Synthesis of monomeric and dimeric acridine compounds as potential therapeutics in Alzheimer and prion diseases

Article abstract of DOI:10.1002/ardp.200900065

Starting from substituted 9-chloroacridines, a series of quinacrine and spacered dimeric acridine compounds was prepared. Their ability to interrupt the protein association of prion- and Alzheimer-specific proteins and Ab peptides was explored using a fast screening system based on FACS analysis. The bis-acridines displayed a higher activity than the corresponding monomers. Among these derivatives, best results were obtained with the 2,4-dimethoxy-6-nitro compound 7h for Aβ-peptides and the 2-methoxy-6-nitro compound 7f for PrP.

Full text of DOI:10.1002/ardp.200900065

Arch. Pharm. Chem. Life Sci. 2009, 342, 699–709
R. Csuk et al.
699
Full Paper
Synthesis of Monomeric and Dimeric Acridine Compounds as
Potential Therapeutics in Alzheimer and Prion Diseases
Renꢀ Csuk1, Alexander Barthel1, Christian Raschke1, Ralph Kluge1, Dieter Strꢁhl1,
Lothar Trieschmann2, and Gerald Bꢁhm3
1 Martin-Luther-Universitꢀt Halle-Wittenberg, Organische Chemie, Halle (Saale), Germany
2 Scil Proteins Production GmbH, Halle (Saale), Germany
3 IGZ BioMed/ZmK Wꢁrzburg, Wꢁrzburg, Germany
Starting from substituted 9-chloroacridines, a series of quinacrine and spacered dimeric acridine
compounds was prepared. Their ability to interrupt the protein association of prion- and Alz-
heimer-specific proteins and Ab peptides was explored using a fast screening system based on
FACS analysis. The bis-acridines displayed a higher activity than the corresponding monomers.
Among these derivatives, best results were obtained with the 2,4-dimethoxy-6-nitro compound
7h for Ab-peptides and the 2-methoxy-6-nitro compound 7f for PrP.
Keywords: Acridines / Anti-Alzheimer / Antiprion / FACS analysis / Quinacrine /
Received: March 26, 2009; Accepted: August 12, 2009
DOI 10.1002/ardp.200900065
Different approaches to inhibit the deposition of amy-
loid proteins are in the focus of scientific research. As for
AD, by inhibition of b- and c-secretases the production of
Ab [1] is significantly lowered. However, these proteases
also act on other substrates e.g., NOTCH1 in the case of c-
secretase [2]. Thus, other detrimental effects are also pos-
sible by inhibiting them. In addition, the deposition of
proteins can be prevented by interrupting the associa-
tion process of the monomers to form oligomers and
fibrils by the addition of b-sheet breakers [3]. Following
this theory, quinacrine (Fig. 1, A) and related compounds
were investigated and shown to give in vitro promising
results against prion diseases [4–7].
Furthermore, Zahn et al. identified the binding side of
quinacrine at the C-terminal helix of PrP [8]. Conse-
quently, dimeric acridine compounds (Fig. 1, B) were syn-
thesized and they exhibited a ten-fold higher activity
than the respective monomeric quinacrines [9]. The best
results were obtained using 1,8-diamino-3,6-dioxaoctane
and 1,4-bis-(3-aminopropyl)piperazine spacers between
the acridine units. Additional QSAR studies suggest the
importance of these spacers and the acridine moiety. So
far, however, only few data are available to establish pos-
sible effects for the substituents of the acridine hetero-
cycle.
Introduction
Alzheimer9s disease (AD) and prion diseases like the
Creutzfeld-Jakob-Disease (CJD) or Kuru in humans and
bovine spongiform encephalopathy (BSE) in cattle are
most prominent examples of neurodegenerative disor-
ders. They are mainly characterized by depositions in the
central nervous system. The peptides and proteins are
deposited as fibrils with enriched b-sheets and have a
high tendency to associate and aggregate. In AD, the
fibrils contain Ab peptides, which are peptides of 39-43
amino acids. These Ab peptides are released from the
amyloid precursor protein (APP) by the action of b- and c-
secretase. The prion protein PrPc consists of 209 amino
acids and is expressed mainly in neurons and follicular
dendritic cells. It can be metabolized by proteinase K but
undergoes a conformational transformation during the
process of establishing a prion disease into the Scrapie
form PrPsc, which is resistant against cleavage by pro-
teases.
Correspondence: Prof. Dr. Renꢂ Csuk, Bereich Organische Chemie,
Martin-Luther-Universitꢀt Halle-Wittenberg, Kurt-Mothes-Strasse 2, D-
06120 Halle (Saale), Germany.
E-mail: rene.csuk@chemie.uni-halle.de
Fax: +49 345 552-7030
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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R. Csuk et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 699–709
Figure 1. Structures of quinacrine A and dimeric acridine B.
Scheme 1. Synthetic routes to N-phenylanthranilic acids.
In this study, we synthesized several quinacrine and
spacered bis-compounds with various different substi-
tuted acridines. An in-vitro assay based on FACS analysis
was used for examining the ability of the substances to
inhibit the association process of amyloid proteins and
peptides. Using this method, we extended the screening
of acridine derivatives to Alzheimer9s disease-specific Ab-
peptides.
Scheme 2. Ring-closure procedure.
Results and discussion
Scheme 3. Synthesis of quinacrine compounds.
For the synthesis of substituted 9-chloroacridines, a syn-
thetic route starting with the synthesis of the corre-
sponding anthranilic acids by applying either Ullmann–
Jourdan reaction or by using a modified Buchwald–Hart-
wig amination was established (Scheme 1) [10].
phenoxyacridine. The quinacrine compounds 4a–4i
(Table 2) were obtained by conversion of the 9-chloroacri-
dines with an excess of 2-amino-5-diethylaminopentane
(Scheme 3).
Starting materials for the copper-catalyzed Ullmann–
Jourdan reaction [11] were substituted 2-chlorobenzoic
acids and the corresponding aniline derivatives. The use
of 3% copper bronze and 15% pyridine in amyl alcohol
were the most suitable conditions and yielded the
anthranilic acids in moderate yields. However, the scope
of the reaction is limited to electron-rich anilines and
electron-deficient benzoic acids, otherwise yields
decreased or no reaction took place at all (e.g., for fluori-
nated aniline derivatives). A more reliable and robust syn-
thesis of anthranilic acids was found by using a palla-
dium-catalyzed Buchwald–Hartwig amination starting
from methyl 2-iodobenzoates and anilines using Pd(ac)2,
DPEPhos and Cs2CO3 as the base. The products were iso-
lated in high yields and subsequent hydrolysis gave the
corresponding acids. These anthranilic acids could be
transformed into the corresponding 9-chloroacridines
easily on reaction with POCl3 (Scheme 2). According to
this procedure, the synthesis of two novel compounds
was performed (Table 1).
The synthesis of the dimeric acridine compounds was
achieved in a quite similar way (Scheme 4). These reac-
tion afforded the bis-acridine derivatives 5a–5e from 1,8-
diaminooctane, whereas compounds 6a–6i were
obtained using 1,8-diamino-3,6-dioxaoctane, and com-
pounds 7a--7r could be accessed from 1,4-bis-(3-aminopro-
pyl)piperazine (Table 3).
Several of these compounds, especially those carrying
a piperazine spacer, displayed only poor solubility in
most organic solvents. Thus, purification of these sub-
stances was tedious resulting in lowered yields. The NMR
spectra of the compounds had to be recorded in DMSO-d6
at higher temperatures applying prolonged recording
time. Nevertheless, for several carbons in the 13C-NMR
spectra significant line broadening was observed. An
unambiguous proof-of-structure was obtained by a sin-
gle-crystal X-ray analysis. An ORTEP plot for compound
7o is depicted in Fig. 2.
The quinacrine and bis-acridines were investigated for
their ability to inhibit the addition of monomeric Ab-pep-
tide or prion proteins to fibrils. The screening of the sub-
stances was performed by an in-vitro assay using FACS
analysis [12, 13]. In order to compare the results from the
FACS analysis with data from the well-established ScN2a
Starting from the 9-chloroacridines, the synthesis of
several quinacrine and spacered bis-acridines was per-
formed according to established procedures [9]. The reac-
tions were carried out in phenol, which acts as catalyst
for the accumulation of the product by formation of 9-
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Arch. Pharm. Chem. Life Sci. 2009, 342, 699–709
Monomeric and Dimeric Acridine Compounds
701
Table 1. Inhibition of Ab-peptide and prion-proteins at 0.1, 1.0,
and 4.0 lM.
Com-
% of control Ab proteins
% of control PrPsc
pound
(lM)
(lM)
0.1
1.0
4.0
0.1
1.0
4.0
Quinacrine
4a
4b
4c
4d
4e
4f
4g
4h
4i
92
77
97
98
85
90
41
92
34
22
54
95
91
67
73
16
52
24
11
98
82
98
99
88
96
81
>100
95
76
76
98
>100
89
94
52
>100
58
>100
>100
98
99
87
96
95
63
>100
>100
88
Scheme 4. Synthesis of bis-acridines
95
>100
>100
92
>100
68
1,8-Diaminooctane
5a
5b
5c
5d
5e
87
64
>100
97
93
54
6
61
87
71
34
4
32
74
72
62
>100
66
97
60
52
41
58
89
43
23
50
87
86
>100
1,8-Diamino-3,6-dioxooctane
6a
6b
6c
6d
6e
6f
85
88
87
82
90
80
87
56
80
50
74
81
50
12
14
56
8
38
64
12
3
70
96
64
>100
>100
>100
74
48
84
43
98
96
73
88
35
76
36
92
94
89
68
Figure 2. ORTEP diagram of compound 7o.
the used spacer. For the 2-methoxy-6-chloro derivatives
the 1,8-diamino-3,6-dioxaoctane spacer exhibited
6g
a
higher activity than the 1,8-diaminooctane analogue. An
even higher inhibitory effect was observed for the 1,4-bis-
(3-aminopropyl)piperazine compound 7a. In order to
evaluate relationships between the substituents and the
activity, a broad variety of derivatives was prepared and
screened. In summary, the attachment of a methoxy
group proved to be beneficial, whereas the Cl substituent
seems to be redundant. Also, the addition of fluor sub-
stituents is unfavorable. However, an improved inhibi-
tory effect was observed when a nitro group was intro-
duced into the molecule additionally to the methoxy sub-
stituents. Therefore, the best compounds in this study
were the 2,4-dimethoxy-6-nitro compound 7h for AD-spe-
cific Ab-peptides and the 2-methoxy-6-nitro compound 7f
for PrP. The low cytotoxicity of these compounds associ-
ated with the inhibitory effect makes them interesting as
starting point to develop new lead compounds, since the
1,4-Bis-(3-aminopropyl)
7a
7b
7c
7d
7e
7f
7g
7h
7i
48
>100
85
80
>100
58
52
80
20
2
93
7
51
53
10
24
6
6
86
92
72
61
96
50
87
51
59
93
79
96
46
68
25
56
79
16
63
32
29
62
72
54
81
>100
81
85
77
88
28
37
14
49
77
5
60
21
26
35
57
49
47
81
46
36
43
58
58
0,3
4
12
5
11
0,6
4
19
12
10
38
4
9
7j
7k
7l
7m
7n
7o
7p
7q
7r
83
87
77
81
69
61
73
68
50
74
12
48
65
7
26
8
51
65
>100
>100
93
90
83
6
3
3
8
98
cell-based assay, the 6-chloro-2-methoxy derivatives 4a– potential of 9-aminoacridines related to quinacrine has
7a were used as standards. Analysis of the data revealed a been demonstrated quite recently [14] and the safety and
dose-dependent inhibition of the association process for efficacy of quinacrine in human prion disease has been
prion proteins as well as for the Alzheimer-specific Ab- investigated [15] in some detail. As far as their mode-of-
peptides. In general, the monomeric quinacrine deriv- action is concerned, one might reason that the identifica-
atives were less active than the spacered bis-acridines. tion of chemical chaperones binding to the PrP structure
The best results for AD-specific Ab-peptides were observed and stabilizing it is one efficient strategy for antiprion
with the 2-nitro-5-thiomethyl derivative 4i. For the drug discovery. However, some compounds have been
dimeric compounds, activity was shown to depend on shown to possess antiprion activities with low affinities
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702
R. Csuk et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 699–709
C(3)), 7.97 (d, 1H, J = 9.1 Hz, H-C(8)), 7.98 (d, 1H, J = 9.5 Hz, H-C(4)),
8.06 (d, 1H, J = 2.1 Hz, H-C(5)) ppm; 13C-NMR (100 MHz, CDCl3)
d: 11.6, 22.3, 24.2, 37.0, 46.9, 52.8, 55.5, 55.9, 99.3, 117.2, 119.2,
123.7, 124.4, 124.8, 128.3, 131.5, 134.5, 146.8, 148.1, 149.0,
156.0 ppm; UV-VIS (methanol) kmax (log e): 287 nm (4.72); MS (ESI,
MeOH) m/z: 400.3 [M + H]+ (100%).
to PrP [16] indicating a mechanism involving additional
modulation factors.
