Synthesis and antimalarial activity evaluation of some isoquine analogues

Article abstract of DOI:10.1007/s00044-010-9460-9

The worldwide diffusion of resistance in malaria parasite, especially the Plasmodium falciparum, towards currently available drugs has become a major health and development challenges to human society. Isoquine, an isomeric analogue of amodiaquine, has be

Full text of DOI:10.1007/s00044-010-9460-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1632–1637
DOI 10.1007/s00044-010-9460-9
ORIGINAL RESEARCH
Synthesis and antimalarial activity evaluation of some isoquine
analogues
•
Suranjana Bora Dipak Chetia Anil Prakash
•
Received: 12 March 2010 / Accepted: 27 September 2010 / Published online: 12 October 2010
Ó Springer Science+Business Media, LLC 2010
Abstract The worldwide diffusion of resistance in
malaria parasite, especially the Plasmodium falciparum,
towards currently available drugs has become a major
health and development challenges to human society.
Isoquine, an isomeric analogue of amodiaquine, has been
reported recently as a second generation lead compound for
development of cost-effective and potentially safer alter-
native to amodiaquine which cause adverse effects
including agranulocytosis and liver damage. In this study, a
series of seven analogues of isoquine have been synthe-
sized and subjected to in vitro antimalarial activity
screening against the chloroquine sensitive 3D7 strain of
Plasmodium falciparum. A simple two-step Mannich
reaction was used to synthesize the compounds. All the
seven compounds possessed little to moderate antimalarial
activity. However, the analogues with aliphatic alcoholic
amino group side chain having promising activity than the
compounds with substituted aromatic ring side chain and
compounds substituted with urea while analogues with
heterocyclic ring side chain exhibits moderate antimalarial
activity.
Introduction
Malaria is probably one of the oldest and most wide-
spread diseases in the world, affecting the population
living in tropical and subtropical areas. In human, malaria
is caused by the four species of the protozoan parasite
of the genus Plasmodium, namely P. falciparum, P. vivax,
P. malariae and P. ovale. P. falciparum is the most
dangerous of these malaria parasites causing heavy mor-
bidity and mortality. Novel, effective, safe and inexpen-
sive antimalarial agents are required for the management
of malaria in the malaria endemic region. After its dis-
covery in 1940 (Loeb et al., 1946), chloroquine (CQ)
among the aminoquinolines has remained the drug of
choice for the treatment of malaria.
Due to worldwide diffusion of resistance in P. falci-
parum to chloroquine, there is a urgent need to develop
newer, potent and cost-effective antimalarial agents. In
1950s, amodiaquine (AQ), a Mannich base derivative,
came into the market which was more effective than
chloroquine (Nevill et al., 1994; Panali et al., 1994;
Muller et al., 1996). However, the clinical use of amo-
diaquine has been restricted due to the hepatotoxicity and
agranulocytosis caused by it (Douer et al., 1985; Neftel
et al., 1986). The drug toxicity is believed to occur due to
the formation of a metabolite quinoneimine which initiate
hypersensitivity reaction. Subsequent research into the
synthesis of Mannich base compounds led to the devel-
opment of amopyroquine and Tebuquine which were
found more active than chloroquine and amodiaquine
though also caused chronic toxicity. Recently, isoquine,
an isomeric analogue of amodiaquine, has been reported
with potent antimalarial activity and a safer alternative to
amodiaquine.
Keywords Antimalarial ꢀ Mannich reaction ꢀ Isoquine
S. Bora (&) ꢀ D. Chetia
Department of Pharmaceutical Sciences,
Dibrugarh University, Dibrugarh 786004, Assam, India
e-mail: sinbora@gmail.com
A. Prakash
Regional Medical Research Centre, ICMR,
Dibrugarh 786001, Assam, India
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Med Chem Res (2011) 20:1632–1637
1633
Cl
OH
OH
NH
OH
NH
N
N
N
N
H
H3C
NH
NH
N
Cl
Cl
N
Cl
N
Cl
N
Chloroquine
Amodiaquine
Amopyroquine
Tebuquine
In the light of these observations, seven new isoquine
analogues were synthesized involving Mannich reaction,
where the diethylamino function of AQ was modified with
primary or secondary amines (Table 1) to possess better
antimalarial activity.
