Synthesis of 4-aminoquinoline-1,2,3-triazole and 4-aminoquinoline-1,2,3-triazole-1,3,5-triazine hybrids as potential antimalarial agents

Article abstract of DOI:10.1111/j.1747-0285.2011.01115.x

We report herein synthesis of a series of 4-aminoquinoline-1,2,3-triazole and 4-aminoquinoline-1,2,3-triazole-1,3,5-triazine hybrids and evaluate their antimalarial activity against D6 and W2 strains of Plasmodium falciparum. To study the structure-activi

Full text of DOI:10.1111/j.1747-0285.2011.01115.x

ª 2011 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2011.01115.x
Chem Biol Drug Des 2011; 78: 124–136
Research Article
Synthesis of 4-aminoquinoline-1,2,3-triazole and
4-aminoquinoline-1,2,3-triazole-1,3,5-triazine
Hybrids as Potential Antimalarial Agents
Sunny Manohar1, Shabana I. Khan2 and
Diwan S. Rawat1,*
and basic side chain at terminal position are important for antima-
larial activity (8). Further studies also proved that modification of
this basic side chain can lead to improved antimalarials active
against drug-resistant P. falciparum strains. The concept of hybrid
molecule was put forward, and aminoquinoline- and trioxane-based
1Department of Chemistry, University of Delhi, Delhi 110007, India
2National Centre for Natural Products Research, University of
hybrid molecules have been synthesized where aminoquinolines or
trioxanes were covalently linked to other different antimalarial enti-
ties (9–13). These hybrid antimalarials are synthesized with an aim
to generate a molecule that can act as a dual drug targeting at
more than one site. The development of these molecules presents
a different approach toward antimalarial chemotherapy. Using this
concept of hybrid chemotherapy in malaria research, many lead
molecules have been developed (14–18), and some of the mole-
cules are in clinical trials (19). In one of the approach, researchers
covalently linked 4-aminoquinolines to triazine molecules and antici-
pated that these kinds of hybrid molecules may solve the problem
of drug resistance (20–23). Cycloguanil, a triazine-based antimalar-
ial compound, exhibits potent antimalarial activity by inhibiting
plasmodial dihydrofolate reductase (DHFR) enzyme. Triazole is
another class of compounds that exhibit variety of biological activ-
ity such as antifungal (24), antibacterial (25,26), antitubercular (27),
etc., and the compound can easily be prepared by click chemistry
(28). Keeping these points in mind, and as a part of our ongoing
program on development of novel antimalarials (29–33), we herein
report synthesis and antimalarial activity evaluation of 4-amino-
quinoline-triazole conjugates (3) and 4-aminoquinoline-triazine-
triazole conjugates (4) (Figure 1).
Mississippi, MS 38677, USA
*Corresponding author: Diwan S. Rawat,
dsrawat@chemistry.du.ac.in
We report herein synthesis of a series of 4-amino-
quinoline-1,2,3-triazole
and
4-aminoquinoline-
1,2,3-triazole-1,3,5-triazine hybrids and evaluate
their antimalarial activity against D6 and W2
strains of Plasmodium falciparum. To study the
structure–activity relationship of substituted 4-
aminoquinoline–based hybrids, 34 structurally
diverse compounds were synthesized and tested
against D6 and W2 strains of P. falciparum. Some
of the compounds have shown promising antima-
larial activity without toxicity against Vero cells.
Key words: antimalarial, hybrids, Plasmodium falciparum
Received 22 October 2010, revised 12 January 2011 and accepted for
publication 6 March 2011
Introduction
H
Malaria poses a great threat to public health, and about 50% of
world population is at risk of suffering from malaria (1). Among
the four Plasmodium species that cause malaria, Plasmodium falci-
parum is the most dangerous and causes severe malaria (2,3).
Chloroquine (1) and quinine (2) are the most widely studied anti-
malarials as they are easy to prepare, have good pharmacokinetic
property, and show low toxicity and side-effects (4–6). They exert
their effect by binding to free heme molecules originated as a
result of degradation of hemoglobin inside the acidic food vacuole
of parasite. This binding inhibits the crystallization of hemozoin
molecules, resulting in the accumulation of heme inside the vacu-
ole to toxic levels which in turn leads to parasitic death (7). Plas-
modium falciparum has developed resistance against chloroquine,
and it has been one of the major setbacks in malaria chemother-
apy. To overcome this problem, plethora of work has been carried
out on this nucleus and structure activity relationship (SAR) study
shows that quinoline nucleus with chloro group at seventh position
N
HO
HN
N
MeO
Cl
N
N
2
1
R1
N
N
N
N
O
N
N
n
N
N
n
R
R2
HN
HN
N
Cl
N
3
Cl
4
Figure 1: Chloroquine (1), quinine (2) and proposed hybrid mole-
cules (3, 4).
124

Synthesis of 4-aminoquinoline-1,2,3-triazole and 4-aminoquinoline-1,2,3-triazole-1,3,5-triazine Hybrids
(m, 1H), 8.39 (brs, 1H); 13C NMR (100 MHz, DMSO-d6): 21.7, 25.3,
Experimental
37.8, 42.7, 47.8, 67.9, 98.6, 116.8, 121.8, 124.7, 124.8, 125.1, 134.9,
145.7, 148.9, 151.7, 155.6; ESI-MS (m ⁄ z): 372.44 (M++H), 374.40
(M++2); Anal. Calcd for C19H22ClN5O: C, 61.37; H, 5.96; N, 18.83;
Found: C, 61.32; H, 6.18; N, 18.96.
Chemistry
All the chemicals used in the synthesis were purchased from
Sigma-Aldrich (Bangalore, Karnataka, India) and were used as such.
Thin layer chromatography was used to monitor the progress of the
reactions. All the compounds were purified over silica gel column.
Solvents were distilled before using for purification purposes. IR
spectra were recorded using Perkin-Elmer FT-IR spectrophotometer
and the values are expressed as kmax per centimetre. Mass spectral
data were recorded on a Jeol (Japan) JMS-DX303 and micromass
1-{1-[3-(7-Chloro-quinolin-4-ylamino)-propyl]-1H-
[1,2,3]triazol-4-yl}-cyclohexanol (3d)
Yield: 70%; mp 158–160 ꢀC; IR ( ⁄ cm, KBr): 3309, 2932, 1582, 1450,
1
1332, 1138, 807; H NMR (400 MHz, DMSO-d6):1.11–1.83 (m, 10H),
LCT, Mass Spectrometer ⁄ Data system. The H NMR and 13C NMR
1
2.21–2.23 (m, 2H), 3.31–3.38 (m, 2H), 4.48 (t, 2H, J = 6 Hz), 4.82
(brs, 1H), 6.53 (d, 1H, J = 5.7 Hz), 7.52–7.54 (m, 1H), 7.82–8.05 (m,
4H), 8.38 (brs, 1H); 13C NMR (100 MHz, DMSO-d6): 21.7, 25.3, 28.5,
31.3, 37.8, 47.1, 67.9, 98.6, 117.2, 121.2, 14.1, 124.7, 125.5, 134.5,
146.6, 149.5, 151.2, 155.7; ESI-MS (m ⁄ z): 386.55 (M++H), 388.40
(M++2); Anal. Calcd for C20H24ClN5O: C, 62.25; H, 6.27; N, 18.15;
Found: C, 62.41; H, 6.36; N, 18.10.
spectra were recorded on Bruker and Jeol Spectrospin spectrometer
at 300 and 400 MHz, while 13C NMR was recorded at 75.5 and
100 MHz, respectively, using TMS as an internal standard. The
chemical shift values are recorded on d scale, and the coupling
constants (J) are in Hz.
{1-[2-(7-chloro-quinolin-4-ylamino)-ethyl]-1H-
[1,2,3]triazol-4-yl}-methanol (3a)
(7-Chloro-quinolin-4-yl)-{2-[4-(tetrahydro-pyran-
2-yloxymethyl)-[1,2,3]triazol-1-yl]-ethyl}-amine
(3e)
To a stirred solution of compound 8 (n = 1) (0.25 g, 1 mmol) and
propargyl alcohol (0.06 g, 1.07 mmol) in t-BuOH (8 mL) was added a
solution of sodium ascorbate (0.08g, 0.40 mmol) and CuSO4Æ5H2O
(0.05 g, 0.20 mmol) in water (8 mL). Reaction mixture was heated
at 40 ꢀC for 3 h. After the completion of reaction, CHCl3 (20 mL)
was added, and organic layer was washed with water
(2 · 100 mL). The organic layer was dried over Na2SO4, and excess
of solvent was evaporated to dryness, and the crude material thus
obtained was purified by SiO2 column using MeOH ⁄ CHCl3 as eluent.
The title compound 3a was obtained in 70% yield. mp 200–
202 ꢀC; IR ( ⁄ cm, KBr): 3428, 3287, 3114, 2841, 1591, 1384, 1040,
Yield: 68%; mp 162–165 ꢀC; IR ( ⁄ cm, KBr): 3246, 2941, 2870, 1578,
1451, 1331, 1032, 873; 1H NMR (400 MHz, DMSO-d6): 1.40–1.64
(m, 6H), 3.700–3.77 (m, 4H), 4.44–4.64 (m, 5H), 6.54 (d, 1H,
J = 5.7 Hz), 7.43–7.45 (m, 2H), 7.79 (s, 1H), 8.07 (s, 1H), 8.14 (d,
1H, J = 9Hz), 8.40 (brs, 1H); 13C NMR (100 MHz, DMSO-d6): 18.9,
24.9, 29.9, 42.4, 47.7, 59.4, 61.2, 96.8, 99.1, 117.6, 123.9, 124.3,
124.5, 127.6, 133.5, 143.8, 149.1, 149.6, 151.8; ESI-MS (m ⁄ z):
388.22, (M++H), 390.13 (M++2); Anal. Calcd for C19H22ClN5O2: C,
58.84; H, 5.72; N, 18.06; Found: C, 58.88; H, 5.76; N, 18.20.
1
806; H NMR (300 MHz, DMSO-d6): 3.84–3.86 (m, 2H), 4.52 (s, 2H),
4.69 (t, 2H, J = 6 Hz), 5.15 (brs, 1H), 6.58 (d, 1H, J = 5.7 Hz), 7.46
(d, 1H, J = 9 Hz), 7.84 (s, 1H), 7.65–7.98 (m, 2H), 8.29 (d, 1H,
J = 9 Hz), 8.42 (brs, 1H); ESI-MS (m ⁄ z): 304.11 (M++H), 306.08
(M++2); Anal. Calcd for C14H14ClN5O: C, 55.36; H, 4.65; N, 23.06;
Found: C, 55.62; H, 4.69; N, 23.34.
{2-[4-(4-Bromo-phenoxymethyl)-[1,2,3]triazol-1-
yl]-ethyl}-(7-chloro-quinolin-4-yl)-amine (3f)
Yield: 75%; mp 155–157 ꢀC; IR ( ⁄ cm, KBr): 3228, 3069, 2924, 1579,
1488, 1244, 1140, 823; 1H NMR (300 MHz, DMSO-d6): 3.76–3.78
(m, 2H), 4.65 (t, 2H, J = 6 Hz), 5.09 (s, 2H), 6.54 (d, 1H, J = 5.7 Hz),
6.95 (d, 2H, J = 9 Hz), 7.39–7.46 (m, 4H), 7.80 (d, 1H, J = 5.7 Hz),
8.15 (d, 1H, J = 9 Hz), 8.23 (s, 1H), 8.40 (brs, 1H); ESI-MS (m ⁄ z):
460.25 (M++H); Anal. Calcd for C20H17BrClN5O: C, 52.36; H, 3.74; N,
15.27; Found: C, 52.72; H, 3.84; N, 15.39.
{1-[3-(7-Chloro-quinolin-4-ylamino)-propyl]-1H-
[1,2,3]triazol-4-yl}-methanol (3b)
Yield: 72%; mp 152–154 ꢀC; IR ( ⁄ cm, KBr): 3350, 3067, 2923, 1586,
1372, 1141, 1051, 797; 1H NMR (400 MHz, DMSO-d6): 2.20–2.22
(m, 2H), 3.40–3.56 (m, 2H), 4.48–4.60 (m, 4H), 5.17 (brs, 1H), 6.51
(d, 1H, J = 5.7 Hz), 7.50–7.52 (m, 1H), 7.78–7.82 (m, 2H), 8.02 (s,
1H), 8.32–8.42 (m, 2H); ESI-MS (m ⁄ z): 318.26 (M++H), 320.13
(M++2); Anal. Calcd for C15H16ClN5O: C, 56.69; H, 5.08; N, 22.04;
Found: C, 56.82; H, 4.92; N, 22.25.
{2-[4-(4-Chloro-phenoxymethyl)-[1,2,3]triazol-1-
yl]-ethyl}-(7-chloro-quinolin-4-yl)-amine (3g)
Yield: 71%; mp 154–156 ꢀC; IR ( ⁄ cm, KBr): 3241, 3063, 2928, 1578,
1491, 1239, 1006, 826; 1H NMR (300 MHz, DMSO-d6): 3.78–3.80
(m, 2H), 4.65 (t, 2H, J = 6 Hz), 5.09 (s, 2H), 6.55 (d, 1H, J = 5.7 Hz),
7.01 (d, 2H, J = 9 Hz), 7.28 (d, 2H, J = 9 Hz), 7.44–7.57 (m, 2H),
7.80 (d, 1H, J = 5.7 Hz), 8.17 (d, 1H, J = 9 Hz), 8.23 (s, 1H), 8.42
(brs, 1H); 13C NMR (100 MHz, DMSO-d6): 42.4, 47.9, 61.3, 99.9,
116.4, 120.5, 124.1, 124.5, 125.2, 127.1, 128.8, 129.2, 133.8, 142.3,
150.1, 151.3, 156.8; ESI-MS (m ⁄ z): 414.99 (M++H); Anal. Calcd for
C20H17Cl2N5O: C, 57.98; H, 4.14; N, 16.90; Found: C, 58.05; H, 4.19;
N, 16.98.
1-{1-[2-(7-Chloro-quinolin-4-ylamino)-ethyl]-1H-
[1,2,3]triazol-4-yl}-cyclohexanol (3c)
Yield: 65%; mp 188–190 ꢀC; IR ( ⁄ cm, KBr): 3400, 3254, 3121, 2929,
1
2853, 1586, 1448, 1333, 1161, 809; H NMR (300 MHz, DMSO-d6):
1.24–1.83 (m, 10H), 3.78–3.83 (m, 2H), 4.64 (t, 2H, J = 6 Hz), 6.46
(d, 1H, J = 5.7 Hz), 7.38–7.52 (m, 2H), 7.77–7.82 (m, 2H), 8.16–8.19
Chem Biol Drug Des 2011; 78: 124–136
125

