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pubs.acs.org/jnp
Anke Wilhelm,*, Pravin Kendrekar, Anwar E. M. Noreljaleel, Efrem T. Abay, Susan L. Bonnet,
,
4 Lubbe Wiesner, Carmen de Kock, Kenneth J. Swart, and Jan Hendrik van der Westhuizen*
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Department of Chemistry and Directorate: Research Development, University of the Free State, Nelson Mandela Drive 205,
Bloemfontein 9301, South Africa
Department of Pharmacology, University of Cape Town, Medical School, Observatory 7925, South Africa
PAREXEL International Clinical Research Organization, Private Bag X09, Brandhof 9324, Bloemfontein 339, South Africa
S Supporting Information
*
ABSTRACT: A series of readily synthesized and inexpensive aminoalkylated chalcones and diarylpropane analogues (155)
were synthesized and tested against chloroquinone-sensitive (D10 and NF54) and -resistant (Dd2 and K1) strains of Plasmodium
falciparum. Hydrogenation of the enone to a diarylpropane moiety increased antiplasmodial bioactivity signicantly. The
inuence of the structure of the amine moiety, A-ring substituents, propyl vs ethyl linker, and chloride salt formation on further
enhancing antiplasmodial activity was investigated. Several compounds have IC50 values similar to or better than chloroquine
(CQ). The most active compound (26) had an IC50 value of 0.01 M. No signs of resistance were detected, as can be expected
from compounds with structures unrelated to CQ and other currently used antimalarial drugs. Toxicity tests (in vitro CHO cell
assay) gave high SI indices.
tionally to treat malaria. Chalcones (1,3-diaryl-2-propen-1ones) are precursors in the biosynthesis of avonoids and occur
widely in medicinal plants. Bioactivity of chalcones includes in
vivo activity against skin carcinogenesis13 and limiting cell
proliferation. The in vivo ecacy and mode of action of
avonoids, including chalcones, is however controversial since
polar polyphenols are poorly absorbed, do not conform to the
Lipinski rules,14 and are rapidly metabolized by liver enzymes in
the plasma,15 leading to insignicant bioavailability. It thus
remains a challenge to reconcile their poor bioavailability with
putative health eects.
Most drugs contain nitrogen, and the introduction of
nitrogen into molecules has often led to enhanced bioactivity.
Dimmock and co-workers reviewed the biological activity of
Mannich bases,16 obtained via the Mannich reaction, and found
properties such as antimalarial,17,18 antiviral,19 and antibacterial20 activity. Flavonoids have also served as scaolds and
inspiration to design new molecules with potential biological
activity. Little research has been reported on the synthesis and
biological activity of chalcones with nitrogen moieties. Reddy
and co-workers21 reported the syntheses and in vitro biological
evaluation of heterocyclic nitrogen-containing chalcones with
dierent substitution patterns in the B-ring, together with a
discussion of structureacitivity relationships. We postulated an
Received: February 4, 2015
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t9
Article
Table 1. 1H NMR (600 MHz) Data for Compounds 1 (Acetone-d6), 3 (Acetone-d6), 20 (CDCl3), 23 (CDCl3), and 24 (CDCl3)
[H, ppm, Mult. (J in Hz)]
proton
H-1
H-2
H-3
H-2/6
H-3/5
H-2
H-3
H-4
H-5
H-6
H-2/6
H-3/5
H-4
OCH3
CH2
a
20
H (J in Hz)
H (J in Hz)
H (J in Hz)
7.69, d (15.6)
7.80, d (15.6)
8.16, d (8.9)
7.07, d (8.9)
7.307.25,a m
7.68,
7.81,
8.18,
7.07,
7.17,
7.307.25,a m
7.307.25,a m
6.956.93,a m
b3
(15.5)
(15.5)
(8.9)
(8.9)
(1.5)
7.09, d (7.5)
7.16, dd (7.5, 1.5)
2.53, br s
1.661.60, m
1.52, br s
3.91, s
3.74, s
3.91, s
Interchangeable.
d
d
d
d
d
d (7.5)
dd (7.6, 1.5)
br s
s
s
6.72, d (7.6)
7.10, t (8.0)
6.64, d (1.5)
24
H (J in Hz)
2.56, t (7.6)
1.911.82, m
2.53, t (7.6)
7.10, d (8.7)
6.82, d (8.7)
6.56, d (1.5)
6.86,
6.86,
2.45,
1.57,
1.46,
3.73,
3.59,
d (7.2)
dd (7.3, 1.5)
br s
p
br s
s
s
JHH. c4JHF.
