Synthesis of Aminoquinoline-Based Aminoalcohols and Oxazolidinones and Their Antiplasmodial Activity

Article abstract of DOI:10.1111/j.1747-0285.2011.01278.x

Novel aminoquinoline β-aminoalcohol and oxazolidinone derivatives were designed, synthesized, and evaluated for in vitro antiplasmodial activity against a chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. A few β-aminoalcohol derivatives were more potent than chloroquine against chloroquine-sensetive Plasmodiums. The potency of these derivatives decreased against chloroquine-resistant species in all cases (higher resistance indices), suggesting a possible cross-resistance between this group of compounds and chloroquine which could be due to their structural similarity. Although changing β-aminoalcohols to their oxazolidinone counterparts decreased the potency in all the cases, the compounds were still active and the resistance indices for these compounds improved significantly in comparison with those of β-aminoalcohols. This may indicate the absence of cross-resistance between these new derivatives and chloroquine.

Full text of DOI:10.1111/j.1747-0285.2011.01278.x

ª 2011 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2011.01278.x
Chem Biol Drug Des 2012; 79: 326–331
Research Article
Synthesis of Aminoquinoline-Based
Aminoalcohols and Oxazolidinones and Their
Antiplasmodial Activity
Farzad Kobarfard1, Vanessa Yardley2,
(1). This is mostly because of the rapid spread of Plasmodium falci-
parum resistance to available antimalarial drugs. Thus, there is a
constant need for developing new antimalarial compounds (2).
Although current efforts in antimalarial drug discovery are focused
Susan Little2, Fereidoon Daryaee3,4,* and
Kelly Chibale5
1Department of Medicinal Chemistry, School of Pharmacy, Shaheed-
on identification of new biological targets, continued research on
new 4-aminoquinoline derivatives 1 is still warranted. This is
because the hemoglobin degradation pathway in P. falciparum has a
proven history as an excellent therapeutic target to which the para-
site has had difficulty in developing resistance. In spite of resis-
tance to chloroquine 2, previous work has shown that modification
of the lateral side chain of chloroquine results in aminoquinoline
derivatives that avoid the chloroquine resistance mechanism (3,4). In
this study, 4-aminoquinoline was used as a scaffold to synthesize a
series of b-aminoalcohol and oxazolidinone derivatives (Scheme 1).
The rationale for choosing these classes of derivatives is based on
the fact that the b-aminoalcohol moiety is present in a number of
potent antimalarial drugs exemplified by quinine 3 and mefloquine
4 (5). On the other hand, the oxazolidinone ring 5 can be viewed as
a rigid form of the b-aminoalcohol moiety (Figure 1). Moreover,
structural requirements for antiplasmodial activity of aminoalcohol
antiplasmodial agents include the presence of an aromatic portion
and aminoalcohol portion in such a way that the amino and alcohol
groups are separated by two to three carbon atoms (6). Thus, the
combination of a potentially active moiety with the 4-aminoquinoline
scaffold can be considered as a logical approach.
Beheshti University of Medical Sciences, Tehran, Iran
2Department of Infectious and Tropical Diseases, London School of
Hygiene and Tropical Medicine, University of London, London, UK
3Neuroscience Research Center, Kerman University of Medical
Sciences, Haft-Bagh Boulevard, Kerman, Iran
4Faculty of Pharmacy, Department of Medicinal Chemistry,
Phramaceutics Research Center, Kerman University of Medical
Sciences, Haft-Bagh Boulevard, Kerman, Iran
5Department of Chemistry and Institute of Infectious Disease and
Molecular Medicine, University of Cape Town, Rondebosch 7701,
South Africa
*Corresponding author: Fereidoon Daryaee, f_daryaee@yahoo.co.uk
Novel aminoquinoline b-aminoalcohol and oxazolid-
inone derivatives were designed, synthesized, and
evaluated for in vitro antiplasmodial activity
against a chloroquine-sensitive (3D7) and chloro-
quine-resistant (K1) strains of Plasmodium falcipa-
rum. A few b-aminoalcohol derivatives were more
potent than chloroquine against chloroquine-sense-
tive Plasmodiums. The potency of these derivatives
decreased against chloroquine-resistant species in
all cases (higher resistance indices), suggesting a
possible cross-resistance between this group of com-
pounds and chloroquine which could be due to their
structural similarity. Although changing b-amino-
alcohols to their oxazolidinone counterparts
decreased the potency in all the cases, the com-
pounds were still active and the resistance indices
for these compounds improved significantly in
comparison with those of b-aminoalcohols. This
may indicate the absence of cross-resistance
between these new derivatives and chloroquine.
This article describes the synthesis of new 4-aminoquinoline deriva-
tives and reports on their in vitro antiplasmodial activity against the
chloroquine-sensitive (3D7) and the chloroquine-resistant (K1) strains
of the malaria parasite P. falciparum.