Manohar et al.
(7-Chloro-quinolin-4-yl)-{2-[4-(2,6-dichloro-
phenoxymethyl)-[1,2,3]triazol-1-yl]-ethyl}-amine
(3h)
(7-Chloro-quinolin-4-yl)-{2-[4-(3,4-dimethyl-
phenoxymethyl)-[1,2,3]triazol-1-yl]-ethyl}-amine
(3l)
Yield: 65%; mp 198–201 ꢀC; IR ( ⁄ cm, KBr): 3327, 3036, 2928,
1584, 1446, 12449, 1060, 788; 1H NMR (300 MHz, DMSO-d6):
3.77–3.78 (m, 2H), 4.67 (t, 2H, J = 6 Hz), 5.07 (s, 2H), 6.58 (d, 1H,
J = 5.7 Hz), 7.11–7.17 (m, 1H), 7.42–7.46 (m, 4H), 7.79 (d, 1H,
J = 5.7 Hz), 8.15 (d, 1H, J = 9 Hz), 8.32 (s, 1H), 8.42 (brs, 1H); 13C
NMR (100 MHz, DMSO-d6): 42.5, 47.8, 66.1, 99.2, 117.7, 124.1,
124.4, 125.6, 126.3, 127.5, 128.8, 129.3, 133.6, 142.1, 148.83,
149.76, 150.12, 151.76; ESI-MS (m ⁄ z): 448.27 (M++H); Anal. Calcd
for C20H16Cl3N5O: C, 53.53; H, 3.59; N, 15.61; Found: C, 53.65; H,
3.47; N, 15.74.
Yield: 75%; mp 168–170 ꢀC; IR ( ⁄ cm, KBr): 3237, 2970, 1578, 1544,
1452, 1251, 1167, 1047, 800; 1H NMR (300 MHz, DMSO-d6): 2.12
(s, 3H), 2.16 (s, 3H), 3.76–3.82 (m, 2H), 4.66 (t, 2H, J = 6 Hz), 5.04
(s, 2H), 6.56 (d, 1H, J = 5.7 Hz), 6.68–6.78 (m, 2H), 6.99 (d, 1H,
J = 9 Hz), 7.44–7.49 (m, 2H), 7.81 (d, 1H, J = 5.7 Hz), 8.16 (d, 1H,
J = 9 Hz), 8.22 (s, 1H), 8.41 (brs, 1H); 13C NMR (100 MHz, DMSO-
d6): 18.4, 19.6, 42.4, 47.8, 61.0, 98.8, 111.5, 116.0, 120.2, 123.9,
124.4, 124.9, 127.5, 128.3, 130.1, 133.6, 137.3, 142.9, 148.9, 149.7,
151.8, 156.1; ESI-MS (m ⁄ z): 408.11 (M++H), 410.02 (M++2); Anal.
Calcd for C22H22ClN5O: C, 64.78; H, 5.44; N, 17.17; Found: C, 64.84;
H, 5.81; N, 17.24.
{2-[4-(4-Chloro-3-methyl-phenoxymethyl)-
[1,2,3]triazol-1-yl]-ethyl}-(7-chloro-quinolin-4-yl)-
amine (3i)
(7-Chloro-quinolin-4-yl)-{2-[4-(4-isopropyl-
phenoxymethyl)-[1,2,3]triazol-1-yl]-ethyl}-amine
(3m)
Yield: 58%; mp 170–172 ꢀC; IR ( ⁄ cm, KBr): 3252, 3064, 2963, 1578,
1479, 1245, 1172, 1043, 801; 1H NMR (300 MHz, DMSO-d6): 2.25
(s, 3H), 3.76–3.78 (m, 2H), 4.64 (t, 2H, J = 6 Hz), 5.07 (s, 2H), 6.54
(d, 1H, J = 5.7 Hz), 6.82–6.85 (m, 1H), 6.99 (d, 1H, J = 2.7 Hz), 7.25
(d, 1H, J = 9 Hz), 7.43–7.45 (m, 2H), 7.78 (d, 1H, J = 5.7 Hz), 8.13
(d, 1H, J = 9 Hz), 8.22 (s, 1H), 8.40 (brs, 1H); 13C NMR (100 MHz,
DMSO-d6): 19.8, 42.4, 47.9, 61.3, 98.9, 113.8, 117.4, 123.9, 124.4,
124.8, 125.1, 127.6, 129.5, 133.5, 136.5, 142.4, 149.1, 149.1, 149.7,
151.8, 156.8; ESI-MS (m ⁄ z): 428.88 (M++H); Anal. Calcd for
C21H19Cl2N5O: C, 58.89; H, 4.47; N, 16.35; Found: C, 58.93; H, 4.55;
N, 16.68.
Yield: 69%; mp 196–198 ꢀC; IR ( ⁄ cm, KBr): 3228, 2955, 1580, 1546,
1
1241, 1013, 837; H NMR (300 MHz, DMSO-d6): 1.11 (d, 6H), 2.74–
2.83 (m, 1H), 3.77–3.79 (m, 2H), 4.64 (t, 2H, J = 6 Hz), 5.09 (s, 2H),
6.53 (d, 1H, J = 5.7 Hz), 6.87 (d, 2H, J = 9 Hz), 7.09 (d, 2H,
J = 9 Hz), 7.43–7.45 (m, 2H), 7.79 (d, 1H, J = 5.7 Hz), 8.15 (d, 1H,
J = 9 Hz), 8.21 (s, 1H), 8.39 (brs, 1H); 13C NMR (100 MHz, DMSO-
d6): 24.1, 32.6, 42.4, 47.8, 61.1, 98.9, 114.4, 117.5, 123.9, 124.4,
124.9, 127.1, 127.5, 133.6, 140.7, 142.9, 148.9, 149.7, 151.8, 156.1;
ESI-MS (m ⁄ z): 422.45 (M++H), 424.15 (M++2); Anal. Calcd for
C23H24ClN5O: C, 65.47; H, 5.73; N, 16.60; Found: C, 65.52; H, 5.77;
N, 16.83.
(7-Chloro-quinolin-4-yl)-[2-(4-p-tolyloxymethyl-
[1,2,3]triazol-1-yl)-ethyl]-amine (3j)
(7-Chloro-quinolin-4-yl)-{2-[4-(4-nitro-
phenoxymethyl)-[1,2,3]triazol-1-yl]-ethyl}-amine
(3n)
Yield: 75%; mp 172–174 ꢀC; IR ( ⁄ cm, KBr): 3245, 3137, 2927, 1577,
1
1511, 1236, 1014, 806; H NMR (300 MHz, DMSO-d6): 2.18 (s, 3H),
3.76–3.78 (m, 2H), 4.64 (t, 2H, J = 6 Hz), 5.03 (s, 2H), 6.54 (d, 1H,
J = 5.7 Hz), 6.85 (d, 2H, J = 9Hz), 7.03 (d, 2H, J = 9 Hz), 7.43–7.53
(m, 2H), 7.79 (d, 1H, J = 5.7 Hz), 8.15 (d, 1H, J = 9 Hz), 8.21 (s,
1H), 8.40 (brs, 1H); 13C NMR (100 MHz, DMSO-d6): 20.1, 42.8, 47.9,
61.1, 98.8, 114.5, 124.1, 124.5, 124.9, 127.3, 129.5, 129.8, 133.7,
142.9, 148.6, 148.8, 149.9, 151.6, 155.9; ESI-MS (m ⁄ z): 394.54
(M++H), 396.22 (M++2); Anal. Calcd for C21H20ClN5O: C, 64.04; H,
5.12; N, 17.78; Found: C, 64.10; H, 5.21; N, 17.99.
Yield: 65%; mp 112–114 ꢀC; IR ( ⁄ cm, KBr): 3348, 3109, 2924, 1588,
1496, 1342, 1258, 1112, 848; H NMR (300 MHz, DMSO-d6): 3.79–
1
3.81 (m, 2H), 4.67 (t, 2H, J = 6 Hz), 5.27 (s, 2H), 6.54 (d, 1H,
J = 5.7 Hz), 7.19 (d, 2H, J = 8 Hz), 7.48–7.50 (m, 2H), 7.78–7.81 (m,
2H), 8.15–8.27 (m, 4H); 13C NMR (100 MHz, DMSO-d6): 42.6, 47.9,
61.8, 79.0, 114.9, 115.3, 124.7, 124.6, 125.0, 125.6, 125.8, 126.9,
134.2, 140.9, 141.7, 150.3, 163.2; ESI-MS (m ⁄ z): 426.11 (M++H),
428.32 (M++2); Anal. Calcd for C20H17ClN6O3: C, 56.54; H, 4.03; N,
19.78; Found: C, 56.91; H, 4.22; N, 19.85.
(7-Chloro-quinolin-4-yl)-[2-(4-m-tolyloxymethyl-
[1,2,3]triazol-1-yl)-ethyl]-amine (3k)
1-(4-{1-[2-(7-Chloro-quinolin-4-ylamino)-ethyl]-
1H-[1,2,3]triazol-4-ylmethoxy}-phenyl)-ethanone
(3o)
Yield: 72%; mp 140–142 ꢀC; IR ( ⁄ cm, KBr): 3235, 3058, 2924, 1579,
1542, 1243, 1160, 1046, 805; 1H NMR (300 MHz, DMSO-d6): 2.23
(s, 3H), 3.77–3.79 (m, 2H), 4.65 (t, 2H, J = 6 Hz), 5.06 (s, 2H), 6.54
(d, 1H, J = 5.7 Hz), 6.71–7.14 (m, 4H), 7.43–7.45 (m, 2H), 7.79 (d,
1H, J = 5.7 Hz), 8.15 (d, 1H, J = 9 Hz), 8.22 (s, 1H), 8.39 (brs, 1H);
13C NMR (100 MHz, DMSO-d6): 21.1, 42.4, 47.9, 60.9, 99.1, 111.6,
114.5, 115.3, 121.6, 123.9, 124.4, 124.9, 127.6, 129.2, 129.8, 135.6,
139.1, 142.8, 149.7, 151.9, 158.1; ESI-MS (m ⁄ z): 394.54 (M++H),
396.22 (M++2); Anal. Calcd for C21H20ClN5O: C, 64.04; H, 5.12; N,
17.78; Found: C, 63.95; H, 5.23; N, 17.86.
Yield: 63%; mp 194–196 ꢀC; IR ( ⁄ cm, KBr): 3225, 3066, 2923, 1669,
1
1578, 1249, 1179, 841; H NMR (400 MHz, DMSO-d6): 2.51 (s, 3H),
3.77–3.78 (m, 2H), 4.65 (t, 2H, J = 6 Hz), 5.20 (s, 2H), 6.53 (d, 1H,
J = 5.7 Hz), 7.09 (d, 2H, J = 9Hz), 7.43–7.60 (m, 2H), 7.79 (s, 1H),
7.90 (d, 2H, J = 9 Hz), 8.13 (d, 1H, J = 9 Hz), 8.26–8.30 (m, 1H),
8.39 (brs, 1H); 13C NMR (100 MHz, DMSO-d6): 26.4, 42.4, 47.9,
61.3, 98.9, 114.5, 117.4, 123.9, 124.4, 125.3, 127.3, 130.1, 130.4,
133.7, 142.1, 148.7, 149.8, 151.6, 161.8, 196.3; ESI-MS (m ⁄ z):
126
Chem Biol Drug Des 2011; 78: 124–136