20
23
24
carbon
C-1
C-2
C-3
C-1
C-2
C-3
C-4
C-5
C-6
C-1
C-2
C-3
C-4
C-5
OCH3
CH2
C-2
C-3
C-4
C-5
C-6
187.4
121.9
143.3
131.1
130.7
113.9
163.6
113.9
130.7
136.7
117.4
157.8
114.9
129.9
55.1
188.2
122.3
144.1
132.1
131.6
114.7
164.5
114.7
131.6
136.5
120.7
159.6
125.6
130.0
56.0
62.4
54.5
26.7
24.6
26.7
54.4
197.8
40.3
30.0
133.3a (3.1)
130.7b (9.1)
115.7c (21.8)
165.7d (254.4)
115.7c (21.8)
130.7b (9.1)
141.7
115.8
158.1
119.5
128.6
34.4
32.9
35.2
134.5
129.3
113.7
157.5
113.7
129.3
144.3
115.4
155.6
112.7
129.4
55.3
35.2
34.2
35.8
135.0
130.1
114.5
159.0
114.5
130.1
143.7
116.4
26.7
24.7
26.7
54.4
62.3
55.4
26.7
24.7
26.7
55.1
b3
6.86,
6.64,
2.47,
1.61,
1.61,
H (J in Hz)
2.572.51, m
1.891.83, m
2.572.51, m
7.06, d (8.5)
6.82, d (8.6)
6.64, d (1.5)
3.76, s
JCF.
t (7.6)
t (7.6)
dd (8.9,b 5.4,c)
t (8.9,b 8.9c)
d (1.5)
3.62, s
a4
3.24,
2.96,
7.97,
7.09,
6.69,
23
61.9
53.9
25.9
24.0
25.9
53.9
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Table 3. Antiplasmodial Activity (IC50) of Aminoalkylated Chalcones (311) Compared with Chalcones Devoid of a Nitrogen
Functionality (1, 2)
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Data shown as means SD where applicable. bD10: chloroquine-sensitive Plasmodium falciparum strain.
EXPERIMENTAL SECTION
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NF54: alternative chloroquine-sensitive Plasmodium falciparum strain. bDd2: chloroquine-resistant Plasmodium falciparum strain. cRI: resistance
index: IC50(Dd2)/IC50(D10). dND: not determined.
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ltered through silica gel, and the ltrate was extracted with EtOAc (2
50 mL) and washed with water (1 30 mL) and brine (1 20 mL).
The organic layer was dried over anhydrous MgSO4, and the solvent
evaporated under reduced pressure. Column chromatography
[hexanes/EtOAc (7:3), 1.5 cm 15 cm] yielded the pure
dihydrochalcones in good yield. This is demonstrated for the synthesis
of 1-(4-uorophenyl)-3-[3-hydroxy-4-(piperidin-1-ylmethyl)phenyl]propan-1-one (20) using 1-(4-uorophenyl)-3-(3-hydroxyphenyl)propan-1-one (0.100 g; 0.41 mmol), paraformaldehyde (0.024 g;
0.80 mmol), and piperidine (0.09 mL; 0.88 mmol).
1-(4-Fluorophenyl)-3-(3-hydroxy-4-(piperidin-1-ylmethyl)phenyl)propan-1-one (20): light yellow oil; 1H NMR (CDCl3, TMS, 600
MHz) 7.97 (2H, dd, 3JHH = 8.9 Hz; 4JHF = 5.4 Hz, H-2, H-6),
7.09 (2H, t, 3JHH = 8.9 Hz; 4JHF = 8.9 Hz, H-3, H-5), 6.86 (1H, d, J
= 7.6 Hz, H-5), 6.69 (1H, d, J = 1.5 Hz, H-2), 6.64 (1H, dd, J = 7.6,
1.5 Hz, H-6), 3.62 (2H, s, CH2), 3.24 (2H, t, J = 7.6 Hz, H-2), 2.96
(2H, t, J = 7.6 Hz, H-3), 2.47 (4H, H-2, H-6), 1.61 (6H, s, H-3,
H-4, H-5); 13C NMR (CDCl3, TMS, 150 MHz) 197.8 (C-1),
165.7 (1C, d, 1JCF = 254.4 Hz, C-4), 158.1 (C-3), 141.7 (C-1),
133.3 (1C, d, 4JCF = 3.1 Hz, C-1), 130.7 (2C, d, 3JCF = 9.1 Hz, C-2,
C-6), 128.6 (C-5), 119.5 (C-4), 119.0 (C-6), 115.8 (C-2), 115.7
(2C, d, 2JCF = 21.8 Hz, C-3, C-5), 61.9 (CH2), 53.9 (C-2, C-6),
40.3 (C-2), 30.0 (C-3), 25.9 (C-3, C-5), 24.0 (C-4); column
chromatography [hexanes/EtOAc (6:4), 1.5 cm 15 cm]; Rf = 0.52;
0.118 g; 84%.