NHR1
OH
OH
(A)
HCHO
2
NH2R1
(a-g)
+
+
NHCOCH3
NHCOCH3
1
3(a-g)
Materials and methods
Scheme 1 Reagents and conditions: (A) ethanol, reflux 24 h
Chemistry
NHR1
OH
The desired compounds 3(a–g) and 5(a–g) were synthe-
sized by the synthetic protocols as outlined in Schemes 1
and 2, respectively (Burckhalter et al., 1948); in these
compounds, the 30-diethylamino function of amodiaquine
was replaced by a 40-primary or secondary amino function.
The synthesis of Mannich substituted amide derivatives
3(a–g) was achieved by Mannich reaction of 3-hydroxy-
acetanilide (1) with different primary amines (a–g) shown
in Table 2 (Blicke, 1942). Finally, new antimalarial com-
pounds 5(a–g) were synthesized by incorporating Mannich
substituted amide derivatives 3(a–g) with 4,7-dichloro-
quinoline (4). All the synthesized compounds were well
characterized by FT-IR, mass, NMR and elemental
analysis.
NHR1
OH
(B)
NH
N
Cl
N
NHCOCH3
3(a-g)
Cl
Cl
4
(C)
5(a-g)
Scheme 2 Reagents and conditions: (B) ethanol/20% HCl reflux 6 h
(C) ethanol, reflux 12 h
Pharmacology
In vitro antimalarial efficacy test
The synthesized compounds were evaluated for in vitro
antimalarial activity. Continuous culture of chloroquine
sensitive strain of P. falciparum (3D7) was maintained in
vitro in O?ve human red blood cells diluted to 6% haema-
tocrit in RPMI 1640 medium supplemented with 25 mmol
HEPES, 1% D-glucose, 0.23% sodium bicarbonate, genta-
mycin (40 lg/ml), amphotericin-B (0.25 lg/ml) and 10%
human AB? serum. Incubations were done at 37°C and 5%
CO2 level in a modular incubator. D-Sorbitol synchronized
1% ring stage parasitaemia in 3% haematocrit was used for
antimalarial assays using 96 well microtitre plate. A stock
solution of 5 mg/ml of the test compound was prepared in
DMSO, and subsequent dilutions were made with incom-
plete RPMI in duplicate. All test compounds were assayed
at a fixed dose of 50 lg/ml. Each test well of the microtitre
plate contained 20 ll of the compound and 180 ll of 1%
Table 1 Antimalarial activity profile of the synthesized compounds
Serial
no.
Compound code
Dosage
(lg/ml)
% (Dead
rings ? schizonts)a
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
50
50
50
50
50
50
50
0.4
34
25.5
24
36.5
33
28.5
6.5
5g
Chloroquine
(standard)
68.5
a
Mean of two replicates. Counted against 100 asexual parasites per
replicate
123

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Med Chem Res (2011) 20:1632–1637
N-substituted aromatic ring side chain (5a, 5b and 5f)
showed much better activity than the N,N di substituted
aromatic ring containing compound (5g). The compound
(5e) with heterocyclic ring (piperazine) at the side chain
showed moderate activity. However, none of the com-
pounds showed activity comparable to chloroquine under
the test conditions.
Table 2 List of targeted compounds
NHR1
OH
NH
Conclusion
In conclusion, we have shown the potential 4-aminoquin-
oline containing substituted 4-aminophenol as antimalarial
agents in vitro and thereby demonstrated a simple approach
to the synthesis of analogues of existing antimalarial drugs.
The efficiency of this approach is manifested in the pre-
clusion of large sized libraries as the SAR libraries would
already be enriched in antimalarial pharmacophores.
Rationally, such a combination of antimalarial pharmaco-
phores and other functionalities offer many attractive fea-
tures for accelerating antimalarial drug discovery.
Cl
N
5(a-g)
Compounds
(a–g)
–R1
a
b
c
d
e
f
COOH
F
O
C
NH2
OH
Experimental
4,7-Dichloroquinoline was obtained from M/s Mangalam
Drug & Organics Ltd., Mumbai, as a gift sample. All the
other chemicals used were of synthetic grade of Aldrich,
Rankem or Merck without further purification and obtained
from commercial suppliers. Analytical thin layer chroma-
tography (TLC) was performed on aluminium sheets pre-
coated with silica gel obtained from Merck. Visualization
was accomplished by UV light (254 nm). UV spectrums
were recorded on Shimadzu UV-1700 UV–Visible spec-
trophotometer. The C, H, N microanalyses of the synthe-
sized compounds were recorded on Perkin Elmer 2400
Series II Analyzer. Infrared (IR) spectra were recorded on
Perkin Elmer Spectrum RX-I spectrophotometers using
KBr pellets. The 1H-NMR and 13C-NMR spectra were
recorded on Bruker Avance-II 400 NMR Spectrometer. The
mass spectra were recorded on LC-MS Waters 4000 ZQ
Mass spectrometer. The antimalarial activity screenings of
the synthesized compounds were done at Regional Medical
Research Centre (ICMR), Dibrugarh.