Synthesis of 4-aminoquinoline-1,2,3-triazole and 4-aminoquinoline-1,2,3-triazole-1,3,5-triazine Hybrids
422.04 (M++H), 424.12 (M++2); Anal. Calcd for C22H20ClN5O2: C,
62.63; H, 4.78; N, 16.60; Found: C, 62.80; H, 4.88; N, 16.57.
Compound 4a was isolated in 58% yield. mp 201–203 ꢀC; IR ( ⁄ cm,
KBr): 3393, 2925, 2854, 1585, 1540, 1420, 1151, 808; 1H NMR
(300 MHz, DMSO-d6): 3.60–3.82 (m, 16H), 4.66 (t, 2H, J = 6 Hz),
5.35 (s, 2H), 6.12 (s, 1H), 6.57 (d, 1H, J = 5.7 Hz), 6.97 (s, 2H), 7.47
(d, 1H, J = 9 Hz), 7.80 (s, 1H), 7.90 (brs, 1H), 8.18–8.23 (m, 2H),
8.23 (brs, 1H), 9.50 (s, 1H); 13C NMR (100 MHz, DMSO-d6): 42.6,
43.6, 47.8, 55.0, 59.2, 65.8, 94.4, 98.1, 98.8, 116.9, 124.3, 124.9,
125.4, 125.56, 134.6, 141.3, 142.3, 146.5, 149.8, 151.1, 160.3,
164.9, 165.5, 169.8; ESI-MS (m ⁄ z): 618.66 (M++H), 620.11 (M++2);
Anal. Calcd for C29H31ClN10O4: C, 56.26; H, 5.05; N, 22.63; Found:
C, 56.05; H, 5.08; N, 22.69.
1-(4-{1-[3-(7-Chloro-quinolin-4-ylamino)-propyl]-
1H-[1,2,3]triazol-4-ylmethoxy}-phenyl)-ethanone
(3p)
Yield: 67%; mp 160–162 ꢀC; IR ( ⁄ cm, KBr): 3213, 3063, 2956, 1674,
1580, 1356, 1261, 1176, 836; 1H NMR (400 MHz, DMSO-d6): 2.51
(s, 3H), 2.21–2.26 (m, 2H), 3.30–3.34 (m, 2H), 4.54 (t, 2H, J = 6 Hz),
5.25 (s, 2H), 6.47 (d, 1H, J = 5.7 Hz), 7.15 (d, 2H, J = 9 Hz), 7.49–
7.56 (m, 2H), 7.81 (d, 1H, J = 5.7 Hz), 7.94 (d, 2H, J = 9 Hz), 8.29–
8.33 (m, 2H), 8.45 (brs, 1H); ESI-MS (m ⁄ z): 436.37 (M++H), 438.11
(M++2); Anal. Calcd for C23H22ClN5O2: C, 63.37; H, 5.09; N, 16.07;
Found: C, 63.35; H, 5.11; N, 16.20.
(7-Chloro-quinolin-4-yl)-(3-{4-[4-(3,5-dimethoxy-
phenylamino)-6-morpholin-4-yl-[1,3,5] triazin-2-
yloxymethyl]-[1,2,3]triazol-1-yl}-propyl)-amine
(4b)
(7-Chloro-quinolin-4-yl)-{3-[4-(naphthalen-2-
yloxymethyl)-[1,2,3]triazol-1-yl]-propyl}-amine
(3q)
Yield: 57%; mp 100–102 ꢀC; IR ( ⁄ cm, Nujol): 2921, 2854, 2723,
1612, 1585, 1463, 1377, 1150, 808; H NMR (300 MHz, DMSO-d6):
1
2.20–2.24 (m, 2H), 3.33–3.72 (m, 16H), 4.51 (t, 2H, J = 6 Hz), 5.37
(s, 2H), 6.12 (s, 1H), 6.48 (d, 1H, J = 5.7 Hz), 6.98 (s, 2H), 7.50 (d,
1H,, J = 9 Hz), 7.82 (s, 1H), 7.92 (brs, 1H), 8.25 (s, 1H), 8.33–8.40
(m, 2H), 9.50 (s, 1H); 13C NMR (100 MHz, DMSO-d6): 28.8, 40.2,
44.0, 47.8, 55.4, 59.8, 66.3, 94.9, 98.5, 99.1, 117.4, 125.1, 125.3,
125.5, 125.6, 135.1, 141.7, 142.8, 146.6, 149.8, 151.9, 160.7, 165.4,
166.0, 170.2; ESI-MS (m ⁄ z): 632.96 (M++H); Anal. Calcd for
C30H33ClN10O4: C, 56.91; H, 5.25; N, 22.12; Found: C, 56.93; H, 5.57;
N, 22.10.
Yield: 70%; mp 164–166 ꢀC; IR ( ⁄ cm, KBr): 3058, 2927, 1580,
1
1467, 1368, 1214, 1179, 808; H NMR (400 MHz, DMSO-d6): 2.23–
2.31 (m, 2H), 3.31–3.39 (m, 2H), 4.57 (t, 2H, J = 6 Hz), 5.28 (s, 2H),
6.48 (d, 1H, J = 5.7 Hz), 7.19–7.22 (m, 1H), 7.35–7.39 (m, 1H),
7.46–7.57 (m, 4H), 7.80–7.86 (m, 4H), 8.31 (d, 1H, J = 9 Hz), 8.37
(s, 1H), 8.41 (brs, 1H); 13C NMR (100 MHz, DMSO-d6): 42.5, 47.9,
61.2, 99.1, 107.1, 118.7, 123.7, 124.2, 124.7, 125.2, 126.5, 126.8,
127.5, 128.6, 129.4, 134.0, 134.2, 142.6, 148.2, 150.3, 151.0, 155.9;
ESI-MS (m ⁄ z): 430.75 (M++H), 430.12 (M++2); Anal. Calcd for
C24H20ClN5O: C, 67.05; H, 4.69; N, 16.29; Found: C, 66.98; H, 4.74;
N, 16.37.
6-((1-(2-(7-Chloroquinolin-4-ylamino)ethyl)-1H-
1,2,3-triazol-4-yl)methoxy)-N2-(3,5-
dimethoxyphenyl)-N4,N4-dimethyl-1,3,5-
triazine-2,4-diamine (4c)
(7-Chloro-quinolin-4-yl)-{2-[4-(naphthalen-2-
yloxymethyl)-[1,2,3]triazol-1-yl]-ethyl}-amine (3r)
Yield: 55%; mp 90–92 ꢀC; IR ( ⁄ cm, KBr): 3253, 3057, 2925, 1578,
Yield: 60%; mp 200–202 ꢀC; IR ( ⁄ cm, KBr): 3316, 2926, 2851, 1597,
1550, 1412, 1315, 1149, 809; 1H NMR (300 MHz, DMSO-d6): 3.03
(s, 3H), 3.10 (s, 3H), 3.68 (s, 6H), 3.80–3.81 (m, 2H), 4.67 (t, 2H,
J = 6 Hz), 5.35 (s, 2H), 6.11 (s, 1H), 6.56 (d, 1H, J = 5.7 Hz), 7.05
(s, 2H), 7.45 (d, 1H, J = 9 Hz), 7.80–7.88 (m, 2H), 8.17–8.23 (m, 2H),
8.40 (d, 1H, J = 5.7 Hz), 9.40 (s, 1H); 13C NMR (100 MHz, DMSO-
d6): 35.9, 36.2, 47.8, 54.9, 59.1, 94.2, 97.9, 98.8, 117.0, 124.2,
124.8, 125.3, 125.8, 134.4, 141.6, 142.5, 146.9, 150.1, 150.9, 160.3,
164.7, 166.0, 169.5; ESI-MS (m ⁄ z): 576.82 (M++H); Anal. Calcd for
C27H29ClN10O3: C, 56.20; H, 5.07; N, 24.27; Found: C, 56.15; H, 5.16;
N, 24.21.
1
1451, 1367, 1214, 1009, 809; H NMR (300 MHz, DMSO-d6): 3.78–
3.79 (m, 2H), 4.65 (t, 2H, J = 6 Hz), 5.19 (s, 2H), 6.56 (d, 1H,
J = 5.7 Hz), 7.10–7.12 (m, 1H), 7.29–7.32 (m, 1H), 7.39–7.44 (m,
3H), 7.68–7.79 (m, 5H), 8.17 (d, 1H, J = 9 Hz), 8.29 (s, 1H), 8.40
(brs, 1H); ESI-MS (m ⁄ z): 444.54 (M++H), 446.12 (M++2); Anal. Calcd
for C25H22ClN5O: C, 67.64; H, 5.00; N, 15.78; Found: C, 67.65; H,
5.21; N, 15.88.
(7-Chloro-quinolin-4-yl)-(2-{4-[4-(3,5-dimethoxy-
phenyl amino)-6-morpholin-4-yl-[1,3,5]triazin-2-
yloxymethyl]-[1,2,3]triazol-1-yl}-ethyl)-amine
(4a)
6-((1-(3-(7-Chloroquinolin-4-ylamino)propyl)-1H-
1,2,3-triazol-4-yl)methoxy)-N2-(3,5-
To a stirred solution of compound 8 (n = 1) (0.1 g, 0.40 mmol) and
alkyne 10a (0.16 g, 0.44 mmol) in t-BuOH (8 mL) was added a solu-
tion of sodium ascorbate (0.03 g, 0.16 mmol) and CuSO4Æ5H2O
(0.02 g, 0.08 mmol) in water (8 mL). Reaction mixture was heated
at 40 ꢀC for 3 h. After the completion of reaction, CHCl3 (20 mL)
was added to the reaction mixture, and organic layer was washed
with water (2 · 100 mL), and dried over Na2SO4. The excess of
solvent was evaporated to dryness, and the crude material
obtained was purified by SiO2 column using MeOH ⁄ CHCl3 as eluent.
dimethoxyphenyl)-N4,N4-dimethyl-1,3,5-
triazine-2,4-diamine (4d)
Yield: 73%; mp 88–90 ꢀC; IR ( ⁄ cm, KBr): 3401, 2930, 1593, 1539,
1
1408, 1151, 807; H NMR (300 MHz, DMSO-d6): 2.12–2.17 (m, 2H),
3.01 (s, 3H), 3.05 (s, 3H), 3.36–3.43 (m, 2H), 3.60 (s, 6H), 4.44 (t,
2H, J = 6 Hz), 5.29 (s, 2H), 6.04 (s, 1H), 6.43 (d, 1H, J = 5.7 Hz),
6.99 (s, 2H), 7.45 (d, 1H, J = 9 Hz), 7.75 (s, 1H), 7.87 (brs, 1H),
8.20–8.34 (m, 3H), 9.41 (s, 1H); 13C NMR (100 MHz, DMSO-d6):
28.8, 36.4, 36.6, 47.8, 55.4, 59.5, 94.7, 98.3, 99.1, 117.4, 125.1,
Chem Biol Drug Des 2011; 78: 124–136
127

