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Synthesis and anticancer activity evaluation of some acridine derivatives

Article in Medicinal Chemistry Research · May 2015

DOI: 10.1007/s00044-014-1268-6

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Med Chem Res (2015) 24:1942–1951 MEDICINAL
DOI 10.1007/s00044-014-1268-6
CHEMISTRY
RESEARCH
ORIGINAL RESEARCH

Synthesis and anticancer activity evaluation of some acridine

derivatives
Surbhi Arya • Anuj Kumar • Nikhil Kumar •

Partha Roy • S. M. Sondhi

Received: 12 June 2014 / Accepted: 17 September 2014 / Published online: 26 September 2014
 Springer Science+Business Media New York 2014

Abstract 9-Amino acridine derivatives (1a–1h) on con- and El-Kazak, 2010; Prabakaran et al., 2011), antituber-
densation with 9, 10-dihydroanthracene-9, 10-a, b-succinic cular (Aly and Abadi, 2004; Tripathi et al., 2006), anti-HIV
anhydride (2) at room temperature gave condensation (Aly et al., 1997), anti herpes (Goodell et al., 2006),
products (3a–3h). Microwave-assisted condensation of antiparasitic (Di Giorgio et al., 2005), antimalarial (Kumar
9-amino acridine derivatives (1a–1d) with phthalic anhydride, et al., 2009; Tomer et al., 2010; Yu et al., 2012), antiviral
cis 1,2,3,6-tetrahydrophthalimide, and 2,5-pyrroledione (Gupta and Jaiswal, 2010; Tonelli et al., 2011), and fun-
gave corresponding condensation products 4a–4d, 5a–5d gicidal (Srivastava and Nizamuddin, 2004) activities are
& 6a–6d, respectively, in good yields. All these com- well documented in the literature. Acridine derivatives are
pounds were screened for in vitro anticancer activity also reported to be useful in the treatment of Alzheimer’s
against five human cancer cell lines i.e., breast (T47D), and Parkinson’s disease (Lp et al., 2008; Wurster et al.,
lung (NCl H-522), colon (HCT-15), ovary (PA-1), and liver 2001) and chronic pulmonary disease (Gopalan et al.,
(Hep G2). Compounds 3a (breast T47D), 3 g (lung NCl 2006). In continuation of our efforts (Sondhi et al., 2010;
H-522), 4a (liver Hep G2), and 6b (colon HCT-15) 2013) in search of potent molecules possessing anticancer
exhibited IC50 values 5.4, 4.2, 4.5, and 2.4 lM, respec- activity, we have synthesized a number of acridine deriv-
tively, and hence possess good anticancer activity. atives and screened them for anticancer activity which we
wish to report in this paper.
Keywords Synthesis  Acridine derivatives 
Human cancer cell lines  Anticancer
Results and discussion

Introduction Chemistry

Acridine derivatives form an important class of heterocy- 9-Amino-3-methylacridine (1a; Scheme 1), 9-amino-2-
clic compounds due to their broad range of pharmaceutical methylacridine (1b), 9-amino-4-methoxyacridine (1c),
properties. Acridine derivatives exhibiting anti-inflamma- 9-amino-4-ethoxyacridine (1d), 9-amino-4-methylacridine
tory (Chen et al., 2002; Yartseva et al., 2003), anticancer (1e), 9-amino-3-methoxyacridine (1f), 9-amino-2-meth-
(El-Deiry, 2008; Maurice et al., 2009), antimicrobial (Ali oxyacridine (1g), and 9-aminoacridine (1h) were synthe-
sized by condensation of corresponding N-arylanthranilic
acid (Allen and Mckee, 1959) with phosphorus oxychloride
S. Arya  A. Kumar  S. M. Sondhi (&)
Department of Chemistry, Indian Institute of Technology- and subsequent conversion of 9-chloroacridines to 9-am-
Roorkee, Roorkee 247667, UK, India inoacridines by following reaction procedure reported in the
e-mail: sondifcy@iitr.ernet.in literature (Albert and Gledhill, 1945; Albert and Ritchie,
1960). 9, 10-dihydroanthracene-9, 10-a, and b-succinic
N. Kumar  P. Roy
Department of Biotechnology, Indian Institute of Technology- anhydride (2; Scheme 1) were synthesized by following
Roorkee, Roorkee 247667, UK, India reaction procedure reported in the literature (Vogel, 1968).

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Med Chem Res (2015) 24:1942–1951 1943

9-Amino-3-methylacridine (1a; Scheme 1) and 9, methoxyacridine (1f), 9-amino-2-methoxyacridine (1g),