Experimental Section
The reagents were obtained from Sigma-Aldrich (Cape Town, South
Africa) and the common solvents were purchased from KIMIX. Col-
umn chromatography was carried out on Merck silica gel 60. All
reactions were monitored using TLC, which was carried out on sil-
ica 60 F254-coated aluminum sheets (Merck). Melting points were
measured on a Reichert-Jung Thermovar hot stage microscope. IR
spectra were recorded using NaCl disks on a Thermo Mattson FTIR
spectrometer in the range of 4000–500 ⁄ cm. High-resolution mass
spectra (HREIMS) were obtained on a VG-70-SEQ mass spectrome-
ter operating at 70 eV. 1H, 13C, HSQC, HMBC, and COSY NMR
spectra were recorded on Varian 300 MHz (VXR 300) or Varian
400 MHz (VXR 400) instruments with TMS as an internal reference.
Key words: aminoalcohol, aminoquinoline, antiplasmodial activity,
malaria, oxazolidinone
Received 13 February 2011, revised 14 May 2011 and accepted for pub-
lication 21 November 2011
Malaria continues to be one of the leading health problems in sub-
Saharan Africa and is responsible for over 1 million deaths per year
326

Synthesis of Aminoquinoline-Based Aminoalcohols and Oxazolidinones
Scheme 1: Synthesis scheme for 4-aminoquinoline-based b-aminoalcohol and oxazolidinone derivatives.
(4 mL ⁄ 1 mmol trisphosgene) was added dropwise. The mixture was
allowed to warm to RT and stirred at this temperature for 3 h. The
resultant mixture was dissolved in dichloromethane and washed
with brine and water. Then the organic layer was decanted, dried,
and evaporated under vacuum. The solidified mixture was purified
by column chromatography.
Structural data
1-(2-(7-chloroquinolin-4-ylamino)ethylamino)-3-
(4-phenylpiperazin-1-yl)propan-2-ol (9a)
1
Mp 35–37 ꢀC. Yield: 25%. H NMR (CDCl3, 400 MHz) d 8.45 (1H; d,
J = 5.6; H-2); 7.91 (1H; d, J = 2.4; H-8); 7.77 (1H; d, J = 8.8; H-5);
7.29 (1H; dd, J = 2.0, 9.0; H-6); 7.27 (2H; m; H-3¢,5¢); 6.89 (3H; m;
H-2¢,4¢,6¢); 6.33 (1H; d, J = 5.6; H-3); 3.95 (1H; m; H-14); 3.35 (2H; t,
J = 5.2; H-10); 3.17 (4H; m; H-17,19); 3.07 (2H; t, J = 5.2; H-11);
2.78 (4H; m; H-16,18); 2.65 (1H; dd, J = 7.6,12.0; H-13a); 2.56 (1H;
m; H-15a); 2.49 (1H; dd, J = 2.4, 12.0; H-13b); 2.39 (1H; dd,
J = 3.6, 12.4; H-15b). m ⁄ z 439.21209 (M)+. Anal. Calcd for
C24H30ClN5O: C, 65.52; H, 6.87; N, 15.92. Found: C, 65.33; H, 6.65,
N, 16.23.
Figure 1: Structures of 4-aminoquinoline 1, chloroquine 2, qui-
nine 3, mefloquine 4, and oxazolidinone ring 5.
Chemical shifts are reported in parts per million (p.p.m.) and cou-
pling constants are given in hertz (Hz). Elemental analyses were
carried out on a HERAEUS CHN rapid elemental analyzer (Heraeus
GmbH, Germany) for C, H, and N, and the results are within €0.4%
of the theoretical values.
General procedure for synthesis of b-
1-(2-(7-chloroquinolin-4-ylamino)ethylamino)-3-
(4-(2-fluorophenyl)piperazin-1-yl)propan-2-ol (9b)
Mp 38–40 ꢀC. Yield: 30%. H NMR (CDCl3, 300 MHz) d 8.42 (1H; d,
aminoalcohols (9a–e, 10b, 11b, and 12b)
mixture of N1-(7-chloro-4-quinolinyl)-alkylenediamine (9–12,
1
A
1.3 mmol) and 1-(R-phenyl)-4-oxiranyl-piperazine (8a–e, 1 mmol) in
methanol (10 mL ⁄ 1 mmol amine) was stirred at 55 ꢀC for 16 h. The
obtained mixture was concentrated under vacuum, and then, it was
purified by column chromatography.
J = 5.4; H-2); 7.87 (1H; d, J = 2.1; H-8); 7.71 (1H; d, J = 9.0; H-5);
7.27 (1H; dd, J = 2.1, 8.7; H-6); 6.92 (4H; m; H-3¢,4¢,5¢,6¢); 6.29 (1H;
d, J = 5.7; H-3); 3.88 (1H; m; H-14); 3.32 (2H; t, J = 5.1; H-10); 3.03
(4H; m; H-17,19); 2.77 (3H; m; H-11,H-13a); 2.66–2.42 (6H; m;