Experimental
N4-9-Acridinyl-N1,N1-diethyl-1,4-pentanediamine 4b [17]
Compound 4b (1.0 g, 65%) was obtained from 9-chloroacridine
(1.0 g, 4.7 mmol) and 2-amino-5-diethylaminopentane (0.80 g,
5.00 mmol) following GP1 as a yellow oil. IR (film) m: 3300br,
3060m, 2968s, 2808m, 1615s, 1558s, 1520s, 1488s, 1422s, 1366m,
1259s, 1213w, 1133m, 1022w cm–1; 1H-NMR (400 MHz, CDCl3)
d: 0.93 (t, 6H, J = 7.0 Hz, CH3), 1.30 (d, 3H, J = 6.2 Hz, CH3(19)),
1.55–1.75 (m, 4H, CH2(39,49)), 2.35 (t, 2H, J = 7.0 Hz, CH2(59)), 2.42
(q, 4H, J = 7.0 Hz, NCH2), 4.10–4.20 (m, 1H, CH (29)), 4.78 (br s, 1H,
NH), 7.38 (ddd, 2H, J = 8.7, 6.7, 1.2 Hz, H-C(2)), 7.67 (ddd, 2H,
J = 8.7, 6.6, 1.2 Hz, H-C(3)), 8.06–8.11 (m, 4H, H-C(1,4)) ppm; 13C-
NMR (100 MHz, CDCl3) d: 11.5, 22.2, 23.9, 37.1, 46.8, 52.7, 56.1,
118.1, 122.6, 123.4, 129.8, 129.9, 149.5, 150.9 ppm; UV-VIS (meth-
anol) kmax (log e): 280 nm (4.74); MS (ESI, MeOH) m/z: 168.8 [M +
2H]2+ (100%), 336.4 [M + H]+ (40%); HRMS for C22H29N3 calcd.:
335.2361; found: 335.2362.
General
Melting points are uncorrected (Leica hot stage microscope,
Leica Microsystems, Germany), nmR spectra were recorded
using the Varian spectrometers Gemini 200, Gemini 2000 or
Unity 500 (Varian, USA; d given in ppm, J in Hz, internal Me4Si
or internal CCl3F), IR spectra (film or KBr pellet) on a Perkin-
Elmer FT-IR spectrometer Spectrum 1000 (Perkin-Elmer, USA),
MS spectra were taken on a Intectra GmbH AMD 402 (electron
impact, 70 eV; Intectra GmbH, Harpsted, Germany)) or on a Fin-
nigan MAT TSQ 7000 (Thermo Electron Corporation, Bremen,
Germany; electrospray, voltage 4.5 kV, sheath gas nitrogen)
instrument. TLC was performed on silica gel (Merck 5554 –
Merck, Darmstadt, Germany; detection by UV absorption). The
solvents were dried according to usual procedures.
Crystal data of 7o
Crystals of 7o were obtained by slow evaporation from a metha-
nolic solution. C40H44NO2, M = 612.80, monoclinic, space group
P21/n, a = 8.5505 (19) ꢀ, b = 21.083 (3) ꢀ, c = 11.274 (3) ꢀ, a =
90.008, b = 93.73 (3)8, c = 90.008, V = 2028.1 (7) ꢀ3, Dx = 1.213 g/
cm3, and Z = 4. A single crystal was used for X-ray diffraction
data collection on an IPDS Stadi IV employing graphite mono-
chromated MoKa radiation. 14351 reflections measured, 3399
unique, 2357 reflections with I>2rI. R[F2>2r(F2)] = 0.0781, wR(F2)
= 0.2059, GoF = 1.072. The structure was solved by direct method
using the SHELX-97 program. Hydrogens were solved by mixed
modes. Lists of atomic coordinates, anisotropic thermal param-
eters, and bond lengths and angles have been deposited at the
Cambridge Crystal Crystallographic Data Centre, UK. CCDC No.
687482.
N4-(2-Methoxy-9-acridinyl)-N1,N1-diethyl-1,4-
pentanediamine 4c
Compound 4c (0.9 g, 60%) was obtained from 9-chloro-2-meth-
oxyacridine (1.0 g, 4.1 mmol) and 2-amino-5-diethylaminopen-
tane (0.7 g, 4.5 mmol) following GP1 as a yellow oil. IR (film) m:
3301br, 3061m, 2967s, 2870m, 2805m, 1922w, 1633s, 1562s,
1524s, 1487s, 1469s, 1434s, 1368s, 1337m, 1282m, 1266m, 1232s,
1
1130m, 1104m, 1032s cm–1; H-NMR (400 MHz, CDCl3) d: 0.93 (t,
6H, J = 7.0 Hz, CH3), 1.25 (d, 3H, J = 6.2 Hz, CH3(19)), 1.53–1.73 (m,
4H, CH2(39, 49)), 2.35 (t, 2H, J = 7.0 Hz, CH2(59)), 2.42 (q, 4H,
J = 7.0 Hz, NCH2), 3.94 (s, 3H, OCH3), 3.99–4.07 (m, 1H, CH (29)),
4.78 (d, 1H, J = 10.4 Hz, NH), 7.25 (d, 1H, J = 2.5 Hz, H-C(1)), 7.37–
7.43 (m, 2H, Harom.), 7.62 (ddd, 1H, J = 8.7, 6.6, 1.2 Hz, Harom.), 8.01–
8.06 (m, 2H, Harom.), 8.09 (d, 1H, J = 8.3 Hz, H-C(4)) ppm; 13C-NMR
(100 MHz, CDCl3) d: 11.5, 22.2, 23.9, 36.9, 46.8, 52.8, 55.5, 55.7,
99.4, 119.2, 119.3, 122.0, 124.1, 124.2, 128.8, 130.3, 131.6, 146.4,
147.9, 148.9, 155.9 ppm; UV-VIS (methanol) kmax (log e): 279 nm
(4.75); MS (ESI, MeOH) m/z: 183.8 [M + 2H]2+ (30%), 366.4 [M + H]+
(100%); HRMS for C23H31N3O calcd.: 365.2467; found: 365.2466.
Chemistry
General procedure for the synthesis of monomeric
acridine compounds GP1
A mixture of 9-chloroacridine (3.6 mmol) in phenol (5 g) was
heated to 1008C for 15 min. Then, 2-amino-5-diethylaminopen-
tane (0.6 g, 3.8 mmol) was added and stirring continued for
30 min. After cooling to 258C, the mixture was chromato-
graphed (SiO2, gradient ethyl acetate, ethyl acetate / methanol /
ammonium hydroxide, 80:20:1)
N4-(2-Trifluoromethoxy-9-acridinyl)-N1,N1-diethyl-1,4-
pentanediamine 4d
Compound 4d (0.4 g, 57%) was obtained from 9-chloro-2-tri-
fluoromethoxyacridine (0.50 g, 1.68 mmol) and 2-amino-5-dieth-
ylaminopentane (0.30 g, 1.85 mmol) following GP1 as a yellow
oil. IR (film) m: 3244br, 2969s, 1633m, 1603m, 1563s, 1494s,
1456s, 1384m, 1258s, 1219s, 1166s cm–1; 1H-NMR (400 MHz,
CDCl3) d: 0.93 (t, 6H, J = 7.0 Hz, CH3), 1.25 (d, 3H, J = 6.2 Hz,
CH3(19)), 1.50–1.80 (m, 4H, CH2(39, 49)), 2.37 (t, 2H, J = 7.0 Hz,
CH2(59)), 2.42 (q, 4H, J = 7.0 Hz, NCH2), 4.05–4.15 (m, 1H, CH(29)),
4.80 (d, 1H, J = 10.4 Hz, NH), 7.43 (ddd, 1H, J = 8.7, 6.6, 1.2 Hz,
Harom.), 7.53 (dd, 1H, J = 9.5, 2.5 Hz, H-C(3)), 7.70 (ddd, 1H, J = 8.7,
6.6, 1.2 Hz, Harom.), 7.92 (d, 1H, J = 2.5 Hz, H-C(1)), 8.02–8.14 (m,
3H, Harom.) ppm; 13C-NMR (100 MHz, CDCl3) d: 11.5, 22.3, 24.0,
37.0, 46.8, 52.7, 56.2, 113.6, 117.4, 118.3, 120.7 (q, JC,F = 263.2 Hz),
122.0, 124.3, 124.4, 130.0, 130.1, 132.1, 144.4, 147.7, 149.5,
150.9 ppm; 19F-NMR (188 MHz, CDCl3) d: –58.5 (s, OCF3) ppm; UV-
N4-(6-Chloro-2-methoxy-9-acridinyl)-N1,N1-diethyl-1,4-
pentanediamine 4a
Compound 4a (0.9 g, 63%) was obtained from 6,9-dichloro-2-
methoxyacridine (1.0 g, 3.6 mmol) and 2-amino-5-diethylamino-
pentane (0.30 g, 1.85 mmol) following GP1 as a yellow oil. IR
(film) m: 3318br, 2968s, 1633s, 1606m, 1563s, 1520m, 1470s,
1435s, 1383m, 1233s, 1071m cm–1; 1H-NMR (400 MHz, CDCl3)
d: 0.92 (t, 6H, J = 7.0 Hz, CH3), 1.24 (d, 3H, J = 6.2 Hz, CH3 (19)),
1.50–1.70 (m, 4H, CH2(39,49)), 2.34 (t, 2H, J = 7.0 Hz, CH2(59)), 2.41
(q, 4H, J = 7.0 Hz, NCH2), 3.94 (s, 3H, OCH3), 3.95–4.04 (m, 1H,
CH(29)), 4.39 (d, 1H, J = 10.4 Hz, NH), 7.19 (d, 1H, J = 2.5 Hz, H-C(1)),
7.30 (dd, 1H, J = 9.1, 2.1 Hz, H-C(7)), 7.40 (dd, 1H, J = 9.5, 2.5 Hz, H-
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Arch. Pharm. Chem. Life Sci. 2009, 342, 699–709
Monomeric and Dimeric Acridine Compounds
703
VIS (methanol) kmax (log e): 282 nm (4.67); MS (ESI, MeOH) m/z:
210.8 [M + 2H]2+ (15%), 420.3 [M + H]+ (100%); HRMS for
C23H28F3N3O calcd.: 335.2361; found: 335.2362.