Manohar et al.
125.3, 125.4, 15.6, 135.1, 141.9, 142.9, 146.5, 149.9, 151.9, 160.7,
165.1, 166.4, 169.9; ESI-MS (m ⁄ z): 592.48 (M++H), 594.30 (M++2);
Anal. Calcd for C28H31ClN10O3: C, 56.90; H, 5.29; N, 23.70; Found:
C, 56.95; H, 5.30; N, 23.91.
6.48 (d, 1H, J = 5.7 Hz), 7.02 (s, 3H), 7.47–7.58 (m, 2H), 7.76–7.81
(m, 2H), 8.30–8.32 (m, 2H), 8.72–8.78 (m, 1H); 13C NMR (100 MHz,
DMSO-d6): 18.2, 18.3, 28.5, 43.1, 43.3, 47.3, 58.9, 59.0, 65.7, 65.9,
98.6, 124.6, 124.9, 125.9, 126.4, 127.6, 134.3, 135.4, 136.0, 142.3,
142.6, 150.1, 150.9, 165.6, 165.7, 166.3, 169.9, 170.1; ESI-MS (m ⁄ z):
600.57 (M++H), 600.22 (M++2); Anal. Calcd for C30H33ClN10O2: C,
59.94; H, 5.53; N, 23.30; Found: C, 60.15; H, 5.58; N, 23.40.
6-((1-(2-(7-Chloroquinolin-4-ylamino)ethyl)-1H-
1,2,3-triazol-4-yl)methoxy)-N2-(2,6-
dimethylphenyl)-N4,N4-dimethyl-1,3,5-triazine-
2,4-diamine (4e)
{2-[4-(4-Butylamino-6-morpholin-4-yl-
Yield: 68%; mp 140–142 ꢀC; IR ( ⁄ cm, KBr): 3392, 2951, 1581,
1534, 1406, 1329, 1214, 1093, 811; H NMR (300 MHz, DMSO-d6):
[1,3,5]triazin-2-yloxymethyl)-[1,2,3]triazol-1-yl]-
ethyl}-(7-chloro-quinolin -4-yl)-amine (4i)
Yield: 68%; mp 210–212 ꢀC; IR ( ⁄ cm, KBr): 3266, 2958, 2857, 1581,
1
2..09 (s, 3H), 2.13 (s, 3H), 3.05 (s, 3H), 3.16 (s, 3H), 3.77–3.83 (m,
2H), 4.62 (t, 2H, J = 6 Hz), 5.25 (s, 2H), 6.58 (d, 1H, J = 5.7 Hz),
6.99–7.05 (m, 3H), 7.48 (d, 1H, J = 9 Hz), 7.68–7.83 (m, 2H), 8.14–
8.42 (m, 3H), 8.69 (s, 1H); 13C NMR (100 MHz, DMSO-d6): 18.3,
18.4, 35.8, 35.9, 42.6, 47.9, 58.9, 99.3, 124.3, 124.7, 125.4, 126.6,
127.6, 134.1, 135.5, 136.0, 142.5, 142.7, 150.4, 150.8, 165.7,
166.2, 166.3, 169.9; ESI-MS (m ⁄ z): 576.95 (M++H); Anal. Calcd for
C27H29ClN10O3: C, 56.20; H, 5.07; N, 24.27; Found: C, 56.28; H,
5.19; N, 24.23.
1
1537, 1446, 1363, 1112, 810; H NMR (300 MHz, DMSO-d6): 0.92 (t,
3H), 1.19–1.50 (m, 4H), 3.15–3.81 (m, 12H), 4.66 (t, 2H, J = 6 Hz),
5.28 (s, 2H), 6.59 (d, 1H, J = 5.7 Hz), 7.27–7.34 (m, 1H), 7.46–7.49
(m, 1H), 7.70–7.82 (m, 2H), 8.11–8.19 (m, 2H), 8.43 (brs, 1H); ESI-
MS (m ⁄ z): 538.75 (M++H), 540.30 (M++2); Anal. Calcd for
C25H31ClN10O2: C, 55.70; H, 5.80; N, 25.98; Found: C, 55.78; H, 5.96;
N, 25.88.
(7-Chloro-quinolin-4-yl)-{2-[4-(4-
6-((1-(3-(7-Chloroquinolin-4-ylamino)propyl)-1H-
1,2,3-triazol-4-yl)methoxy)-N2-(2,6-
dimethylphenyl)-N4,N4-dimethyl-1,3,5-triazine-
2,4-diamine (4f)
Yield: 49%; mp 215–218 ꢀC; IR ( ⁄ cm, KBr): 3401, 2926, 1581, 1541,
1406, 1324, 1215, 811; 1H NMR (300 MHz, DMSO-d6): 2.08–2.21
(m, 8H), 3.07 (s, 6H); 3.35–3.55 (m, 2H), 4.45 (t, 2H, J = 6 Hz), 5.21
(s, 2H), 6.55 (d, 1H, J = 5.7 Hz), 7.02–7.05 (m, 3H), 7.47 (d, 1H,
J = 9 Hz), 7.58–7.92 (m, 3H), 8.26–8.35 (m, 2H), 8.67 (s, 1H); ESI-
MS (m ⁄ z): 560.78 (M++H); Anal. Calcd for C28H31ClN10O: C, 60.15;
H, 5.59; N, 25.05; Found: C, 60.10; H, 5.67; N, 24.88.
cyclopropylamino-6-morpholin-4-yl-
[1,3,5]triazin-2-yloxymethyl)-[1,2,3]triazol-1-yl]-
ethyl}-amine (4j)
Yield: 65%; mp 104–106 ꢀC; IR ( ⁄ cm, KBr): 3293, 2924, 2854, 1581,
1534, 1363, 1112, 810; 1H NMR (300 MHz, DMSO-d6): 0.43–0.59
(m, 4H), 2.65–2.78 (m, 1H), 3.56–3.80 (m, 10H), 4.65 (t, 2H,
J = 6 Hz), 5.27 (s, 2H), 6.59 (d, 1H, J = 5.7 Hz), 7.45–7.48 (m, 2H),
7.78–7.90 (m, 2H), 8.18–8.29 (m, 2H), 8.50 (brs, 1H); 13C NMR
(100 MHz, DMSO-d6): 6.0, 6.2, 23.4, 42.6, 43.3, 47.8, 58.8, 65.9,
98.9, 124.3, 124.8, 125.3, 126.2, 134.3, 142.6, 150.4, 150.7, 165.7,
167.6, 168.0, 169.5, 169.9; ESI-MS (m ⁄ z): 522.45 (M++H), 524.22
(M++2); Anal. Calcd for C24H27ClN10O2: C, 55.12; H, 5.20; N, 26.78;
Found: C, 55.16; H, 5.25; N, 26.99.
(7-Chloro-quinolin-4-yl)-(2-{4-[4-(2,6-dimethyl-
phenylamino)-6-morpholin-4-yl-[1,3,5]triazin-2-
yloxymethyl]-[1,2,3]triazol-1-yl}-ethyl)-amine (4g)
Yield: 56%; mp 218–220 ꢀC; IR ( ⁄ cm, KBr): 3246, 2957, 2854, 1581,
1534, 1446, 1272, 1112, 811; 1H NMR (300 MHz, DMSO-d6): 2.08
(s, 3H), 2.10 (s, 3H), 3.37–3.69 (m, 10H), 4.61 (t, 2H, J = 6 Hz), 5.25
(s, 2H), 6.54 (d, 1H, J = 5.7 Hz), 7.03 (s, 3H), 7.45 (d, 1H, J = 9 Hz),
7.65–7.81 (m, 2H), 8.14–8.42 (m, 3H), 8.70–8.76 (m, 1H); 13C NMR
(100 MHz, DMSO-d6): 18.3, 18.4, 43.2, 43.3, 47.8, 58.9, 59.0, 65.8,
65.9, 98.8, 124.2, 124.6, 125.3, 126.7, 127.6, 134.0, 135.6, 136.0,
142.3, 142.5, 150.2, 151.0, 165.6, 165.7, 166.4, 169.9; ESI-MS
(m ⁄ z): 588.26 (M++H), 590.21 (M++2); Anal. Calcd for C29H31ClN10O2:
C, 59.33; H, 5.32; N, 23.86; Found: C, 59.27; H, 5.31; N, 23.94.
(7-Chloro-quinolin-4-yl)-{3-[4-(4-
cyclopropylamino-6-morpholin-4-yl-
[1,3,5]triazin-2-yloxymethyl)-[1,2,3]triazol-1-yl]-
propyl}-amine (4k)
Yield: 62%; mp 97–99 ꢀC; IR ( ⁄ cm, KBr): 3401, 2960, 2855, 1581,
1534, 1362, 1112, 810; 1H NMR (300 MHz, DMSO-d6): 0.44–0.61
(m, 4H), 2.19–2.23 (m, 2H), 2.68–2.80 (m, 1H), 3.57–3.62 (m, 10H),
4.50 (t, 2H, J = 6 Hz), 5.28 (s, 2H), 6.49 (d, 1H, J = 5.7 Hz), 7.44–
7.52 (m, 2H), 7.82–7.90 (m, 2H), 8.20 (s, 1H), 8.32 (d, 1H,
J = 5.7 Hz), 8.41 (brs, 1H); ESI-MS (m ⁄ z): 538.19 (M++H); Anal.
Calcd for C25H29ClN10O2: C, 55.91; H, 5.44; N, 26.08; Found: C,
56.00; H, 5.41; N, 26.11.
(7-Chloro-quinolin-4-yl)-(3-{4-[4-(2,6-dimethyl-
phenylamino)-6-morpholin-4-yl-[1,3,5]triazin-2-
yloxymethyl]-[1,2,3]triazol-1-yl}-propyl)-amine
(4h)
(7-Chloro-quinolin-4-yl)-{2-[4-(4-
cyclopropylamino-6-piperidin-1-yl-[1,3,5]triazin-
2-yloxymethyl)-[1,2,3]triazol-1-yl]-ethyl}-amine
(4l)
Yield: 72%; mp 174–176 ꢀC; IR ( ⁄ cm, KBr): 3297, 2935, 1582, 1532,
1447, 1358, 1138, 810; 1H NMR (300 MHz, DMSO–d6): 0.40–0.55
Yield: 72%; mp 138–141 ꢀC; IR ( ⁄ cm, KBr): 3401, 2923, 2853, 1581,
1
1534, 1363, 1271, 1113, 811; H NMR (300 MHz, DMSO-d6): 2.09–
2.28 (m, 8H), 3.15–3.70 (m, 10H), 4.46 (t, 2H, J = 6 Hz), 5.28 (s, 1H),
128
Chem Biol Drug Des 2011; 78: 124–136