H-13b,H-16,18,H-15a); 2.35 (1H; dd, J = 3.9, 12.6; H-15b). m ⁄ z
457.20576 (M)+. Anal. Calcd for C24H29ClFN5O: C, 62.94; H, 6.38; N,
15.29. Found: C, 62.82; H, 6.42; N, 15.59.
General procedure for synthesis of
oxazolidinone derivatives (9ar-er, 10br, 11br,
and 12br)
A mixture of synthesized aminoalcohol (9a–e, 10b, 11b, 12b,
1 mmol) and anhydrous triethylamine (6 mmol) in dried dichloro-
methane (4 mL ⁄ 1 mmol b-aminoalcohol) was stirred at 0 ꢀC, and
then, a solution of trisphosgene (0.5 mmol) in dried dichloromethane
1-(2-(7-chloroquinolin-4-ylamino)ethylamino)-3-
(4-(4-fluorophenyl)piperazin-1-yl)propan-2-ol (9c)
Mp 53–55 ꢀC. Yield: 30%. H NMR (CD3OD, 300 MHz) d 8.34 (1H;
1
d, J = 6.0; H-2); 8.09 (1H; d, J = 8.4; H-5); 7.76 (1H; d, J = 2.4;
Chem Biol Drug Des 2012; 79: 326–331
327

Kobarfard et al.
H-8); 7.38 (1H; dd, J = 2.1, 9.0; H-6); 6.96–6.84 (4H; m; H-
2¢,3¢,5¢,6¢); 6.59 (1H; d, J = 5.0; H-3); 3.92 (1H; m; H-14); 3.53 (2H;
t, J = 6.0; H-10); 3.30 (4H; m; H-17,19); 3.00 (2H; t, J = 5.7; H-11);
2.80 (1H; dd, J = 4.5, 12.0; H-13a); 2.69–2.60 (5H; m; H-13b, H-
16,18); 2.43 (2H; m; H-15). 13C NMR (CDCl3, 400 MHz) d 158.707
(C-2); 151.815 (C-8a); 150.370 (C-4); 148.879 (C-4¢); 148.010 (C-7);
135.273 (C-8); 128.498 (C-6); 125.531 (C-5); 121.776 (C-4a); 118.150
(C-3¢); 118.078 (C-5¢); 117.539 (C-1¢); 115.874 (C-2¢); 115.654 (C-6¢);
99.328 (C-3); 66.110 (C-14); 61.945 (C-10); 53.562 (C-17, C-19);
53.096 (C-11); 50.475 (C-16, C-18); 47.736 (C-13); 42.274 (C-15). IR
(KBr) mmax 3320 (OH); 1996.74, 1993.48; 1579.69 (ArC-N, quinoline);
1508.02,1452.63 (ArC-C). m ⁄ z 457.20307 (M)+. Anal. Calcd for
C24H29ClFN5O: C, 62.94; H, 6.38; N, 15.29. Found: C, 62.56; H, 6.42;
N, 15.17.
1-(4-(7-chloroquinolin-4-ylamino)butylamino)-3-
(4-(2-fluorophenyl)piperazin-1-yl)propan-2-ol (11b)
Mp 32–34 ꢀC. Yield: 25%. H NMR (CDCl3, 400 MHz) d 8.28 (1H; d,
J = 5.6; H-2); 7.92 (1H; d, J = 8.8; H-5); 7.75 (1H; d, J = 2.0; H-8);
7.16 (1H; dd, J = 2.0, 8.8; H-6); 6.89 (4H; m; H-3¢,4¢,5¢,6¢); 6.18 (1H;
d, J = 6.0; H-3); 4.04 (1H; m; H-16); 3.22 (2H; br s; H-10); 2.99 (4H;
br s; H-19, 21); 2.85 (3H; br s; H-18, H-15a); 2.68 (3H; m; H-15b, H-
20); 2.55 (2H; m; H-17); 2.42 (2H; m; H-13); 1.79 (4H; br s; H-11,12).
m ⁄ z 485.23247 (M)+. Anal. Calcd for C26H33ClFN5O: C, 64.25; H,
6.84; N, 14.41. Found: C, 64.56; H, 6.47; N, 14.72.
1
1-(6-(7-chloroquinolin-4-ylamino)hexylamino)-3-
(4-(2-fluorophenyl)piperazin-1-yl)propan-2-ol
(12b)
1
Mp 45–47 ꢀC. Yield: 21%. H NMR (CDCl3, 400 MHz) d 8.33 (1H; d,
1-(2-(7-chloroquinolin-4-ylamino)ethylamino)-3-
(4-(2-chlorophenyl)piperazin-1-yl)propan-2-ol
(9d)
J = 5.6; H-2); 7.95 (1H; d, J = 8.8; H-5); 7.8 (1H; d, J = 2.0; H-8);
7.23 (1H; dd, J = 2.0, 8.8; H-6); 6.88 (4H; m; H-3¢,4¢,5¢,6¢); 6.26 (1H;
d, J = 5.6; H-3); 6.22 (1H; br s; H-9); 4.088 (1H; m; H-18); 3.22 (2H;
br t; H-10); 3.00 (6H; br m; H-21,23, H-17); 2.81–2.38 (8H; m; H-19,
H-20,22, H-15); 1.66 (4H; br s; H-11,14); 1.38 (4H; br s; H-12,13).
m ⁄ z 513.26846 (M)+. Anal. Calcd for C28H37ClFN5O: C, 65.42; H,
7.25; N, 13.62. Found: C, 65.13; H, 7.63; N, 13.70.
