Synthesis, docking and in vitro antimalarial evaluation of bifunctional hybrids derived from β-lactams and 7-chloroquinoline using click chemistry

Article abstract of DOI:10.1016/j.bmcl.2011.11.082

1,2,3-Triazole tethered β-lactam and 7-chloroquinoline bifunctional hybrids were synthesized and evaluated as potential antimalarial agents. Activity against cultured Plasmodium falciparum was dependent on the N-substituent of the β-lactam ring as well as

Full text of DOI:10.1016/j.bmcl.2011.11.082

Bioorganic & Medicinal Chemistry Letters 22 (2012) 57–61
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, docking and in vitro antimalarial evaluation of bifunctional
hybrids derived from b-lactams and 7-chloroquinoline using click chemistry
Pardeep Singh a, Parvesh Singh c, Malkeet Kumar a, Jiri Gut d, Philip J. Rosenthal d, Kewal Kumar a,
Vipan Kumar a, , Mohinder P. Mahajan a,b, Krishna Bisetty c
⇑
a Department of Chemistry, Guru Nanak Dev University, Amritsar 143 005, India
b Apeejay Stya Research Foundation, Gurgaon, India
c Department of Chemistry, Durban University of Technology, Durban 4000, South Africa
d Department of Medicine, University of California, San Francisco, CA, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
1,2,3-Triazole tethered b-lactam and 7-chloroquinoline bifunctional hybrids were synthesized and eval-
uated as potential antimalarial agents. Activity against cultured Plasmodium falciparum was dependent on
the N-substituent of the b-lactam ring as well as the presence of bis-triazole at the C-3 position. The
observed activity profiles were further substantiated by docking studies via inhibition of P. falciparum
dihydrofolate reductase (PfDHFR), a potential target for the development of new anti-malarials.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 10 September 2011
Revised 16 November 2011
Accepted 19 November 2011
Available online 28 November 2011
Malaria is a tropical parasitic disease and one of the top three
killers among communicable diseases.1 It is a public health problem
in more than 90 countries inhabited by about 40% of the world pop-
ulation. Despite decades of research and successful development of
combination therapy, malaria remains a devastating disease in part
because of resistance of Plasmodium falciparum to standard antima-
larial drugs including chloroquine.2 Chloroquine probably acts
against P. falciparum by inducing heme accumulation in the parasite
membrane, consequently disturbing cation homeostasis and result-
ing in parasite death.3,4 CQ resistance had largely been attributed to
mutations in the PfCRT gene that encodes for the protein believed to
mediate efflux of the drug from the digestive vacuole of the para-
site,5 leading to sub-optimal drug concentrations. Resistance is also
increasing to multiple other antimalarial drugs, and of particular
concern are early signs of resistance to new artemisinin-based
therapies.6
Development of antiplasmodial agents aimed at a single parasite
target or specialized process has failed to stem the tide of drug
resistance. In this sense, double-drug development and multi-ther-
apeutic strategies, which utilize heterocyclic skeleton of two drugs,
are promising.7–9 These strategies have the potential to overcome
resistance mechanisms. Given the unique pharmacological effect
of quinoline based antimalarials, we are interested in the design
and synthesis of quinoline-containing dual inhibitors or ‘double
drugs’ that will potentially inhibit hemozoin formation, but not
be recognized by the proteins involved in chloroquine efflux.10
R
R
O
R
O
N
N
N
(i)
+
N
H
R
O
3
2
N
O
N
NH2
N
(ii)
1
3
Scheme 1. Reagents and conditions: (i) K2CO3 (1.2 mmol), propargyl bromide (1.1 mmol), DMF, rt, 6 h; (ii) K2CO3 (2.2 mmol), propargyl bromide (2.5 mmol), DMF, rt, 6 h.
⇑
Corresponding author.