10-dihydroanthracene-9, 10-a, b-succinic anhydride were and 9-amino acridine (1h) with 9, 10-dihydroanthracene-9,
taken in equimolar ratio and dissolved separately in mini- 10-a, b-succinic anhydride (2) gave corresponding con-
mum amount of dry tetrahydrofuran (THF). These two densation products 3b–3h (Scheme 1). All the condensa-
solutions were mixed together and allowed to stand at room tion products were purified by crystallization and structures
temperature for 20 h. Solvent was removed under reduced assigned to 3a–3h are fully supported by spectral data i.e.,
pressure and crude product so obtained was washed with IR, 1H NMR, 13C NMR, GC–MS, LC–MS, and elemental
chilled THF and then crystallized from methanol to give analysis reported in experimental section of this paper.
pure yellow product N-(3-methylacridin-9-yl)-9,10-dihydro- Condensation of 9-amino-3-methylacridine (1a) with
9,10-ethanoanthracene-11, 12-dicarbiximide (3a; Scheme 1) phthalic anhydride (Scheme 1) was carried out by mixing
in 89 % yield. IR spectrum of 3a shows absorption bands at both the reactants in equimolar ratio and then irradiating
1691 (C=O), 1657 (C=N), and 1586 and 1493 (C=C, Ar) the reaction mixture in a microwave reactor at 120 C for
cm-1. 1H NMR (500 MHz, DMSO-d6) d: 2.93 (s, 2H, 5 min. TLC of reaction mixture over silica gel using
2 9 CH), 2.97 (s, 3H, CH3), 4.65 (s, 2H, 2 9 CH), 7.15 (s, CHCl3:MeOH (8.5:1.5) as mobile phase shows the pre-
1H, Ar–H), 7.04–8.45 (m, 14H, Ar–H). 13C NMR sence of starting materials. Reaction mixture was again
(125 MHz, DMSO-d6) d: 18.15, 46.64, 48.79, 112.38, irradiated at 120 C for 5 min. TLC of reaction mixture
112.49, 121.82, 122.28, 122.69, 123.84, 123.80, 124.89, showed the absence of starting materials and the presence
125.20, 125.64, 132.25, 135.04, 141.46, 143.65, 148.49, of a new compound. The crude product so obtained was
154.99 173.44. APCI-MS: m/z 467.6 (M??H, 100 %). purified by crystallization from methanol to give pure
Elemental Anal. Calcd. for C32H22N2O2 C 82.40, H 4.72, N yellow product 2-(3-methylacridin-9-yl) isoindoline-1,3-
6.00; Found C 82.43, H 4.75, N 6.00 %. Spectral and dione (4a) in 93 % yield.
analytical data of 3a fully support the structure assigned Alternatively, both the reactants were mixed in equi-
to it. molar ratio and then irradiated in a domestic microwave
Similarly condensation of 9-amino-2-methylacridine oven at a power level of 600 Watt for 5 min. TLC of
(1b), 9-amino-4-methoxyacridine (1c), 9-amino-4-ethoxy- reaction mixture over silica gel using CHCl3:MeOH
acridine (1d), 9-amino-4-methylacridine (1e), 9-amino-3- (8.5:1.5) as mobile phase shows the presence of starting

Scheme 1 Synthesis of R2 R3
acridine derivatives R2 R3
R1 O
R1 O THF
N N
N NH2 + O RT, 20 h
O
O
1a-h 2 3a-h

O O
R2 R3 R2 R3
O O
R1 O R1 O
O O
N N 1a-d N N
MWI MWI
O O 600W O
600W
10-14 min MWI 10-12 min
4a-d O 600W 5a-d

O 10-14 min

R2 R3

R1 O

N N

6a-d

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1944 Med Chem Res (2015) 24:1942–1951

materials. This reaction mixture was again irradiated for Table 1 In vitro anticancer activity of acridine derivatives 3a–3h,
5 min and TLC of reaction mixture showed the absence of 4a–4d, 5a–5d & 6a–6d
starting materials and formation of new product. This crude Compd. no. aAnticancer activity (% growth inhibition) at a
product was crystallized from methanol to give the pure concentration of 1 9 10-5 M
product 4a in 92 % yield. Breast Lung Colon Ovary Liver
Reaction products obtained from both the methods were T47D NCI H-522 HCT-15 PA-1 HepG2
found to be same as monitored by TLC and co-TLC. Both
3a 67 70 70 67 72
the methods gave quantitative yield of condensed product.
3b 62 54 50 67 54
IR spectrum of 4a shows absorption bands at 1653 (C=O),
3c 61 60 64 69 68
1588, 1549 & 1481 (C=C, Ar) cm-1. 1H NMR (500 MHz,
DMSO-d6) d: 2.99 (s, 3H, CH3), 7.33–8.59 (m, 11H, 3d 65 54 57 70 70
Ar–H). 13C NMR (125 MHz, DMSO-d6) d: 23.66, 111.95, 3e 58 50 54 68 70
113.26, 117.14, 118.68, 124.20, 124.89, 127.30, 128.60, 3f 41 50 32 65 50
130.97, 132.89, 135.18, 135.74, 137.89, 138.98, 141.63, 3g 64 73 69 68 71
159.73, 168.83, APCI-MS: m/z 339.1 (M??H, 100 %). 3h 37 34 35 56 46
Elemental Anal. Calcd. for C22H14N2O2: C 78.10, H 4.14, 4a 61 65 74 70 74
N 8.28; Found C 78.19, H 4.21, N 8.38 %. Spectral and 4b 66 71 74 70 76
analytical data of 4a are in full agreement with the struc- 4c 53 58 44 68 55
ture assigned to it. 4d 65 60 69 66 71
Similarly, condensation of 9-amino-3-methylacridine 5a 68 65 73 67 73
(1a), 9-amino-2-methylacridine (1b), 9-amino-4-methoxy- 5b 65 70 72 65 72
acridine (1c), and 9-amino-4-ethoxyacridine (1d) with 5c 58 60 65 67 63
phthalic anhydride, cis-1,2,3,6-tetrahydrophthalimide, and 5d 64 60 68 68 66
2,5-pyrroledione gave corresponding condensation pro- 6a 57 60 62 66 70
ducts 4a–4d, 5a–5d, and 6a–6d, respectively, (Scheme 1). 6b 65 71 70 66 73
All these compounds were purified by crystallization. 6c 07 11 17 03 26
Spectral (IR, 1H NMR, 13C NMR, GC–MS & LC–MS) 6d 62 54 54 67 66
data and elemental analysis of 4a–4d, 5a–5d, and 6a–6d 5-FU 20 27 23 21 22
(Scheme 1) reported in experimental section of this paper CYC-PHO 27 17 17 35 29
are in agreement with structures assigned to them. CYC-HEXI 18 20 17 35 18
Compounds 3a–3h, 4a–4d, 5a–5d, and 6a–6d were
Bold values represent compounds showing good anticancer activity
screened for in vitro anticancer activity (Mosmann, 1983)
5-FU 5-fluorouracil, CYC-PHO cyclophosphamide, CYC-HEXI
against five human cancer cell lines i.e., breast (T47D), cycloheximide
lung (NCl H-522) colon (HCT-15), ovary (PA-1), and liver a
Compounds tested in triplicate, data expressed as mean value of
(Hep G2) at a concentration of 1 9 10-5M and results are three independent experiments
summarized in Table 1. A look at Table 1 indicates that
compounds 3a, 3d, 4b, 4d, 5a, 5b, 6b (breast T47D); 3a,
3g, 4b, 5b, 6b (lung NCl H-522); 3a, 3g, 4a, 4b, 4d, 5a, 5b, Structure–activity relationship
6b (colon HCT-15); 3d, 4a, 4b (ovary PA-1); and 3a, 3g,
4a, 4b, 4d, 5a, 5b, 6b (liver Hep G2) exhibited good Four series of acridine derivatives i.e., 3a–3h, 4a–4d, 5a–
anticancer activity against various cancer cell lines men- 5d, and 6a–6d are screened for in vitro anticancer activity
tioned above. Compounds 3a, 3d, 3g, 4a, 4b, 4d, 5a, 5b, against five human cancer cell lines i.e., breast (T47D),
and 6b which showed good anticancer activity were further lung (NCl H-522), colon (HCT-15), ovary (PA-1), and
studied and their IC50 values for various cancer cell lines liver (Hep G2). Compounds 3a, 3g, 4a, and 6b exhibited
and normal cell line (COS-1) are determined and reported good anticancer activity with IC50 values 5.4, 4.2, 4.5,
in Table 2. Compounds 4b and 3a, 5b, 6b showed good and 2.4 lM. A look at structures of these molecules
anticancer activity against five and four cancer cell lines, shows that substitution at position 7 or 8 of acridine
respectively. Compounds 3a (breast T47D), 3g (lung NCl moiety with electron-donating group makes these mole-
H-522), 4a (liver Hep G2), and 6b (colon HCT-15) cules more active. This may be due to effective interac-
exhibited IC50 values 5.4, 4.2, 4.5, and 2.4 lM, respec- tion of these molecules with the DNA as compared to
tively, and hence possess good anticancer activity. other derivatives.