2H, Harom.), 7.30 (dd, 1H, J = 7.9, 7.5 Hz, Harom.), 7.65 (dd, 1H, J = 7.9,
7.5 Hz, Harom), 7.77–7.83 (m, 1H, Harom.), 8.04 (d, 1H, J = 8.7 Hz,
Harom.), 8.17 (d, 1H, J = 8.7 Hz, Harom.) ppm; 13C-NMR (100 MHz,
CDCl3) d: 11.3, 14.5, 22.1, 23.6, 36.9, 46.7, 52.6, 56.0, 117.6, 118.1,
118.5, 122.1, 122.3, 123.1, 123.8, 129.4, 130.4, 140.4, 146.6,
148.3, 150.9 ppm; UV-VIS (methanol) kmax (log e): 288 nm (4.72);
MS (ESI, MeOH) m/z: 191.7 [M + 2H]2+ (100%), 382.3 [M + H]+ (80%);
HRMS for C23H31N3S calcd.: 381.2239; found: 381.2238.
N4-(2,4-Difluoro-9-acridinyl)-N1,N1-diethyl-1,4-
pentanediamine 4e
Compound 4e (0.57 g, 57%) was obtained from 9-chloro-2,4-
difluoroacridine (1.0 g, 2.7 mmol) and 2-amino-5-diethylamino-
pentane (0.5 g, 3.1 mmol) following GP1 as a yellow oil. IR (film)
m: 3317br, 3042m, 2969s, 2871m, 2806m, 2360w, 1645s, 1567s,
1531s, 1486s, 1433s, 1383m, 1337s, 1280s, 1230m, 1126s,
N4-(3-Chloro-5-methoxy-9-acridinyl)-N1,N1-diethyl-1,4-
pentanediamine 4h [18]
1
1055m cm–1; H-NMR (400 MHz, CDCl3) d: 0.94 (t, 6H, J = 7.0 Hz,
Compound 4h (1.0 g, 70%) was obtained from 3,9-dichloro-5-
methoxyacridine (1.0 g, 3.6 mmol) and 2-amino-5-diethylamino-
pentane (0.6 g, 3.8 mmol) following GP1 as a yellow oil. IR (film)
m: 3288br, 2968s, 1669m, 1606s, 1564s, 1520m, 1456s, 1435s,
1388s, 1252s, 1132m, 1076s cm–1; 1H-NMR (400 MHz, CDCl3)
d: 0.94 (t, 6H, J = 7.0 Hz, CH3), 1.26 (d, 3H, J = 6.2 Hz, CH3(19)), 1.50-
1.73 (m, 4H, CH2(39, 49)), 2.37 (t, 2H, J = 7.0 Hz, CH2(59)), 2.46 (q, 4H,
J = 7.0 Hz, NCH2), 4.08 (s, 3H, OCH3), 4.09–4.14 (m, 1H, CH(29)),
4.80 (br s, 1H, NH), 6.96 (d, 1H, J = 7.5 Hz, Harom.), 7.26–7.32 (m, 2H,
Harom.), 7.58 (d, 1H, J = 8.7 Hz, Harom.), 8.00 (d, 1H, J = 9.1 Hz, Harom.),
8.21 (br s, 1H, H-C(3)) ppm; 13C-NMR (100 MHz, CDCl3) d: 11.1,
22.1, 23.5, 36.8, 46.6, 52.4, 56.1, 55.9, 106.9, 114.1, 116.6, 119.1,
123.5, 124.5, 124.7, 129.5, 135.4, 148.4, 151.0 ppm; UV-VIS (meth-
anol) kmax (log e): 290 nm (4.76); MS (ESI, MeOH) m/z: 400.2 [M +
H]+ (100%); HRMS for C23H30ClN3O calcd.: 399.2077; found:
399.2079.
CH3), 1.29 (d, 3H, J = 6.2 Hz, CH3(19)), 1.52–1.76 (m, 4H, CH2(39, 49)),
2.37 (t, 2H, J = 7.0 Hz, CH2(59)), 2.42 (q, 4H, J = 7.0 Hz, NCH2), 4.05–
4.15 (m, 1H, CH(29)), 4.74 (d, 1H, J = 10.4 Hz, NH), 7.23 (ddd, 1H,
J = 10.4, 8.3, 2.5 Hz, H-C(3)), 7.44 (ddd, 1H, J = 8.7, 6.6, 1.2 Hz,
Harom.), 7.50 (ddd, 1H, J = 10.4, 2.5, 1.6 Hz, H-C(1)), 7.69 (ddd, 1H,
J = 8.7, 6.6, 1.2 Hz, Harom.), 8.05 (d, 1H, J = 8.7 Hz, Harom.), 8.19 (d,
1H, J = 8.7 Hz, Harom.) ppm; 13C-NMR (100 MHz, CDCl3) d: 11.5,
22.3, 24.0, 37.0, 46.9, 52.7, 55.9, 101.4 (dd, JC,F = 23.0, 5.0 Hz),
105.3 (dd, JC,F = 30.7, 23.0 Hz), 118.6 (d, JC,F = 6.0 Hz), 118.8, 122.1,
124.8, 130.0, 130.7, 138.1 (d, JC,F = 13.0 Hz), 148.8, 150.4, 157.0
(dd, JC,F = 245.0, 12.0 Hz), 159.0(dd, JC,F = 260.5, 12.0 Hz) ppm; 19F-
NMR (188 MHz, CDCl3) d: –113.8 (m, F), –118.4 (m, F) ppm; UV-VIS
(methanol) kmax (log e): 280 nm (4.73); MS (ESI, MeOH) m/z: 186.8
[M + 2H]2+ (100%), 372.3 [M + H]+ (90%); HRMS for C22H29F2N3 calcd.:
371.2173; found: 371.2173.
N4-(5-Methoxy-3-nitro-9-acridinyl)-N1,N1-diethyl-1,4-
pentanediamine 4f
N4-(2-Nitro-5-thiomethyl-9-acridinyl)-N1,N1-diethyl-1,4-
Compound 4f (0.9 g, 63%) was obtained from 9-chloro-5-
methoxy-3-nitroacridine (1.0 g, 3.5 mmol) and 2-amino-5-di-
ethylaminopentane (0.6 g, 3.8 mmol) following GP1 as an
orange-colored oil. IR (film) m: 3313br, 2968s, 2361w, 1673m,
1624m, 1568s, 1515s, 1463s, 1421m, 1345s, 1256s, 1137m,
1073m cm–1; 1H-NMR (400 MHz, CDCl3) d: 0.93 (t, 6H, J = 7.0 Hz,
CH3), 1.32 (d, 3H, J = 6.2 Hz, CH3(19)), 1.50–1.80 (m, 4H, CH2(39, 49)),
2.36 (t, 2H, J = 7.0 Hz, CH2(59)), 2.42 (q, 4H, J = 7.0 Hz, NCH2), 4.10–
4.22 (m, 4H, OCH3, CH(29)), 5.06 (d, 1H, J = 9.9 Hz, NH), 7.04 (d, 1H,
J = 7.5 Hz, H-C(6)), 7.40 (dd, 1H, J = 8.7, 7.5 Hz, H-C(7)), 7.62 (d, 1H,
J = 8.7 Hz, H-C(8)), 8.06 (dd, 1H, J = 9.5, 2.5 Hz, H-C(2)), 8.20 (d, 1H,
J = 9.5 Hz, H-C(1)), 9.18 (d, 1H, J = 2.5 Hz, H-C(4)) ppm; 13C-NMR
(100 MHz, CDCl3) d: 11.3, 22.2, 23.8, 37.0, 46.8, 52.6, 56.2, 56.3,
107.4, 113.8, 116.0, 119.7, 120.0, 125.1, 127.2, 127.5, 143.7,
147.0, 148.0, 150.9, 155.7 ppm; UV-VIS (methanol) kmax (log e):
297 nm (4.48); MS (ESI, MeOH) m/z: 411.6 [M + H]+ (100%), 843.3
[M2 + Na]+ (15%); HRMS for C23H30NO3 calcd.: 410.2318; found:
410.2319.
pentanediamine 4i
Compound 4i (0.12 g, 11%) was obtained from 9-chloro-2-nitro-5-
thiomethylacridine 3b (0.8 g, 2.6 mmol) and 2-amino-5-diethyla-
minopentane (0.5 g, 3.2 mmol) following GP1 as a red solid.
M.p.: 93–958C; IR (KBr) m: 2967s, 2923s, 1617s, 1600m, 1572s,
1510s, 1493s, 1432m, 1310s, 1233m, 1204w, 1130w, 1076w cm–1;
1H-NMR (400 MHz, CDCl3) d: 0.93 (t, 6H, J = 7.0 Hz, CH3), 1.40 (d,
3H, J = 6.2 Hz, CH3(19)), 1.54–1.84 (m, 4H, CH2(39, 49)), 2.40 (t, 2H,
J = 7.0 Hz, CH2(59)), 2.44 (q, 4H, J = 7.0 Hz, NCH2), 2.55 (s, 3H,
SCH3), 4.26–4.36 (m, 1H, CH(29)), 5.66 (d, 1H, J = 10.4 Hz, NH),
7.36–7.39 (m, 2H, H-C(6,7)), 7.75 (dd, 1H, J = 7.3, 2.4 Hz, H-C(8)),
8.13 (d, 1H, J = 9.2 Hz, H-C(4)), 8.31 (dd, 1H, J = 9.2, 2.4 Hz, H-C(3)),
9.15 (d, 1H, J = 2.4 Hz, H-C(1)) ppm; 13C-NMR (100 MHz, CDCl3)
d: 11.8, 14.6, 22.5, 24.3, 37.2, 46.9, 52.5, 56.5, 114.5, 116.0, 116.9,
117.5, 122.7, 124.1, 124.5, 131.5, 141.5, 142.5, 148.2, 150.1,
153.9 ppm; UV-VIS (methanol) kmax (log e): 268 nm (4.45); MS (ESI,
MeOH) m/z: 427.2 [M + H]+ (100%); HRMS for C23H30NO2S calcd.:
426.2089; found: 426.2088.
N4-(4-Thiomethyl-9-acridinyl)-N1,N1-diethyl-1,4-
pentanediamine 4g
General procedure for the synthesis of dimeric acridine
compounds GP2
Compound 4g (1.0 g, 68%) was from obtained 9-chloro-4-thiome-
thylacridine 3a (1.0 g, 3.9 mmol) and 2-amino-5-diethylamino-
pentane (0.7 g, 4.6 mmol) following GP1 as a yellow oil. IR (KBr)
m: 3057m, 2967s, 2869m, 2808m, 1671w, 1618m, 1599s, 1553m,
1487s, 1418s, 1381s, 1359s, 1256m, 1200m, 1124s, 1036w cm–1;
1H-NMR (400 MHz, CDCl3) d: 0.94 (t, 6H, J = 7.1 Hz, CH3), 1.26 (d,
3H, J = 6.2 Hz, CH3(19)), 1.50–1.70 (m, 4H, CH2(39, 49)), 2.35 (t, 2H,
J = 7.1 Hz, CH2(59)), 2.43 (q, 4H, J = 7.1 Hz, NCH2), 2.56 (s, 3H,
SCH3), 4.08–4.18 (m, 1H, CH(29)), 4.72 (br s, 1H, NH), 7.28–7.34 (m,
A mixture of 9-chloroacridine (3.6 mmol) in phenol (5 g) was
heated to 1008C for 15 min. Then, 1,4-bis-(3-aminopropyl)pipera-
zine (0.28 g, 1.4 mmol) was added and stirring continued for
30 min. After cooling to 258C, methanol (10 mL) was added and
the resulting solution poured into diethyl ether under vigorous
stirring. The product was collected by filtration and purified by
column chromatography (SiO2, dichloromethane / methanol /
ammonium hydroxide, 80 : 20 : 1).