NH
OH
Br
F
g
ring stage parasitaemia in 3% haematocrit. In addition,
drug-free negative control to assess the parasite growth and
chloroquine diphosphate, at predetermined 50% inhibitory
concentration (IC50) dose, as positive control to assess the
integrity of the assay were also maintained in duplicate in
the microtitre plate. After 40 h of incubation, the smears
were prepared from each well, stained with 3% Giemsa and
scanned under light microscope to ascertain % dead rings
and trophozoites by examining a minimum of 200 asexual
parasites (Smilkstein et al., 2004).
General procedure for the synthesis of compounds
Results and discussion
3(a–g)
Out of seven synthesized compounds 5(a–g), six com-
pounds 5(a–f) exhibited good antimalarial activity, the best
activity recorded by the compound (5d) with an aliphatic
alcoholic amino group side chain. The compounds having
3-Hydroxyacetanilide (1) (5 g, 33.1 mmol) was added
to 100-ml round-bottomed flask followed by ethanol
(23.6 ml). One equivalent of different primary amines
(a–g) shown in Table 2 (33.1 mmol) and aqueous
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Med Chem Res (2011) 20:1632–1637
1635
Synthesis of 5-(7-chloroquinolin-4-ylamino)-
formaldehyde (2) (2.46 ml) was added, and the solution
was allowed to heat under reflux for 24 h. After this reflux
period, the solvent was removed under reduced pressure
and the crude product was purified by silica gel flash col-
umn chromatography using 20–30% Methanol/dichloro-
methane as eluent. This gave the desired amide product
3(a–g).
2-((4-fluorophenylamino) methyl) phenol (5b)
(% Yield: 78.50); mp: 130–132°C; Rf value: 0.73 (Propa-
nol:Cyclohexane:: 4:6); UV (kmax): 260 nm (DMSO); IR
(KBr cm-1): 3187, 3006, 2905, 1654, 1585, 1452, 1367,
1291, 1211, 1152, 1167, 965, 869, 823, 762; 1H NMR
(400 MHz, DMSOd6): d 8.97 (d, 1H, J = 9.2 Hz, quino-
line–H), d 8.56 (d, 1H, J = 4 Hz, quinoline–H), d 8.26 (s,
1H, quinoline–H), d 8.10 (d, 1H, J = 12 Hz, quinoline–H),
d 7.99 (d, 1H, J = 8 Hz, quinoline–H), d 7.92 (t, 1H,
J = 8 Hz, quinoline–H), d 7.75 (s, 1H, OH) d 7.59 (t, 1H,
J = 4.00 Hz, quinoline–H), d 7.47 (m, 1H, J = 8 Hz,
Ar–H), d 6.78 (d, 1H, J = 6.8 Hz, Ar–H), d 6.14 (d, 1H,
J = 7.6 Hz, Ar–H), d 6.05 (d, 1H, J = 7.2 Hz, Ar–H), d
4.992 (m, 1H, J = 5.2 Hz, Ar–NH), d 4.18 (s, 1H, OH), d
2.55 (s, 2H, CH2), d 2.21 (m, 1H, amine); 13C NMR
(100 MHz, DMSOd6): d 162.05, 159.62, 155.14, 143.25,
138.94, 138.35, 133.19, 127.94, 127.30, 126.23, 119.08,
116.89, 116.66, 115.81, 100.14, 40.04; Mass: 394.2 (m?);
