Synthesis of new chalcone derivatives containing acridinyl moiety with potential antimalarial activity

Article abstract of DOI:10.1016/j.ejmech.2009.11.022

A series of novel chalcones bearing acridine moiety attached to the amino group in their ring A have been synthesized through noncatalyzed nucleophilic aromatic substitution reaction between various 3′-aminochalcone or 4′-aminochalcones and 9-chloroacridine. The synthesized chalcone derivatives have been characterized and screened for in vitro antimalarial activity against Plasmodium falciparum NF-54. All the chalcones showed complete inhibition at concentration of 10 μg/mL and above while three compounds showed significant inhibition at concentration of 2 μg/mL. The three most active chalcone derivatives were screened for in vivo activity as well, but no significant inhibition in parasitaemia was observed when given intraperitoneally to Plasmodium yoelii infected mice model.

Full text of DOI:10.1016/j.ejmech.2009.11.022

European Journal of Medicinal Chemistry 45 (2010) 745–751
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of new chalcone derivatives containing acridinyl moiety with potential
antimalarial activity
,
a
b
b
b
V. Tomar a, G. Bhattacharjee a , Kamaluddin , S. Rajakumar , Kumkum Srivastava , S.K. Puri
*
a Department of Chemistry, Indian Institute of Technology Roorkee (IIT R), Roorkee-247667, Uttarakhand, India
b Division of Parasitology, Central Drug Research Institute, Lucknow-226001, Uttar Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel chalcones bearing acridine moiety attached to the amino group in their ring A have been
synthesized through noncatalyzed nucleophilic aromatic substitution reaction between various 30-ami-
nochalcone or 40-aminochalcones and 9-chloroacridine. The synthesized chalcone derivatives have been
characterized and screened for in vitro antimalarial activity against Plasmodium falciparum NF-54. All the
Received 14 June 2009
Received in revised form
8 November 2009
Accepted 12 November 2009
Available online 20 November 2009
chalcones showed complete inhibition at concentration of 10
mg/mL and above while three compounds
showed significant inhibition at concentration of 2 g/mL. The three most active chalcone derivatives
m
were screened for in vivo activity as well, but no significant inhibition in parasitaemia was observed
when given intraperitoneally to Plasmodium yoelii infected mice model.
Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords:
Acdridne containing chalcones
Plasmodium falciparum NF-54
Plasmodium yoelii N-67
1. Introduction
2,4-dimethoxy-40-butoxychalcone, a novel compound [13] also
possessed outstanding antimalarial activities both against human
In developing countries diseases particularly of protozoan origin
such as malaria, amoebiosis, sleeping sickness, leishmaniasis and
others are prevalent and is of great concern. The world is still under
the devastating effects of malaria caused by various species of
Plasmodium, especially Plasmodium malariae, Plasmodium ovale,
Plasmodium falciparum, and Plasmodium vivax. Among all these
agents, P. falciparum resistance to common antimalarials is a major
obstacle for malaria control [1,2]
(in vitro) and rodent (in vivo) parasites with no observable signs of
toxicity. Studies by Li et al. [14], Liu et al. [15] and Go et al. [16] have
revealed in vitro antimalarial activity of chalcones against a chlo-
roquine-resistant human malarial parasite, P. falciparum (K1).
Natural chalcones, 5-Prenylbutein, licoagrochalcone A and homo-
butein [17] showed in vitro antiplasmodial activity against the
chloroquine-sensitive (D6) and the chloroquine-resistant (W2)
strains of P. falciparum with IC50 values in the range 10.3–16.1 mM.
Attempts to develop chloroquine-resistant strains of Plasmo-
dium, particularly of P. falciparum have been continuing [3,4] for
several decades.
The identification of new targets, that are critical to the disease
process or essential for the survival of the parasite are of major
concern. The design of noble chemical entities specifically affecting
these targets could lead to availability of better drugs for the
treatment of malaria [5].
In the same context, chalcones have gained strong ground for
various biological and antioxidant activities [6–10]. Some new
chalcones having potent antimicrobial activities have been evalu-
ated by our group [11]. The antimalarial activity of chalcones was
apparent after the first report on licochalcone A with potent in vivo
and in vitro antimalarial activity [12]. Another synthetic analogue,
Another prenylated chalcone, Crotaorixin [18] exhibited 100%
inhibition of maturation of P. falciparum NF-54.
Reports on various quinolinyl chalcone analogues [19], preny-
lated chalcones [20], sulfonamide chalcones [21], phenylsulphonyl
urenyl chalcones [22], ferrocenyl chalcones [23,24] are available in
the literature. The in vivo antimalarial activity of Retinoid-like
chalcones [25] and bischalcones against chloroquine-sensitive and
resistant strains of Plasmodium berghei in mice has also been
reported [26,27].
Acridines are being extensively explored in several therapeutic
areas and reported to possess potent antimalarial activities [28–31].
The reported diverse biological activities of the chalcone
derivatives and acridines are really inspiring and provided impetus
to synthesize substituted analogue at 4-position of the styryl
phenyl ring (ring B), as this site is especially prone to metabolic
oxidation [32]. In this paper synthesis, characterization and anti-
malarial activity of eleven new 9-acridinylamino chalcone deriva-
tives are presented and discussed.
* Corresponding author. Tel.: þ91 1332 285793; fax: þ91 1332 286202.
E-mail address: wordgfcy@iitr.ernet.in (G. Bhattacharjee).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.11.022

746
V. Tomar et al. / European Journal of Medicinal Chemistry 45 (2010) 745–751
COOH
2. Chemistry
COOH
Cl
Cu, K2CO3
heat, 2.5 hrs
Chemically chalcone is a generic term given to compounds
bearing the 1,3-diphenylprop-2-en-1-one framework. Chalcones
have shown potent pharmacological profile and are associated with
a plethora of biological activities.