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704
R. Csuk et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 699–709
4H, CH2(39, 69)), 1.67–1.77 (m, 4H, CH2(29, 79)), 3.70–3.80 (m, 4H,
CH2(19, 89)), 5.00 (br s, 2H, NH), 7.39 (ddd, 1H, J = 8.7, 6.6, 1.2 Hz,
Harom.), 7.51 (dd, 1H, J = 9.5, 2.5 Hz, H-C(3)), 7.67 (ddd, 1H, J = 8.7,
6.6, 1.2 Hz, Harom.), 7.92 (d, 1H, J = 2.5 Hz, H-C(1)), 8.01–8.12 (m,
3H, Harom.) ppm; 13C-NMR (125 MHz, CDCl3) d: 26.6, 29.0, 31.6,
50.7, 113.9, 115.8, 116.7, 119.8, 120.7 (q, JC,F = 257.8 Hz), 121.8,
124.0, 124.5, 129.6, 130.3, 144.1, 147.8, 149.4, 151.3, 155.6 ppm;
19F-NMR (188 MHz, CDCl3) d: -58.5 (s, OCF3) ppm; UV-VIS (metha-
nol) kmax (log e): 282 nm (5.42); MS (ESI, MeOH) m/z: 334.2 [M +
2H]2+ (20%), 667.4 [M + H]+ (100%); HRMS for C36H32F6NO2 calcd.:
666.2429; found: 666.2430.
N,N-Bis-(6-chloro-2-methoxy-9-acridinyl)-1,8-
octanediamine 5a [9]
Compound 5a (0.8 g, 80%) was obtained from 6,9-dichloro-2-
methoxyacridine (1.0 g, 3.6 mmol) and 1,8-octanediamine
(0.23 g, 1.60 mmol) following GP2 as a yellow solid. M.p.: 1658C
(lit: 166.5–167.58C [19]); IR (KBr) m: 2929s, 1631s, 1563s, 1525s,
1
1437s, 1258s, 1234m, 1077w cm–1; H-NMR (400 MHz, DMSO-d6)
d: 1.05-1.21 (m, 8H, CH2(39, 49, 59, 69)), 1.55–1.64 (m, 4H, CH2(29, 79)),
3.60–3.70 (m, 4H, CH2(19, 89)), 3.87 (s, 6H, OCH3), 6.90 (br s, 2H,
NH), 7.28 (dd, 2H, J = 9.1, 2.1 Hz, H-C(7)), 7.37 (dd, 2H, J = 9.5,
2.5 Hz, H-C(3)), 7.57 (d, 2H, J = 2.5 Hz, H-C(1)), 7.75–7.84 (m, 4H, H-
C(5, 8)), 8.26 (d, 2H, J = 9.5 Hz, H-C(4)) ppm; 13C-NMR (100 MHz,
DMSO-d6) d: 26.0, 28.5, 30.4, 49.3, 55.5, 100.8, 114.4, 117.0, 122.3,
123.9, 126.4, 133.4, 147.7, 150.4, 154.9 ppm; UV-VIS (methanol)
kmax (log e): 299 nm (4.94); MS (ESI, MeOH + TFA) m/z: 314.4 [M +
2H]2+ (100%), 627.6 [M + H]+ (40%).
N,N-Bis-(2,4-difluoro-9-acridinyl)-1,8-diaminooctane 5e
Compound 5e (0.42 g, 37%) was obtained from 9-chloro-2-tri-
fluoromethoxyacridine (1.0 g, 4.0 mmol) and 1,8-diaminooctane
(0.27 g, 1.80 mmol) following GP2 as a yellow oil. IR (KBr) m:
3050m, 2934s, 2853m, 1647m, 1605m, 1592m, 1570m, 1537s,
1511s, 1476s, 1458s, 1437s, 1395m, 1356m, 1282s, 1244s, 1124s,
1070w, 1000m cm–1; 1H-NMR (400 MHz, CD3OD) d: 1.42–1.53 (m,
8H, CH2(39, 49, 59, 69)), 1.95–2.04 (m, 4H, CH2(29, 79)), 4.12–4.18 (m,
4H, CH2(19, 89)), 5.00 (br s, 2H, NH), 7.59 (ddd, 2H, J = 8.7, 6.2,
1.3 Hz, H-C(6)), 7.81 (ddd, 2H, J = 11.2, 8.3, 2.5 Hz, H-C(3)), 7.98
(ddd, 2H, J = 8.7, 6.2, 1.3 Hz, H-C(7)), 8.02 (dd, 2H, J = 8.7, 2.5 Hz, H-
C(1)), 8.14–8.25 (m, 2H, H-C(5)), 8.02 (d, 2H, J = 8.3, H-C(8)) ppm;
13C-NMR (100 MHz, CD3OD) d: 27.7, 30.1, 30.4, 50.6, 111.1, 119.9,
122.7 (d, JC,F = 18.9 Hz), 125.3 (d, JC,F = 29.2 Hz), 136.8, 153.5 (dd,
JC,F = 254.0, 12.7 Hz), 159.0 ppm; 19F-NMR (188 MHz, CDCl3) d:
–115.1 (br s, F), –125.4 (m, F) ppm; UV-VIS (methanol) kmax (log e):
279 nm (5.05); MS (ESI, MeOH) m/z: 571.4 [M + H]+ (100%); HRMS
for C32H28F2NO2 calcd.: 570.2407; found: 570.2407.
N,N-Bis-9-acridinyl-1,8-octanediamine 5b
Compound 5b (1.0 g, 82%) was obtained from 9-chloroacridine
(1.0 g, 4.7 mmol) and 1,8-octanediamine (0.30 g, 2.10 mmol) fol-
lowing GP2 as a yellow solid. M.p.: 1958C (lit: 197–2008C [20],
1658C [21]); IR (KBr) m: 3055m, 2930s, 2855s, 1614s, 1558s, 1520s,
1506s, 1468s, 1448m, 1426s, 1397w, 1371m, 1339s, 1288w,
1
1265m, 1222w, 1136m, 1122m, 1024w cm–1; H-NMR (500 MHz,
CDCl3) d: 1.25–1.30 (m, 4H, CH2(49, 59)), 1.33–1.40 (m, 4H,
CH2(39, 69)), 1.67–1.77 (m, 4H, CH2(29, 79)), 3.78 (t, 4H, J = 7.3 Hz,
CH2(19, 89)), 7.33 (ddd, 4H, J = 8.7, 6.4, 0.9 Hz, H-C(2)), 7.63 (ddd,
4H, J = 8.7, 6.4, 0.9 Hz, H-C(3)), 8.03–8.10 (m, 8H, H-C(1,4)) ppm;
13C-NMR (100 MHz, CDCl3 + CD3OD) d: 26.4, 28.8, 31.1, 50.2,
115.7, 122.5, 122.7, 127.5, 130.1, 148.2, 152.0 ppm; UV-VIS [22]
(methanol) kmax (log e): 282 nm (5.32); MS (ESI, MeOH) m/z: 250.3
[M + 2H]2+ (100%), 499.4 [M + H]+ (20%); HRMS for C34H34N calcd.:
498.2783; found: 498.2784.
N,N-Bis-(6-chloro-2-methoxy-9-acridinyl)-1,8-diamino-
3,6-dioxaoctane 6a [9]
Compound 6a (0.8 g, 80%) was obtained from 6,9-dichloro-2-
methoxyacridine (1.0 g, 3.6 mmol) and 1,8-diamino-3,6-dioxaoc-
tane (0.23 g, 1.60 mmol) following GP2 as a yellow solid. M.p.:
1708C; IR (KBr) m: 2924s, 1629s, 1560s, 1465s, 1230m, 1130m,
N,N-Bis-(2-methoxy-9-acridinyl)-1,8-octanediamine 5c
Compound 5c (0.9 g, 92%) was obtained from 9-chloro-2-meth-
oxyacridine (1.0 g, 4.1 mmol) and 1,8-octanediamine (0.26 g,
1.80 mmol) following GP2 as a yellow solid. M.p.: 1908C (lit: 186–
187.58C [23]); IR (KBr) m: 3252m, 2962s, 2919s, 2822s, 1734w,
1633s, 1613s, 1555s, 1513s, 1459s, 1435s, 1386m, 1357s, 1341s,
1312s, 1272m, 1256m, 1229m, 1211m, 1176m, 1132s, 1085m,
1057m, 1028s, 1019m cm–1; 1H-NMR (400 MHz, CDCl3) d: 1.20–
1.28 (m, 4H, CH2(49, 59)), 1.30–1.40 (m, 4H, CH2(39, 69)), 1.62–1.72
(m, 4H, CH2(29, 79)), 3.60–3.70 (m, 4H, CH2(19, 89)), 3.94 (s, 6H,
OCH3), 4.71 (br s, 2H, NH), 7.26 (d, 2H, J = 2.9 Hz, H-C(1)), 7.35–7.42
(m, 4H, Harom.), 7.62 (ddd, 2H, J = 8.7, 6.6, 1.2 Hz, Harom.), 8.00–8.10
(m, 6H, Harom.) ppm; 13C-NMR (100 MHz, CDCl3) d: 26.8, 29.2, 31.8,
50.6, 55.5, 117.8, 118.0, 121.9, 123.6, 123.9, 128.1, 128.7, 129.8,
131.5, 146.2, 147.9, 149.4, 155.6 ppm; UV-VIS (methanol) kmax
(log e): 278 nm (5.09); MS (ESI, MeOH) m/z: 280.3 [M + 2H]2+
(100%), 559.4 [M + H]+ (30%); HRMS for C36H38NO2 calcd.:
558.2995; found: 558.2996.
1
1030m cm–1; H-NMR (400 MHz, DMSO-d6) d: 3.48 (s, 4H, CH2(49,
59)), 3.64 (t, 4H, J = 4.5 Hz, CH2(29, 79)), 3.77–3.82 (m, 4H, CH2(19, 89)),
3.85 (s, 6H, OCH3), 7.23 (dd, 2H, J = 9.1, 2.1 Hz, H-C(7)), 7.32 (dd,
2H, J = 9.5, 2.5 Hz, H-C(3)), 7.54 (d, 2H, J = 2.5 Hz, H-C(1)), 7.65 (d,
2H, J = 9.1 Hz, H-C(8)), 7.70 (d, 2H, J = 2.1 Hz, H-C(5)), 8.26 (d, 2H,
J = 9.5 Hz, H-C(4)) ppm; 13C-NMR (125 MHz, 508C, DMSO-d6)
d: 49.0, 55.4, 69.5, 69.8, 101.2 , 114.8, 117.3, 122.5, 123.9, 125.0,
127.3, 129.0, 133.7, 144.4, 146.7, 150.7, 154.9 ppm; UV-VIS (meth-
anol) kmax (log e): 283 nm (5.00); MS (ESI, MeOH + TFA) m/z: 316.5
[M + 2H]2+ (100%), 631.5 [M + H]+ (90%).