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Med Chem Res (2015) 24:1942–1951 1945

Table 2 IC50 values of in vitro anticancer activity of active compounds

Compd. no. IC50 (lM)
Breast Lung Colon Ovary Liver Normal cell
T47D NCI-H522 HCT-15 PA-1 HepG2 COS-1

3a 5.4 – 1.28 4.78 ± 3.7 4.9 ± 1.2 8.56 ± 1.18 5 ± 2.11 28 ± 4.2
3d 7.89 ± 3.01 11.3 ± 2.3 10.12 ± 1.2 5.98 ± 1.23 5.7 ± 1.11 76.55 ± 9.57
3g 7.9 ± 1.11 4.2 – 1.3 7 ± 2.1 5.6 – 1.6 5.3 ± 1.4 17.38 ± 2.0
4a 9.2 ± 1.16 8.5 ± 2.87 4.98 ± 1.11 7.2 ± 2.1 4.5 – 1.6 45.84 ± 3.24
4b 8.23 ± 3.10 4.5 ± 2.10 5.76 ± 1.23 7.17 ± 0.83 4.73 ± 1.13 15.24 ± 2.1
4d 8 ± 2.91 9.0 ± 3.1 6.2 ± 1.09 8.7 ± 2.01 5.2 ± 1.32 20.97 ± 2.5
5a 7.9 ± 2.12 8.64 ± 2.8 5.02 ± 1 8.5 ± 3.01 5.2 ± 2.01 7.2 – 1.3
5b 8.14 ± 1.17 5.65 ± 2.0 6.2 ± 2.8 7.11 ± 1.33 4.98 ± 1.05 8.4 ± 1.11
6b 8.04 ± 1.39 4.6 ± 1.06 2.4 – 2.7 7.89 ± 2.8 5.11 ± 1.62 17.18 ± 1.94
5-FU 51.8 ± 2.34 53.76 ± 3.4 43.01 ± 1.45 36.5 ± 3.32 29.87 ± 1.82 110 ± 8.98
CYC-PHO 70.1 ± 2.32 63.9 ± 3.79 72.32 ± 4.68 63.12 ± 5.43 51.3 ± 3.59 125.43 ± 9.24
CYC-HEXI 65.13 ± 7.31 57.1 ± 5.34 51.13 ± 3.65 40.6 ± 2.09 57.12 ± 4.65 128.31 ± 7.89
Bold values represent compounds showing good anticancer activity
50 % growth inhibition as determined by MTT assay (24 h drug exposure). Compounds tested in triplicate, data expressed as mean value ± SD
of three independent experiments
5-FU 5-fluorouracil, CYC-PHO cyclophosphamide, CYC-HEXI cycloheximide

Conclusion Synthesis of 9-amino acridine derivatives 1a–1h

A number of acridine derivatives 3a–3h, 4a–4d, 5a–5d, 9-Amino acridine derivatives 1a–1h were synthesized by
and 6a–6d have been synthesized in high yields using following reaction procedure reported in the literature
environment friendly reaction conditions. In vitro screen- (Albert and Gledhill, 1945; Albert and Ritchie, 1960; Allen
ing for anticancer activity was carried out against five and Mckee, 1959).
human cancer cell lines. Compounds 3a (breast T47D), 3g
(lung NCl H-522), 4a (liver Hep G2), and 6b (colon HCT- Synthesis of 9, 10-dihydroanthracene-9, 10-a, b-
15) exhibited good anticancer activity. succinic anhydride (2)

9, 10-Dihydroanthracene-9, 10-a, b-succinic anhydride (2)