E-mail address: vipan_org@yahoo.com (V. Kumar).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.11.082

58
P. Singh et al. / Bioorg. Med. Chem. Lett. 22 (2012) 57–61
dependency of activity on the substituents at N-1 of the b-lactam
Cl
N
N3
N
ring and C-3 of the substituted triazole ring.12
(i)
In continuation of our pursuit of the synthesis of biologically
potent novel functional entities,13 we present herein the synthesis
and evaluation of triazole tethered bifunctional hybrids of
7-chloroquinoline with substituted b-lactams. We envisaged that
combining two intrinsically antimalarial moieties, 7-chloroquino-
line (hemozoin formation inhibitor) and a b-lactam (potential
inhibitor of dihydrofolate reductase)14 linked via a triazole (struc-
turally related to triazine) would result in the development of po-
tent antimalarials. The styryl group has been introduced at C-4
position of the b-lactam ring because of its well documented
Cl
Cl
4
5
Scheme 2. Reagents and conditions :(i) NaN3, DMF, 65 °C, 6h.
Further, rationalization of literature have revealed the increased
utility of b-lactams as potential antimalarials.11 Recent reports from
our group have described the synthesis and antimalarial/anticancer
evaluation of C-3 functionalized b-lactam derivatives with marked
R
O
N
Entry
R
%yield
R
O
N
NH
6a
6b
6c
6d
6e
p-C6H5-CH3
C6H5
p-C6H5-F
C6H11
C6H5CH2
84
82
85
84
83
N
H
N
N
(i)
N
N
2
Cl
6
R
N
R
O
O
Entry
R
%yield
N
N
7a
7b
7c
7d
7e
p-C6H5-CH3
C6H5
p-C6H5-F
C6H11
C6H5CH2
85
87
85
88
86
N
(ii)
N
N
N
N
N
N
3
Cl
Cl
N
N
7
Scheme 3. Reagents and conditions: (i) 5 (1 mmol), CuSO4Á5H2O (0.05 mmol), sodium ascorbate (0.13 mmol), EtOH–H2O, rt, 8 h; (ii) 5 (2 mmol), sodium ascorbate
(0.26 mmol), CuSO4Á5H2O (0.1 mmol), EtOH–H2O, rt, 8 h.
Table 1
Antimalarial and docking results of the test compounds
Compound
R
W2 (CQ-R)a
IC50 (lM)
clogPb
Wild type
Donor/acceptor hydrogen
Mutant type
Binding energyc
(Kcal/mol)
Donor/acceptor
hydrogen bond
Binding energyc
(Kcal/mol)
bond
6a
6b
p-C6H5–CH3
C6H5
>10
1.9
7.16
6.66
Triazole-NÁ Á ÁHO-SER108
Quinoline-NÁ Á ÁHN-GLY44
Triazole-HÁ Á ÁHN-SER108
Triazole-NÁ Á ÁHO-SER108
NHÁ Á ÁO-SER111
1.2
À13.3
——
À5.9
NHÁ Á ÁO-ASN108
À11.0
6c
6d
6e
7a
p-C6H5–F
C6H11
C6H5CH2
p-C6H5–CH3
>10
4.3
5.9
1.5
7.52
6.76
6.48
10.32
À4.5
——
20.0
À17.2
À16.5
À42.5
Triazole-NÁ Á ÁHO-SER111
——
À15.1
À11.2
À53.5
Quinoline-ClÁ Á ÁHO-THR107
Triazole-NÁ Á ÁHN-SER22
Triazole-NÁ Á ÁHO-SER22
Triazole-NÁ Á ÁHO-SER22
Lactam-OÁ Á ÁHN-ARG38
Lactam-OÁ Á ÁHN-ARG38
Triazole-NÁ Á ÁHO-SER22
7b
7c
C6H5
2.1
1.1
9.82
À39.8
À49.4
Lactam-OÁ Á ÁHN-ARG38
Triazole-NÁ Á ÁHO-THR36
Triazole-NÁ Á ÁHN-SER22
Triazole-NÁ Á ÁHO-SER22
Lactam-OÁ Á ÁHN-ARG38
Quinoline-ClÁ Á ÁHN-ASN595
Lactam-OÁ Á ÁHN-ARG38
Triazole-NÁ Á ÁHO-SER22
Triazole-NÁ Á ÁHO-SER22
Quinoline-ClÁ Á ÁHN-THR36
À51.2
À61.3
p-C6H5–F
10.68
Triazole-NÁ Á ÁHN-SER22
Triazole-NÁ Á ÁHO-SER22
Lactam-OÁ Á ÁHN-ARG38
7d
7e
C6H11
2.8
2.7
9.92
9.64
Triazole-NÁ Á ÁHN-SER22
Triazole-NÁ Á ÁHO-SER22
À50.1
À41.6
À62.4
À55.1
C6H5CH2
Quinoline-ClÁ Á ÁHN-THR36
a
b
c
CQ-R: chloroquine resistant.