N,N-Bis -9-acridinyl-1,8-diamino-3,6-dioxaoctane 6b
Compound 6b (0.4 g, 38%) was obtained from 9-chloroacridine
(1.0 g, 4.7 mmol) and 1,8-diamino-3,6-dioxaoctane (0.31 g,
2.10 mmol) following GP2 as a yellow solid. M.p.: 1548C (lit: 150–
1538C [24]); IR (KBr) m: 3166m, 3058m, 2889s, 1625s, 1595s, 1561s,
1521s, 1488s, 1471s, 1418m, 1396w, 1350s, 1288w, 1256s, 1121s,
N,N-Bis-(2-trifluoromethoxy-9-acridinyl)-1,8-
octanediamine 5d
1
1090m, 1028w cm–1; H-NMR (400 MHz, CDCl3) d: 3.64–3.72 (m,
Compound 5d (0.5 g, 50%) was obtained from 9-chloro-2-tri-
fluoromethoxyacridine (1.0 g, 3.4 mmol) and 1,8-octanediamine
(0.23 g, 1.60 mmol) following GP2 as a yellow oil. IR (film) m:
3063w, 2931m, 2857w, 1618w, 1591m, 1565s, 1506s, 1475s,
1431m, 1357m, 1258s, 1218s, 1163s, 1024w cm–1; 1H-NMR
(500 MHz, CDCl3) d: 1.27–1.32 (m, 4H, CH2(49, 59)), 1.34–1.41 (m,
8H, CH2(29, 49, 59, 79)), 3.87–3.95 (m, 4H, CH2(19, 89)), 5.65 (br s, 2H,
NH), 7.29 (ddd, 4H, J = 8.7, 6.4, 0.9 Hz, H-C(2)), 7.60 (ddd, 4H,
J = 8.7, 6.4, 0.9 Hz, H-C(3)), 7.99–8.12 (m, 8H, H-C(1, 4)) ppm; 13C-
NMR (100 MHz, CDCl3) d: 50.4, 70.3, 70.6, 117.6, 122.8, 123.2,
128.1, 129.8, 150.5, 151.3 ppm; UV-VIS (methanol) kmax (log e):
277 nm (4.94); MS (ESI, MeOH) m/z: 252.3 [M + 2H]2+ (15%), 503.3
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Arch. Pharm. Chem. Life Sci. 2009, 342, 699–709
Monomeric and Dimeric Acridine Compounds
705
[M + H]+ (100%); HRMS for C32H30NO2 calcd.: 502.2369; found:
502.2368.
N,N-Bis-(4-thiomethyl-9-acridinyl)-1,8-diamino-3,6-
dioxaoctane 6g
Compound 6g (1.0 g, 80%) was obtained from 9-chloro-4-thiome-
thylacridine 3a (1.2 g, 4.6 mmol) and 1,8-diamino-3,6-dioxaoc-
tane (0.31 g, 2.10 mmol) following GP2 as a yellow solid. M.p.:
95–978C; IR (KBr) m: 2914s, 1622s, 1597s, 1565s, 1509s, 1457s,
1419s, 1336m, 1256m, 1123s cm–1; 1H-NMR (400 MHz, DMSO-d6)
d: 2.47 (s, 6H, SCH3), 3.70 (s, 4H, CH2(49, 59)), 3.74–3.80 (m, 4H,
CH2(29, 79)), 3.90–3.96 (m, 4H, CH2(19, 89)), 7.16 (dd, 2H, J = 7.5,
7.1 Hz, Harom.), 7.21–7.26 (m, 2H, Harom.), 7.29 (d, 2H, J = 7.1 Hz,
N,N-Bis-(2-methoxy-9-acridinyl)-1,8-diamino-3,6-
dioxaoctane 6c
Compound 6d (0.8 g, 77%) was obtained from 9-chloro-2-meth-
oxyacridine (1.0 g, 4.1 mmol) and 1,8-diamino-3,6-dioxaoctane
(0.28 g, 1.90 mmol) following GP2 as a yellow solid. M.p.: 181–
1828C; IR (KBr) m: 3384s, 2991m, 2897m, 2869m, 1633s, 1561s,
1524w, 1488s, 1472s, 1456m, 1436m, 1421s, 1395w, 1370w,
1334w, 1320w, 1280w, 1257w, 1236s, 1150w, 1124s, 1114s,
1103s, 1032s cm–1; 1H-NMR (400 MHz, CDCl3) d: 3.60 (t, 4H,
J = 4.5 Hz, CH2(29, 79)), 3.68 (s, 4H, CH2(49, 59)), 3.87–3.95 (m, 4H,
CH2(19, 89)), 3.90 (s, 6H, OCH3), 5.25 (br s, 2H, NH), 7.30–7.40 (m, 6H,
Harom.), 7.59 (ddd, 2H, J = 8.7, 6.6, 1.2 Hz, Harom.), 7.99–8.14 (m, 6H,
Harom.) ppm; 13C-NMR (100 MHz, CDCl3) d: 49.9, 55.5, 70.4, 70.6,
99.5, 119.0, 119.1, 122.0, 124.0, 128.7, 129.9, 131.6, 146.3, 147.9,
149.1, 155.9 ppm; UV-VIS (methanol) kmax (log e): 279 nm (4.96);
MS (ESI, MeOH) m/z: 282.3 [M + 2H]2+ (100%), 563.4 [M + H]+ (99%);
HRMS for C34H34NO4 calcd.: 562.2580; found: 562.2580.
Harom.), 7.53 (ddd, 2H, J = 7.5, 7.1, 1.3 Hz, Harom.), 7.90–8.03 (m, 4H,
Harom.), 8.17 (d, 2H, J = 8.7 Hz, Harom.) ppm; 13C-NMR (100 MHz,
DMSO-d6) d: 15.6, 50.0, 70.0, 70.2, 116.2, 116.8, 120.0, 122.9,
123.4, 130.4, 144.6, 146.1, 152.8, 154.9 ppm; UV-VIS (methanol)
kmax (log e): 285 nm (4.88); MS (ESI, MeOH + TFA) m/z: 298.3 [M +
2H]2+ (100%), 595.3 [M + H]+ (75%); HRMS for C34H34NO2S2 calcd.:
594.2123; found: 594.2124.
N,N-Bis-(2-nitro-5-thiomethyl-9-acridinyl)-1,8-diamino-
3,6-dioxaoctane 6h
Compound 6h (0.26 g, 80%) was obtained from 9-chloro-2-nitro-
5-thiomethylacridine 3b (1.2 g, 3.9 mmol) and 1,8-diamino-3,6-
dioxaoctane (0.23 g, 1.60 mmol) following GP2 as a red solid.
M.p.: 205–2078C; IR (KBr) m: 2921s, 1618s, 1598s, 1571s, 1515s,
1492s, 1435m, 1331s, 1309s, 1230m, 1130m, 1104m cm–1;1H-NMR
(400 MHz, DMSO-d6) d: 2.43 (s, 6H, SCH3), 3.55 (s, 4H, CH2(49, 59)),
3.73 (t, 4H, J = 5.3 Hz, CH2(29, 79)), 3.90–3.94 (m, 4H, CH2(19, 89)),
7.25 (dd, 2H, J = 8.3, 7.5 Hz, H-C(7)), 7.33 (d, 2H, J = 7.5 Hz, H-C(6)),
7.77 (d, 2H, J = 9.2 Hz, H-C(4)), 7.98 (d, 2H, J = 8.3 Hz, H-C(8)), 8.14
(dd, 2H, J = 9.2, 2.4 Hz, H-C(3)), 9.26 (d, 2H, J = 2.4 Hz, H-C(1)) ppm;
13C-NMR (125 MHz, 508C, DMSO-d6) d: 13.4, 48.7, 69.2, 69.7, 114.7,
118.5, 122.0, 122.7, 123.7, 128.9, 130.0, 131.1, 139.6, 140.6,
146.8, 148.8, 154.1 ppm; UV-VIS (methanol) kmax (log e): 266 nm
(4.53); MS (ESI, MeOH + TFA) m/z: 346.3 [M + 2H]2+ (100%), 685.4 [M
+ H]+ (100%); HRMS for C34H32N6O6S2 calcd.: 684.1825; found:
684.1827.
N,N-Bis-(2-trifluoromethoxy-9-acridinyl)-1,8-diamino-3,6-
dioxaoctane 6e
Compound 6e (0.36 g, 36%) was obtained from 9-chloro-2-tri-
fluoromethoxyacridine (1.0 g, 3.4 mmol) and 1,8-diamino-3,6-
dioxaoctane (0.22 g, 1.50 mmol) following GP2 as a yellow oil. IR
(film) m: 3386m, 2922m, 1631s, 1563s, 1522s, 1478s, 1431s,
1338m, 1259s, 1219s, 1162s cm–1; 1H-NMR (400 MHz, CDCl3)
d: 3.62–3.80 (m, 8H, CH2(29, 49, 59, 79)), 3.84–3.87 (m, 4H, CH2(19, 89)),
5.50 (br s, 2H, NH), 7.34 (ddd, 2H, J = 8.7, 6.6, 1.2 Hz, Harom.), 7.51
(dd, 2H, J = 9.5, 2.5 Hz, H-C(3)), 7.64 (ddd, 2H, J = 8.7, 6.6, 1.2 Hz,
Harom.), 7.95 (d, 2H, J = 2.5 Hz, H-C(1)), 8.02–8.14 (m, 6H, Harom.
)
ppm; 13C-NMR (125 MHz, CDCl3) d: 49.9, 70.3, 113.6, 117.1, 117.8,
120.6 (q, JC,F = 257.8 Hz) 122.1, 124.2, 124.5, 129.5, 130.2, 132.2,
144.4, 147.7, 149.6, 151.3 ppm; 19F-NMR (188 MHz, CDCl3)
d: –58.4 (s, OCF3) ppm; UV-VIS (methanol) kmax (log e): 280 nm
(5.00); MS (ESI, MeOH) m/z: 336.3 [M + 2H]2+ (100%), 671.4 [M + H]+
(45%); HRMS for C34H28F6NO4 calcd.: 670.2015; found: 670.2016.
N,N-Bis-(6-chloro-2-methoxy-9-acridinyl)-1,4-bis(3-
aminopropyl)piperazine 7a [9], [25]
Compound 7a (0.5 g, 52%) was obtained 6,9-dichloro-2-methoxy-
acridine (1.0 g, 3.6 mmol) and 1,4-bis-(3-aminopropyl)piperazine
(0.28 g, 1.4 mmol) following GP2 as a yellow solid. M.p.: 233–
2358C (lit: 231–2348C [19]); IR (KBr) m: 3284s, 2922s, 2819s, 1633s,
1606m, 1560s, 1516s, 1463s, 1442m, 1427s, 1375w, 1346m,
1307w, 1254s, 1238s, 1141m, 1071w, 1035w, 1002w cm–1; 1H-
NMR (500 MHz, 808C, DMSO-d6) d: 1.80–1.88 (m, 4H, CH2(29)), 2.23
(s, 8H, CH2(pip.)), 2.34 (t, 4H, J = 6.9 Hz, CH2(39)), 3.75–3.82 (m, 4H,
CH2(19)), 3.92 (s, 6H, OCH3), 7.25 (dd, 2H, J = 9.1, 2.1 Hz, H-C(7)),
7.40 (dd, 2H, J = 9.5, 2.5 Hz, H-C(3)), 7.60 (d, 2H, J = 2.5 Hz, H-C(1)),
7.78–7.85 (m, 4H, H-C(5,8)), 8.31 (d, 2H, J = 9.5 Hz, H-C(4)) ppm;
13C-NMR (125 MHz, 808C, DMSO-d6) d: 27.2, 47.7, 52.3, 54.9, 55.4,
101.4, 114.4, 116.9, 122.1, 123.3, 124.0, 126.0, 129.3, 133.2,
147.3, 150.3, 154.8 ppm; UV-VIS (methanol) kmax (log e): 285 nm
(4.23); MS (ESI, MeOH + TFA) m/z: 342.5 [M + 2H]2+ (100%), 683.6 [M
+ H]+ (40%).