General Procedure for the Synthesis of the Diarylpropanes.
The appropriate chalcone (1 equiv) was dissolved in a 1:3 (v/v)
hydroxy-4-(piperidin-1-ylmethyl)phenyl]-1-(4-methoxyphenyl)prop2-en-1-one (3) using (E)-3-(3-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (1) (0.609 g; 2.4 mmol), paraformaldehyde (0.145 g;
4.8 mmol), and piperidine (0.50 mL; 5.1 mmol).
(E)-3-(3-Hydroxy-4-[piperidin-1-ylmethyl)phenyl]-1-(4methoxyphenyl)prop-2-en-1-one (3): beige crystals39 (EtOH); mp
120121 C; IR (KBr) max 2945.44, 2159.13, 2031.94, 1598.90,
1256.25 cm1; 1H NMR (acetone-d6, TMS, 600 MHz) 8.18 (2H, d, J
= 8.9 Hz, H-2, H-6), 7.81 (1H, d, J = 15.5 Hz, H-3), 7.68 (1H, d, J =
15.5 Hz, H-2), 7.17 (1H, d, J = 1.5 Hz, H-2), 7.16 (1H, dd, J = 7.5,
1.5 Hz, H-6), 7.09 (1H, d, J = 7.5 Hz, H-5), 7.07 (2H, d, J = 8.9 Hz,
H-3, H-5), 3.91 (3H, s, OCH3), 3.74 (2H, s, CH2), 2.53 (4H, br s, H2, H-6), 1.661.60 (4H, m, H-3, H-5), 1.52 (2H, br s, H-4);
13
C NMR (acetone-d6, TMS, 150 MHz) 188.2 (C-1), 164.5 (C-4),
159.6 (C-3), 144.1 (C-3), 136.5 (C-1), 132.1 (C-1), 131.6 (C-2,
C-6), 130.0 (C-5), 125.6 (C-4), 122.3 (C-2), 120.7 (C-2), 115.6
(C-6), 114.7 (C-3, C-5), 62.4 (CH2), 56.0 (OCH3), 54.5 (C-2, C6), 26.7 (C-3, C-5), 24.6 (C-4); HREIMS m/z 351.1826 (calcd
for C22H25NO3, 351.1824); HPLC purity 99.1%, tR = 1.54 min;
column chromatography [toluene/acetone (5:5), 1.5 cm 20 cm]; Rf
= 0.42; 0.520 g, 62%.
General Procedure for the Synthesis of the Dihydrochalcones. The appropriate chalcone (1 equiv) was dissolved in a 1:3 (v/
v) solution of EtOAc/H2O. Pd(OH)2/C (0.060 g) was added, and the
system ushed with hydrogen. The reaction mixture was left to stir at
room temperature for 2448 h under H2 at atmospheric pressure.
After completion of the reaction (TLC) the reaction mixture was
F
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34.4 (C-1), 32.9 (C-2); HREIMS m/z 242.1306 (calcd for C16H18O2,
242.1307); Rf = 0.55, 0.185 g; 97%.
General Procedure for the Synthesis of Aminoalkylated
Diarylpropanes. A mixture of the appropriate diarylpropane (1
equiv), paraformaldehyde (1.5 equiv), and the appropriate amine (2
equiv) was dissolved in EtOH (2 mL) and concentrated HCl (5
drops). The reaction mixture was reuxed for 9 h until TLC showed
the disappearance of the starting material. The reaction mixture was
quenched with solid NaHCO3 and extracted with EtOAc (2 50 mL),
and the extract was washed with water (2 50 mL). The organic layer
was dried over Na2SO4, and the solvent evaporated under reduced
pressure. This is demonstrated for the synthesis of 5-[3-(4methoxyphenyl)propyl]-2-(piperidin-1-ylmethyl)phenol (24) using
3-[3-(4-methoxyphenyl)propyl]phenol (23) (0.165 g; 0.68 mmol),
paraformaldehyde (0.037 g; 1.23 mmol), and piperidine (0.1 mL; 1.0
mmol).