H2N
N
H
2-(phenylamino)benzoic acid
Cl
Heteroaryl-substituted chalcones are of special interest because
of their potent biological activites. Acridine derivatives are known for
antibacterial, metabolic, parasitologic and antiprotozoal activities
[33,34]. With this view in mind we decided to synthesize various
COOH
POCl3
reflux, 120oC, 4 hrs
N
H
N
9-chloroacridine
9-substituted acridine derivatives.
is a special structural feature of chalcones with the phenyl ‘ ring A’
attached to C-1 and phenyl ‘ring B’ attached to C-3 of the
-unsaturated carbonyl system [35]. Hence various 30 and 40 amino
a,b-Unsaturated carbonyl system
Scheme 2. Synthesis of 9-chloroacridine.
a,
method described by Trager and Jensen [45] with minor modifi-
cations. Of the eleven new acridinyl chalcone derivatives, five
showed enhanced activity.
b
(attached to ring A) chalcones were reacted with 9-chloroacridine to
obtain the desired acridinyl chalcone derivatives
Synthesis and evaluation of the activity of new acridinyl chal-
cone detrivatives against a chloroquine-sensitive strain, P. falcipa-
rum are described in this paper. Syntheses of 40-aminochalcone or
30-aminochalcone derivatives 1a–k were carried out through
Claisen–Schmidt condensation [36] of 3- or 4-amino acetophe-
nones with the corresponding substituted benzaldehyde (where
R2 ¼ H, 3-NO2, 3-CH3, 4-CH3, 4-OCH3, 4-Cl, 3,4,5-tri-OCH3) and also
with cinnamaldehyde derivatives using sodium hydroxide as
catalyst in methanol at room temperature (Scheme 1).
3.1. In vitro antimalarial assay
The in vitro antimalarial assay was carried out in 96 well
microtitre plates according to the microassay protocol of Rieck-
mann et al. [46] with minor modifications. The cultures of P. falci-
parum NF-54 strain were routinely maintained in medium RPMI
1640 supplemented with 25 mM HEPES, 1%
sodium bicarbonate and 0.5% ALBUMAX-II. The asynchronous
parasites of P. falciparum were synchronized after 5% -sorbitol
D-glucose, 0.23%
The chalcones were obtained in high yields (>80%). 9-Chlor-
oacridine was synthesized by the condensation of N-arylanthranilic
acid with phosphorus oxychloride [37] (Scheme 2).
D
treatment to obtain only the ring stage parasitized cells. For
carrying out the assay, an initial ring stage parasitaemia of 1.0–1.5%
Subsequent treatment of chalcone derivatives 1a–k with
9-chloroacridine in 2-butanol yielded compounds, 1–11 (Scheme 3)
which were purified by column chromatography to get pure solid
compounds. The final yield of the derivatives was in the range of
59–67%. The compounds obtained were stable in the solid as well as
in the solution state. The compounds have been characterized by IR,
UV–Visible, 1H and 13C NMR and mass spectral data.
at 3% haematocrit in a total volume of 200 mL of medium RPNI with
10% fetal bovine serum [47] was uniformly maintained. A stock
5 mg/mL concentrate of the given test sample was prepared in
DMSO and subsequent dilutions were prepared with culture
medium. The diluted test samples in 20
the test wells so as to obtain final concentrations (at five fold
dilutions) ranging between 0.4 g/mL and 100 g/mL in duplicate
mL volume were added to
m
m
wells containing parasitized cell preparation. The culture plates
were incubated at 37 ꢀC in a CO2 incubator. After 36–40 h incuba-
tion, the blood smears from each well were prepared and stained
with Giemsa stain. The slides were microscopically observed to
record maturation of ring stage parasites into trophozoites and
schizonts with different concentrations of the compounds.
3. Pharmacology
Chalcone derivatives possess a diverse range of pharmacological
activities, like antiplasmodial [17], inhibitory effect on COX-2 and 5-
lipoxygenase [22], antimalarial [2,3,25,28–31], antileishmanial
[38,39], antiviral [40], anti-inflammatory [41], antiprotozoal [42],
antiplatelet [43], anti-AIDS [44] and so on.
4. Results and discussion
Hence all the acridinyl chalcone derivatives,1–11, were screened
for in vitro antimalarial activity against chloroquine-sensitive NF-54
strain of P. falciparum which was cultured in vitro according to the
For in vitro antimalarial assay, the test concentration, which
inhibited the complete maturation into schizonts, was recorded as
NaOH
MeOH
R2
+
R1
R1
R2
H
O
O
O
(1a) R1 = 4-NH2 R2 = H
(1f) R1 = 4-NH2 R2 = 3,4,5-triOCH3
(1b) R1 = 4-NH2 R2 = 3-NO2 (1g) R1 = 4-NH2 R2 = 4-Cl
(1c) R1 = 4-NH2 R2 = 3-CH3 (1i) R1 = 3-NH2 R2 = H,
(1d) R1 = 4-NH2 R2 = 4-CH3 (1j) R1 = 3-NH2 4-OCH3
(1e) R1 = 4-NH2 R2 = 4-OCH3 (1k) R1 = 3-NH2 R2 = 4-Cl
H2N
H2N
NaOH
+
H
MeOH
O
O
O
1h
Scheme 1. Synthesis of 1-(4(or 3-)-aminophenyl)-3-(substituted)phenyl- prop-2-en-1-one.