Synthesis of 4-aminoquinoline-1,2,3-triazole and 4-aminoquinoline-1,2,3-triazole-1,3,5-triazine Hybrids
(m, 4H), 1.39–1.52 (m, 6H), 2.62–2.75 (m, 1H), 3.40–3.76 (m, 6H),
4.63 (t, 2H, J = 6 Hz), 5.25 (s, 2H), 6.65 (d, 1H, J = 5.7 Hz), 7.29 (s,
1H), 7.43 (d, 1H, J = 9 Hz), 7.68–7.92 (m, 2H), 8.13–8.27 (m, 2H);
ESI-MS (m ⁄ z): 522.40 (M++H), 524.30 (M++2); Anal. Calcd for
C25H29ClN10O: C, 57.63; H, 5.61; N, 26.88; Found: C, 57.64; H, 5.72;
N, 26.89.
(4,6-Dichloro-[1,3,5]triazin-2-yl)-phenyl-amine
(12a)
To a stirred suspension of cyanuric chloride (5 g, 27.1 mmol) (11)
and NaHCO3 (6.83 g, 81.3 mmol) in 30 mL THF, aniline (2.52 g,
27 mmol) was added slowly at 0 ꢀC. The reaction mixture was stir-
red at 0–5 ꢀC for 2–3 h. After completion of reaction, NaHCO3 was
removed by filtration and excess of solvent was removed under vac-
uum. The crude product thus obtained was dissolved in 100 mL
CHCl3 and washed with water (2 · 200 mL) and finally with brine.
The CHCl3 layer was dried over Na2SO4, and after removal of sol-
vent, residue was purified over SiO2 column using EtOAc:Hexane as
an eluent to yield compound 12a as white solid. Yield: 82%; mp
135–138 ꢀC [Lit 136–138 ꢀC (42)].
(7-Chloro-quinolin-4-yl)-{3-[4-(4-
cyclopropylamino-6-piperidin-1-yl-[1,3,5]triazin-
2-yloxy methyl)-[1,2,3]triazol-1-yl]-propyl}-amine
(4m)
Yield: 52%; mp 90–92 ꢀC; IR ( ⁄ cm, KBr): 3292, 2933, 2854, 1582,
1533, 1499, 1356, 1136, 810; 1H NMR (300 MHz, DMSO-d6):
0.43–0.60 (m, 4H), 1.37–1.55 (m, 6H), 2.18–2.23 (m, 2H), 2.65–
2.78 (m, 1H), 3.28–3.63 (m, 6H), 4.50 (t, 2H, J = 6 Hz), 5.27 (s, 2H),
6.46 (d, 1H, J = 5.7 Hz), 7.35 (s, 1H), 7.48 (d, 1H, J = 9 Hz), 7.58–
7.80 (m, 2H), 8.18 (s, 1H), 8.44 (d, 1H, J = 5.7 Hz), 8.51 (brs, 1H);
ESI-MS (m ⁄ z): 534.91 (M++H), 536.55 (M++2); Anal. Calcd for
C26H31ClN10O: C, 58.36; H, 5.84; N, 26.18; Found: C, 58.40; H, 6.11;
N, 26.23.
(4,6-Dichloro-[1,3,5]triazin-2-yl)-(2,6-dimethyl-
phenyl)-amine (12b)
Yield: 85%; mp 192–194 ꢀC; IR ( ⁄ cm, KBr): 3221, 2958, 1609, 1556,
1518, 1398, 1201, 1017; 1H NMR (300 MHz, CDCl3): 2.23 (s, 6H),
7.12–7.23 (m, 3H), 7.63 (brs, 1H); ESI-MS (m ⁄ z): 240.10 (M++H);
Anal. Calcd for C9H6Cl2N4: C, 44.84; H, 2.51; N, 23.24; Found: C,
44.92; H, 2.45; N, 23.30.
{3-[4-(4-Chloro-6-cyclopropylamino-
[1,3,5]triazin-2-yloxymethyl)-[1,2,3]triazol-1-yl]-
propyl}-(7-chloro-quinolin -4-yl)-amine (4n)
Yield: 65%; mp 242–244 ꢀC; IR ( ⁄ cm, KBr): 3235, 3089, 2925, 1580,
Cyclopropyl-(4,6-dichloro-[1,3,5]triazin-2-yl)-
amine (12c)
Yield: 80%; mp 111–112 ꢀC; IR ( ⁄ cm, KBr): 3257, 2918, 1744, 1594,
1
1
1528, 1420, 1326, 1209, 1010, 807; H NMR (300 MHz, DMSO-d6):
1555, 1500, 1351, 1163, 850; H NMR (300 MHz, CDCl3): 0.52–1.00
0.55–0.86 (m, 4H), 2.26–2.33 (m, 2H), 2.77–2.82 (m, 1H), 3.56–3.71
(m, 2H), 4.56 (t, 2H, J = 6Hz), 5.39 (s, 2H), 6.65 (d, 1H, J = 5.7 Hz),
7.10 (s, 1H), 7.58 (d, 1H, J = 9 Hz), 7.83–7.94 (m, 2H), 8.30–8.52
(m, 3H); ESI-MS (m ⁄ z): 486.06 (M++H), 488.22 (M++2); Anal. Calcd
for C21H21Cl2N9O: C, 51.86; H, 4.35; N, 25.92; Found: C, 51.93; H,
4.56; N, 125.95.
(m, 4H), 2.70–3.00 (m, 1H,); ESI-MS (m ⁄ z): 204.66 (M++H); Anal.
Calcd for C6H6Cl2N4: C, 35.15; H, 2.95; N, 27.32; Found: C, 35.37; H,
3.05; N, 27.28.
(4,6-Dichloro-[1,3,5]triazin-2-yl)-(3,5-dimethoxy-
phenyl)-amine (12d)
Yield: 85%; mp 188–190 ꢀC; IR ( ⁄ cm, KBr): 3291, 2926, 1631, 1548,
1
{3-[4-(4-Chloro-6-phenylamino-[1,3,5]triazin-2-
yloxymethyl)-[1,2,3]triazol-1-yl]-propyl}-(7-
chloro-quinolin-4-yl)-amine (4o)
1391, 1175, 1071; H NMR (300 MHz, CDCl3): 3.81 (s, 6H), 6.32 (s,
1H), 6.77 (s, 2H), 7.47 (brs, 1H); ESI-MS (m ⁄ z): 302.82 (M++H); Anal.
Calcd for C11H10Cl2N4O2: C, 43.87; H, 3.35; N, 18.61; Found: C,
43.99; H, 3.61; N, 18.60.
Yield: 78%; mp 236–238 ꢀC; IR ( ⁄ cm, KBr): 3241, 3095, 2926, 1558,
1
1428, 1364, 1207, 1003, 806; H NMR (300 MHz, DMSO-d6): 2.24–
2.27 (m, 2H), 3.70–3.82 (m, 2H), 4.54 (t, 2H, J = 6 Hz), 5.46 (s, 2H),
6.70 (d, 1H, J = 5.7 Hz), 6.97–7.37 (m, 4H), 7.61–7.68 (m, 4H), 7.90
(s, 1H), 8.42–8.54 (m, 3H); ESI-MS (m ⁄ z): 522.96 (M++H), 524.12
(M++2); Anal. Calcd for C24H21Cl2N9O: C, 55.18; H, 4.05; N, 24.13;
Found: C, 55.28; H, 4.18; N, 24.32.
(4-Chloro-6-prop-2-ynyloxy-[1,3,5]triazin-2-yl)-
phenyl-amine (13a)
Propargyl alcohol (0.46 g, 8.2 mmol) was added slowly to a suspen-
sion of (4,6-dichloro-[1,3,5]triazin-2-yl)-phenyl-amine (2 g, 8.2 mmol)
(12a) in 20 mL THF at room temperature followed by K2CO3
(3.43 g, 24.8 mmol). Reaction mixture was allowed to stir at room
temperature for 3–4 h. The progress of reaction was monitored by
thin layer chromatography. After completion, the reaction mixture
was filtered and excess of solvent was evaporated under vacuum.
The residue was dissolved in 50 mL CHCl3, and organic layer was
washed with water (2 · 200 mL). The chloroform layer was dried
over anhydrous Na2SO4, and excess of solvent was removed under
vacuum to give crude product that was purified over SiO2 column
using EtOAc:Hexane as eluent. The title compound (13a) was
obtained in 51% yield. mp 115–118 ꢀC; IR ( ⁄ cm, KBr): 3350, 3277,
1607, 1572, 1547, 1436, 1333, 1019; 1H NMR (300 MHz, CDCl3):
(3-{4-[4-Chloro-6-(2,6-dimethyl-phenylamino)-
[1,3,5]triazin-2-yloxymethyl]-[1,2,3]triazol-1-yl}-
propyl)-(7-chloro-quinolin-4-yl)-amine (4p)
Yield: 63%; mp 248–250 ꢀC; IR ( ⁄ cm, KBr): 3233, 3081, 2925,
1577, 1458, 1364, 1207, 999, 809; 1H NMR (300 MHz, DMSO-d6):
2.08–2.21 (m, 8H), 3.62–3.90 (m, 2H), 4.49 (t, 2H, J = 6 Hz), 5.24
(s, 2H), 6.70–7.13 (m, 5H), 7.48–7.73 (m, 2H), 8.18 (brs, 1H), 8.45–
8.93 (m, 3H); ESI-MS (m ⁄ z): 550.99 (M++H); Anal. Calcd for
C26H25Cl2N9O: C, 56.73; H, 4.58; N, 22.90; Found: C, 56.75; H,
4.68; N, 22.96.
Chem Biol Drug Des 2011; 78: 124–136
129