Experimental was synthesized by following reaction procedure reported
in the literature (Vogel, 1968).
Microwave reactor Anton Paar (monowave 300) and
microwave oven model M197DL (Samsung) were used for General procedure for synthesis of acridine derivatives
microwave irradiation. Melting points (mp) were deter- (3a–3h)
mined on a JSGW apparatus and are uncorrected. IR
spectra were recorded using a Perkin Elmer 1600 FT Synthesis of N-(3-methylacridin-9-yl)-9,10-dihydro-9,10-
spectrometer. 1H and 13C NMR spectra were recorded on a ethanoanthracene-11, 12-dicarboximide (3a)
Bruker WH-500 spectrometer at a ca 5–15 % (w/v) solu-
tion in deuterated solvent. APCI mass was recorded using 9-Amino-3-methylacridine (1a; 208 mg; 1 mmol) was
Finnigan Mat LCQ Mass Spectrometer. GC–MS was dissolved in dry THF (&30 ml). 9, 10-dihydroanthracene-
recorded on Perkin Elmer Clarus 500 gas chromatograph, 9, 10-a, b-succinic anhydride (2; 276 mg; 1 mmol) was
where built in MS detector was used. Elemental analysis dissolved in dry THF (&40 ml). Clear solution of both the
was carried out on a Vario EL III elementor. Thin layer reactants was mixed and kept at room temperature for
chromatography (TLC) was performed on silica gel G for about 20 h. Solvent of reaction mixture was removed under
TLC (Merck) and spots were visualized by iodine vapor or reduced pressure and the solid residue left behind was
by irradiation with ultraviolet light (254 nm). washed with chilled THF and the crude product so obtained

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1946 Med Chem Res (2015) 24:1942–1951

was crystallized from methanol to give pure product N-(3-

+
O
methylacridin-9-yl)-9,10-dihydro-9,10-ethanoanthracene-11, 100 %), 274.3 ( N+ , 11 %), 208.1 ( ,
N
12-dicarbiximide 3a. Yield 410 mg (89 %). Yellow solid, O OCH3
mp 236–239 C. IR (KBr) mmax: 1691 (C=O), 1657 (C=N),
3 %). Elemental Anal. Calcd for C32H22N2O3: C 79.66, H
1586 and 1493 (C=C, Ar) cm-1. 1H NMR (500 MHz,
4.56, N 5.80; Found C 79.78, H 4.64, N 5.89 %.
DMSO-d6) d: 2.93 (s, 2H, 2 9 CH), 2.97 (s, 3H, CH3),
4.65 (s, 2H, 2 9 CH), 7.15 (s, 1H, Ar–H), 7.04–8.45 (m,
14H, Ar–H). 13C NMR (125 MHz, DMSO-d6) d: 18.15,
N-(4-ethoxyacridin-9-yl)-9,10-dihydro-9,10-
46.64, 48.79, 112.38, 112.49, 121.82, 122.28, 122.69,
ethanoanthracene-11,12-dicarboximide (3d)
123.84, 123.80, 124.89, 125.20, 125.64, 132.25, 135.04,
141.46, 143.65, 148.49, 154.99 173.44. APCI-MS: m/z
Solvent of crystallization methanol. Yield 92 %. Yellow
O solid, mp 185–186 C. IR (KBr) tmax: 1671 (C=O), 1633
467.6 (M??H, 100 %), 274.3 ( N+ , 11 %), Ele- (C=N), 1588 & 1517 (C=C, Ar) cm-1. 1H NMR (500 MHz,
O
DMSO-d6) d: 1.48–1.51 (t, 3H, J = 7 Hz, CH3), 2.92 (s,
mental Anal. Calcd. for C32H22N2O2 C 82.40, H 4.72, N 2H, 2 9 CH), 4.26–4.30 (q, 2H, J = 7 & 14 Hz, OCH2),
6.00; Found C 82.43, H 4.75, N 6.00 %. 4.66 (s, 2H, 2 9 CH), 7.03–8.50 (m, 15H, Ar–H). 13C
Similarly, other acridine derivatives 3b–3h were syn- NMR (125 MHz, DMSO-d6) d: 14.18, 48.12, 48.72, 64.60,
thesized. Physical constants and spectral data of 3b–3h are 111.84, 112.30, 112.39, 114.61, 122.63, 123.23, 123.41,
summarized below. 123.74, 124.78, 125.40, 125.71, 132.21, 135.31, 141.21,
143.42, 154.71, 174.39, APCI-MS m/z 497.0 (M??H,

+
O
N-(2-methylacridin-9-yl)-9,10-dihydro-9,10- 100 %), 274.1 ( N+ , 11 %), 222.1 ( ,
ethanoanthracene-11,12-dicarboximide (3b) N
O OC2H5