V. Tomar et al. / European Journal of Medicinal Chemistry 45 (2010) 745–751
747
N
Cl
N
HN
H2N
2-butanol
reflux
R2
R2
+
O
O
1-7
5. R2 = 4-OCH3
1. R2 = H
2. R2 = 3-NO2
3. R2 = 3-CH3
4. R2 = 4-CH3
6. R2 = 3,4,5-Trimethoxy
7. R2 = 4-Cl
N
Cl
N
HN
H2N
+
2-butanol
reflux
O
8
O
N
NH
NH2
Cl
2-butanol
reflux
R2
+
R2
N
O
O
9-11
9. R2 = H
10. R2 = 4-OCH3
11. R2 = 4-Cl
Scheme 3. Synthesis of 1-(4-(9-acridinylamino)phenyl)-3(substituted) phenylprop-2-en-1-one.
the minimum inhibitory concentration (MIC). Chloroquine was
used as the standard reference drug. The mean number of rings,
trophozoites and schizonts recorded per 100 parasites from
duplicate wells after incubation for 38 h and percent maturation
inhibition with respect to untreated control group are shown in
Table 1.
of the compounds were prepared after making a paste with a few
drops of Tween-80. The volume was adjusted so as to obtain the
required 50 mg/kg doses in 0.5 mL volume. The treatment to each
of the three groups of P. yoelii infected mice was administered via
intraperitoneal route, once daily for four consecutive days from
day 0 to day 3. One group of 6 mice was administered the aqueous
vehicle used for preparing suspension and served as untreated
control. The thin blood smears were prepared from each animal
on day 4 i.e. 24 h after the last treatment dose and again on day 6.
The degree of infection was microscopically recorded in terms of
number of P. yoelii infected cells per 100 RBC (i.e. percent para-
sitaemia). The mean value determined for a group of 6 mice was
used to calculate the percent suppression of parasitaemia with
respect to the untreated control group. The degree of parasitaemia
on day 4 and day 6 for the treated groups and the relative
suppression of parasitaemia with respect to control group are
indicated in Table 2.
All the anilinoacridine chalcone derivatives inhibited the
maturation of parasite fully at 10
showed activity upto 2 g/mL concentration. Chalcones 1, 4, 6 and 8
showed 42.8, 42.8, 57.1 and 64.3% maturation inhibition respec-
tively at 2 g/mL. Out of eleven, three samples 5, 9 and 10 exhibited
>70% inhibition at 2 g/mL concentration. Particularly compound 5
inhibited 85.7%, 71.4% and 14.3% maturation of parasite into
schizonts at 2 g/mL, 0.4 g/mL and 0.08 g/mL concentrations
respectively, while 9 and 10 showed 97.1% and 71.4% inhibition of
parasite at 2 g/mL level followed by low inhibition of 4.3% and 7.1%
at 0.4
g/mL levels. In a broad sense compounds with 30-amino
mg/mL level. Seven compounds
m
m
m
m
m
m
m
m
group were more reactive compared to 40-amino chalcones.
Alkoxylated chalcones 5 and 10 showed good antimalarial activity
but trialkyloxy-substituted chalcones showed reduced activity.
Investigation on the activity of chalcones resulted in the identifi-
cation of three inhibitors with low micromolar efficacy against P.
falciparum strain (NF-54) in vitro.
These new chalcone derivatives showed much enhanced
activity relative to other chalcone derivatives [8,14,18,23,24].
Three compounds (5, 9 and 10) were further screened for in vivo
efficacy against a chloroquine-resistant rodent malaria parasite
Plasmodium yoelii (strain N-67) in Swiss mice model. The out-bred
Swiss mice (weights ¼ 23 ꢁ 2 g) of either sex were inoculated
intraperitoneally with 1 ꢂ106 P. yoelii parasitized RBC and the day
of inoculation was designated as ‘Day 0’.The aqueous suspensions
These inhibitors were found to be inactive when given intra-
peritoneally in a P. yoelii infected mice model. Metabolic instability
may be responsible for the lack of activity in vivo due to possible
significant degradation of compounds upon their exposure to
a
liver microsome preparation. The degree of parasitaemia
suppression on day 4 and day 6 for the treated groups and the
relative suppression of parasitaemia with respect to control group
is indicated in Table 2 that indicates no significant inhibition in
parasitaemia with any of the three samples.
From the results of in vitro study on the antimalarial activity it
is evident that 1-(3-(Acridin-9-ylamino)phenyl)-3-phenylprop-2-
en-1-one derivatives are more potent than 1-(4-(Acridin-9-yla-
mino)phenyl)-3-phenylprop-2-en-1-one derivatives. In the latter
case, substituents at 40 position of ring B were more potent than

748
V. Tomar et al. / European Journal of Medicinal Chemistry 45 (2010) 745–751
Table 1
In vitro antimalarial activity of acridinyl chalcone derivatives.
Compound
Concentrations evaluated (
mg/mL)
Number of parasites/100 infected RBCs
Percent schizont maturation
inhibition
Rings
Trophozoites
Schizonts
Control
1
–
0
30
0
0
0
60
70
0
0
0
40
–
100
50
10
2.0
100
100
100
0
100
100
100
42.8
2
3
4
5
100
50
10
100
100
30
0
0
70
30
0
0
0
100
100
100
0
2.0
0
70
100
50
10
100
100
100
0
0
0
0
0
0
0
100
100
100
0
2.0
30
70
100
50
10
100
100
100
0
0
0
0
0
0
0
100
100
100
42.8
2.0
60
40
100
50
10
2.0
0.4
0.08
100
100
100
50
5
0
0
0
40
75
40
0
0
0
10
20
60
100
100
100
85.7
71.4
14.3
0
6
100
50
10
2.0
0.4
100
100
100
0
0
0
0
70
34
0
0
0
30
66
100
100
100
57.1
5.7
0
7
8
100
50
10
100
100
100
0
0
0
0
0
0
0
100
100
100
0
2.0
30
70
100
50
10
2.0
0.4
100
100
100
15
0
0
0
60
30
0
0
0
25
70
100
100
100
64.3
0
0
9
100
50
10
2.0
0.4
100
100
100
25
0
0
0
73
30
0
0
0
02
67
100
100
100
97.1
4.3
3
10
100
50
10
2.0
0.4
100
100
60
20
0
0
0
40
60
35
0
0
0
20
65
100
100
100
71.4
7.1
11
100
50
10
100
100
100
0
0
0
0
0
0
0
100
100
100
0
2.0
30
70
Chloroquine
0.50
0.25
0.125
0.0625
0.50
100
100
95
70
100
0
0
3
32
0
0
0
2
18
0
100
100
97.1
74.3
100
30-substituents. It is evident that substituents play a vital role in
interaction with the enzyme that perturb the concerned chalcone
from binding on the active site of the enzyme. It seems that
chalcones exert their antimalarial efficacy through multiple
mechanisms and different substituted chalcones exert their anti-
malarial activity through different pathways.