Mp 59–61 ꢀC. Yield: 30%. 1H NMR (CDCl3, 300 MHz) d 8.33
(1H; d, J = 5.7; H-2); 8.06 (1H; d, J = 8.7; H-5); 7.74 (1H; d,
J = 1.8; H-8); 7.34 (1H; dd, J = 2.1, 9.0; H-6); 7.28 (1H; dd,
J = 1.8, 8.4; H-3¢); 7.18 (1H; td, J = 1.5, 7.8; H-5¢); 6.93 (2H; m;
H-4¢,6¢); 6.53 (1H; d, J = 5.7; H-3); 3.92 (1H; m; H-14); 3.49 (2H;
t, J = 5.7; H-10); 2.99 (2H; t, J = 6.0; H-11); 2.92 (4H; br t;
H-17,19); 2.79 (1H; dd, J = 4.5,12.6; H-13a); 2.68–2.61 (5H; bm;
H-13b,H-16,18); 2.43 (2H; m; H-15). m ⁄ z 473.17621 (M)+. Anal.
Calcd for C24H29Cl2N5O: C, 60.76; H, 6.16; N, 14.76. Found: C,
60.71; H, 6.21; N, 14.95.
3-(2-(7-chloroquinolin-4-ylamino)ethyl)-5-((4-
phenylpiperazin-1-yl)methyl)oxazolidin-2-one
(9ar)
1
Mp 67–69 ꢀC. Yield: 23%. H NMR(CDCl3, 400 MHz) d 8.4 (1H; d,
J = 5.6; H-2); 7.87 (1H; d, J = 2.0; H-8); 7.74 (1H; d, J = 8.8; H-5); 7.3
(1H; dd, J = 2.0, 8.8; H-6); 7.16 (2H; m; H-3¢,5¢); 6.75 (3H; m;
H-2¢,4¢,6¢); 6.37 (1H; br s; H-9); 6.29 (1H; d, J = 5.6; H-3); 4.68 (1H; m;
H-15); 3.67 (3H; m; H-10, H-16a); 3.46 (3H; m; H-16b, H-11); 2.99 (4H;
m; H-19,21); 2.60 (6H; m; H-17, H-18,20). IR (KBr) mmax 3340 (NH);
1996.74, 1993.48; 1732.83 (CO); 1579.69 (ArC-N, quinoline); 1449.37,
1429.8 (ArC-C). m ⁄ z 465.19135 (M)+. Anal. Calcd for C25H28ClN5O2: C,
64.44; H, 6.06; N, 15.03. Found: C, 64.63; H, 6.59; N, 14.85.
1-(2-(7-chloroquinolin-4-ylamino)ethylamino)-3-
(4-(2-ethoxyphenyl)piperazin-1-yl)propan-2-ol
(9e)
1
Mp 36–38 ꢀC. Yield: 30%. H NMR (CDCl3, 400 MHz) d 8.34 (1H; d,
J = 5.6; H-2); 8.07 (1H; d, J = 9.2; H-5); 7.76 (1H; d, J = 2.0; H-8);
7.34 (1H; dd, J = 2.4, 9.2; H-6); 6.92–6.82 (4H; m; H-3¢,4¢,5¢,6¢); 6.54
(1H; d, J = 5.6; H-3); 4.01 (2H; q, J = 7.2; H-7¢); 3.93 (1H; m; H-14);
3.49 (2H; t, J = 6.0; H-10); 3.30 (1H; m; H-13a); 3.01–2.96 (6H; br
m; H-13b, H-17,19, H-15a); 2.78 (1H; dd, J = 4.0, 12.0; H-15b); 2.64
(4H; m; H-16,18); 2.44 (2H; t, J = 7.2; H-11); 1.38 (3H; t, J = 6.8;
H-8¢). m ⁄ z 483.24136 (M)+. Anal. Calcd for C26H34ClN5O2: C, 64.52;
H, 7.08; N, 14.47. Found: C, 64.23; H, 7.35, N, 14.20.
3-(2-(7-chloroquinolin-4-ylamino)ethyl)-5-((4-(2-
fluorophenyl)piperazin-1-yl)methyl)oxazolidin-2-
one (9br)
1
Mp 64–66 ꢀC. Yield: 23%. H NMR (CDCl3, 400 MHz) d 8.43 (1H; d,
J = 5.6; H-2); 7.87 (1H; d, J = 2.0; H-8); 7.18 (1H; d, J = 9.2; H-5);
7.31 (1H; dd, J = 2.4, 9.2; H-6); 6.88 (3H; m; H-3¢,5¢,6¢); 6.58 (1H; td,
J = 1.6, 8.8; H-4¢); 6.26 (1H; d, J = 5.2; H-3); 4.66 (1H; m; H-15); 3.67
(3H; m; H-10, H-16a); 3.44 (3H; m; H-16b, H-11); 2.88 (4H; m; H-19,21);
2.61 (6H; m; H-17, H-18,20). IR (KBr) mmax 3366 (NH); 1996.74,
1993.48; 1732.83 (CO); 1579.69 (ArC-N, quinoline); 1498.24, 1452.63,
1429.82 (ArC-C). m ⁄ z 483.18148 (M)+. Anal. Calcd for C25H27ClFN5O2:
C, 62.04; H, 5.62; N, 14.47. Found: C, 61.74; H, 5.45; N, 14.72.