N,N-Bis-(2,4-difluoro-9-acridinyl)-1,8-diamino-3,6-
dioxaoctane 6f
Compound 6f (0.36 g, 16%) was obtained from 9-chloro-2-tri-
fluoromethoxyacridine (1.0 g, 4.0 mmol) and 1,8-diamino-3,6-
dioxaoctane (0.27 g, 1.80 mmol) following GP2 as a yellow solid.
M.p.: 115–1168C; IR (KBr) m: 3056m, 2926m, 2873m, 1643m,
1604w, 1592m, 1565s, 1533s, 1514s, 1473s, 1433s, 1394m,
1334m, 1282m, 1240m, 1126s, 1514s, 1082m, 1031w cm–1; H-
1
NMR (400 MHz, CDCl3) d: 3.69 (t, 4H, J = 4.5 Hz, CH2(29, 79)), 3.73 (s,
4H, CH2(49, 59)), 3.85–3.95 (m, 4H, CH2(19, 89)), 5.45 (br s, 2H, NH),
7.18–7.25 (m, 2H, Harom.), 7.36 (ddd, 2H, J = 8.3, 6.6, 0.9 Hz, Harom.),
7.56 (ddd, 2H, J = 10.7, 2.1, 2.1 Hz, H-C(1)), 7.64 (ddd, 2H, J = 8.3,
6.6, 0.9 Hz, Harom.), 8.05–8.20 (m, 4H, Harom.) ppm; 13C-NMR
(100 MHz, CDCl3) d: 49.9, 70.3, 101.4, 105.3 (dd, JC,F = 31.0,
23.1 Hz), 118.3, 118.4, 122.3, 124.6, 130.1, 131.1, 137.7, 148.8,
150.4, 155.8, 158.1 ppm; 19F-NMR (188 MHz, CDCl3) d: -113.7 (m,
F), –118.2 (m, F) ppm; UV-VIS (methanol) kmax (log e): 278 nm
(4.92); MS (ESI, MeOH) m/z: 575.5 [M + H]+ (100%); HRMS for
C32H28F2NO2 calcd.: 538.2180; found: 538.2182.
N,N-Bis-9-acridinyl-1,4-bis-(3-aminopropyl)piperazine 7b
[20], [26]
Compound 7b (0.84 g, 72%) was obtained from 9-chloroacridine
(1.0 g, 4.7 mmol) and 1,4-bis-(3-aminopropyl)piperazine (0.42 g,
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

706
R. Csuk et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 699–709
2.1 mmol) following GP2 as a yellow solid. M.p.: 250–2518C. IR
(KBr) m: 2935m, 2821s, 1616s, 1561s, 1519s, 1436m, 1396m,
Harom.), 8.23 (d, 2H, J = 8.7 Hz, Harom.) ppm; 13C-NMR (125 MHz,
DMSO-d6) d: 23.9, 45.7, 49.1, 53.9, 109.9 (ddd, JC,F = 30.5, 21.2 Hz),
111.9, 113.4, 118.4, 124.6, 135.9, 136.2, 139.4, 151.6 (dd, JC,F =
1
1338m, 1310w, 1267m, 1139m, 1023w cm–1; H-NMR (400 MHz,
CDCl3) d: 2.00–2.05 (m, 4H, CH2(29)), 2.65–2.85 (m, 12H,
CH2(11,12)), 4.03–4.09. (m, 4H, CH2(19)), 7.32 (ddd, 4H, J = 8.7, 6.4,
0.9 Hz, H-C(2)), 7.66 (ddd, 4H, J = 8.7, 6.4, 0.9 Hz, H-C(3)), 8.05–8.12
(m, 4H, H-C(4)) 8.24 (dd, 4H, J = 8.7, 0.9 Hz, H-C(1)) ppm; 13C-NMR
(125 MHz, 458C, DMSO-d6) d 27.2, 48.7, 52.6, 55.6, 112.4, 122.0,
123.5, 125.6, 131.2, 145.9, 152.1 ppm; UV-VIS (methanol) kmax
(log e): 281 nm (4.93); MS (ESI, MeOH + TFA) m/z: 278.4 [M + 2H]2+
(100%), 555.5 [M + H]+ (18%); HRMS for C36H38N6 calcd.: 554.3158;
found: 554.3157.
253.3, 13.3 Hz), 156.8 (dd, JC,F = 254.0, 13.3 Hz), 157.4 ppm; 19F-
NMR (188 MHz, CDCl3) d: -115.7 (m, F), –119.6 (m, F) ppm; UV-VIS
(methanol) kmax (log e): 284 nm (4.88); MS (ESI, MeOH) m/z: 314.3
[M + 2H]2+ (70%), 627.5 [M + H]+ (100%); HRMS for C36H36F2N6 calcd.:
590.2970; found: 590.2971.
N,N -Bis-(5-methoxy-3-nitro-9-acridinyl)-1,4-bis-(3-
aminopropyl)piperazine 7f
Compound 7f (0.22 g, 17%) was obtained from 9-chloro-5-
methoxy-3-nitro-acridine (1.2 g, 4.2 mmol) and 1,4-bis-(3-amino-
propyl)piperazine (0.38 g, 1.9 mmol) following GP2 as a red
solid. M.p.: 2508C (dec.); IR (KBr) m: 2925s, 1626s, 1577s, 1542s,
1473m, 1350s, 1268s, 1101s cm–1; 1H-NMR (500 MHz, DMSO-d6)
d: 2.31–2.45 (m, 4H, CH2(29)), 3.40–3.60 (m, 12H, CH2(39, pip.)), 4.15
(s, 6H, OCH3), 4.19–4.29 (m, 4H, CH2(19)), 7.55 (dd, 2H, J = 8.5,
7.9 Hz, H-C(7)), 7.60 (d, 2H, J = 7.9 Hz, H-C(1)), 8.15 (dd, 2H, J = 7.9,
2.4 Hz, H-C(2)), 8.18–8.34 (m, 2H, Harom.), 8.84–9.00 (m, 2H, Harom.),
9.20 (d, 2H, J = 2.4 Hz, H-C(4)) ppm; 13C-NMR (125 MHz, 808C,
DMSO-d6) d: 29.0, 48.3, 53.0, 56.0, 56.4, 113.3, 114.5, 114.6, 117.0,
121.6, 121.9, 123.3, 128.2, 132.3, 140.3, 148.0, 150.0, 157.8 ppm;
UV-VIS (methanol) kmax (log e): 289 nm (4.75); MS (ESI, MeOH) m/z:
353.3 [M + 2H]2+ (100%), 700.5 [M + H]+ (45%); HRMS for C38H40N8O6
calcd.: 704.3071; found: 704.3072.
N,N-Bis-(2-methoxy-9-acridinyl)-1,4-bis-(3-
aminopropyl)piperazine 7c
Compound 7c (0.67 g, 61%) was obtained from 9-chloro-2-
methoxyacridine (1.0 g, 4.1 mmol) and 1,4-bis-(3-aminopropyl)-
piperazine (0.26 g, 1.8 mmol) following GP2 as a yellow solid.
M.p.: 191–1928C; IR (KBr) m: 2924s, 2815s, 1632s, 1561s, 1517s,
1488s, 1467m, 1426s, 1352m, 1308w, 1270m, 1233s, 1139m,
1034m cm–1; 1H-NMR (400 MHz, DMSO-d6) d: 1.76–1.86 (m, 4H,
CH2(29)), 2.18 (br s, 8H, CH2(pip.)), 2.29 (t, 4H, J = 6.6 Hz, CH2(39)),
3.70–3.80 (m, 4H, CH2(19)), 3.90 (s, 6H, OCH3), 6.73 (br s, 2H, NH),
7.30 (ddd, 2H, J = 7.8, 7.0, 1.2 Hz, Harom.), 7.37 (dd, 2H, J = 8.7,
2.1 Hz, H-C(3)), 7.55–7.62 (m, 4H, Harom.), 7.78–7.88 (m, 4H, Harom.),
8.29 (d, 2H, J = 8.7 Hz, H-C(4)) ppm; 13C-NMR (100 MHz, DMSO-d6)
d: 27.5, 47.9, 52.6, 55.3, 55.5, 100.3, 116.4, 116.8, 120.0, 121.7,
122.2, 122.7, 123.3, 123.8, 128.5, 147.9, 150.0, 154.5 ppm; UV-VIS
(methanol) kmax (log e): 289 nm (4.81); MS (ESI, MeOH + TFA) m/z:
308.4 [M + 2H]2+ (100%), 615.6 [M + H]+ (20%); HRMS for C38H32N6O2
calcd.: 614.3369; found: 614.3370.
N,N-Bis-(2-methoxy-6-nitro-9-acridinyl)-1,4-bis-(3-
aminopropyl)piperazine 7g
Compound 7g (0.22 g, 17%) was obtained from 9-chloro-2-
methoxy-6-nitro-acridine (1.2 g, 4.2 mmol) and 1,4-bis-(3-amino-
propyl)piperazine (0.38 g, 1.90 mmol) following GP2 as a red
solid. M.p.: 2628C (dec.); IR (KBr) m: 2925s, 2830m, 1634s, 1573s,
1540s, 1515s, 1482m, 1430m, 1342s, 1236s, 1139m, 1077m,
1030m cm–1; 1H-NMR (500 MHz, 808C, DMSO-d6) d: 1.84–1.97 (m,
4H, CH2(29)), 2.25 (br s, 8H, CH2(pip.)), 2.37 (t, 4H, J = 6.6 Hz,
CH2(39)), 3.80–3.90 (m, 4H, CH2(19)), 3.96 (s, 6H, OCH3), 7.42 (dd, 2H,
J = 7.5, 2.5 Hz, H-C(3)), 7.66 (d, 2H, J = 2.5 Hz, H-C(1)), 7.86–7.98 (m,
N,N-Bis-(2-trifluoromethoxy-9-acridinyl)-1,4-bis-(3-
aminopropyl)piperazine 7d
Compound 7d (0.14 g, 15%) was obtained from 9-chloro-2-tri-
fluoromethoxyacridine (1.0 g, 3.4 mmol) and 1,4-bis-(3-amino-
propyl)piperazine (0.30 g, 1.5 mmol) following GP2 as a yellow
solid. M.p.: 200–2018C; IR (KBr) m: 2925m, 2825m, 1618m, 1561s,
1517s, 1439m, 1356m, 1266s, 1218s, 1143s, 1004w cm–1; 1H-NMR
(500 MHz, 808C, DMSO-d6) d: 1.82–1.90 (m, 4H, CH2(29)), 2.27 (br s,
8H, CH2(pip.)), 2.37 (t, 4H, J = 6.6 Hz, CH2(39)), 3.80–3.90 (t, 4H,
CH2(19)), 7.25–7.32 (m, 2H, Harom.), 7.50–7.90 (m, 8H, Harom.), 8.20–
8.30 (m, 4H, Harom.) ppm; 13C-NMR (125 MHz, 808C, DMSO-d6)
d: 27.2, 48.3, 52.3, 55.2, 115.3, 120.7 (q, JC,F = 263.2 Hz), 121.8,
123.2, 129.7, 142.2, 151.3 ppm; 19F-NMR (188 MHz, DMSO-d6) d:
–57.5 (s, OCF3) ppm; UV-VIS (methanol) kmax (log e): 285 nm (4.77);
MS (ESI, MeOH) m/z: 362.3 [M + 2H]2+ (100%), 723.5 [M + H]+ (30%),
HRMS for C38H36F6N6O2 calcd.: 722.2804; found: 722.2805.