5. Conclusion
A series of novel chalcones bearing acridine moiety in one of the
rings has been synthesized through noncatalysed nucleophilic
aromatic substitution with 30-aminochalcone and also with
40-aminochalcone.

V. Tomar et al. / European Journal of Medicinal Chemistry 45 (2010) 745–751
749
Table 2
In vivo antimalarial activity of acridinyl chalcone derivatives.
Code of test sample
Dose (mg/kg)
No. of mice
Mean percent parasitaemia on
Suppression of parasitaemia on
Mean survival time ꢁ SE (days)
Day 4
Day 6
Day 4
Day 6
5
9
50
50
50
–
6
6
6
6
6.48 ꢁ 0.94
6.45 ꢁ 0.54
6.03 ꢁ 0.43
6.43 ꢁ 0.73
14.58 ꢁ 1.20
15.0 ꢁ 0.93
15.0 ꢁ 0.41
15.08 ꢁ 0.88
Nil
Nil
6.22
–
Nil
Nil
Nil
–
10.67 ꢁ 2.17
15.50 ꢁ 2.23
15.20 ꢁ 1.45
15.83 ꢁ 1.25
10
Control
All the synthesized chalcones have been evaluated for in vitro
antimalarial activity against P. falciparum NF-54. All of them
added to the reaction mixture to catalyse the reaction. The contents
were refluxed at 110 ꢀC over a silicone oil bath for 6–8 h. The
completion of the reaction was checked by TLC. The reaction
mixture was allowed to cool to room temperature and then poured
into ice water (25 mL). The precipitate formed, was filtered off with
suction, washed with water, and chromatographed on a silica gel
column (6 ꢂ 25 cm) using PE/EA (8:2 v/v) as the eluant. The frac-
tions containing the product were combined and evaporated in
vacuo to dryness. The solid residue was recrystallized from meth-
anol to get 1: Orange crystals (methanol); Yield ¼ 1.18 g (59%); m.p.
205–206 ꢀC; tR (min): 5.215; Anal calc. for (C28H20N2O) C, 83.98,
H,5.03; N, 7.00; %; found; C,83.53; H, 5.23; N, 7.14%; UV/VIS; lmax
(nm): 208, 250, 319, 398; IR: nmax (cmꢃ1), 3428 (NH), 2925 (C–H),
1638 (C]O), 1621 (C]C), 1589 (C]N), 1470, 1409, 1336, 1172, 1016
(C–N), 931(trans ethylenic H), 841, 779 (CH arom bend); FAB–MS m/
inhibited the maturation of parasite at concentration of 10
and above.
mg/mL
Chalcone derivatives 5, 9 and 10 exhibited >71% inhibition at
mg/mL concentration. Compound 5 showed 71.4% inhibition of
2
parasite even at a low concentration of 0.4 mg/mL.
It is also evident that location and nature of the substituent(s) in
ring B of the chalcone derivative are crucial. Derivatives 5, 9 and 10
have potent antimalarial activity and are likely to be useful as drugs
after further refinement. These derivatives will encourage to help
design future antimalarials with therapeutic potentials.
6. Experimental protocol
All the organic solvents used were of high purity unless other-
wise stated. The reactions were monitored by TLC on precoated TLC
aluminium plate (Merck Germany) silica gel 60F254 thin layer
plates. Elemental analysis (C, H, N; Elementar Vario EL III Instru-
ment), Melting points (open capillary method on a Perfit Melting
Point apparatus), Electronic spectra (Shimadzu-1601 PC UV–VIS
spectrophotometer), IR spectra (Nexus FT-IR spectrophotometer),
1HNMR and 13C NMR (Bruker Spectrospin 500 MHz Spectrometer)
spectra have been recorded. The EI Mass spectra of the compounds
were recorded on a Perkin–Elmer Clarus 500 GC-Mass Spectrom-
eter. Fab Mass spectra of the final compounds were recorded on
a JEOL JMS600 Mass Spectrometer. Analytical HPLC was performed
on an Agilent 1100 preparative HPLC system employing a VWL
z: 401.14 [M þ H]þ; 1H NMR (DMSO-d6) (
d, ppm): 11.21 (1H, s,
exchangeable NH), 8.39 (2H, d, J ¼ 8.0 Hz, ArH), 8.21 (1H, d,
J ¼ 15.5 Hz, Hb), 7.97 (2H, d, J ¼ 8.5 Hz), 7.78 (2H, t, J ¼ 7.5 Hz, Acri),
7.59–7.52 (3H, m, J1 ¼8.0 Hz, J2 ¼15.5 Hz, Ha), 7.47 (2H, d,
J ¼ 8.5 Hz), 7.34 (2H, t, J ¼ 7.5 Hz, Acri), 6.92–6.86 (3H, m) 6.65 (2H,
d, J ¼ 8.0 Hz, ArH); 13C NMR (DMSO-d6) (
d, ppm): 182.9,153.8,149.8,
142.3, 140.3, 137.1, 135.2, 131.4, 130.9, 130.2, 129.4, 129.3, 128.9,
127.6, 126.7, 126.4, 121.9, 119.4, 115.9,
6.2.2. 1-(4-(Acridin-9-ylamino)phenyl)-3-(3-nitrophenyl)prop-2-
en-1-one (2)
Compound 2 was prepared as per procedure followed for 1, using
1-(4-aminophenyl)-3-(3-nitrophenyl)prop-2-en-1-one (1b) instead
of 1-(4-aminophenyl)-3-phenylprop-2-en-1-one (1a). Bright yellow
crystals (methanol); Yield: 1.51 g (68%); m.p.: 248 ꢀC (d); tR (min):
5.714; Anal calc. for (C28H19N3O3) C, 75.49; H, 4.30; N, 9.43; found; C,
75.80, H, 4.04, N, 9.57%; UV/VIS; lmax (nm): 213, 250, 398; IR: nmax
(cmꢃ1), 3455 (NH), 2834 (C–H), 1664 (C]O), 1630 (C]C), 1582
(C]N), 1530 and 1350 (-NO2), 1272, 1219, 1170, 1033 (C–N), 969
(trans ethylenic H), 804, 752 (CH arom bend); FAB–MS m/z: 445.23
detector. The compounds were analyzed in solution (1
MeOH) by HPLC with ZORBAX EclipseXDB-C8 column
(4.6 ꢂ 150 mm, 5 m) using elution system (system: 50% MeOH in
mM in
a
m
H2O; gradient elution 10/90–90/10 at a flow rate of 0.5 mL/min).