Manohar et al.
2.54 (s, 1H), 5.00 (d, 2H, J = 2.5 Hz), 7.15–7.59 (m, 5H), 7.65 (brs,
1H); ESI-MS (m ⁄ z): 260.95 (M++H), 262.30 (M++2); Anal. Calcd for
C12H9ClN4O: C, 55.29; H, 3.48; N, 21.49; Found: C, 54.98; H, 3.44;
N, 21.52.
1H), 6.80–6.82 (m, 2H), 7.12 (brs, 1H); ESI-MS (m ⁄ z): 370.85 (M++H);
Anal. Calcd for C18H21N5O4: C, 58.21; H, 5.70; N, 18.86; O, 17.23;
Found: C, 58.15; H, 5.76; N, 18.92.
N2-(3,5-dimethoxyphenyl)-N4,N4-dimethyl-6-
(prop-2-ynyloxy)-1,3,5-triazine-2,4-diamine (10b)
Yield: 88%; mp 148–150 ꢀC; IR ( ⁄ cm, KBr): 3281, 3127, 2934, 1598,
1548, 1410, 1151, 831; 1H NMR (400 MHz, CDCl3): 2.47 (t, 1H),
3.17–3.19 (m, 6H), 3.77 (s, 6H), 4.95 (d, 2H, J = 2.5 Hz), 6.17 (s,
1H), 6.88–6.89 (m, 2H), 7.32 (brs, 1H); 13C NMR (100 MHz, CDCl3):
36.4, 36.6, 53.9, 55.2, 74.5, 78.5, 95.2, 97.9, 140.5, 160.8, 164.9,
166.5, 169.4; ESI-MS (m ⁄ z): 330.05 (M++H); Anal. Calcd for
C16H19N5O3: C, 58.35; H, 5.81; N, 21.26; Found: C, 58.22; H, 5.74;
N, 21.33.
(4-Chloro-6-prop-2-ynyloxy-[1,3,5]triazin-2-yl)-
(2,6-dimethyl-phenyl)-amine (13b)
Yield: 54%; mp 126–128 ꢀC; IR ( ⁄ cm, KBr): 3304, 3226, 2956, 1601,
1576, 1457, 1337, 1017; 1H NMR (300 MHz, CDCl3): 2.23 (s, 6H),
2.52 (t, 1H), 4.99 (d, 2H, J = 2.5 Hz), 7.10–7.16 (m, 3H), 7.46 (brs,
1H); ESI-MS (m ⁄ z): 288.89 (M++H), 290.22 (M++2); Anal. Calcd for
C14H13ClN4O: C, 58.24; H, 4.54; N, 19.40; Found: C, 58.34; H, 4.60;
N, 19.38.
(4-Chloro-6-prop-2-ynyloxy-[1,3,5]triazin-2-yl)-
cyclopropyl-amine (13c)
N-(2,6-dimethylphenyl)-4-morpholino-6-(prop-2-
ynyloxy)-1,3,5-triazin-2-amine (10c)
Yield: 50%; mp 120–122 ꢀC; IR ( ⁄ cm, KBr): 3258, 3142, 2940, 1625,
1
1570, 1519, 1335, 1011; H NMR (300 MHz, CDCl3): 0.53–0.64 (m,
Yield: 90%; mp 158–161 ꢀC; IR ( ⁄ cm, KBr): 3227, 2920, 2852, 1552,
1501, 1409, 1114, 808; 1H NMR (400 MHz, CDCl3): 2.32 (s, 6H),
2.32–2.46 (m, 1H), 3.49–3.81 (m, 8H), 4.93 (d, 2H, J = 2.5 Hz), 6.76
(brs, 1H), 7.07–7.10 (m, 3H); 13C NMR (100 MHz, CDCl3): 18.6, 43.7,
54.0, 66.6, 74.6, 78.3, 126.7, 127.9, 134.6, 135.8, 136.2, 165.6, 165.8,
169.5; ESI-MS (m ⁄ z): 340.86 (M++H); Anal. Calcd for C18H21N5O2: C,
63.70; H, 6.24; N, 20.64; Found: C, 63.98; H, 6.26; N, 20.44.
2H), 0.85–0.89 (m, 2H), 2.51 (t, 1H), 2.79–2.89 (m, 1H), 5.02 (d, 2H,
J = 2.5 Hz), 5.97 (brs, 1H); ESI-MS (m ⁄ z): 224.32 (M++H), 226.11
(M++2); Anal. Calcd for C9H9ClN4O: C, 48.12; H, 4.04; N, 24.94;
Found: C, 48.22; H, 4.21; N, 24.99.
(4-Chloro-6-prop-2-ynyloxy-[1,3,5]triazin-2-yl)-
(3,5-dimethoxy-phenyl)-amine (13d)
Yield: 58%; mp 130–133 ꢀC; IR ( ⁄ cm, KBr): 3307, 2925, 1634, 1576,
1456, 1335, 1164; H NMR (300 MHz, CDCl3): 2.54 (t, 1H), 3.81 (s,
6H), 5.03 (d, 2H, J = 2.5 Hz), 6.29 (t, 2H, J = 6 Hz), 6.80 (s, 1H),
7.41 (brs, 1H); ESI-MS (m ⁄ z): 320.78 (M++H), 322.18 (M++2); Anal.
Calcd for C14H13ClN4O3: C, 52.43; H, 4.09; N, 17.47; Found: C,
52.38; H, 4.10; N, 17.55.
N2-(2,6-dimethylphenyl)-N4,N4-dimethyl-6-
(prop-2-ynyloxy)-1,3,5-triazine-2,4-diamine (10d)
Yield: 85%; mp 166–168 ꢀC; IR ( ⁄ cm, KBr): 3184, 2928, 1605, 1558,
1512, 1406, 1111, 807; 1H NMR (400 MHz, CDCl3): 2.23 (s, 6H),
2.36–2.45 (m, 1H), 3.09–3.15 (m, 6H), 4.95 (d, 2H, J = 2.5 Hz), 6.29
(brs, 1H), 7.05–7.11 (m, 3H); ESI-MS (m ⁄ z): 298.58 (M++H); Anal.
Calcd for C16H19N5O: C, 64.63; H, 6.44; N, 23.55; Found: C, 64.60;
H, 6.21; N, 23.58.
1
4-(4-Chloro-6-(prop-2-ynyloxy)-1,3,5-triazin-2-
yl)morpholine (13e)
Yield: 55%; mp 130–132 ꢀC; IR ( ⁄ cm, KBr): 3300, 2963, 2867, 1585,
1502, 1343, 11283, 1039; H NMR (300 MHz, CDCl3): 2.50 (t, 1H),
N2-butyl-N4-cyclopropyl-6-(prop-2-ynyloxy)-
1,3,5-triazine-2,4-diamine (10e)
1
3.73 (t, 4H), 3.86 (t, 4H), 4.95 (d, 2H, J = 2.5 Hz); ESI-MS (m ⁄ z):
354.96 (M++H), 356.30 (M++2); Anal. Calcd for C10H11ClN4O2: C,
47.16; H, 4.35; N, 22.00; Found: C, 47.40; H, 4.42; N, 22.01.
Yield: 88%; mp 135–137 ꢀC; IR ( ⁄ cm, KBr): 3246, 2957, 1581, 1508,
1334, 1110, 808; H NMR (400 MHz, CDCl3): 0.91 (t, 3H), 1.31–1.40
(m, 2H), 1.48–1.57 (m, 2H), 2.40 (t, 1H), 3.34–3.36 (m, 2H), 3.68–
3.79 (m, 8H), 4.87 (d, 2H, J = 2.5 Hz), 5.05 (brs, 1H); ESI-MS (m ⁄ z):
262.18 (M++H); Anal. Calcd for C13H19N5O: C, 59.75; H, 7.33; N,
26.80; Found: C, 59.77; H, 7.25; N, 26.90.
1
N-(3,5-dimethoxyphenyl)-4-morpholino-6-
(prop-2-ynyloxy)-1,3,5-triazin-2-amine (10a)
To a solution of compound 13d (0.5 g, 1.5 mmol) in THF (20 mL)
was added morpholine (0.40 g, 4.5 mmol). Reaction mixture was
stirred at room temperature for 4 h. After the completion of reac-
tion, CHCl3 (20 mL) was added and organic layer was washed with
water (2 · 100 mL). The organic layer was dried over Na2SO4, and
excess of solvent was evaporated to dryness, and the crude mate-
rial thus obtained was purified by SiO2 column using EtOAC ⁄ Hexane
as eluent. The title compound 10a was obtained in 86% yield. mp
139–142 ꢀC; IR ( ⁄ cm, KBr): 3347, 3306, 2938, 1595, 1563, 1412,
N-cyclopropyl-4-morpholino-6-(prop-2-ynyloxy)-
1,3,5-triazin-2-amine (10f)
Yield: 92%; mp 167–170 ꢀC; IR ( ⁄ cm, KBr): 3258, 2959, 1572, 1502,
1332, 1109, 1022, 808; 1H NMR (400 MHz, CDCl3): 0.42–0.52 (m,
2H), 0.64–0.76 (m, 2H), 2.39 (t, 1H, J = 6 Hz), 2.67–2.85 (m, 1H),
3.65–3.74 (m, 8H), 4.84 (d, 2H, J = 2.5 Hz), 5.26–5.60 (m, 1H); 13C
NMR (100 MHz, CDCl3): 6.9, 23.3, 43.6, 53.8, 66.6, 74.3, 78.5,
165.8, 168.4, 169.9; ESI-MS (m ⁄ z): 274.88 (M++H); Anal. Calcd for
C13H17N5O2: C, 56.71; H, 6.22; N, 25.44; Found: C, 56.80; H, 6.16;
N, 25.40.
1
1203, 1151, 807; H NMR (400 MHz, CDCl3):2.47 (t,1H), 3.72 (t, 4H),
3.78 (s, 6H), 3.85 (t, 4H), 4.94 (d, 2H, J = 2.5 Hz); 6.19–6.20 (m,
130
Chem Biol Drug Des 2011; 78: 124–136