1-(3-(7-chloroquinolin-4-ylamino)propylamino)-3-
(4-(2-fluorophenyl)piperazin-1-yl)propan-2-ol
(10b)
1
Mp 40–42 ꢀC. Yield: 22%. H NMR (CDCl3, 300 MHz) d 8.35 (1H;
d, J = 5.4; H-2); 7.81 (1H; d, J = 2.1; H-8); 7.76 (1H; d, J = 8.7;
H-5); 7.16 (1H; dd, J = 2.1, 8.7; H-6); 6.91 (4H; m; H-3¢,4¢,5¢,6¢);
6.20 (1H; d, J = 5.4; H-3); 3.93 (1H; m; H-15); 3.32 (2H; br t; H-
10); 3.03 (4H; m; H-18,20); 2.89 (2H; m; H-12); 2.71 (4H; m; H-
17,19); 2.59 (1H; dd, J = 7.8, 12.3; H-14a); 2.52 (1H; m; H-16a);
2.39 (1H; dd, J = 2.7, 12.0; H-14b); 2.33 (1H; dd, J = 3.9, 12.0; H-
16b); 1.88 (2H; quin, J = 5.4; H-11). m ⁄ z 471.22059 (M)+. Anal.
Calcd for C25H31ClFN5O: C, 63.62; H, 6.62; N, 14.84. Found: C,
63.44; H, 6.55; N, 14.90.
3-(2-(7-chloroquinolin-4-ylamino)ethyl)-5-((4-(4-
fluorophenyl)piperazin-1-yl)methyl)oxazolidin-2-
one (9cr)
1
Mp 75–77 ꢀC. Yield: 25%. H NMR (CDCl3, 300 MHz) d 8.4 (1H; d,
J = 5.4; H-2); 7.85 (1H; d, J = 2.4; H-8); 7.71 (1H; d, J = 9; H-5);
328
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Synthesis of Aminoquinoline-Based Aminoalcohols and Oxazolidinones
7.29 (1H; dd, J = 2.1, 8.7; H-6); 6.85 (2H; m; H-3¢,5¢); 6.63 (2H; m;
497.19713 (M)+. Anal. Calcd for C26H29ClFN5O2: C, 62.71; H, 5.87;
N, 14.06. Found: C, 62.34; H, 6.19; N, 14.03.
H-2¢,6¢); 6.25 (1H; d, J = 5.4; H-3); 4.66 (1H; m; H-15); 3.66 (2H; m;
H-10); 3.42 (6H; m; H-16, H-19,21); 2.89 (3H; m; H-11, H-17a); 2.59
(5H; m; H-17b, H-18,20). 13C NMR (CDCl3, 400 MHz) d 160.035
(C13); 159.06 (C2); 151.69 (C8a); 150.262 (C4); 148.80 (C4¢); 147.84
(C7); 135.53 (C8); 128.34 (C6); 126.07 (C5); 122.11 (C4a); 118.04
(C3¢); 117.91 (C5¢); 117.32 (C1¢); 115.85 (C2¢); 115.556 (C6¢); 98.54
(C3); 73.19 (C15); 60.92(C10); 54.31 (C19, C21); 50.93 (C11); 50.32
(C18); 49.09 (C20); 43.46 (C16); 42.68(C17). IR (KBr) mmax 3352.94
3-(4-(7-chloroquinolin-4-ylamino)butyl)-5-((4-(2-
fluorophenyl)piperazin-1-yl)methyl)oxazolidin-2-
one (11br)
1
Mp 43–45 ꢀC. Yield: 19%. H NMR (CDCl3, 400 MHz) d 8.39 (1H; d,
J = 5.2; H-2); 7.88 (1H; d, J = 2.4; H-8); 7.82 (1H; d, J = 8.8; H-5);
7.27 (1H; dd, J = 2.4, 8.8; H-6); 6.87 (4H; m; H-3¢,4¢,5¢,6¢); 6.32 (1H;
d, J = 5.6; H-3); 5.84 (1H; br s; H-9); 4.62 (1H; m; H-17); 3.56 (1H; t,
J = 8.4; H-18a); 3.31 (5H; m; H-10, H-18b,19); 3.00 (4H; t, J = 5; H-
21,23); 2.64 (6H; m; H-13, H-20,22); 1.76 (2H; quin, J = 6.8; H-11);
1.68 (2H; quin, J = 6.8; H-12). IR (KBr) mmax 3340 (NH); 1996.7,
1993.48; 1732.83 (CO); 1579.69 (ArC-N, quinoline); 1498.24, 1452.63
(ArC-C). m ⁄ z 511.21551 (M)+. Anal. Calcd for C27H31ClFN5O2: C,
63.34; H, 6.10; N, 13.68. Found: C, 63.25; H, 6.35; N, 13.84.
(NH); 1996.74, 1993.48; 1732.83(CO); 1579.69(ArC-N
, quinoline);
1508.02, 1452.63 (ArC-C). m ⁄ z 483.18421 (M)+. Anal. Calcd for
C25H27ClFN5O2: C, 62.04; H, 5.62; N, 14.47. Found: C, 62.25; H,
5.35; N, 14.62.