4 %). Elemental Anal. Calcd for C33H24N2O3: C 79.83, H

Solvent of crystallization methanol. Yield 89 %. Yellow
4.83, N 5.64; Found C 79.91, H 4.93, N 5.70 %.
solid, mp [ 300 C. IR (KBr) tmax: 1716, 1676 (C=O),
1645 (C=N), 1582 & 1489 (C=C, Ar) cm-1. 1H NMR
(500 MHz, DMSO-d6) d: 2.82 (s, 2H, 2 9 CH), 3.18 (s,
N-(4-methylacridin-9-yl)-9,10-dihydro-9,10-
3H, CH3), 4.64 (s, 2H, 2 9 CH), 7.03–8.49 (m, 14H, Ar–
ethanoanthracene-11,12-dicarboximide (3e)
H), 8.30 (s, 1H, Ar–H). 13C NMR (125 MHz, DMSO-d6) d:
21.15, 47.64, 48.29, 112.02, 112.09, 121.82, 122.28,
Solvent of crystallization methanol. Yield 92 %. Yellow
122.66, 123.26, 123.80, 124.84, 125.20, 125.62, 132.49,
solid, mp 225–227 C. IR (KBr) tmax: 1676 (C=O), 1633
135.04, 141.44, 143.65, 148.25, 155.32, 173.44, APCI-MS
(C=N), 1573, 1514 & 1467 (C=C, Ar) cm-1.1H NMR
O (500 MHz, DMSO-d6) d: 2.70 (s, 3H, CH3), 2.96 (s, 2H,
m/z 467.4 (M??H, 100 %), 274.8 ( N+ , 11 %). 2 9 CH), 4.60 (s, 2H, 2 9 CH), 7.02–8.43 (m, 15H, Ar–
O
H). 13C NMR (125 MHz, DMSO-d6) d: 18.55, 46.97,
Elemental Anal. Calcd for C32H22N2O2: C 82.40, H 4.72, N 47.69, 112.31, 112.49, 121.44, 121.84, 122.32, 123.35,
6.00; Found C 82.53, H 4.82, N 6.09 %. 123.42, 124.90, 125.24, 125.70, 131.23, 135.03, 141.25,
143.49, 148.84, 155.23, 172.96, APCI-MS m/z 467.2
O
N-(4-methoxyacridin-9-yl)-9,10-dihydro-9,10-
ethanoanthracene-11,12-dicarboximide (3c) (M??H, 100 %), 274.5 ( N+ , 11 %). Elemental
O

Solvent of crystallization methanol. Yield 91 %. Yellow Anal. Calcd for C32H22N2O2: C 82.40, H 4.72, N 6.00;
solid, mp 206–207 C. IR (KBr) tmax: 1676 (C=O), 1635 Found C 82.52, H 4.79, N 6.10 %.
(C=N), 1588 & 1516 (C=C, Ar) cm-1. 1H NMR (500 MHz,
DMSO-d6) d: 2.93 (s, 2H, 2 9 CH), 4.04 (s, 3H, OCH3),
4.66 (s, 2H, 2 9 CH), 7.03–8.52 (m, 15H, Ar–H). 13C N-(3-methoxyacridin-9-yl)-9,10-dihydro-9,10-
NMR (125 MHz, DMSO-d6) d: 48.20, 48.85, 56.14, ethanoanthracene-11,12-dicarboximide (3f)
111.59, 111.74, 112.17, 114.72, 123.21, 123.35, 123.69,
123.77, 124.77, 125.39, 125.70, 132.78, 134.98, 141.22, Solvent of crystallization methanol. Yield 90 %. Yellow
143.42, 154.59, 174.63, APCI-MS m/z 483.4 (M??H, solid, mp 230–231 C. IR (KBr) tmax: 1669 (C=O), 1639

123
Med Chem Res (2015) 24:1942–1951 1947

(C=N), 1583, 1552, 1497 (C=C, Ar) cm-1. 1H NMR C31H20N2O2: C 82.30, H 4.42, N 6.19; Found C 82.42, H
(500 MHz, DMSO-d6) d: 2.93 (s, 2H, 2 9 CH), 4.26 (s, 4.54, N 6.27 %.
3H, OCH3), 4.65 (s, 2H, 2 9 CH), 7.15 (s, 1H, Ar–H),
7.03–8.44 (m, 14H, Ar–H). 13C NMR (125 MHz, DMSO- General procedure for synthesis of acridine derivatives
d6) d: 48.21, 48.85, 56.17, 111.70, 111.74, 112.21, 114.72, (4a–4d, 5a–5d & 6a–6d)
123.21, 123.39, 123.69, 123.77, 124.79, 125.38, 125.74,
132.76, 134.96, 141.23, 143.44, 154.69, 174.69, APCI-MS Synthesis of 2-(3-methylacridin-9-yl) isoindoline-1,3-dione
O
(4a)
m/z 483.0 (M??H, 100 %), 274.1 ( N+ , 11 %),
O 9-Amino-3-methylacridine (1a; 208 mg; 1 mmol) and
phthalic anhydride (148 mg; 1 mmol) were mixed together
O

208.3 ( ,3 %). Elemental Anal. Calcd for and then subjected to microwave irradiation at 120 C for
N+

O 5 min. TLC of reaction mixture over silica gel G using

C32H22N2O3: C 79.66, H 4.56, N 5.80; Found C 79.72, H CHCl3:MeOH (8.5:1.5) as mobile phase showed the pre-
4.64, N 5.90 %. sence of starting materials. This reaction mixture was
further irradiated for 5 min at 120 C. TLC of reaction
N-(2-methoxyacridin-9-yl)-9,10-dihydro-9,10- mixture showed completion of reaction. This crude product
ethanoanthracene-11,12-dicarboximide (3g) was crystallized from methanol to give pure product 4a.
Yield 310 mg (&93 %). Yellow solid, mp 195–197 C. IR
Solvent of crystallization methanol. Yield 94 %. Yellow (KBr) mmax: 1653 (C=O), 1588, 1549 & 1481 (C=C, Ar)
solid, mp 183–185 C. IR (KBr) tmax: 1667 (C=O), 1639 cm-1. 1H NMR (500 MHz, DMSO-d6) d: 2.99 (s, 3H,
(C=N), 1583, 1552, 1497 (C=C, Ar) cm-1. 1H NMR CH3), 7.33–8.59 (m, 11H, Ar–H). 13C NMR (125 MHz,
(500 MHz, DMSO-d6) d: 2.95 (s, 2H, 2 9 CH), 3.94 (s, DMSO-d6) d: 23.66, 111.95, 113.26, 117.14, 118.68,
3H, OCH3), 4.63 (s, 2H, 2 9 CH), 7.03–8.45 (m, 15H, Ar– 124.20, 124.89, 127.30, 128.60, 130.97, 132.89, 135.18,
H). 13C NMR (125 MHz, DMSO-d6) d: 48.21, 48.83, 135.74, 137.89, 138.98, 141.63, 159.73, 168.83, APCI-MS:

+
56.16, 111.59, 111.74, 112.17, 114.72, 123.26, 123.35,
m/z 339.1 (M??H, 100 %), 192.2 ( ,
123.69, 123.76, 124.77, 125.39, 125.70, 133.86, 134.98, N CH3
141.21, 143.43, 154.43, 174.65, APCI-MS m/z 483.7 11 %). Elemental Anal. Calcd. for C22H14N2O2: C 78.10,
O H 4.14, N 8.28; Found C 78.19, H 4.21, N 8.38 %.
(M??H, 100 %), 274.2 ( N+ , 11 %), 208.1 Alternatively, above reaction mixture was subjected to
O microwave irradiation at a power level of level of 600 Watt
+ for 5 min. TLC of reaction mixture over silica gel G using
OCH3
( , 3 %). CHCl3:MeOH (8.5:1.5) as mobile phase showed the pre-
N sence of starting materials. This reaction mixture was
Elemental Anal. Calcd for C32H22N2O3: C 79.66, H further irradiated for 5 min. TLC of reaction mixture
4.56, N 5.80; Found C 79.76, H 4.64, N 5.88 %. showed completion of reaction. This crude product was
crystallized from methanol to give pure product 4a. Yield
N-(acridin-9-yl)-9,10-dihydro-9,10-ethanoanthracene- 306 mg (&90 %).
11,12-dicarboximide (3h) Similarly, other acridine derivatives 4b–4d, 5a–5d, and
6a–6d were synthesized. Physical constants and spectral
Solvent of crystallization methanol. Yield 91 %. Yellow data of 4b–4d, 5a–5d, and 6a–6d are summarized below.
solid, mp [ 300 C. IR (KBr) tmax: 1682 (C=O), 1648
(C=N), 1581 & 1487 (C=C, Ar) cm-1. 1H NMR (500 MHz, 2-(2-Methylacridin-9-yl)isoindoline-1,3-dione (4b)
DMSO-d6 ? D2O) d: 2.92 (s, 2H, 2 9 CH), 4.61 (s, 2H,
2 9 CH), 7.03–8.48 (m, 16H, Ar–H). 13C NMR Microwave irradiation at 120 C for 5 9 2 min (at power
(125 MHz, DMSO-d6) d: 47.79, 48.44, 111.89, 123.04, level of 600 Watt for 5 9 2 min). Solvent of crystallization
123.27, 123.77, 124.82, 125.34, 125.72, 133.00, 141.24, methanol. Yield 87 %. Greenish yellow solid, mp
143.45, 174.00, APCI-MS m/z 453.7 (M??H, 100 %), 163–165 C. IR (KBr) tmax: 1687 (C=O), 1586, 1551, 1490
(C=C, Ar) cm-1. 1H NMR (500 MHz, DMSO-d6) d: 2.98
+

274.1 ( , 11 %). Elemental Anal. Calcd for (s, 3H, CH3), 7.33–8.54 (m, 11H, Ar–H). 13C NMR
N OCH3 (125 MHz, DMSO-d6) d: 21.48, 111.96, 112.02, 119.47,

123
1948 Med Chem Res (2015) 24:1942–1951

122.59, 123.48, 124.24, 124.98, 130.76, 132.89, 134.06, 2-(3-Methylacridin-9-yl)-3a,4,7,7a-tetrahydro-2H-

135.43, 135.76, 137.98, 138.37, 139.76, 157.51, 168.53, isoindole-1, 3-dione (5a)
.
GC–MS: m/z 338 (M?, 100 %), 192 ( + ,
Microwave irradiation at 120 C for 5 9 2 min (at power
level of 600 Watt for 5 9 2 min). Solvent of crystallization
+
N CH3 methanol. Yield 88 %. Yellow solid, mp 200–202 C. IR
5 %), 76 ( , 25 %). Elemental Anal. Calcd for
(KBr) tmax: 1670 (C=O), 1631(C=N), 1587, 1549 & 1512
C22H14N2O2 C 78.10, H 4.14, N 8.28; Found C 78.25, H (C=C, Ar) cm-1. 1H NMR (500 MHz, DMSO-d6) d:
4.21, N 8.34 %. 2.08–2.12 (dd, 2H, J = 4.5, 16 Hz, CH2), 2.31–2.36 (dd,
2H, J = 6, 15.5 Hz, CH2), 2.70–2.73 (t, 2H, J = 5.5 Hz,
2-(4-Methoxyacridin-9-yl)isoindoline-1, 3-dione (4c) 2 9 CH), 2.98 (s, 3H, CH3), 5.57 (s, 2H, CH=CH),
7.24–8.55 (m, 7H, Ar–H). 13C NMR (125 MHz, DMSO-
Microwave irradiation at 120 C for 7 9 2 min (at power d6) d: 21.89, 28.18, 41.76, 112.69, 113.09, 115.68, 123.60,
level of 600 Watt for 7 9 2 min). Solvent of crystallization 124.08, 125.59, 126.65, 127.46, 128.30, 129.66, 134.25,
methanol. Yield 90 %. Yellow solid, mp 258–260 C. IR 138.29, 139.16, 155.54, 175.14, GC–MS: m/z 342 (M?;