Synthesis of 4-aminoquinoline-1,2,3-triazole and 4-aminoquinoline-1,2,3-triazole-1,3,5-triazine Hybrids
N-cyclopropyl-4-(piperidin-1-yl)-6-(prop-2-
ynyloxy)-1,3,5-triazin-2-amine (10g)
mixture was mixed with 100 lL of the Malstatꢁ reagent (Flow Inc.,
Portland, OR, USA) and incubated at room temperature for 30 min.
Twenty microliters of a 1:1 mixture of NBT ⁄ PES (Sigma, St Louis,
MO, USA) was then added, and the plate is further incubated in
the dark for 1 h. The reaction was then stopped by the addition of
100 lL of a 5% acetic acid solution. The plate was read at
650 nm. Artemisinin and chloroquine were included in each assay
as antimalarial drug controls. IC50 values were computed from the
dose–response curves. To determine the selectivity index of antima-
larial activity of compounds, their in vitro cytotoxicity to mammalian
cells was also determined. The assay was performed in 96-well tis-
sue culture–treated plates as described earlier (45). Vero cells (mon-
key kidney fibroblasts) were seeded to the wells of 96-well plate at
a density of 25 000 cells ⁄ well and incubated for 24 h. Samples at
different concentrations were added and plates were again incu-
bated for 48 h. The number of viable cells was determined by Neu-
tral Red assay. IC50 values were obtained from dose–response
curves. Doxorubicin was used as a positive control for cytotoxicity.
Yield: 90%; mp 144–146 ꢀC; IR ( ⁄ cm, KBr): 3249, 2941, 2856, 1581,
1
1542, 1329, 1296, 1100, 809; H NMR (400 MHz, CDCl3): 0.44–0.47
(m, 2H), 0.62–0.76 (m, 2H), 1.50–1.60 (m, 6H), 2.38 (t, 1H,
J = 6 Hz), 2.71–2.72 (m, 1H), 3.62–3.82 (m, 4H), 4.85 (d, 2H,
J = 2.5 Hz), 5.32 (brs, 1H); 13C NMR (100 MHz, CDCl3): 6.9, 23.4,
24.7, 25.7, 44.3, 53.7, 74.1, 78.7, 165.3, 168.3, 169.7; ESI-MS (m ⁄ z):
274.62 (M++H); Anal. Calcd for C14H19N5O: C, 61.52; H, 7.01; N,
25.62; Found: C, 61.48; H, 7.08; N, 25.71.
Assay for in vitro antimalarial activity and
cytotoxicity
The antimalarial activity was determined by measuring plasmodial
LDH activity as described earlier (43). A suspension of red blood
cells infected with D6 or W2 strain of P. falciparum (200 lL, with
2% parasitemia and 2% hematocrit in RPMI 1640 medium supple-
mented with 10% human serum and 60 lg ⁄ mL amikacin) was
added to the wells of a 96-well plate containing 10 lL of serially
diluted test samples. The plate was flushed with a gas mixture of
90% N2, 5% O2, and 5% CO2 and incubated at 37 ꢀC for 72 h in a
modular incubation chamber (Billups-Rothenberg Inc., Del Mar, CA,
USA). Parasitic LDH activity was determined according to the proce-
dure of Makler and Hinrichs (44). Briefly, 20 lL of the incubation
Result and Discussion
Chemistry
The target compounds were prepared as outlined in Scheme 1. Aro-
matic nucleophilic substitution of commercially available starting
N3
n
OH
n
OMs
n
HN
Cl
N
HN
N
HN
a
b
c
Cl
N
Cl
Cl
Cl
N
8
7
5
6
N
N
N
n
R
HN
N
(9)
R
Cl
N3
n
3a-r
HN
N
R1
d
N
N
O
N
N
Cl
N
N
HN
N
8
n
R2
10a-10g
Cl
4a-p
Scheme 1: Reagents and conditions: (a) 2-aminoethanol or 3-amino-1-propanol, 130–150 ꢀC, N2, 12–15 h, 85–88%; (b) MsCl, Et3N, THF,
N2, 0 ꢀC-RT, 1 h, 70–75%; (c) NaN3, DMF, 50 ꢀC, 4–5 h, 85–90%; (d) CuSO4Æ5H2O, Sodium Ascorbate, t-BuOH:water (1:1), 40 ꢀC, 3 h, 50–
75%.
O
N
Cl
Cl
N
O
N
N
N
N
N
N
N
a
b
N
N
c
R2
R1
Cl
N
Cl
Cl
R1
Cl
R1
10a-10g
12a-12d
11
13a-13e
Scheme 2: Reagents and conditions: (a) aliphatic or aromatic amines, K2CO3, THF, 0 ꢀC, 3 h, 80–85%; (b) propargyl alcohol, K2CO3, THF,
0 ꢀC-RT, 5–8 h, 50–60%; (c) aliphatic amines (3 eq), rt, 4–5 h, 85–90%.
Chem Biol Drug Des 2011; 78: 124–136
131