4H, Harom.), 8.51 (d, 2H, J = 9.1 Hz, H-C(4)), 8.60–8.70 (m, 2H, Harom
)
ppm; 13C-NMR (125 MHz, 458C, DMSO-d6) d: 28.4, 47.8, 52.0, 55.4,
55.7, 101.1, 105.0, 113.3, 113.7, 114.0, 114.6, 119.4 124.5, 125.0,
125.9, 126.6, 150.0, 155.8 ppm; UV-VIS (methanol) kmax (log e):
287 nm (4.85); MS (ESI, MeOH) m/z: 353.3 [M + 2H]2+ (100%), 700.5
[M + H]+ (25%); HRMS for C38H40N8O6 calcd.: 704.3071; found:
704.3072.
N,N-Bis-(2,4-dimethoxy-9-acridinyl)-1,4-bis-(3-
aminopropyl)piperazine 7h
Compound 7h (1.1 g, 65%) was obtained from 9-chloro-2,4-di-
methoxy-acridine (1.5 g, 5.5 mmol) and 1,4-bis-(3-aminopropyl)-
piperazine (0.50 g, 2.50 mmol) following GP2 as a yellow solid.
M.p.: 2248C; IR (KBr) m: 2934s, 1628s, 1570m, 1530s, 1466s, 1422s,
1343m, 1285s, 1209m, 1159s, 1056w cm–1; 1H-NMR(400 MHz,
CDCl3) d: 1.92–2.00 (m, 4H, CH2(29)), 2.55–2.65 (m, 12H, CH2(39,
pip.)), 3.73–3.83 (m, 4H, CH2(19)), 3.94 (s, 6H, OCH3), 4.07 (s, 6H,
OCH3), 6.69 (d, 2H, J = 2.5 Hz, Harom.), 6.95 (d, 2H, J = 2.5 Hz, Harom.),
7.37 (ddd, 2H, J = 8.7, 6.6, 1.2 Hz, Harom.), 7.60 (ddd, 2H, J = 8.7, 6.6,
1.2 Hz, Harom.), 8.16 (d, 2H, J = 8.7 Hz, Harom.), 8.21 (d, 2H, J = 8.7 Hz,
N,N-Bis-(2,4-difluoro-9-acridinyl)-1,4-bis-(3-
aminopropyl)piperazine 7e
Compound 7e (0.08 g, 7%) was obtained from 9-chloro-2,4-
difluoroacridine (1.0 g, 4.0 mmol) and 1,4-bis-(3-aminopropyl)pi-
perazine (0.36 g, 1.8 mmol) following GP2 as a yellow solid. M.p.:
220–2218C; IR (KBr) m: 1626s, 1593s, 1540m, 1472m, 1329m,
1290m, 1199w, 1138m, 1006w cm–1; 1H-NMR (400 MHz, DMSO-d6)
d: 2.28–2.34 (m, 4H, CH2(29)), 3.25 (t, 4H, J = 6.6 Hz, CH2(39)), 3.47
(br s, 8H, CH2(pip.)), 4.10–4.20 (m, 4H, CH2(19)), 7.49 (ddd, 2H,
J = 8.7, 6.6, 0.9 Hz, H-C(6 oder 7)), 7.62 (ddd, 2H, J = 10.7, 8.7,
2.1 Hz, H-C(3)), 7.75 (d, 2H, J = 8.7 Hz, Harom.), 7.83–7.91 (m, 4H,
H
arom.) ppm; 13C-NMR(100 MHz, CDCl3) d: 27.3, 50.0, 53.5, 55.5,
56.2, 57.4, 92.3, 101.2, 118.2, 118.3, 122.3, 123.8, 128.4, 130.15,
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2009, 342, 699–709
Monomeric and Dimeric Acridine Compounds
707
139.2, 146.6, 150.1, 155.5, 156.1 ppm; UV-VIS (methanol) kmax
(log e): 286 nm (4.82); MS (ESI, MeOH) m/z: 339.0 [M + 2H] 2+ (25%),
675.7 [M + H]+ (100%); HRMS for C40H46N6O4 calcd.: 674.3581;
found: 674.3582.
282 nm (5.03); MS (ESI, MeOH) m/z: 296.3 [M + 2H]2+ (100%), 591.5
[M + H]+ (40%); HRMS for C36H36F2N6 calcd.: 590.2970; found:
590.2969.
N,N-Bis-(2-trifluoromethoxy-7-nitro-9-acridinyl)-1,4-bis-
(3-aminopropyl)piperazine 7l
N,N-Bis-(2,4-dimethoxy-6-nitro-9-acridinyl)-1,4-bis-(3-
aminopropyl)piperazine 7i
Compound 7l (0.07 g, 12%) was obtained from 9-chloro-2-tri-
fluoromethoxy-7-nitroacridine (0.6 g, 1.8 mmol) and 1,4-bis-(3-
aminopropyl)piperazine (0.14 g, 0.70 mmol) following GP2 as a
red solid. M.p.: 2218C (dec.); IR (KBr) m: 2944m, 2822m, 1618m,
1578s, 1524s, 1490s, 1450m, 1324s, 1253s, 1222s, 1205s, 1170s,
1102m, 1011w cm–1; 1H-NMR (400 MHz, 508C, CD3OD) d: 2.03–
2.13 (m, 4H, J = 6.6 Hz, CH2(29)), 2.48 (br s, 8H, CH2(pip.)), 2.50–
2.60 (m, 4H, CH2(39)), 4.02–4.12 (m, 4H, CH2(19)), 7.63 (dd, 2H,
J = 9.5, 2.5 Hz, H-C(3)), 7.75 (d, 2H, J = 9.5 Hz, Harom.), 7.85 (d, 2H,
J = 9.5 Hz, Harom.), 8.20 (d, 2H, J = 2.5 Hz, H-C(1)), 8.33 (dd, 2H,
J = 9.5, 2.5 Hz, H-C(6)), 9.27 (d, 2H, J = 2.5 Hz, H-C(8)) ppm; 13C-
NMR (125 MHz, 908C, DMSO-d6) d: 28.9, 49.9, 53.5, 56.2, 114.0,
115.7, 121.1 (q, JC,F = 250.0 Hz), 123.1, 123.9, 125.4, 126.6, 141.2,
143.9, 149.8, 154.5 ppm; 19F-NMR (188 MHz, DMSO-d6) d: –60.0 (s,
OCF3) ppm; UV-VIS (methanol) kmax (log e): 262 nm (4.65); MS (ESI,
MeOH) m/z: 407.3 [M + 2H]2+ (10%), 813.4 [M + H]+ (100%); HRMS
for C36H34F6N8O6 calcd.: 812.2506; found: 812.2505.
Compound 7i (0.6 g, 42%) was obtained from 9-chloro-2,4-di-
methoxy-6-nitro-acridine (1.3 g, 4.2 mmol) and 1,4-bis-(3-amino-
propyl)piperazine (0.38 g, 1.90 mmol) following GP2 as a red
solid. M.p.: 1558C; IR (KBr) m: 2935s, 2832s, 1630s, 1615s, 1568s,
1519s, 1466s, 1432s, 1373m, 1341s, 1292s, 1209s, 1165s, 1148s,
1
1108s, 1048m, 1006m cm–1; HNMR (400 MHz, CD3OD) d: 2.42–
2.52 (m, 4H, CH2(29)), 3.30 (br s, 8H, CH2(pip.)), 3.40 (t, 4H,
J = 6.6 Hz, CH2(39)), 3.98 (s, 6H, OCH3), 4.14 (s, 6H, OCH3), 4.24–4.33
(m, 4H, CH2(19)), 7.14 (d, 2H, J = 2.5 Hz, Harom.), 7.38 (d, 2H,
J = 2.5 Hz, Harom.), 8.16 (dd, 2H, J = 9.5, 2.5 Hz, H-C(7)) 8.64 (d, 2H,
J = 9.5 Hz, H-C(8)), 9.00 (d, 2H, J = 2.5 Hz, H-C(5)) ppm; 13C-NMR
(125 MHz, 458C, DMSO-d6) d: 29.6, 48.5, 53.3, 56.3, 56.7, 57.4,
92.8, 103.4, 114.8, 115.5, 119.6, 127.0, 127.4, 140.4, 145.6, 147.6,
155.7, 156.9, 157.4 ppm; UV-VIS (methanol) kmax (log e): 287 nm
(4.85); MS (ESI, MeOH) m/z: 383.3 [M + 2H]2+ (100%), 765.5 [M + H]+
(20%); HRMS for C40H44N8O8 calcd.: 764.3282; found: 764.3284.
N,N-Bis-(3-fluoro-9-acridinyl)-1,4-bis-(3-
aminopropyl)piperazine 7j
N,N-Bis-(3-chloro-9-acridinyl)-1,4-bis-(3-
Compound 7j (0.74 g, 36%) was obtained from 9-chloro-3-fluoro-
acridine (2.0 g, 8.6 mmol) and 1,4-bis-(3-aminopropyl)piperazine
(0.70 g, 3.50 mmol) following GP2 as a red solid. M.p.: 2708C
(dec.); IR (KBr) m: 3238m, 3045m, 2938m, 2823m, 2610m, 1639s,
1591s, 1540s, 1477s, 1362m, 1270s, 1189m, 1161m, 1142m,
aminopropyl)piperazine 7m
Compound 7m (0.66 g, 44%) was obtained from 3,9-dichloroacri-
dine (1.5 g, 6.0 mmol) and 1,4-bis-(3-aminopropyl)piperazine
(0.48 g, 2.40 mmol) following GP2 as a yellow solid. M.p.: 1828C
(dec.); IR (KBr) m: 3287s, 2925m, 2824m, 1607s, 1563s, 1521s,
1449s, 1383w, 1355m, 1343m, 1310m, 1252m, 1140m, 1080m,
1028w cm–1; 1H-NMR (400 MHz, 508C, CD3OD) d: 2.42–2.52 (m,
4H, CH2(29)), 3.50–3.59 (m, 12H, CH2(39, pip.)), 4.27–4.38 (m, 4H,
CH2(19)), 7.55 (d 2H, J = 8.7 Hz, Harom.), 7.61 (dd, 2H, J = 7.9, 7.1 Hz,
Harom.), 7.79–7.85 (m, 4H, Harom.), 7.99 (dd, 2H, J = 7.9, 7.1 Hz, Harom.),
8.57 (m, 4H, Harom.) ppm; UV-VIS (methanol) kmax (log e): 289 nm
(4.54); MS (ESI, MeOH) m/z: 312.4 [M + 2H]2+ (100%), 623.4 [M + H]+
(40%); HRMS for C36H36Cl2N6 calcd.: 622.2379; found: 622.2379.
1
1116w, 1098w, 1082w cm–1; H-NMR (500 MHz, 808C, DMSO-d6)
d: 1.92–2.02 (m, 4H, CH2(29)), 2.38 (br s, 8H, CH2(pip.)), 3.22–3.31
(m, 4H, CH2(39)), 3.99–4.07 (m, 4H, CH2(19)), 7.25 (ddd, 2H, J = 9.5,
7.5, 2.5 Hz, Harom.), 7.37–7.44 (m, 2H, Harom.), 7.50 (dd, 2H, J = 10.4,
2.5 Hz, H-C(4)), 7.75–7.82 (m, 4H, Harom.), 8.41 (d, 2H, J = 8.5 Hz,
Harom.), 8.50 (d, 2H, J = 9.1, 6.1 Hz, H-C(1)) ppm;13C-NMR (125 MHz,
808C, DMSO-d6) d: 27.5, 49.5, 52.2, 55.1, 105.3, 121.1, 122.0,
122.5, 124.2, 124.8, 127.7, 129.3, 129.8, 130.3, 151.2, 158.5 (d,
JC,F = 250.9 Hz), 160.7 ppm; 19F-NMR (188 MHz, DMSO-d6) d: –112.0
(m, F) ppm; UV-VIS (methanol) kmax (log e): 283 nm (4.99); MS (ESI,
MeOH) m/z: 296.3 [M + 2H]2+ (100%), 591.5 [M + H]+ (30%); HRMS
for C36H36F2N6 calcd.: 590.2970; found: 590.2970.