+
(KBr) tmax: 1663 (C=O), 1591, 1552, 1510 (C=C, Ar)
100 %), 192 ( , 13 %). Elemental Anal.
cm-1. 1H NMR (500 MHz, DMSO-d6) d: 4.00 (s, 3H, N CH3
OCH3), 7.33–8.42 (m, 11H, Ar–H). 13C NMR (125 MHz, Calcd for C22H18N2O2 C 77.19, H 5.26, N 8.18; Found C
DMSO-d6) d: 56.88, 111.84, 112.29, 113.44, 116.46, 77.30, H 5.32, N 8.25 %.
119.81, 124.18, 124.42, 124.58, 131.11, 131.17, 132.94,
134.91, 135.57, 139.25, 148.43, 157.72, 169.15, GC–MS: 2-(2-Methylacridin-9-yl)-3a,4,7,7a-tetrahydro-2H-
m/z 355 (M?•?1, 3 %), 354 (M?•, 24 %), 353 (M?•–H, isoindole-1, 3-dione (5b)
.
+
O Microwave irradiation at 120 C for 6 9 2 min (at power
100 %), 324 ( , 16 %). Elemental Anal. Calcd
N N level of 600 Watt for 6 9 2 min). Solvent of crystallization
O methanol. Yield 89 %. Yellow solid, mp 211–213 C. IR
for C22H14N2O3 C 74.57, H 3.95, N 7.90; Found C 74.63, (KBr) tmax: 1669 (C=O), 1631(C=N), 1587, 1549 & 1512
H 4.08, N 8.04 %. (C=C, Ar) cm-1. 1H NMR (500 MHz, DMSO-d6) d:
2.08–2.12 (dd, 2H, J = 4.5, 16 Hz, CH2), 2.31–2.36 (dd,
2-(4-Ethoxyacridin-9-yl)isoindoline-1,3-dione (4d) 2H, J = 6.5, 15.5 Hz, CH2), 2.70–2.73 (t, 2H, J = 7 Hz,
2 9 CH), 2.98 (s, 3H, CH3), 5.57 (s, 2H, CH=CH),
Microwave irradiation at 120 C for 6 9 2 min (at power 7.24–8.57 (m, 7H, Ar–H). 13C NMR (125 MHz, DMSO-
level of 600 Watt for 6 9 2 min). Solvent of crystallization d6) d: 21.90, 28.26, 41.83, 112.74, 113.10, 115.66, 123.62,
methanol. Yield 92 %. Yellow solid, mp 239–241 C. IR 124.10, 125.60, 126.61, 127.54, 128.36, 129.72, 134.30,
(KBr) tmax: 1669 (C=O), 1631 (C=N), 1587, 1549 & 1512 138.34, 139.22, 154.94, 175.17, APCI-MS m/z 343.1
(C=C, Ar) cm-1. 1H NMR (500 MHz, DMSO-d6) d:
+

CH3
1.50–1.53 (t, 3H, J = 7 Hz, CH3), 4.38–4.43 (q, 2H, (M??H, 100 %), 192.2 ( , 10 %). Elemen-
N
J = 7, 14 Hz, OCH2), 7.48–8.62 (m, 11H, Ar–H). 13C
tal Anal. Calcd for C22H18N2O2:C 77.19, H 5.26, N 8.18;
NMR (125 MHz, DMSO-d6) d:14.75, 65.48, 112.23,
Found C 77.26, H 5.29, N 8.33 %.
112.83, 114.47, 115.60, 120.35, 124.31, 124.62, 124.77,
130.80, 131.80, 132.93, 135.40, 135.66, 139.75, 147.85,
2-(4-Methoxyacridin-9-yl)-3a,4,7,7a-tetrahydro-2H-
158.08, 168.59, GC–MS: m/z 368 (M?, 5 %), 323 (M?–
isoindole-1, 3-dione (5c)
O
.
OC2H5, 3 %), 222 ( + , 20 %), 146 ( N+ , Microwave irradiation at 120 C for 6 9 2 min (at power
O level of 600 Watt for 6 9 2 min). Solvent of crystallization
methanol. Yield 89 %. Yellow solid, mp 280 C. IR (KBr)
+

30 %), 76 ( , 46 %). Elemental Anal. Calcd for tmax: 1697 (C=O), 1623, 1573 & 1528 (C=C, Ar) cm-1. 1H
N
OC2H5 NMR (500 MHz, DMSO-d6) d: 2.22–2.27 (dd, 2H, J = 5,
C23H16N2O3 C 75.00, H 4.34, N 7.60; Found C 75.12, H 16 Hz, CH2), 2.38–2.43 (dd, 2H, J = 5, 16 Hz, CH2),
4.41, N 7.73 %. 2.86–2.88 (t, 2H, J = 5.5 Hz, 2 9 CH), 4.05 (s, 3H,

123
Med Chem Res (2015) 24:1942–1951 1949

OCH3), 5.62 (s, 2H, CH=CH), 7.18–8.23 (m, 7H, Ar–H). 1-(2-Methylacridin-9-yl)-1H-pyrrole-2,5-dione (6b)
13
C NMR (125 MHz, DMSO-d6) d: 28.16, 41.74, 56.79,
112.65, 113.07, 115.65, 123.59, 124.05, 125.49, 126.63, Microwave irradiation at 120 C for 5 9 2 min (at power
127.45, 128.32, 129.63, 134.20, 138.26, 139.17, 155.44, level of 600 Watt for 5 9 2 min). Solvent of crystallization
175.17, APCI-MS: m/z 359.1 (M??H, 100 %), 208.1 methanol. Yield 90 %. Greenish yellow solid, mp
250–252 C. IR (KBr) tmax: 1642 (C=O), 1584, 1492
+

( , 5 %). Elemental Anal. Calcd for (C=C, Ar) cm-1. 1H NMR (500 MHz, DMSO-d6 ? D2O)
N
OCH3 d: 2.48 (s, 3H, CH3), 6.10 (s, 2H, CH=CH), 7.53–8.51 (m,
C22H18N2O3: C 73.74, H 5.02, N 7.82; Found C 73.83, H 7H, Ar–H). 13C NMR (125 MHz, DMSO-d6) d: 21.46,
5.09, N 7.91 %. 111.90, 111.96, 119.18, 119.28, 124.29, 126.99, 127.14,
134.14, 135.70, 135.90, 137.69, 138.09, 139.50, 157.69,
167.67, APCI-MS: m/z 289.1 (M??H, 100 %), 192.1