3-(2-(7-chloroquinolin-4-ylamino)ethyl)-5-((4-(2-
chlorophenyl)piperazin-1-yl)methyl)oxazolidin-2-
one (9dr)
1
Mp 68–70 ꢀC. Yield: 24%. H NMR (CDCl3, 400 MHz) d 8.43 (1H; d,
J = 5.6; H-2); 7.89 (1H; d, J = 2.4; H-8); 7.74 (1H; d, J = 8.8; H-5);
7.31 (1H; dd, J = 2.0, 8.8; H-6); 7.24 (1H; dd, J = 1.8, 8.0; H-3¢);
7.09 (1H; td, J = 1.6, 8.0; H-5¢); 6.87 (1H; td, J = 1.6, 8.0; H-4¢);
6.63 (1H; dd, J = 1.6, 8.0; H-6¢); 6.35 (1H; br s; H-9); 6.28 (1H; d,
J = 5.6; H-3); 4.69 (1H; m; H-15); 3.68 (3H; m; H-10, H-16a); 3.46
(3H; m; H-16b, H-11); 2.85 (6H; m; H-17, H-19,21); 2.63 (4H; m; H-
18,20). IR (KBr) mmax 3352 (NH); 1996.74, 1993.48; 1732.83(CO);
1579.69 (ArC-N, quinoline); 1478.69, 1449.37 (ArC-C). m ⁄ z 499.15544
(M)+. Anal. Calcd for C25H27Cl2N5O2: C, 60.00; H, 5.44; N, 13.99.
Found: C, 60.35; H, 5.23; N, 14.25.
3-(6-(7-chloroquinolin-4-ylamino)hexyl)-5-((4-(2-
fluorophenyl)piperazin-1-yl)methyl)oxazolidin-2-
one (12br)
1
Mp 67–69 ꢀC. Yield: 17%. H NMR (CDCl3, 400 MHz) d 8.398 (1H;
d, J = 5.2; H-2); 7.906 (1H; d, J = 2.0; H-8); 7.78 (1H; d, J = 8.8; H-
5); 7.29 (1H; dd, J = 2.0, 8.8; H-6); 6.89 (4H; m; H-3¢,4¢,5¢,6¢); 6.32
(1H; d, J = 5.4; H-3); 5.63 (1H; br s; H-9); 4.61 (1H; m; H-19); 3.54
(1H; t, J = 8.8; H-20a); 3.26 (5H; m; H-10, H-20b,21); 3.024 (4H; t,
J = 4.8; H-23,25); 2.65 (6H; m; H-15, H-22,24); 1.69 (2H; quin,
J = 6.8; H-14); 1.53 (2H; quin, J = 7.2; H-11); 1.45 (2H; quin,
J = 8.0; H-12); 1.34 (2H; quin, J = 6.8; H-13). IR (KBr) mmax 3340
(NH); 1996.7, 1993.48; 1736.09 (CO); 1579 (ArC-N
, quinoline);
3-(2-(7-chloroquinolin-4-ylamino)ethyl)-5-((4-(2-
ethoxyphenyl)piperazin-1-yl)methyl)oxazolidin-
2-one (9er)
1498.24, 1449.37 (ArC-C). m ⁄ z 539.24453 (M)+. Anal. Calcd for
C29H35ClFN5O2: C, 64.49; H, 6.53; N, 12.97. Found: C, 64.63; H,
6.75; N, 12.59.
Mp 55–57 ꢀC. Yield: 22%. 1H NMR (CDCl3, 400 MHz) d 8.4 (1H;
d, J = 5.6; H-2); 7.90 (1H; br s; H-8); 7.76 (1H; d, J = 9.2; H-5);
7.31 (1H; dd, J = 2.0, 8.8; H-6); 6.82 (3H; m; H-4¢,5¢,6¢); 6.63 (1H;
dd, J = 1.2, 7.6; H-3¢); 6.28 (1H; d, J = 5.6; H-3); 4.69 (1H; m;
H-15); 3.96 (2H; q, J = 7.2; H-7¢); 3.679 (3H; m; H-10, H-16a);
3.46 (3H; m; H-16b, H-11); 2.92 (4H; br m; H-19,21); 2.63 (6H; m;
H-17, H-18,20); 1.34 (3H; t, J = 7.2; H-8¢). IR (KBr) mmax 3366.01
(NH); 1996.74, 1993.48; 1732.83 (CO); 1579.69 (ArC-N, quinoline);
1498.24, 1449.37 (ArC-C). m ⁄ z 509.21608 (M)+. Anal. Calcd for
C27H32ClN5O3: C, 63.58; H, 6.32; N, 13.73. Found: C, 63.20; H,
6.57; N, 13.76.