N,N-Bis-(2,3,4-trifluoro-9-acridinyl)-1,4-bis-(3-
aminopropyl)piperazine 7n
Compound 7n (0.26 g, 17%) was obtained from 9-chloro-2,3,4-tri-
fluoroacridine (1.5 g, 5.6 mmol) and 1,4-bis-(3-aminopropyl)pi-
perazine (0.46 g, 2.30 mmol) following GP2 as a yellow solid.
M.p.: 2248C; IR (KBr) m: 2925m, 1629s, 1596s, 1544m, 1518m,
1481m, 1402m, 1300m, 1262m, 1150m, 1065m cm–1; 1H-NMR
(400 MHz, CD3OD) d: 2.42–2.52 (m, 4H, CH2(29)), 3.34 (br s, 4H,
CH2(39)), 3.58 (br s, 8H, CH2(pip.)), 4.30–4.40 (m, 4H, CH2(19)), 7.62–
7.68 (m, 2H, Harom.), 8.00–8.05 (m, 4H, Harom.), 8.44–8.57 (m, 4H,
Harom.) ppm;13C-NMR (125 MHz, 808C, DMSO-d6) d: 25.5 (t, CH2(29)),
47.9 (t, CH2(19)), 50.7 (t, CH2(pip.)), 55.1 (t, CH2(39)), 108.5, 110.1,
N,N-Bis-(1-fluoro-9-acridinyl)-1,4-bis-(3-
aminopropyl)piperazine 7k
Compound 7k (0.71 g, 47%) was obtained from 9-chloro-1-fluoro-
acridine (1.5 g, 6.5 mmol) and 1,4-bis-(3-aminopropyl)piperazine
(0.52 g, 2.60 mmol) following GP2 as a yellow solid. M.p.: 1828C;
IR (KBr) m: 3252s, 2919s, 2822s, 1633m, 1613m, 1555s, 1513s,
1461s, 1435m, 1386m, 1357m, 1341m, 1312m, 1272w, 1229w,
1210w, 1131m, 1028w, 1019m cm–1; 1H-NMR (500 MHz, 808C,
DMSO-d6) d: 1.74–1.84 (m, 4H, CH2(29)), 2.22 (s, 8H, CH2(pip.)), 2.32
(t, 4H, J = 6.7 Hz, CH2(39)), 3.63–3.73 (m, 4H, CH2(19)), 6.93 (dd, 2H,
J = 12.8, 7.9 Hz, Harom.), 7.23 (dd, 2H, J = 7.3, 7.3 Hz, Harom.), 7.40–
7.64 (m, 8H, Harom.), 8.13 (d, 2H, J = 7.9 Hz, Harom.) ppm; 13C-NMR
(125 MHz, 458C, DMSO-d6) d: 23.1, 45.7, 47.7, 52.9, 55.4, 102.9,
109.2, 111.4, 112.9, 118.2, 123.7, 125.7, 135.1 135.7, 139.3, 141.6,
157.4, 165.1 (d, JC,F = 251.6 Hz) ppm; 19F-NMR (188 MHz, 508C,
DMSO-d6) d: –101.8 (m, F) ppm; UV-VIS (methanol) kmax (log e):
114.0, 117.1, 119.9, 126.0, 130.3, 131.1, 137.3, 141.7 (dd, JC,F
254.0, 15.7 Hz), 147.0, 144.6 (dd, JC,F = 250.4, 12.0 Hz), 146.5 (dd,
C,F = 250.1, 10.7 Hz), 149.6, 159.5 ppm; 19F-NMR (188 MHz, DMSO-
=
J
d6) d: –139.4 (m, F), –150.6 (m, F), –151.8 (m, F) ppm; UV-VIS (meth-
anol) kmax (log e): 283 nm (4.81); MS (ESI, MeOH) m/z: 332.3 [M +
2H]2+ (20%), 663.4 [M + H]+ (100%); HRMS for C36H32F6N6 calcd.:
662.2593; found: 662.2593.
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www.archpharm.com

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R. Csuk et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 699–709
1545s, 1521s, 1478s, 1437s, 1336s, 1240m, 11182m, 1137m,
1102w cm–1; 1H-NMR (400 MHz, 508C, DMSO-d6) d: 2.40–2.44 (m,
4H, CH2(29)), 2.63 (s, 6H, SCH3), 3.20–3.40 (m, 12H, CH2(39, pip.)),
4.22–4.28 (m, 4H, CH2(19)), 7.56 (dd, 2H, J = 8.3, 7.5 Hz, H-C(7)),
8.06 (d, 2H, J = 7.5 Hz, H-C(6)), 8.43–8.62 (m, 6H, Harom.), 9.42 (br s,
2H, H-C(1)) ppm; 13C-NMR (125 MHz, DMSO-d6) d: 17.6, 22.9, 46.7,
53.0, 56.0, 113.0, 119.2, 120.3, 121.2, 122.4, 123.0, 124.8, 125.7,
127.2, 136.1, 139.1, 141.2, 144.5 ppm; UV-VIS (methanol) kmax
(log e): 283 nm (4.64); MS (ESI, MeOH + TFA) m/z: 369.3 [M + 2H]2+
(25%), 737.4 [M + H]+ (100%); HRMS for C36H40N8O4S2 calcd.:
736.2614; found: 736.2615.
N,N-Bis-(4-methoxy-9-acridinyl)-1,4-bis-(3-
aminopropyl)piperazine 7o
Compound 7o (1.23 g, 82%) was obtained from 9-chloro-4-
methoxyacridine (1.5 g, 6.2 mmol) and 1,4-bis-(3-aminopropyl)-
piperazine (0.50 g, 2.50 mmol) following GP2 as a yellow solid.
M.p.: 1948C; IR (KBr) m: 3252s, 2914s, 2826s, 1614m, 1570s, 1524s,
1467s, 1431s, 1331m, 1312m, 1269s, 1249s, 1134s, 1083s,
1025w cm–1; 1H-NMR (400 MHz, DMSO-d6) d: 1.80–1.88 (m, 4H,
CH2(29)), 2.31 (br s, 8H, CH2(pip.)), 2.38 (t, 4H, J = 6.7 Hz, CH2(39)),
3.81–3.86 (m, 4H, CH2(19)), 3.96 (s, 6H, OCH3), 7.06 (d, 2H,
J = 7.5 Hz, Harom.), 7.18 (dd, 2H, J = 7.9 Hz, Harom.), 7.27 (dd, 2H,
J = 7.9 Hz, Harom.), 7.80–7.88 (m, 4H, Harom.), 8.28 (d, 2H, J = 8.7 Hz,
Harom.) ppm; 13C-NMR (125 MHz, 808C, DMSO-d6) d: 27.3, 48.8,
52.4, 55.5, 55.6, 108.1, 116.0, 116.7, 117.3, 120.9, 121.4, 124.3
125.7, 129.1, 138.7, 145.4, 151.3, 152.7 ppm; UV-VIS (methanol)
kmax (log e): 284 nm (5.25); MS (ESI, MeOH) m/z: 308.4 [M + 2H]2+
(100%), 615.5 [M + H]+ (40%); HRMS for C38H42N6O2 calcd.:
614.3369; found: 614.3369.
The authors are grateful to Miki Tachibana for assistance in the synthe-
sis. Many thanks are due to Dr. C. Wagner for performing the crystal
structure analysis.
The authors have declared no conflict of interest.
N,N-Bis-(4-thiomethyl-9-acridinyl)-1,4-bis-(3-
aminopropyl)piperazine 7p
References
Compound 7p (0.84 g, 62%) was obtained from 9-chloro-4-thio-
methylacridine 3a (1.2 g, 4.6 mmol) and 1,4-bis-(3-aminopropyl)-
piperazine (0.42 g, 2.10 mmol) following GP2 as a yellow solid.
M.p.: 177–1788C; IR (KBr) m: 2921s, 2819s, 1618s, 1599m, 1557m,
1511s, 1456m, 1437s, 1336m, 1306m, 1257m, 1137s cm–1; 1H-
NMR (400 MHz, 508C, DMSO-d6) d: 1.80–1.94 (m, 4H, CH2(29)), 2.34
(s, 6H, SCH3), 2.40–2.54 (m, 12H, CH2(39, pip.)), 3.81–3.90 (m, 4H,
CH2(19)), 7.23–7.40 (m, 6H, Harom.), 7.65 (dd, 2H, J = 7.9, 7.5 Hz,
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arom.), 7.89 (d, 2H, J = 7.9 Hz, Harom.), 8.08 (d, 2H, J = 8.7 Hz, Harom.),
8.35 (d, 2H, J = 8.7 Hz, Harom.) ppm; 13C-NMR (125 MHz, 908C,
DMSO-d6) d: 17.6, 26.3, 47.9, 51.7, 54.8, 114.9, 115.8, 119.2, 121.6,
122.0, 123.2, 123.6, 128.0, 129.4, 138.0, 145.2, 146.9, 151.8 ppm;
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325.1 [M + 2H]2+ (100%), 647.5 [M + H]+ (20%); HRMS for C38H42N6S2
calcd.: 646.2912; found: 646.2910.
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N,N-Bis-(3-chloro-5-methoxy-9-acridinyl)-1,4-bis-(3-
aminopropyl)piperazine 7q
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Compound 7q (1.0 g, 57%) was obtained from 3,9-dichloro-5-
methoxyacridine (1.5 g, 6.1 mmol) and 1,4-bis-(3-aminopropyl)-
piperazine (0.50 g, 2.50 mmol) following GP2 as a yellow solid.
M.p.: 224–2258C; IR (KBr) m: 2930s, 2826s, 1618s, 1564s, 1522s,
1458s, 1437s, 1348m, 1310m, 1250s, 1147m, 1084s cm–1; 1H-NMR
(400 MHz, 458C, CDCl3) d: 1.92–2.00 (m, 4H, CH2(29)), 2.66–2.74 (m,
12H, CH2(39, pip.)), 3.94–3.98 (m, 4H, CH2(19)), 4.08 (s, 6H, OCH3),
6.97 (d, 2H, J = 7.5 Hz, Harom.), 7.17–7.23 (m, 4H, Harom.), 7.73 (d, 2H,
J = 8.7 Hz, Harom.), 8.11–8.16 (m, 4H, Harom.); 13C-NMR (125 MHz,
508C, DMSO-d6) d: 27.2, 47.7, 52.3, 54.9, 56.3, 101.4, 114.4, 116.9,
122.1, 123.3, 124.0, 126.0, 129.3, 133.2, 147.3, 150.3, 154.8 ppm;
UV-VIS (methanol) kmax (log e): 288 nm (4.64); MS (ESI, MeOH +
TFA) m/z: 342.4 [M + 2H]2+ (40%), 683.6 [M + H]+ (100%); HRMS for
C38H40Cl2N6O2 calcd.: 682.2590; found: 682.2591.
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N,N-Bis-(2-nitro-5-thiomethyl-9-acridinyl)-1,4-bis-(3-
aminopropyl)piperazine 7r
Compound 7r (0.5 g, 45%) was obtained from 9-chloro-2-nitro-5-
thiomethylacridine 3b (1.2 g, 3.9 mmol) and 1,4-bis-(3-aminopro-
pyl)piperazine (0.30 g, 1.50 mmol) following GP2 as an orange-
colored solid. M.p.: 246–2488C; IR (KBr) m: 2923s, 1631s, 1598s,
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Arch. Pharm. Chem. Life Sci. 2009, 342, 699–709
Monomeric and Dimeric Acridine Compounds
709
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i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com