+
2-(4-Ethoxyacridin-9-yl)-3a,4,7,7a-tetrahydro-2H- CH3
( , 3 %). Elemental Anal. Calcd for
isoindole-1, 3-dione (5d) N
C18H12N2O2: C 75.00, H 4.16, N 9.72; Found C 75.09, H
Microwave irradiation at 120 C for 6 9 2 min (at power 4.23, N 9.79 %.
level of 600 Watt for 6 9 2 min). Solvent of crystallization
methanol. Yield 91 %. Yellow solid, mp 198–200 C. IR 1-(4-Methoxyacridin-9-yl)-1H-pyrrole-2,5-dione (6c)
(KBr) tmax: 1639 (C=O), 1572 & 1511 (C=C, Ar) cm-1. 1H
NMR (500 MHz, DMSO-d6) d: 1.47–1.49 (t, 3H, Microwave irradiation at 120 C for 7 9 2 min (at power
J = 7 Hz, CH3), 2.06–2.09 (dd, 2H, J = 5 & 10.5 Hz, level of 600 Watt for 7 9 2 min). Solvent of crystallization
CH2), 2.31–2.35 (dd, 2H, J = 5.5 & 14 Hz, –CH2), 2.69 (s, methanol. Yield 90 %. Yellow solid, mp 279 C. IR (KBr)
2H, 2 9 CH), 4.32–4.35 (q, 2H, J = 6.5, 13.5 Hz, OCH2), tmax: 1717 (C=O), 1623, 1576, 1528, 1470 (C=C, Ar)
5.66 (s, 2H, CH=CH), 7.40–8.56 (m, 7H, Ar–H). 13C NMR cm-1. 1H NMR (500 MHz, DMSO-d6) d: 4.05 (s, 3H,
(125 MHz, DMSO-d6) d: 14.85, 28.06, 41.76, 56.78, OCH3), 6.12 (s, 2H, CH=CH), 7.18–8.23 (m, 7H, Ar–H).
112.62, 113.08, 115.65, 123.57, 124.03, 125.49, 126.62, 13
C NMR (125 MHz, DMSO-d6) d: 56.69, 112.80, 118.78,
127.42, 128.32, 129.62, 134.17, 138.28, 139.19, 155.42, 121.00, 121.04, 121.57, 121.74, 126.20, 129.07, 131.99,
175.12, APCI-MS: m/z 373.1 (M??H, 100 %), 222.3 132.32, 133.58, 141.14, 148.29, 155.23, 166.22, APCI-MS:
+

+
( , 7 %). Elemental Anal. Calcd for m/z 305.0 (M??H, 100 %), 208.1 ( , 7 %).
N
OC2H5 N
OCH3
C23H20N2O3: C 74.19, H 5.37, N 7.52; Found C 74.27, H
Elemental Anal. Calcd for C18H12N2O3: C 71.05, H 3.94, N
5.43, N 7.59 %.
9.21; Found C 71.11, H 4.05, N 9.29 %.

1-(4-Ethoxyacridin-9-yl)-1H-pyrrole-2,5-dione (6d)
1-(3-Methylacridin-9-yl)-1H-pyrrole-2,5-dione (6a)
Microwave irradiation at 120 C for 6 9 2 min (at power
Microwave irradiation at 120 C for 6 9 2 min (at power
level of 600 Watt for 6 9 2 min). Solvent of crystallization
level of 600 Watt for 6 9 2 min). Solvent of crystallization
methanol. Yield 90 %. Yellow solid, mp 222–224 C. IR
methanol. Yield 91 %. Yellow solid, mp 196–198 C. IR
(KBr) tmax: 1664 (C=O), 1630 (C=N), 1577, 1510 (C=C,
(KBr) tmax: 1644 (C=O), 1580, 1486 (C=C, Ar) cm-1. 1H
Ar) cm-1. 1H NMR (500 MHz, DMSO-d6) d: 1.49–1.52 (t,
NMR (500 MHz, DMSO-d6) d: 3.00 (s, 3H, CH3), 6.06 (s,
3H, J = 7 Hz, CH3), 4.37–4.41 (q, 2H, J = 7, 14 Hz,
2H, CH=CH), 7.33–8.52 (m, 7H, Ar–H). 13C NMR
OCH2), 6.03 (s, 2H, CH=CH), 7.48–8.59 (m, 7H, Ar–H).
(125 MHz, DMSO-d6) d: 23.65, 111.78, 113.10, 116.94, 13
C NMR (125 MHz, DMSO-d6) d: 14.59, 65.36, 111.81,
118.47, 124.23, 124.82, 127.34, 134.45, 135.23, 135.80,
112.35, 113.96, 115.06, 120.20, 122.60, 124.36, 124.66,
137.84, 138.75, 141.40, 159.71, 167.78, APCI-MS: m/z
131.63, 135.51, 136.40, 139.53, 147.85, 157.38, 168.33,
+

289.0 (M??H, 100 %), 192.1 ( , 11 %). GC–MS: m/z 318 (M?, 5 %), 273 (M?–OC2H5; 10 %), 222
N CH3 O
+

Elemental Anal. Calcd for C18H12N2O2: C 75.00, H 4.16, N ( , 20 %), 96 ( N+ , 20 %). Elemental Anal.
9.72; Found C 75.12, H 4.23, N 9.81 %. N
OC2H5
O

123
1950 Med Chem Res (2015) 24:1942–1951

Calcd for C19H14N2O3: C 71.69, H 4.40, N 8.80; Found C facility. Ms. Surbhi Arya (SRF) to CSIR New Delhi and Mr. Anuj
71.76, H 4.53, N 8.95 %. Kumar to MHRD, New Delhi are thankful for financial assistance.

Pharmacology
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