Biological activity
In vitro activities of compounds against 3D7
and K1 Plasmodium falciparum
Two clones of P. falciparum are used: (i) the 3D7 clone of NF54
which is known to be sensitive to all antimalarials, (ii) the K1 strain
originating from Thailand that is resistant to chloroquine and pyri-
methamine, but sensitive to mefloquine. The cultures are naturally
asynchronous (65–75% ring stage) and are maintained in continu-
ous log-phase growth in PRMI1640 medium supplemented with 5%
washed human A+ erythrocytes, 25 mM HEPES, 32 mM NaHCO3,
and lipid-rich bovine serum albumin (complete medium). All cultures
and assays are conducted at 37 ꢀC under atmosphere of 5% CO2
and 5% O2, with a balance of N2. Antimalarial activity is assessed
with an adaptation of the 48-h sensitivity assay of Desjardins et al.
(7) using [3H]-hypoxanthine incorporation as an assessment of para-
site growth.
3-(3-(7-chloroquinolin-4-ylamino)propyl)-5-((4-(2-
fluorophenyl)piperazin-1-yl)methyl)oxazolidin-2-
one (10br)
1
Mp 56–58 ꢀC. Yield: 19%. H NMR (CDCl3, 400 MHz) d 8.48 (1H; d,
J = 5.4; H-2); 7.95 (1H; d, J = 1.8; H-8); 7.89 (1H; d, J = 8.4; H-5);
7.38 (1H; dd, J = 1.8, 8.4; H-6); 6.98 (4H; m; H-3¢,4¢,5¢,6¢); 6.39 (1H;
d, J = 5.4; H-3); 4.7 (1H; m; H-16); 3.64 (1H; t, J = 8.7; H-17a); 3.45
(5H; m; H-10, H-17b,18) 3.09 (4H; t, J = 5; H-20,22); 2.72 (2H; t,
J = 5.4; H-12); 2.65 (4H; t, J = 5.4; H-19,21); 1.91 (2H; quin,
J = 5.7; H-11). IR (KBr) mmax 3340 (NH); 1996.74, 1993.48; 1732.83
(CO); 1579.69 (ArC-N, quinoline); 1498.24, 1452.63 (ArC-C). m ⁄ z
Sensitivity assays
Stock solutions of chloroquine and test compounds are prepared
in 100% dimethylsulfoxide (DMSO) at 20 mg ⁄ mL. The compound is
Chem Biol Drug Des 2012; 79: 326–331
329

Kobarfard et al.
further diluted to the appropriate concentration using complete
medium. Assays are performed in sterile 96-well microtiter plates,
each plate contained 100 lL of parasite culture (0.5% parasitemia
and 2.5% hematocrit) with or without 10 lL compound dilutions.
Each compound is tested in triplicate and parasite growth com-
pared with control and blank (uninfected erythrocytes) wells. After
24 h of incubation at 37 ꢀC, 0.5 lCi of [3H]hypoxanthine is added
to each well. Cultures are incubated for a further 24 h before they
are harvested onto glass–fiber filter mats. The radioactivity is
counted using a Wallac Microbeta 1450 scintillation counter. The
results are recorded as counts per minute (c.p.m.) per well at each
compound concentration, control and blank wells. Percentage inhi-
bition is calculated from comparison of blank and control wells,
and IC50 values calculated using Microsoft XLFit line fitting soft-
ware (IDBS, London, UK).
Table 1: Antiplasmodial activities of b-aminoalcohol derivatives
[CH2]n
HN
N
H
N
N
OH
R
Cl
N
3D7 IC50
(nM)
K1 IC50
(nM)
Compound
R
n
RIa
30.33
5.19
1.62
183.75
13.67
2.68
9a
9b
H
2-F
4-F
2-Cl
2-OEt
2-F
2
2
2
2
2
3
4
6
9
21
13
0.8
6
63
41
77
15
273
109
21
147
82
169
329
604
1681
9c
9d
9e
10b
11b
12b
CQ
2-F
2-F
8.02
7.84
112.07
Primary screening
aResistant index (RI): K1 IC50 ⁄ 3D7 IC50.
The preliminary screening uses the 3D7 strain. The compounds are
tested at six concentrations (30, 10, 3, 1, 0.3, and 0.1 lg ⁄ mL). If
the compound does not affect parasite growth at 10 lg ⁄ mL, it
is classified as inactive, between 10 and 1 lg ⁄ mL, the compound
is designated as partially active, and if <1 lg ⁄ mL, the compound is
classified as active and is further evaluated by threefold serial dilu-
tions in a repeat test.
Table 2: Antiplasmodial activities of oxazolidinone derivatives
[CH2]n
HN
N
N
O
N
O
Cl
N
R
Secondary screening
3D7 IC50
(nM)
K1 IC50
(nM)
Compound
R
n
RIa
0.90
1.00
1.66
1.00
0.50
1.13
2.76
Both the 3D7 clone and the K1 line are used. The compound is
diluted threefold over 12 different concentrations with an appropri-
ate starting concentration based on the preliminary screening. The
IC50 is determined by a sigmoidal dose response analysis using
Microsoft XLFitꢁ (IDBS). For each assay, the IC50 values for each
parasite line are determined against the known antimalarial chloro-
quine.
9ar
H
2
2
2
2
2
3
4
6
430
207
62
387
207
103
80
9br
9cr
2-F
4-F
2-Cl
2-OEt
2-F
9dr
9er
80
196
160
78
115
15
98
10br
11br
12br
CQ
181
215
129
1681
2-F
2-F
1.12
112.07
Results and Discussion
aResistant index (RI): K1 IC50 ⁄ 3D7 IC50.