System was used with UV (254 nm) detection and tR values were
reported in min with the analytical data.
6.1. Synthesis and characterisation of the compounds
[M]þ; 1H NMR (DMSO-d6) (
d, ppm): 11.37 (1H, s, exchangeable NH),
8.41 (1H, s), 8.24 (2H, d, J ¼ 8.0 Hz, ArH), 8.10 (1H, d, J ¼ 15.5 Hz, Hb),
7.99 (2H, d, J ¼ 8.5 Hz, ArH), 7.84 (1H, d, J ¼ 15.5 Hz, Ha), 7.73 (2H, t,
J ¼ 7.5 Hz, Acri), 7.57 (2H, d, J ¼ 8.5 Hz, ArH), 7.49 (1H, t, J ¼ 8.5 Hz,
ArH), 7.38 (2H, d, J ¼ 8.5 Hz, ArH), 7.26 (2H, t, J ¼ 8.0 Hz, Acri), 6.94
6.1.1. Synthesis of chalcones 1a–k
The amino chalcones were synthesized by using general
Claisen–Schimdt condensation (Scheme 1).
(2H, d, J ¼ 8.5 Hz, ArH); 13C NMR (DMSO-d6) (
d, ppm):183.8, 149.8,
6.1.2. Synthesis of 9-chloroacridine
147.5, 142.1, 132.9, 132.8, 132.7, 131.9, 131.1, 130.42, 129.8, 128.5, 127.9,
127.2, 126.4, 122.3, 120.1, 115.5, 113.1.
9-chloroacridine was synthesized by the cyclisation of N-ary-
lantranilinic acid with phosporus oxychloride as reported [37]
(Scheme 2)
6.2.3. 1-(4-(Acridin-9-ylamino)phenyl)-3-m-(tolyl)prop-2-en-1-
one (3)
6.2. Synthesis of acridinyl chalcone derivatives
Compound 3 was prepared using 1-(4-aminophenyl)-3-(3-
methylphenyl)prop-2-en-1-one (1c) instead of 1-(4-aminophenyl)-
3-phenylprop-2-en-1-one (1a). Orange crystals (methanol); Yield:
1.39 g (67%); m.p.: 185–186 ꢀC; tR (min): 5.281; Anal calc. for
(C29H22N2O) C, 84.03; H, 5.35; N, 6.76%; found; C, 84.36; H, 5.66; N,
6.47%; UV/VIS; lmax (nm): 213, 250, 320, 397; IR: nmax (cmꢃ1), 3414
(NH), 3235, 2852 (C–H), 1637 (C]O), 1619 (C]C), 1589 (C]N),
1470, 1385, 1336, 1172, 1095 (C–N), 939 (trans ethylenic H), 752 (CH
Synthesis of acridinyl chalcones was carried out on a millimolar
scale. The method used is as follows:
6.2.1. 1-(4-(Acridin-9-ylamino)phenyl)-3-phenylprop-2-en-1-one (1)
Chalcone 1a 1-(4-aminophenyl)-3-phenylprop-2-en-1-one
(1.12 g, 5 mM) and 9-chloroacridine (1.07 g, 5 mM) were dissolved
in minimum amount of 2-butanol (15 mL). One drop of HCl was
arom bend); FAB–MS m/z: 415.24 [M þ H]þ; 1H NMR (DMSO-d6) (
d,

750
V. Tomar et al. / European Journal of Medicinal Chemistry 45 (2010) 745–751
ppm): 11.64 (1H, s, exchangeable NH), 8.41 (1H, s), 8.32 (2H, d,
J ¼ 8.0 Hz, ArH), 8.18 (1H, d, J ¼ 15.5 Hz, Hb), 8.07–7.84 (4H, m), 7.71
(1H, d, J ¼ 15.5 Hz, Ha), 7.59 (2H, d, J ¼ 8.5 Hz, ArH), 7.38 (2H, t,
J ¼ 7.5 Hz, Acri), 7.29 (2H, d, J ¼ 8.5 Hz, ArH), 7.16 (1H, t, J ¼ 8.5 Hz,
ArH), 6.72 (2H, d, J ¼ 8.5 Hz, ArH), 2.83 (3H, s-CH3); 13C NMR
ppm): 186.3, 149.3, 147.5, 132.9, 132.8, 132.5, 131.9, 131.1, 130.4, 128.8,
127.2, 122.4, 122.3, 120.1, 115.5, 106.3, 62.1, 56.6.