Manohar et al.
Table 1: In vitro antimalarial activity and cytotoxicity of 4-aminoquinoline-triazole hybrids
N
N
R
N
HN
n
Cl
N
3a-3r
Plasmodium falciparum (D6 clone)
P. falciparum (W2 clone)
Cytotoxicity
(Vero)
IC50
(lM)
Mean
Mean €
IC50
(lM)
Mean
Mean €
Compound no.
n
R
cLogP*
IC50 (lM) SEM
SI
IC50 (lM) SEM
SI
3a
3b
1
2
CH2OH
CH2OH
1.77
2.05
6.58 7.90 7.24
3.05 3.77 3.41
0.66
0.36
>2.4 10.86 12.18 11.52
0.66
0.31
>1.4 NC
>3.4 NC
>4.9
4.40 5.03
4.71
HO
HO
3c
3d
3e
3f
1
2
1
1
1
1
3.79
4.07
3.19
5.50
5.35
5.65
6.45 6.72 6.58
2.22 2.20 2.21
4.89 4.64 4.76
1.39 1.41 1.40
1.27 1.30 1.28
1.29 1.33 1.31
0.13
0.01
0.12
0.01
0.01
0.02
>20.0
>5.5
>2.5
>7.4
>9.0
>8.2
7.26 5.64
6.45
0.81
0.13
0.64
0.00
0.30
0.33
>1.8 NC
3.36 3.10
6.44 7.73
1.37 1.37
1.44 2.05
1.78 2.45
3.23
7.08
1.37
1.74
2.11
>3.7 NC
>1.9 NC
>7.6 NC
>7.9 NC
>6.0 NC
O
H2CO
H CO
Br
Cl
2
3g
3h
H CO
2
Cl
Cl
H2CO
Me
3i
1
5.85
1.35 1.75 1.55
0.20
>8.2
1.93 2.33
2.13
0.20
>5.7 NC
H2CO
H2CO
Cl
3j
1
1
4.99
4.99
1.39 1.47 1.43
1.47 1.52 1.49
0.04
0.02
>8.7
>8.2
1.34 1.72
1.47 1.65
1.53
1.56
0.19
0.09
>9.0 NC
>8.2 NC
Me
Me
3k
H CO
2
Me
3l
1
5.44
2.32 2.94 2.63
0.31
>5.0
1.86 1.71
1.78
0.07
>6.3 NC
H2CO
Me
3m
3n
3o
3p
3q
1
1
1
2
1
5.92
4.54
4.23
4.51
5.67
1.42 1.37 1.39
1.29 1.24 1.26
0.92 0.90 0.91
0.71 0.59 0.65
1.46 1.34 1.40
0.02
0.02
0.01
0.06
0.06
>7.9
>8.7
1.49 1.58
1.64 1.24
1.37 1.13
1.10 1.14
1.62 2.09
1.53
1.44
1.25
1.12
1.85
0.04
0.20
0.12
0.02
0.23
>7.6 NC
>6.8 NC
>8.2 NC
>9.9 NC
>6.8 NC
H CO
2
H2CO
NO2
>12.2
>15.4
>7.6
H CO
2
COCH
COCH
3
3
H CO
2
H2CO
3r
2
5.94
0.99 1.21 1.10
0.11
>10.8
0.92 1.57
1.24
0.32
>11.6 NC
H2CO
Chloroquine
Artimisinin
0.04
0.03
>300
>500
0.42
0.025
>30
>670
132
Chem Biol Drug Des 2011; 78: 124–136

Synthesis of 4-aminoquinoline-1,2,3-triazole and 4-aminoquinoline-1,2,3-triazole-1,3,5-triazine Hybrids
Table 2: In vitro antimalarial activity and cytotoxicity of 4-aminoquinoline-triazole-triazine hybrids
R
1
N
N
N
O
N
N
N
R
2
HN
N
n
Cl
4a-4p
Plasmodium falciparum (D6 Clone)
P. falciparum (W2 Clone)
IC50
Mean
IC50
Mean
Cytotoxicity
(Vero)
Compound no.
n
R1
R2
cLogP* (lM) IC50 (lM) Mean € SEM SI
(lM) IC50 (lM) Mean € SEM SI
OCH
3
4a
1
5.20
5.48
5.54
3.71 4.43
5.16
0.72
0.00
0.03
>2.1 6.46 5.97
0.48
0.16
0.20
>1.2 NC
N
O
O
5.49
HN
OCH
OCH
3
3
4b
4c
2
1
0.83 0.83
0.83
>9.0 1.57 1.73
1.89
>4.8 NC
N
HN
HN
OCH
OCH
3
Me
Me
3
1.00 0.96
0.93
>8.2 1.35 1.15
0.95
>6.1 NC
>9.0 NC
N
N
OCH
OCH
3
Me
Me
3
4d
2
5.82
0.93 0.91
0.89
0.02
>8.7 0.89 1.20
1.52
0.31
HN
OCH
3
Me
Me
4e
4f
1
2
6.65
6.93
1.00 0.98
0.97
0.01
0.01
>8.7 1.55 1.69
1.83
0.14
0.02
>5.6 NC
N
N
HN
Me
Me
0.57 0.58
0.59
>14.9 0.76 0.73
0.71
>11.1 NC
HN
4g
4h
1
2
6.30
6.58
3.74 3.14
2.55
0.59
0.08
>2.2 4.76 4.84
4.93
0.08
0.08
>1.7 NC
>6.0 NC
N
N
O
O
HN
HN
2.16 2.24
2.32
>3.7 1.33 1.24
1.16
4i
4j
1
1
4.91
3.68
2.04 2.31
2.59
0.27
0.28
>4.3 3.15 3.24
3.33
0.09
0.09
>2.8 NC
>1.6 NC
HN
N
N
O
O
3.44 3.72
4.01
>2.6 5.54 5.63
5.73
HN
Chem Biol Drug Des 2011; 78: 124–136
133

Manohar et al.
Table 2: (Continued)
Plasmodium falciparum (D6 Clone)
P. falciparum (W2 Clone)
IC50 Mean
cLogP* (lM) IC50 (lM) Mean € SEM SI
IC50
Mean
Cytotoxicity
(Vero)
Compound no.
n
R1
R2
(lM) IC50 (lM) Mean € SEM SI
4k
2
3.96
5.22
5.50
4.05
5.68
6.68
1.39 1.38
1.37
0.01
0.10
0.09
0.03
0.09
0.09
>6.3 1.30 1.24
0.05
0.29
0.18
0.18
0.38
0.09
>6.8 NC
HN
N
O
1.19
4l
1
2
2
2
2
3.83 3.93
4.03
>2.4 4.03 3.74
3.45
>2.3 NC
>5.3 NC
>1.8 NC
>2.8 NC
>3.2 NC
HN
HN
HN
N
4m
4n
4o
4p
2.42 2.51
2.61
>3.7 1.68 1.86
2.05
N
Cl
4.93 4.89
4.86
>2.0 5.55 5.73
5.92
Cl
Cl
5.16 5.25
5.35
>1.8 3.25 3.63
4.01
HN
3.08 3.17
3.27
>2.8 2.72 2.81
2.90
HN
Chloroquine
Artimisinin
0.04
0.03
>300
>500
0.42
0.025
>30
>670
NC, no cytotoxicity upto 12 lM; SI, selectivity index (IC50 for cytotoxicity ⁄ IC50 for antimalarial activity).
*CHEMBIODRAW 11 Software, Cambridge, MA, USA.
material 4,7-dichloroquinoline (5) with an excess of aliphatic linear
chain aminoalcohols in neat conditions as reported in literature (34–
36) afforded substituted 4-aminoquinolines (6) in excellent yield. The
free hydroxyl group was then chemoselectively o-mesylated using
mesyl chloride and triethylamine as base to yield mesylated 4-am-
inoquinolines (7) (15,34). The acidification of these mesylated prod-
ucts was then carried using sodium azide as nucleophile and DMF
as solvent at 50 ꢀC to obtain the corresponding azides (8) (37).
Finally, these azides were reacted with substituted terminal alkynes
to generate 1,2,3-triazoles by click chemistry using standard protocol
of sodium ascorbate and copper sulfate as catalyst and an equimolar
ratio of water and t-butanol as solvents to yield the final target
compounds (3 and 4) in moderate to good yield.
a clear drift toward rise in activity. Among these, compounds with
aryl groups having halogen (3f–3i, IC50 ranging from 1.28 to
1.55 lM) and alkyl (3j–3m, IC50 ranging from 1.39 to 2.63 lM) side
chains at different positions of the aromatic ring exhibited similar
activity profile. Interestingly, introduction of COCH3 functionality at
para position of aromatic nucleus (3o and 3p) improved antimalar-
ial activity against both CQ-sensitive and CQ-resistant strains with
IC50 values of 0.91–0.65 lM and 1.12–1.25 lM, respectively, with
an increase in selectivity index. Changing the phenyl ring to biphe-
nyl moiety (3q and 3r) also improves antimalarial activity. The anti-
malarial activity profile of these compounds clearly demonstrates
that compounds with C-3 spacer (3b, 3d, 3p, 3r) showed better
antimalarial activity than their C-2 counterparts (3a, 3c, 3e–o,
3q). This trend may be due to the increase in lipophilicity as we
move from C-2 spacer to C-3 spacer. Another set of compounds
having three pharmacophore together (4a–p) showed a similar
trend of increase in activity with increasing length of carbon spacer.
Introduction of basic moieties like piperidine, morpholine, and dim-
ethylamine (4a–4m) in place of chloro group (4n–4p) boosts up
the activity. This is in accordance with the fact that basic side
chain at the terminal position of 4-aminoquinolines is important for
better activity (8). Among this series of analogues, 4f (having 2,6-
dimethyl anilino and dimethyl amino moiety attached at 4 and 6
position of triazine nucleus) was the most active analogue exhibit-
ing IC50 of 0.58 lM against D6 strain and 0.73 lM against W2
strain of P. falciparum. The substitution of 2,6-dimethyl anilino
group at 4 position (4f) with less lipophilic 3,5-dimethoxy anilino
group (4d) leads to a decrease in activity. Substitution of both the
position of triazine nucleus with aliphatic moieties (4i, 4j, 4l, 4m)
also leads to further decrease in activity with an exception of com-
pound 4k that showed moderate activity.
Substituted alkynes (9) were prepared by literature method using
propargyl bromide as a starting material under basic conditions (38–
40), while synthesis of alkynes with general structure 10a–10g is
described in Scheme 2. All of the compounds of Schemes 1 and 2
were purified over SiO2 column.
Antimalarial activity
In vitro antimalarial activity of compounds 3a–3r (Table 1) and
4a–4p (Table 2) was determined against chloroquine-sensitive (D6)
and chloroquine-resistant (W2) strains of P. falciparum, while the
cytotoxicity was determined against Vero cell line. Among the ser-
ies of eighteen 4-aminoquinoline-triazole hybrids (3a–3r), simple
aliphatic analogues containing polar hydroxy group (3a–3d) dis-
played mild to moderate activity against both strains of P. falcipa-
rum. The protection of hydroxyl group by THP group (3e) did not
enhance the activity, but incorporation of aryl groups (3f–3r) gave
134
Chem Biol Drug Des 2011; 78: 124–136

Synthesis of 4-aminoquinoline-1,2,3-triazole and 4-aminoquinoline-1,2,3-triazole-1,3,5-triazine Hybrids
8
7
6
5
4
3
2
1
0
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