Anal Calcd for C22H17ClFN3O: C, 67.09; H, 4.35; N,
10.67. Found: C, 53.50; H, 4.81; N, 8.31.
General procedure for the synthesis of compounds
5(a–g)
Aqueous hydrochloric acid (20%, 25 ml) was added
to a round-bottomed flask containing the amide 3(a–
g) (18.9 mmol), and solution heated under reflux for 6 h. The
solvent was then removed in vacuum, and the resulting res-
idue co-evaporated with ethanol to give the corresponding
hydrochloride salt. 4,7-Dichloroquinoline (4) (4.12 g,
20.8 mmol) and ethanol (30 ml) were added, and the reac-
tion was heated under reflux for 12 h until completion of the
reaction (determined by TLC). Then the solvent was
removed under reduced pressure. Then the product was
purified by silica gel flash column chromatography using
20–80% MeOH/dichloromethane as eluent to yield the
quinoline hydrochloride salt as a solid. To liberate the free
base compound, this solid was dissolved in distilled water
(18 ml), and the solution basified by careful addition of
saturated sodium bicarbonate (added until no more precipi-
tate formed). Dichloromethane was added (100 ml), and the
free base was extracted into the organic layer. Subsequent
drying and removal of solvent in vacuo afforded the desired
product 5(a–g).
Synthesis of 1-((4-(7-chloroquinolin-4-ylamino)-
2-hydroxyphenyl) methyl) urea (5c)
(% Yield: 64.09); mp: 122–124°C; Rf value: 0.86 (Ethyl
acetate: Acetone:: 5:5); UV (kmax): 265 nm (DMSO); IR
(KBr cm-1): 3221, 2897, 1846, 1751, 1685 1609, 1534,
1448, 1374, 1374, 1238, 1098, 856, 815; 1H NMR (400 MHz
DMSOd6): d 8.60 (d, 1H, J = 8.8 Hz, quinoline–H), d 8.51
(t, 1H, J = 8Hz, quinoline–H), d 8.20 (d, 1H, J = 8.8 Hz,
quinoline–H), d 8.11 (d, 1H, J = 8.4 Hz, quinoline–H), d
7.99 (d, 1H, J = 10.8 Hz, quinoline–H), d 7.71 (m, 1H,
J = 10.4 Hz, quinoline–H), d 7.29 (d, 1H, J = 8.00 Hz,
quinoline–H), d 7.36 (d, 1H, J = 8.8 Hz, Ar–H), d 7.12 (m,
1H, J = 8 Hz, Ar–H)), d 7.07 (d, 1H, J = 4 Hz, Ar–H), d
6.98 (d, 1H, J = 4 Hz, Ar–H), d 6.87 (d, 1H, J = 7.2 Hz,
Ar–H), d 6.71 (m, 1H, J = 8 Hz, Ar–H), d 6.30 (s, 1H, OH), d
6.12 (d, 1H, J = 7.2 Hz, Ar–H), d 5.55 (s, 1H, Ar–NH), d
4.64 (s, 1H, Ar–OH), d 3.99 (d, 2H, J = 6.4 Hz, CH2), d 2.56
(s, 1H, amine); 13C NMR (100 MHz, DMSOd6): d 158.35,
153.05, 139.96, 136.16, 135.26, 135.00, 131.29, 130.18,
127.39, 127.22, 127.13, 126.13, 125.89, 125.44, 124.92,
124.24, 123.43, 117.40, 113.72, 110.08, 109.20; Mass: 342.9
(m?); Anal Calcd for C17H15ClN4O2: C, 59.57; H, 4.41; N,
16.34. Found: C, 56.71; H, 5.31; N, 7.97.
Synthesis of 4-((4-(7-chloroquinolin-4-ylamino)-3-
hydroxyphenyl) methylamino) benzoic acid (5a)
(% Yield: 60.56); mp: 214–216°C; Rf value: 0.85 (Propa-
nol:Cyclohexane::1:3); UV(kmax): 363.5 nm (DMSO); IR
(KBr cm-1) 3231, 3057, 3109, 1624, 1584, 1447, 1375,
1288, 1176, 1097, 852, 821; 1H NMR (400 MHz,
DMSOd6): d 8.79 (d, 1H, J = 8.80 Hz, quinoline–H), d
8.44 (d, 1H, J = 6.80 Hz, quinoline–H), d 8.07 (d, 1H,
J = 9.60 Hz, quinoline–H), d 7.91 (d, 1H, J = 8.0 Hz,
quinoline–H), d 7.65 (d, 1H, J = 8.8 Hz, quinoline–H), d
6.91 (d, 1H, J = 6.80 Hz, Ar–H), d 6.42 (d, 1H,
J = 8.0 Hz, Ar–H), d 6.51 (s, 1H, OH), d 6.63 (d, 1H,
J = 6.8 Hz, Ar–H), 4.178 (t, 1H, Ar–NH), d 2.36 (s, 2H,
CH2), d 2.36 (s, 2H, amine); 13C NMR (100 MHz,
DMSOd6): d 166.57, 153.41, 144.33,1 41.61, 140.04,
138.01, 130.86, 129.85, 128.48, 127.22, 126.29, 125.31,
123.99, 119.92, 119.10, 116.59, 112.52, 101.31, 60.80.