6.2.7. 1-(4-(9-Acridinylamino)phenyl)-3-(4-chlorophenyl)prop-2-
en-1-one (7)
(DMSO-d6) (
d
, ppm): 189.6, 153.8, 146.3, 142.2, 141.7, 136.4, 130.9,
Compound 7 was prepared using 1-(4-aminophenyl)-3-(4-
130.6, 129.7, 129.2, 126.6, 126.5, 123.3, 121.9, 120.8, 119.5, 115.9, 27.7.
chlorophenyl)prop-2-en-1-one (1g) instead of 1-(4-aminophenyl)-
3-phenylprop-2-en-1-one (1a). Orange-red crystals (methanol);
Yield: 1.37 g (63%); m.p. 227–228 ꢀC; tR (min): 6.383; Anal calcd. for
(C28H19ClN2O) C, 77.33; H, 4.40; N, 6.44%; found; C, 77.63; H, 4.63; N,
6.48%; UV/VIS; lmax (nm): 205, 246, 317, 420; IR: nmax (cmꢃ1), 3434
(NH), 2921, 2737, 1637 (C]O), 1614 (C]C), 1579 (C]N), 1513, 1416,
1327, 1272,1213,1169, 1092,1014 (C–N), 970 (trans ethylenic H), 815,
6.2.4. 1-(4-(Acridin-9-ylamino)phenyl)-3-p-(tolyl)
prop-2-en-1-one (4)
Compound 4 was prepared as per method used for synthesis of
1, using 1-(4-aminophenyl)-3-(4-methylphenyl)prop-2-en-1-one
(1d) instead of 1-(4-aminophenyl)-3-phenylprop-2-en-1-one (1a).
Orange-red crystals (methanol); Yield: 1.53 g (74%); m.p.:
144–146 ꢀC; tR (min): 5.233; Anal calc. for (C29H22N2O) C, 84.03; H,
5.35; N, 6.76%; found; C, 84.34; H, 5.63; N, 6.51%; UV/VIS; lmax
(nm): 249, 327, 400; IR: nmax (cmꢃ1), 3454 (NH), 2929, 2855 (C–H),
1602 (C]O), 1587 (C]C), 1551(C]N), 1511, 1482, 1340, 1227, 1175,
1023 (C–N), 987 (trans ethylenic H), 808, 761 (CH arom bend); FAB–
753 (CH arom bend); EI-MS m/z: 435 [M þ H]þ; 1H NMR (CD3OD) (
d,
ppm): 11.63 (1H, s, exchangeable NH), 8.32 (2H, d, J ¼ 8.5 Hz, ArH),
8.26 (2H, d, J ¼ 8.5 Hz, ArH), 8.17 (1H, d, J ¼ 17.5 Hz, Hb), 8.09 (2H, t,
J ¼ 7.5 Hz, Acri), 8.05 (2H, d, J ¼ 8.5 Hz, ArH), 7.99 (1H, d, J ¼ 17.5 Hz,
Ha), 7.86 (2H, d, J ¼ 8.0 Hz, ArH), 7.81 (2H, d, J ¼ 8.0 Hz ArH), 7.57 (2H,
t, J ¼ 7.5 Hz, ArH), 7.49 (2H, d, J ¼ 7.5 Hz, ArH); 13C NMR (DMSO-d6)
MS m/z: 415.04 [M þ H]þ; 1H NMR (DMSO-d6) (
d
, ppm): 10.81 (1H,
(d, ppm): 187.5, 148.1, 143.2, 141.4, 140.8, 133.9, 132.6, 131.9, 131.3,
s, exchangeable NH), 8.42 (2H, d, J ¼ 7.5 Hz), 8.32 (2H, d, J ¼ 7.5 Hz),
8.08 (1H, d, J ¼ 15.5 Hz, Hb), 7.92 (2H, d, J ¼ 7.5 Hz), 7.86 (1H, d,
J ¼ 15.5 Hz, Ha), 7.72 (2H, t, J ¼ 8.5 Hz, Acri), 7.42 (2H, d, J ¼ 8.0 Hz),
7.24 (2H, t, J ¼ 8.5 Hz, Acri), 7.06 (2H, d, J ¼ 8.5 Hz), 6.82 (2H, d,
130.7, 129.9, 129.2126.5, 121.5, 120.9, 117.8, 115.8, 113.5, 112.7.
6.2.8. 1-(4-(Acridin-9-ylamino)phenyl)-5-(phenyl)penta-2,4-dien-
1-one (8)
J ¼ 8.5 Hz), 2.21 (3H, s, -CH3); 13C NMR (DMSO-d6) (
d, ppm): 186.5,
Compound 8 was prepared following procedure for the
148.2, 144.5, 137.6, 132.8, 132.1, 130.9, 129.7, 129.4, 128.5, 127.9,
126.3, 121.7, 120.8, 120.0, 115.4, 108.5, 108.1, 26.4.
synthesis of 1, using 1-(4-aminophenyl)-5-phenylpenta-2,4-dien-
1-one (1h) instead of 1-(4-aminophenyl)-3-phenylprop-2-en-1-
one (1a). Yellow powder (methanol); Yield: 1.09 g (51%); m.p.