5-[3-(4-Methoxyphenyl)propyl]-2-(piperidin-1-ylmethyl)phenol
(24): light yellow oil; IR (KBr) max 2932.41, 2360.34, 1510.49,
1242.60 cm1; 1H NMR (acetone-d6, TMS, 600 MHz) 7.10 (2H, d, J
= 8.7 Hz, H-2, H-6), 6.86 (1H, d, J = 7.2 Hz, H-5), 6.82 (2H, d, J =
8.7 Hz, H-3, H-5), 6.586.54 (1H, d, J = 1.5 Hz, H-2, 1H, dd, J =
7.3, 1.5 Hz, H-6), 3.73 (3H, s, OCH3), 3.59 (2H, s, CH2), 2.56 (2H,
t, J = 7.6 Hz, H-1), 2.53 (2H, t, J = 7.6 Hz, H-3), 2.45 (4H, br s, H-2,
H-6), 1.911.82 (2H, m, H-2), 1.57 (4H, p, H-3, H-5), 1.46 (2H,
br s, H-4); 13C NMR (acetone-d6, TMS, 150 MHz) 159.0 (C-4),
158.8 (C-3), 143.7 (C-1), 135.0 (C-1), 130.1 (C-2, C-6), 129.3
(C-5), 120.0 (C-4), 119.6 (C-6), 116.4 (C-2), 114.5 (C-3, C-5),
62.3 (CH2), 55.4 (C-2, C-6), 54.4 (OCH3), 35.8 (C-3), 35.2 (C-1),
34.2 (C-2), 26.7 (C-3, C-5), 24.7 (C-4); HREIMS m/z 339.2198
(calcd for C22H29NO2, 339.2200); ash column chromatography
[hexanes/EtOAc (6:4), 1.5 cm 15 cm]; Rf = 0.52; 0.095 g; 41%.
General Synthesis of HCl Salts of the Aminoalkylated
Diarylpropanes. The appropriate aminoalkyldiarylpropane was
dissolved in dry DCM (10 mL) at 0 C. HCl gas was bubbled
through the reaction mixture for 60 min. Precipitation indicated the
formation of the salt. The excess solvent was removed under a stream
of N2 gas, and the product was lyophilized overnight. This is
demonstrated for the synthesis of 1-[2-hydroxy-4-{3-(4methoxyphenyl)propyl}benzyl]piperidinium chloride (40) using 5[3-(4-methoxyphenyl)propyl]-2-(piperidin-1-ylmethyl)phenol (26)
(0.200 g, 0.59 mmol).
1-[2-Hydroxy-4-{3-(4-methoxyphenyl)propyl}benzyl]piperidinium
chloride (40): white, amorphous solid; IR (neat) max 2935.94,
1511.06, 1242.36, 1033.16, 827.06 cm1; 1H NMR (acetone-d6, TMS,
600 MHz) 7.47 (1H, d, J = 7.8 Hz, H-5), 7.13 (2H, d, J = 8.6 Hz,
H-2, H-6), 6.98 (1H, d, J = 1.2 Hz, H-2), 6.84 (2H, d, J = 8.6 Hz, H3, H-5), 6.76 (1H, dd, J = 7.6, 1.5 Hz, H-6), 4.18 (2H, d, J = 4.7 Hz,
CH2), 3.76 (3H, s, OCH3), 3.42 (2H, d, J = 11.6 Hz, H-2), 2.96
2.87 (6H, m, H-3, H-4, H-5), 2.632.53 (4H, m, H-1, H-3),
1.941.85 (2H, m, H-2, H-6), 1.82 (2H, d, J = 14.5 Hz, H-6); 13C
H
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Table 9. Toxicity Values (IC50) of the Most Promising Analogues against CHO Cell Lines and SI Values
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ASSOCIATED CONTENT
473
S Supporting Information
*
474
AUTHOR INFORMATION
*Tel: +27 (0)51 401 9305. Fax: +27 (0)51 401 7295. E-mail:
wilhelma@ufs.ac.za (A. Wilhelm).
*Tel: +27 (0)51 401 2782. Fax: +27 (0)51 401 7295. E-mail:
vdwestjh@ufs.ac.za (J. H. van der Westhuizen).
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REFERENCES
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ACKNOWLEDGMENTS
We thank Dr. C. Edlin, previously from iThemba Pharmaceuticals, for his valuable input toward the structural modications
of compounds in this study. Financial support by the University
of the Free State is acknowledged.
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Notes
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