Mass: 420.2 (m?); Anal Calcd for C23H18ClN3O3: C,
65.79; H, 4.32; N, 10.01. Found: C, 54.36; H, 4.92; N, 7.74.
Synthesis of 5-(7-chloroquinolin-4-ylamino)-2-
((2-hydroxyethylamino) methyl) phenol (5d)
(% Yield: 89.86); mp: 268–270°C; Rf value: 0.9 (Methanol:
Dichloromethane:: 5:5); UV(kmax): 259.5 nm (DMSO);
123

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Med Chem Res (2011) 20:1632–1637
IR(KBr cm-1): 3411, 3233, 2913, 2768, 1654, 1534, 1449,
1375, 1238, 1122, 908, 854, 816; 1H NMR (400 MHz,
DMSOd6): d 8.69 (d, 1H, J = 4.8 Hz, quinoline–H), d 8.49
J = 7.2 Hz, quinoline–H), d 7.31 (d, 1H, J = 8.4, quino-
line–H), d 7.17 (d, 1H, J = 8 Hz, Ar–H), d 6.94 (m, 1H,
J = 8.8 Hz, Ar–H), d 6.71 (dd, 1H, J = 5.2, 8.4 Hz,
Ar–H), d 6.58 (d, 1H, J = 9.2 Hz, Ar–H), d 6.39 (d, 1H,
J = 7.6 Hz, Ar–H), d 5.83 (d, 1H, J = 6.8 Hz, Ar–OH), d
5.77 (d, 1H, J = 7.2 Hz, CH2); 13C NMR (100 MHz,
DMSOd6): d 158.32, 155.41, 151.03, 150.77, 149.93,
148.61, 140.83, 134.22, 130.01, 127.19, 126.69, 126.34,
124.98, 124.79, 123.38, 118.09, 117.84, 117.43, 117.21,
116.07, 113.30, 111.55, 109.68, 109.17,101.17, 100.25,
40.01; Mass: 392.1 (m?); Anal Calcd for C21H16ClN3O2:
C, 66.76; H, 4.27; N, 11.12. Found: C, 55.46; H, 4.48; N,
7.78.
(d, 1H, J = 8.8 Hz, quinoline–H),
d 8.43 (d, 1H,
J = 5.2 Hz, quinoline–H), d 8.09 (d, 1H, J = 8.8 Hz,
quinoline–H), d 8.04 (d, 1H, J = 8.4 Hz, quinoline–H), d
7.90(t, 1H, J = 14.8 Hz, quinoline–H), d 7.66 (s, 1H, OH),
d 7.55 (m, 1H, J = 10 Hz, Ar–H), d 7.31 (d, 1H,
J = 8.4 Hz, Ar–H), d 7.21 (t, 1H, J = 8 Hz, quinoline–H),
d 6.99 (m, 1H, J = 4.8 Hz, Ar–H), d 6.80 (d, 1H,
J = 6.8 Hz, Ar–H), d 6.63 (d, 1H, J=8 Hz, Ar–H), d 6.5 (s,
1H, OH), d 4.09 (s, 1H, Ar–OH), d 4.01 (s, 1H, Ar–NH), d
3.82 (s, 2H, CH2), d 2.84 (s, 1H, acetylene); 13C NMR
(100 MHz, DMSOd6): d 158.30, 153.03, 150.16, 149.99,
147.39, 140.46, 138.29, 136.19, 134.72, 131.30, 130.13,
127.19, 126.12, 125.64, 119.29, 117.79, 113.59, 111.92,
110.84, 109.94, 109.17, 101.98, 67.34, 64.42, 57.36, 41.14;
Mass: 343.0 (m?); Anal Calcd for C18H18ClN3O2: C,
62.88; H, 5.28; N, 12.22. Found: C, 51.32; H, 5.53; N, 8.30.