196–197 ꢀC; tR (min): 5.856; Anal calc. for (C30H22N2O) C, 84.48; H,
5.20; N, 6.57%; found; C, 84.26; H, 5.21; N, 6.85%; UV/VIS; lmax
(nm): 213, 248, 360; IR: nmax (cmꢃ1), 3472 (NH), 2913, 2833 (C–H),
1635 (C]O), 1592 (C]C), 1571 (C]N), 1469, 1384, 1265, 1165, 1030
(C–N), 934 (trans ethylenic H), 812, 752(CH arom bend); ESI–MS m/
6.2.5. 1-(4-(Acridin-9-ylamino)phenyl)-3-(4-methoxyphenyl)prop-
2-en-1-one (5)
Compound 5 was prepared using 1-(4-aminophenyl)-3-(4-
methoxyphenyl)prop-2-en-1-one (1e) instead of 1-(4-amino-
phenyl)-3-phenylprop-2-en-1-one (1a). Yellow-orange crystals
(methanol); Yield: 1.68 g (78%); m.p.: 159–161 ꢀC; tR (min): 5.650;
Anal calc. for (C29H22N2O2) C, 80.91; H, 5.15; N, 6.51%; found;
C,80.63; H, 5.61; N, 6.4; UV/VIS; lmax (nm): 208, 248, 341, 399; IR:
nmax (cmꢃ1) 3462 (NH), 2952, 2832 (C–H), 1626 (C]O), 1595 (C]C),
1511 (C]N), 1443, 1378, 1252, 1178, 1026 (C–N), 920 (trans ethyl-
enic H), 834, 747 (CH arom bend); FAB–MS m/z: 431.02 [M þ H]þ;
z: 427 [M þ H]þ; 1H NMR (DMSO-d6) (
d, ppm): 11.77 (1H, s,
exchangeable NH), 8.34 (2H, d, J ¼ 8.0 Hz, ArH), 8.23–8.12 (3H, m,
ArH), 7.83 (2H, t, J ¼ 7.5 Hz, Acri), 7.77 (1H, d, J ¼ 15.5 Hz, Ha),
7.69–7.53 (4H, m), 7.48 (2H, t, J ¼ 7.5 Hz, Acri), 7.34 (1H, d, J ¼ 8.5 Hz,
ArH), 7.21–7.08 (3H, m), 6.91 (1H, d, J ¼ 14.5 Hz, ArH), 6.79 (2H, d,
J ¼ 8.5 Hz, ArH); 13C NMR (DMSO-d6) (
d, ppm): 184.7, 153.5, 148.7,
1H NMR (DMSO-d6) (
d, ppm): 11.12 (1H, s, exchangeable NH), 8.43
144.1, 140.3, 137.4, 136.2, 135.9, 131.8, 131.3, 129.5, 128.9, 128.2,
126.8, 121.8, 120.1, 119.6, 115.8.
(2H, d, J ¼ 8.0 Hz, ArH), 8.07 (2H, d, J ¼ 8.0 Hz, ArH), 7.99 (1H, d,
J ¼ 16.5 Hz, Hb), 7.95–7.82 (4H, m), 7.78 (1H, d, J ¼ 16.5 Hz, Ha), 7.73
(2H, d, J ¼ 8.0 Hz, ArH), 7.44 (2H, t, J ¼ 8.5 Hz, Acri), 7.10 (2H, d,
6.2.9. 1-(3-(Acridin-9-ylamino)phenyl)-3-(phenyl)prop-2-en-1-
one (9)
J ¼ 8.0 Hz, ArH), 6.86(2H, d, J ¼ 8.5 Hz, ArH), 3.85 (3H, s, –OCH3); 13
C
NMR (DMSO-d6) (
d
, ppm): 181.6, 152.4, 140.1, 135.5, 134.9, 132.4,
Compound 9 was prepared as per method used for synthesis of
1, using 1-(3-aminophenyl)-3-phenylprop-2-en-1-one (1i) instead
of 1-(4-aminophenyl)-3-phenylprop-2-en-1-one (1a). Bright
yellow crystals (methanol); Yield: 1.38 g (69%); m.p. 201–202 ꢀC; tR
(min): 5.133; Anal calc. for (C28H20N2O) C, 83.98; H, 5.03; N, 7.00%;
found; C,83.53; H, 5.13; N, 7.11%; UV/VIS; lmax (nm): 250, 319, 398;
IR: nmax (cmꢃ1), 3452 (NH), 2925, 2822 (C–H), 1638 (C]O), 1625
(C]C),1529 (C]N),1475,1338,1186,1035 (C–N), 847, 743 (CH arom
130.1, 126.2, 124.8, 121.7, 121.6, 120.4, 120.1, 119.7, 117.3, 113.5, 112.4,
111.9, 110.2, 108.4, 108.2 57.6.
6.2.6. 1-(4-(Acridin-9-ylamino)phenyl)-3-(3,4,5-
trimethoxyphenyl)prop-2-en-1-one (6)
Compound 6 was prepared as per procedure for the synthesis of
1, using 1-(4-aminophenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-
1-one (1f) instead of 1-(4-aminophenyl)-3-phenylprop-2-en-1-one
(1a). Orange crystals (methanol); Yield: 1.08 g (44%); mp
175–176 ꢀC; tR (min): 6.017; Anal calc. for (C31H26N2O4) C, 75.90; H,
5.34; N, 5.71%; found; C,75.63; H, 5.63; N, 5.48%; UV/VIS; lmax (nm):
212, 249, 327, 360; IR: nmax (cmꢃ1), 3434 (NH), 2920, 2737 (C–H),
1635 (C]O), 1580 (C]C), 1513 (C]N), 1416, 1327, 1272, 1216, 1168,
1091, 1014 (C–N), 970 (trans ethylenic H), 815, 753 (CH arom bend);
bend); FAB–MS m/z: 401.24 [M þ H]þ; 1H NMR (DMSO-d6) (
d, ppm):
11.74 (1H, s, exchangeable NH), 8.39 (2H, d, J ¼ 8.0 Hz), 8.21 (1H, d,
J ¼ 15.5 Hz, Hb), 7.97 (2H, d, J ¼ 8.5 Hz), 7.91 (1H, s), 7.85–7.76
(1H, m), 7.69 (2H, t, J ¼ 7.5 Hz Acri), 7.63 (1H, d, J ¼ 15.5 Hz, Ha), 7.51
(2H, d, J ¼ 8.0 Hz), 7.39 (2H, t, J ¼ 7.5 Hz, Acri), 7.27–7.18 (3H, m), 7.13
(2H, d, J ¼ 8.0 Hz); 13C NMR (DMSO-d6) (
d, ppm): 183.1, 153.7, 148.0,
145.1,143.5,141.9,140.2,135.3,134.9,128.8,128.2,127.1,125.7,123.9,
123.8, 119.3, 115.4, 114.2.
