
C7H13
n-Bu
n-Bu
i-Bu
1
2
1
2
1
2
1
2
1
2
1
2
1
2
0
1
2
4
0
1
2
4
0
1
2
4
0
1
2
4
0
1
2
4
94.3
164.1
59.6
6–7
5–6
8–10
10
7–8
ND
10
6–7
ND
5c
5d
204.2
135.3
188.1
138.9
143.1
122.3
176.0
611.8
397.7
424.6
410.3
482.7
112.5
79.5
5e
5f
5g
5h
5i
5j
5k
5
10–15
ND
ND
ND
>100
5
>100
>100
80
6–7
8–10
10–15
10–20
7.5
10
7.5–10
ND
5–7.5
5
7.5–10
20
15–20
10–15
15
5l
5m
5n
7a
i-Bu
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-CH3
p-C6H4-F
p-C6H4-F
p-C6H4-F
p-C6H4-F
C6H11
C6H11
C6H11
C6H11
C7H13
C7H13
C7H13
C7H13
i-Bu
i-Bu
i-Bu
i-Bu
7b
7c
7d
7e
89.8
400.9
148.2
142.1
187.4
570.3
432.6
556.7
186.7
1145
378.1
275.8
152.0
1027.5
565.3
675.6
355.1
99.0
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
7t
Chloroquine
Cephalexin
Isoniazid (INH)
Rifampicin (RIF)
Ethionamide (ETH)
25
0.4
0.1
15
CQR, chloroquine-resistant; ND, not determined.
introduction of amide functionality except 7c and 7d,
which have shown comparable activity with CQ. An inter-
esting SAR was revealed that among conjugates 7a–7t
with the compounds (7a, 7e, 7i, 7m, 7q), having a
methyl spacer showed poor activity irrespective of the
substituent on the N-1 atom of the 2-azetidinone ring,
while the replacement of the methyl linker with an ethyl
linker improved the activity (7b, 7f, 7j, 7n, 7r). The con-
jugates 7b and 7f with N-aryl substituted 2-azetidinones
showed better activity than N-alkyl analogues, viz. 7j, 7n,
and 7r. Further, an increase in chain length via introduc-
tion of a propyl linker improved antiplasmodial activity,
with effects more pronounced in the case of 7c and 7g,
with an IC50 values of 79.5 and 142.1 nM, respectively.
The introduction of an n-pentyl chain as a spacer sub-
stantially improved the antimalarial activity of all the con-
jugates, viz. 7d, 7h, 7l, 7p, and 7t irrespective of the
substituent at N-1 of the 2-azetidinone ring. The hybrid
7d with a p-tolyl substituent at N-1 and an n-pentyl
linker exhibited the best activity among the test
compounds, with an IC50 of 89.8 nM. The antiplasmodial
data of the precursor, viz. 3-amino-b-lactam, were recently
published by our group, and the observed improvement
in antimalarial efficacy of the synthesized conjugates
ascertained the significance of hybridization strategy in the
present context (35).
The synthesized scaffolds were also evaluated for their
antitubercular activity (Table 1). The MIC values were cal-
culated and compared with those for the standard drugs
Chem Biol Drug Des 2014; 83: 191–197
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Raj et al.
isoniazid, rifampicin, ethionamide, and cephalexin. When
analyzing the antitubercular profile among 5a–5n,
whereas the present compounds are not as active as iso-
niazid or rifampicin, most of the compounds exhibited
better antitubercular activity than ethionamide (up to 3
times) and cephalexin (up to five times) (36). A closer
inspection of the series revealed that antitubercular pro-
files were independent of the nature of substituents at the
N-1 atom of the 2-azetidinone ring as well as the length
of the alkyl chain. Similar comparison between amide-
tethered conjugates 7a–7t revealed the dependence of
activity on the substituent at N-1 position with a prefer-
ence for alkyl substituent as evidenced by compounds
7i–7t. The N-aryl substituted conjugates proved inactive
in inhibiting the growth of M. tuberculosis even at the
highest tested concentration (7a, 7c, and 7d). Further-
more, the observed antitubercular efficacy in the amide
series seems to be independent of the alkyl chain length
as was observed in the conjugates 5a–5n. The effects of
cephalexin and the test compounds against M. tuberculo-
sis mc27000 are illustrated in electronic supplementary
information.
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Conclusion
In conclusion, a series of 4-aminoquinoline-b-lactam con-
jugates were synthesized and evaluated for their antimalar-
ial and antitubercular profiles. On comparing the activities
among alkyl chain and amide-tethered series, the alkyl
chain-linked conjugates showed better efficacy in inhibiting
the growth of P. falciparum and M. tuberculosis, while the
introduction of an amide functionality adversely affected
the activity profiles. Most of the synthesized conjugates
showed poor antiplasmodial profile except 5a, 7c, and 7d,
while their anti-TB efficacy was better than ethionamide
and cephalexin. Further work on the extension of above
protocol via introduction of urea, thiourea, and oxalamide
functionalities is currently underway in the laboratory and
will soon be communicated.
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ꢀ
13. Nava-Zuazo C., Estrada-Soto S., Guerrero-Alvarez J.,
ꢀ
Rivera I.L., Molina-Salinas G.M., Said-Fernandez S.,
Acknowledgment
Chan-Bacab M.J., Cedillo-Rivera R., Moo-Puc R.,
ꢀ
Miron-Lopez G., Navarrete-Vazquez G. (2010) Design,
Financial assistance from DST New Delhi under Fast Track
Young Scientist Scheme (VK) is gratefully acknowledged.
synthesis, and in vitro antiprotozoal, antimycobacterial
activities of N-{2-[(7-chloroquinolin-4-yl)amino]ethyl}
ureas. Bioorg Med Chem;18:6398–6403.
ꢀ
14. Candea A.L.P., Ferreira M.L., Pais K.C., Cardoso
Conflict of Interest
L.N.F., Kaiser C.R., Henriques M.G.M.O., Lourenco
ß
M.C.S., Bezerra F.A.F.M., De Souza M.V.N. (2009)
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The authors declare no competing financial interest.
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Appendix S1. The characterization of compounds 5a–5n
and 7a–7t, scanned 1H and 13C spectra of 5a, 5b, 5e,
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