Synthesis of 2-((4-bromo-2-fluorophenylamino)
methyl)-5-(7-chloroquinolin-4-ylamino) phenol (5g)
(% Yield: 61.26); mp: 258-260°C; Rf value: 0.86(Dichlo-
romethane: Methanol:: 5:5); UV(kmax): 342.5 nm (DMSO);
IR(KBr cm-1): 3568, 3205, 2957, 2874, 1654, 1560, 1458,
1363, 1206, 1075, 1010, 873, 815, 764, 572; 1H NMR
(400 MHz, DMSOd6): d 8.18 (d, 1H, J = 8.8 Hz, quino-
line–H), d 8.05 (d, 1H, J = 9.6 Hz, quinoline–H), d 7.93
Synthesis of 5-(7-chloroquinolin-4-ylamino)-
2-((piperidin-4-ylamino) methyl) phenol (5e)
(% Yield: 92.54); mp: 94–96°C; Rf value: 0.89 (Methanol:
Dichloromethane:: 5:5); UV(kmax): 335.0 nm (DMSO); IR
(KBr cm-1): 3246, 2800, 2700, 1654, 1560, 1438, 1376,
(d, 1H, J = 7.2 Hz, quinoline–H), d 7.63 (d, 1H,
J = 8.8 Hz, quinoline–H), d 7.47 (m, 1H, J = 7.2 Hz,
quinoline–H), d 7.33 (d, 1H, J = 8.4 Hz, Ar–H), d 7.24 (s,
1H, OH), d 7.16 (d, 1H, J = 5.2 Hz, Ar–H), d 7.11 (s, 1H,
OH), d 6.07 (d, 1H, J = 7.2 Hz, Ar–H), d 4.36 (m, 2H,
CH2); 13C NMR (100 MHz, DMSOd6): d 140.56, 132.76,
132.72, 129.19, 129.14, 129.11, 128.68, 128.57, 128.53,
127.74, 127.38, 124.64, 124.02, 119.99, 119.73, 117.90,
65.70; Mass: 475.5 (m?); Anal Calcd for C22H16BrClFN3O:
C, 55.89; H, 3.41; N, 8.89. Found: C, 49.86; H, 5.02; N
2.85.
1
1274, 1210, 873, 822; H NMR (400 MHz, DMSOd6): d
8.72 (d, 1H, J = 4.4 Hz, quinoline–H), d 8.07 (d, 1H,
J = 9.6 Hz, quinoline–H), d 7.99 (s, 1H, quinoline–H), d
7.92 (d, 1H, J = 7.2 Hz, quinoline–H), d 7.78 (d, 1H,
J = 7.2 Hz, quinoline–H), d 7.66 (s, 1H, OH), d 7.56 (m,
1H, J = 8.4 Hz, quinoline–H), d 7.30 (dd, 1H, J = 8,
8.8 Hz, Ar–H), d 7.08 (d, 1H, J = 4.8 Hz, Ar–H), d 6.96
(d, 1H, J = 14.4 Hz, Ar–H), d 6.75 (s, 1H, OH), d 6.07 (d,
1H, J = 7.2 Hz, Ar–H), d 4.10 (s, 1H, Ar–NH), d 3.32 (s,
2H, CH2), d 2.79 (s, 1H, amine), d 2.66 (s, H, piperidine–
H), d 2.49 (s, H, piperidine–H); 13C NMR (100 MHz,
DMSOd6): d 155.68, 151.71, 148.84, 140.05, 134.07,
127.42, 127.21, 126.20, 126.16, 123.54, 120.92, 117.41,
109.66, 109.17; Mass: 367.9 (m?); Anal Calcd for
C21H23ClN4O: C, 65.87; H, 6.05; N, 14.63. Found: C,
55.06; H, 4.44; N, 7.65.
Acknowledgments Authors are thankful to M/s Mangalam Drug &
Organics Ltd., Mumbai, for supplying the gift samples of 4,7-
dichloroquinoline. Authors extend gratefulness to the Director,
NEHU, Shillong; Director, Regional Medical Research Centre,
ICMR, Dibrugarh; Head, Department of Pharmaceutical Sciences,
Dibrugarh University, Assam, for providing the necessary infra-
structural facilities.
Conflict of interest Authors declare no conflict of interest.
Synthesis of 4-((4-(7-chloroquinolin-4-ylamino)-
2-hydroxyphenyl)methyl amino) phenol (5f)
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1
1242, 976, 908, 819; H NMR (400 MHz, DMSOd6): d
8.32 (dd, 1H, J = 13.2, 14 Hz, quinoline–H), d 8.13 (d,
1H, J = 4.8 Hz, quinoline–H), d 7.82 (d, 1H, J = 8.8 Hz,
quinoline–H), d 7.67 (s, 1H, OH), d 7.56 (d, 1H,
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