EI-MS m/z: 491 [M þ H]þ; 1H NMR (DMSO-d6) (
d, ppm): 11.17 (1H, s,
exchangeable NH), 8.24 (2H, d, J ¼ 8.0 Hz, ArH), 7.97 (1H, d,
J ¼ 16.0 Hz, Hb), 7.81 (2H, d, J ¼ 8.5 Hz, ArH), 7.74 (2H, t, J ¼ 8.0 Hz,
Acri), 7.56 (2H, d, J ¼ 8.0 Hz, ArH), 7.48 (1H, d, J ¼ 16.5 Hz, Ha), 7.39
(2H, s, ArH), 7.27 (2H, t, J ¼ 8.0 Hz, Acri), 7.19 (2H, d, J ¼ 8.5 Hz, ArH),
6.2.10. 1-(3-(Acridin-9-ylamino) phenyl)-3-(4-methoxyphenyl)
prop-2-en-1-one (10)
Compound 10 was prepared according to the synthesis of 1,
using 1-(3-aminophenyl)-3-(4-methoxyphenyl) prop-2-en-1-one
3.88 (6H, s, –OCH3), 3.72 (3H, s, –OCH3); 13C NMR (DMSO-d6) (
d,

V. Tomar et al. / European Journal of Medicinal Chemistry 45 (2010) 745–751
751
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(1j) instead of 1-(4-aminophenyl)-3-phenylprop-2-en-1-one (1a).
Yellow-orange powder (methanol); Yield: 1.53 g (71%); mp
225–226 ꢀC; tR (min): 4.466; Anal calc. for (C29H22N2O2) C, 80.91; H,
5.15; N, 6.51%; found; C,80.21; H, 5.55; N, 6.67%; UV/VIS; lmax (nm):
212, 249, 341, 397; IR: nmax (cmꢃ1), 3462 (NH), 2931, 2846 (C–H),
1626 (C]O),1595 (C]C), 1579 (C]N), 1473, 1252, 1178, 1026 (C–N),
920 (trans ethylenic H), 747(CH arom bend); FAB–MS m/z: 431.06
[M þ H]þ; 1H NMR (DMSO-d6) (
d, ppm): 11.11 (1H, s, exchangeable
NH), 8.17 (2H, d, J ¼ 8.0 Hz, ArH), 7.79 (1H, d, J ¼ 17.5 Hz, Hb), 7.66
(2H, t, J ¼ 8.5 Hz, acri), 7.59–7.46 (2H, m, J1 ¼8.5 Hz, J2 ¼ 17.5 Hz,
Ha), 7.41 (2H, d, J ¼ 8.5 Hz), 7.37 (1H,s), 7.32 (1H, d, J ¼ 8.5 Hz), 7.25
(2H, t, J ¼ 7.5 Hz, acri), 7.13 (1H, d, J ¼ 8.5 Hz), 7.09 (2H, d, J ¼ 8.5 Hz),
6.86 (2H, d, J ¼ 8.0 Hz), 3.81 (3H, s, –OCH3); 13C NMR (DMSO-d6) (
d,
ppm): 182.3, 148.3, 144.6, 142.3, 140.5, 135.4, 134.6, 133.8, 130.1,
129.9, 128.7, 128.1, 125.4, 124.8, 122.0, 119.6, 115.1, 60.1.
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6.2.11. 1-(3-(Acridin-9-ylamino)phenyl)-3-(4-chlorophenyl)prop-
2-en-1-one (11)
Compound 11 was prepared according to the synthesis of 1, using
1-(3-aminophenyl)-3-(4-chlrophenyl)prop-2-en-1-one (1k) instead
of 1-(4-aminophenyl)-3-phenylprop-2-en-1-one (1a). Bright-orange
crystals (methanol); Yield: 1.22 g (56%); m.p. 215–216 ꢀC; tR (min):
5.091; Anal calc. for (C28H19ClN2O) C, 77.33; H, 4.40; N, 6.44%; found;
C,77.63; H, 4.63; N, 6.48%; UV/VIS; lmax (nm): 214, 248, 313, 399; IR:
nmax (cmꢃ1), 3459 (NH), 2923, 2851(C–H), 1628 (C]O), 1596 (C]C),
1561 (C]N), 1474, 1341, 1262, 1193, 1028 (C–N), 939 (trans ethylenic
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(DMSO-d6) (d, ppm): 11.86 (1H, br s, exchangeable NH), 8.22 (1H, d,
J ¼ 8.0 Hz, ArH), 8.15 (2H, d, J ¼ 8.0 Hz, ArH), 7.91 (1H, d, J ¼ 15.5 Hz,
Hb), 7.86 (2H, d, J ¼ 8.0 Hz, ArH), 7.82 (3H, m, J1 ¼8.5 Hz, J2 ¼15.5 Hz,
Ha), 7.70 (2H, t, J ¼ 8.5 Hz, Acri), 7.62 (2H, d, J ¼ 9.0 Hz, ArH), 7.47(2H, d,
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J ¼ 8.5 Hz, Acri), 7.22 (2H, d, J ¼ 7.5 Hz, ArH); 13C NMR (DMSO-d6) (
d,
ppm):175.5, 161.1, 148.4, 143.4, 141.1, 134.4, 133.1, 131.6, 129.4, 129.1,
128.7, 128.3, 128.2, 127.6, 126.4, 123.3.
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Acknowledgement
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One of the authors (V. Tomar) is thankful to the Ministry of
Human Resource Development (MHRD), New Delhi for financial
assistance
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