Calculated using Chemdraw Ultra 10.0.
Binding energy = energy of complex À energy of ligand À energy of receptor.19

P. Singh et al. / Bioorg. Med. Chem. Lett. 22 (2012) 57–61
59
Figure 2. Docked conformations of compound 6a (a), 6d (b), 7a (c) and 7d (d)
showing important amino acid residues of quadruple mutant type PfDHFR. All
interacting amino acids are presented in ball and stick form, while ligands are
shown as sticks. Amino acids exhibiting cation-
ligands are colored in red, while those participating in hydrogen bond formation are
colored in pink. Hydrogen bonds are shown as dotted green lines.
p and p-p interactions with the
Figure 1. Docked conformations of compound 6a (a), 6d (b), 7a (c) and 7d (d)
showing important amino acid residues of wild-type PfDHFR. All interacting amino
acids are presented in ball and stick form, while ligands are shown as sticks. Amino
acids exhibiting cation-p and p–p interactions with the ligands are colored in red,
while those participating in hydrogen bond formation are colored in pink. Hydrogen
bonds are shown as dotted green lines.
reaction mixture. Both the products were isolated using column
chromatography eluting with a mixture of EtOAc–hexane (10:90
for compound 2 and 30:70 for compound 3). The treatment of 1
with 2.1 equiv of propargyl bromide resulted in the isolation of
exclusive di-propargylated product 3 in good yields. The structures
of compounds 2 and 3 were assigned on the basis of analytical
evidences and spectral data (Scheme 1). The cis-stereochemistry
to the products was assigned on the basis of observed coupling
constant J = 5.4 Hz between H1 and H2.
potential in enhancing the anticancer profiles against KB cells.15
molecular docking study was conducted to gain insight into the
mechanism of action of the novel compounds.
3-Amino-2-azetidinone 1, required for the synthesis of the
desired hybrids was synthesised by a previously reported proce-
dure.12 The N-alkylation of 1 was carried out using propargyl bro-
mide in anhydrous DMF in the presence of potassium carbonate as
a base. Interestingly, use of 1.1 equiv of propargyl bromide resulted
in the isolation of mono as well as di-propargylated products in the
ratio of 75:25 as evidenced by the 1H NMR analysis of the crude
A
4-Azido-7-chloroquinoline 5, another precursor required for the
synthesis of target scaffolds was prepared by the method described
by de Souza et al.16 involving the treatment of 4,7-dichloroquinoline

60
P. Singh et al. / Bioorg. Med. Chem. Lett. 22 (2012) 57–61
the lower BEs and higher stability of these complexes. The triazole
ring of compounds 7 was predicted to be predominantly engaged
in hydrogen bonding with key amino acid residues (Ser22, Arg38,
Thr36) of both PfDHFR enzymes, suggesting a role in the biological
activity of these compounds. Similarly, the absence or lower extent
of intermolecular hydrogen bonding and non-bonded interactions
in the mono-triazole compounds 6a and 6c could be responsible
for the higher BEs of their complexes with both enzymes, and these
results substantiate a good relationship between the anti-malarial
activity and BEs of the complexes. Furthermore, the anti-malarial
effect of compounds bearing alkyl substituents on their lactam-
nitrogens (6 and 7) (Table 1), can also be explained on the basis
of the stability of their complexes with the PfDHFR enzymes. For
example, all N-alkyl compounds, except 7e, irrespective of the
PfDHFR enzymes studied, exhibited lower BEs for their complexes
compared to their corresponding N-aryl analogues. Finally, the pre-
dicted binding conformations of selective inhibitors (WR99210 and
NDP 610, for wild type and quadruple mutant PfDHFR, respec-
tively) with a root mean square deviation (all atoms) <1 Å, with re-
spect to their X-ray structures (http://www.pdb.org), clearly
validated the proposed binding conformations of the synthesized
compounds (Figs. 3a and b).