Chemistry
The synthesis of the key intermediate oxirane derivatives 8a–e is
shown in Scheme 1 starting with commercially available piperazines
(6a–e) and epichlorohydrin 7. The b-aminoalcohol derivatives
(Table 1) were synthesized after reaction of the oxirane derivatives
(8a–e) with the appropriate diamines 9–12 (8,9). Subsequent reac-
tion of the b-aminoalcohols with triphosgene was carried out to
produce oxazolidinone derivatives (Scheme 1) (10). All synthesized
compounds were characterized by spectroscopic and analytical tech-
niques, and the data obtained were found to be consistent with
the expected structures.
Ethanolamine derivatives are more active against the CQ-sensitive
plasmodiums than the CQ-resistant strains. In general, ethanolam-
ines are significantly less active against CQ-resistant strains in com-
parison with the CQ-sensitive plasmodiums. This is expressed as
high resistant indices for these compounds in Table 1. Within etha-
nolamine series, some are more active (9d, 9e, and 9a) and some
are less active than CQ against CQ-sensitive strains. However, this
trend is not followed against CQ-resistant strains so that all the
ethanolamine compounds are more active against CQ-resistant
strains than chloroquine. When ethanolamines are changed to oxa-
zolidinones a drastic drop in activity against CQ-sensitive plasmodi-
ums is obvious while their activities against CQ-resistant strains
have not decreased as much, and therefore, the resistant indices
among these compounds vary in a narrow range from 0.5 to 2.75.
Biology
The abilities of the synthesized compounds to inhibit the growth of
the chloroquine-sensitive (3D7) and the chloroquine-resistant (K1)
strains were determined, and data are displayed in Tables 1 and 2.
The following facts could be extracted from the data presented in
these tables:
Considering the aforementioned facts, the following suggestions
could be made about these series of antiplasmodium compounds.
330
Chem Biol Drug Des 2012; 79: 326–331

Synthesis of Aminoquinoline-Based Aminoalcohols and Oxazolidinones
Comparing the structure of chloroquine 2 and ethanolamine deriva-
References
tives shows that these compounds have some structural features in
common with CQ. They both have quinoline ring with an alkylenedi-
amine side chain at position 4 of quinoline ring. Therefore, it would
be possible that these compounds exert part of their antiplasmodi-
um activity through a mechanism similar to that of CQ. On the
other hand, they have a 4-phenyl-piperazine moiety in their struc-
tures which makes them similar to another group of antiplasmodium
compounds, that is, arylpiperazines (11). The hybrid structural fea-
tures of these series of compounds could be responsible for their
high potency against CQ-sensitive plasmodium strains (IC50 ranging
from 0.8 to 78 nM). These same compounds are much less active
against CQ-resistant strains probably because they cannot act
through their chloroquine-alike moiety anymore, and they are in
essence disarmed against CQ-resistant plasmodiums. However, they
are all still significantly more active than chloroquine, and this
could be due to the possession of arylpiperazine moiety in their
structure whose mechanism of antiplasmodium activity is different
from that of chloroquine (11). Within the oxazolidinone series, all
the compounds are significantly less active than CQ against the CQ-
sensitive strains. In these series of compounds, the alkylenediamine
moiety (which is essential for the activity of chloroquine-type ana-
logs) has been changed to an oxazolidinone ring, and therefore, the
antiplasmodium activity of these compounds could not be exerted
through chloroquine-like mechanism. These compounds are less
active than their ethanolamine counterparts probably because the
latter compounds have both chloroquine-like and arylpiperazine moi-
eties in their structures, and hence, they are more effective against
CQ-sensitive plasmodium strains. No significant difference is
observed between the activity of oxazolidinones against CQ-sensi-
tive plasmodiums and CQ-resistant strains, and this may also sug-
gest that the oxazolidinone derivatives do not exert their activity
via chloroquine mechanism(s), and therefore, they are not sensitive
to the chloroquine resistance mechanisms (12,13). The other point
that supports the previously mentioned suggestion is the fact that
the IC50s for oxazolidinones and ethanolamones against CQ-resis-
tant plasmodium strains are almost in the same range (80–387 ver-
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In conclusion, based on the data obtained in this study, we introduce
ethanolamine derivatives as a new group of compounds with a pos-
sible dual antiplasmodium activity. They have great activity against
CQ-sensitive plasmodium strains and also good activity against CQ-
resistant strains. Their oxazolidinone congeners also show consider-
able activities against both CQ-sensitive and CQ-resistant strains.
Both groups of compounds exhibit higher IC50s than CQ against CQ-
resistant plasmodium strains. This may imply the absence of cross-
resistance between these compounds and chloroquine.
Stereoselective activity for some of the well-known quinolinic anti-
plasmodium compounds such as quinine 3 is well documented (14).
As both group of compounds studied in this research contain a chi-
ral center in their structures, further studies are being conducted to
evaluate the activity of stereoisomers of the synthesized compounds
in this research.
Chem Biol Drug Des 2012; 79: 326–331
331