Figure 3. (a) Overlay of the WR99210 conformations obtained from docking (in
Pink) and the X-ray complex (in Light Blue) of wild-type PfDHFR. (b) Overlay of the
NDP610 conformations obtained from docking (in Pink) and the X-ray structure (in
Light Blue) of mutant PfDHFR. Ligands are shown in sticks while proteins are
presented in ribbon format.
with 2 equiv of sodium azide in anhydrous DMF at 60 °C for 6 h
(Scheme 2).
The desired hybrids 6 and 7 were synthesized using Huisgen’s
1,3-dipolar cycloaddition reaction of 2 or 3 with 4-azido-7-chloro-
quinoline 5 (Scheme 3). The structures of the hybrids were
assigned on the basis of analytical and spectral data.17
The antimalarial activities of synthesized b-lactam based
hybrids 6a–e and 7a–e were evaluated against the chloroquine
resistant strain of P. falciparum using methods as previously
described18 (Table 1). The test compounds were not as active as
the control drugs, However, with the exception of 6a and 6c, all
the test compounds showed a reasonable antimalarial activity with
In conclusion the present Letter describes the synthesis of b-lac-
tam-7-chloroquinoline bifunctional hybrids and their evaluation as
antimalarial agents against W2 strain of P. falciparum. The ob-
served activity profile were further corroborated via docking sim-
ulations performed using the ligand fit module. Further studies
in order to improve the activity profiles of the scaffolds are under-
way in the lab and will soon be communicated.
Acknowledgement
IC50s ranging from 1.1 to 5.9 lM. The presence of mono- and bis-
1,2,3-triazole tethered 7-chloroquinolines considerably influence
the antimalarial profile with bis-compounds exhibiting better
activity than corresponding mono-scaffolds except for 6b and 7b.
The increase in antimalarial activity in the bis-triazole might be
attributed to either solubility enhancing properties of triazole rings
or increased heme-binding of 7-chloroquinolines. Further, the
presence of a substituent on the nitrogen of the b-lactam ring also
influenced activity with the antimalarial potency of N-aryl substi-
tuted hybrids influenced by the presence of a C-3 triazole ring
while this effect was minimal in the case of N-alkyl derivatives
(compare 6d–e with 7d–e), substantiating our previous observa-
tion of activity enhancement by an N-alkyl group on b-lactams.
In order to substantiate the observed activity profile and to offer
insight into the mechanisms of action of the test compounds,
molecular docking studies were performed into the binding pocket
of P. falciparum dihydrofolate reductase (PfDHFR) considering both
the wild type (1J3I.pdb) and a quadruple mutant (N51I, C59R,
S108 N, I164L, 3QG2.pdb). The docking simulations were per-
formed using the Ligand Fit19,20 module of the Discovery Studio
(DS, version 2.5, Accelrys Software Inc.). The docked conformations
of some compounds (6a, 6d, 7a, and 7d) in the active site of wild
type and mutant PfDHFR enzymes are diagrammatically repre-
sented in Figures 1 and 2, respectively, while the corresponding
docking results viz donor–acceptor H bond and binding energy
for each compound are summarized in Table 1. The results reveal
a significant difference in the predicted binding energies (BEs) of
the complexes of mono-triazoles (6) and bis-triazoles (7) especially
in the case of the mutant PfDHFR. For instance, compound 7c, ob-
served to be the most potent anti-malarial compound (IC50 = 1.1),
Financial assistance from DST New Delhi under Fast Track
Young Scientist Scheme (VK) is gratefully acknowledged.
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exhibited the lowest BEs for both wild type (À49.4 kcalmolÀ1
)
and mutant (À61.3 kcalmolÀ1)-PfDHFR complexes. The greater
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and cation-p interactions) between the amino acid residues
of both enzymes, as depicted in Figures 1 and 2, may account for

P. Singh et al. / Bioorg. Med. Chem. Lett. 22 (2012) 57–61
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49.1, 60.1, 61.3, 115.7, 117.2, 120.3, 122.2, 123.9, 124.7, 126.5, 127.4, 127.7,
128.7, 128.9, 129.4, 129.6, 132.4, 134.2, 135.2, 135.7, 136.8, 142.7, 150.1, 151.2,
172.1; MS m/z 522(M+); Analysis calculated for C30H25ClN6O: C, 69.16 H, 4.84;
N, 16.13. Found: C, 69.12; H, 4.79; N, 16.10.
3-{Bis-[1-(7-chloroquinolin-4-yl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-1-
cyclohexyl-4-styryl-azetidin-2-one (7d): White solid, Yield 88%; mp 133–
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17. General procedure and analytical data for b-lactam-chloroquinoline hybrids (6 and
7): To a stirred solution of azide 5 (1 mmol for 2 and 2 mmol for 3) in ethanol–
water (10:1) was added in succession appropirate acetylenic lactam 2 or 3
(1 mmol), copper sulphate (0.055 mmol for 2 and 0.1 mmol for 3) and sodium
134 °C; IR (KBr) m ;
max: 1755, 1512 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.09–1.96
(m, 10H, cyclohexyl ring), 3.56 (m, 1H, cyclohexyl H), 4.28 (AB quartet, J = 13.7,
7.5 Hz, 4H, 2x-CH2–), 4.41 (dd, J = 5.1, 8.7 Hz, 1H, H2), 4.6 (d, J = 5.1 Hz, 1H, H1),
6.32 (dd, J = 8.7, 15.9 Hz, 1H, H3), 6.74 (d, J = 15.9 Hz, 1H, H4), 7.12–7.29 (m, 5H,
ArH), 7.35 (d, J = 4.4 Hz, 2H, H8) 7.55 (dd, J = 2.1 Hz, 9.3 Hz, 2H, H10), 8.01 (d,
J = 9.3 Hz, 2H, H9), 8.19 (s, 2H, triazole ring), 8.26 (d, J = 2.1 Hz, 2H, H7), 9.01 (d,
J = 4.4 Hz, 2H, H6); 13C NMR (CDCl3, 75 Hz): 22.4, 27.3, 30.9, 47.2, 58.3, 59.9,
60.8, 122.2, 124.5, 125.5, 126.6, 128.5, 128.6, 129.4,129.6, 132.4, 134.3, 134.8,
135.4, 136.4, 136.9, 143.2, 150.1, 151.3 173.2.; MS m/z 755(M+); Analysis
calculated for C41H36Cl2N10O: C, 65.16 H, 4.80; N, 18.53. Found: C, 65.31; H,
4.68; N, 18.77.
ascorbate (0.13 mmol for
2 and 0.26 for 3) at room temperature. On
completion, as monitored by tlc, water (15 ml) was added to the reaction
mixture and extracted with chloroform (2 Â 50 ml). Combined organic layers
were dried over anhydrous sodium sulphate and concentrated under reduced
pressure to result in
chromatography.
a crude product which was purified by silica gel
18. Coteron, J. M.; Catterick, D.; Castro, J.; Chaparro, M. J.; Diaz, B.; Fernandez, E.;
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Miguel, J.; Munoz, V.; Porras, E.; de la Rosa, J. C.; Ruiz, J. R.; Sandoval, E.;
Ventosa, P.; Rosenthal, P. J.; Fiandor, J. M. J. Med. Chem. 2010, 53, 6129.
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2003, 21, 289.
3-{[1-(7-Chloroquinolin-4-yl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-4-styryl-
1-p-tolyl-azetidin-2-one (6a): White solid, Yield 84%; mp 157–158 °C; IR (KBr)
m
max: 3017, 1747, 1523 cmÀ1 1H NMR (300 MHz, CDCl3): d 2.29 (s, 3H, –CH3),
,
4.29 (AB quartet, J = 7.5, 13.7 Hz, 2H, –CH2–), 4.74 (d, J = 5.1 Hz, 1H, H1), 4.92
(dd, J = 5.1, 8.1 Hz, 1H, H2), 6.44 (dd, J = 8.1, 15.9 Hz, 1H, H3), 6.79(d, J = 15.9 Hz,
1H, H4), 7.09–7.32 (m, 9H, ArH), 7.35 (d, J = 4.2 Hz, 1H, H5) 7.54 (dd, J = 1.8,
9.0 Hz, 1H, H8), 8.01 (d, J = 9.0 Hz, 1H, H9), 8.21 (s, 1H, triazole ring), 8.23 (d,
J = 1.8 Hz, 1H, H7), 8.97 (d, 1H, J = 4.2 Hz, H6); 13C NMR: (CDCl3, 75 Hz): 20.9,
20. Choi, Y.; Kim, D. W.; Park, H.; Hwang, S.; Jeong, K.; Jung, S. Bull. Korean Chem.
Soc. 2005, 26, 769.