Synthesis of 2-[3-(7-Chloro-quinolin-4-ylamino)-alkyl]-1-(substituted phenyl)-2,3,4,9-tetrahydro-1H-β-carbolines as a new class of antimalarial agents

Article abstract of DOI:10.1016/j.bmcl.2008.04.030

A series of hybrid molecules 2-[3-(7-Chloro-quinolin-4-ylamino)-alkyl]-1-(substituted phenyl)-2,3,4,9-tetrahydro-1H-β-carbolines have been synthesized and screened for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum. Compounds 26, 32, and 34 have shown MIC in the range of 0.05-0.11 μM and are in vitro several folds more active than chloroquine.

Full text of DOI:10.1016/j.bmcl.2008.04.030

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 3306–3309
Synthesis of 2-[3-(7-Chloro-quinolin-4-ylamino)-
alkyl]-1-(substituted phenyl)-2,3,4,9-tetrahydro-1H-b-carbolines as
a new class of antimalarial agents
Leena Gupta,a Kumkum Srivastava,b Shubhra Singh,b
S. K. Purib and Prem M. S. Chauhana,*
aDivision of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
bDivision of Parasitology, Central Drug Research Institute, Lucknow 226001, India
Received 12 March 2008; revised 7 April 2008; accepted 11 April 2008
Available online 15 April 2008
Abstract—A series of hybrid molecules 2-[3-(7-Chloro-quinolin-4-ylamino)-alkyl]-1-(substituted phenyl)-2,3,4,9-tetrahydro-1H-b-
carbolines have been synthesized and screened for their in vitro antimalarial activity against chloroquine-sensitive strains of Plas-
modium falciparum. Compounds 26, 32, and 34 have shown MIC in the range of 0.05–0.11 lM and are in vitro several folds more
active than chloroquine.
Ó 2008 Elsevier Ltd. All rights reserved.
Despite over 100 years of drug development efforts, ma-
laria remains one of the most devastating infectious dis-
eases in the world.1,2 Furthermore, the worldwide
burden of malaria is increasing in part due to the spread
of resistance to the available anti-malarials especially
chloroquine (CQ) and related quinoline-based agents.3,4
CQ had been the prime therapy for nearly half a cen-
tury. It was safe, effective, widely available, and remark-
ably inexpensive and could also be administered to
pregnant women and infants, but P. falciparum, the
cause of the most deadly variety of malaria, is now
CQ-resistant (CQR) in all epidemic regions of malaria.
This rapid spread of resistance has highlighted the need
to identify alternative anti-malarials.
inhibiting haemozoin formation, and also increases
accumulation of the drug due to the protonatable quin-
oline nitrogen.6
Moreover, a number of alkaloids containing a b-carbo-
line moiety, derived from marine sponges, represent
important lead structures for the development of anti-
infectives.7–11 Manzamine alkaloids, the most unique
group of b-carboline, first isolated in 1986, was found
to exhibit significant anticancer activity against P-388
mouse leukemia.12 More recently, manzamine A has
been found to have potent antimalarial activity.13–15
These b-carbolines interact with DNA through GC-
selective intercalation,16 therefore compounds contain-
ing b-carboline moiety can bind to the plasmodial
DNA and thereby the inhibition of DNA synthesis of
the malarial parasites.
Recent approaches are aimed to increase the potency of
quinoline-based anti-malarials against the resistant par-
asite, have included the design and synthesis of quino-
line-containing dual inhibitors that would potentially
inhibit haemozoin formation and also another target
within P. falciparum.5 The 7-chloroquinoline moiety
binds to haematin in parasite’s acidic food vacuole, thus
On the basis of these above observations, we have designed
and synthesized a class of hybrid molecules consisting of 7-
chloroquinoline (haemozoin inhibitor) as a base moiety
and tetrahydro-b-carboline moiety (DNA intercalator)-
linked diamino alkyl chain at 4-position of 7-chloroquino-
line. This letter describes the synthesis and in vitro antimalar-
ial activity of these hybrid molecules.
Keywords: Malaria; Plasmodium falciparum; Chloroquine; Tetrahydro-
b-carboline.
*
Corresponding author. Tel.: +91 522 2262411; fax: +91 522
2623405; e-mail addresses: prem_chauhan_2000@yahoo.com;
premsc58@ hotmail.com
To synthesize these hybrid molecules (23–45), compound
(3) was reacted with different tetrahydro-b-carbolines
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.04.030

L. Gupta et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3306–3309
3307
derivatives (5– 22) in DMF at high temperature and
pressure. These cis/trans isomers of b-carboline deriva-
tives were prepared by the reaction of D/L tryptophan
(4) with thionyl chloride in methanol and then the
methyl ester (4a) was cyclized by Pictet–Spingler cycliza-
tion in the presence of different aromatic aldehydes.17–21
Compound (3) was prepared from intermediate (2)
which was obtained by the reaction of 4,7-dichloroquin-
oline (1) and aminopropanol/aminoethanol in DMF,
with methane sulfonylchloride in pyridine at 0 °C.5,22
(Scheme 1.) All the synthesized compounds were well
characterized by spectroscopic methods such as IR,
mass, NMR, and elemental analysis.25
schizonts was recorded as the minimum inhibitory con-
centration (MIC). Activities of all tested compounds are
shown in Table 1.
Among 23 compounds screened against P. falciparum,
three compounds 26, 32, and 34 showed MIC of 0.05,
0.06, and 0.11 lM respectively, whereas three com-
pounds (23–25) showed MIC of 0.22 lM. On analyzing
their biological activity data we found good structure–
activity relationship among these compounds. Com-
pounds (23–26) having isopropyl substitution at para-
position of phenyl ring and having propyl chain at 2-po-
sition of tetrahydro-b-carboline showed MIC in the
range 0.05–0.22 lM. While compounds (27–30) having
same isopropyl-substituted phenyl ring, but having ethyl
chain showed MIC of 18.12 lM. Similarly compounds
31 and 32 having methyl-substituted phenyl ring and
propyl chain at 2-position of tetrahydro-b-carboline,
also showed good MIC of 0.46 and 0.05 lM respectively,
but compound (33) having same methyl-substituted phe-
nyl ring and ethyl chain, showed MIC of 19.08 lM.
Compound (34) also showed good MIC of 0.11 lM as
it has ethyl-substituted phenyl ring and propyl chain at
2-position of tetrahydro-b-carboline. Substituting the
phenyl ring with methoxy group at para-position the
MIC of 35, 36 and 37 decreases to 3.61 lM and with
three methoxy group for 39 and 40, it goes down to
16.28 lM. Compounds 44 and 45 also showed MIC of
17.54 lM only, as they have thiomethoxy substitution
at para position of phenyl ring. Substitution of chloro
group at para position in compounds 42 and 43 showed
MIC of 3.58 and 1.79 lM, respectively, while with
bromo group (41) it decreases to 16.58 lM. If we see
the stereochemistry of these compounds we found that
compound (26) which is prepared from D isomer of
tryptophan has MIC of 0.05 lM, while compound (24)
The in vitro antimalarial assay was carried out in 96-well
microtitre plates according to the microassay of Rieck-
mann et al.23 The culture of P. falciparum NF-54 strain
is routinely being maintained in medium RPMI-1640
supplemented with 25 mM HEPES 1% D-glucose,
0.23% sodium bicarbonate, and 10% heat-inactivated
human serum.24 The asynchronous parasite of P. falci-
parum was synchronized after 5% D-sorbitol treatment
to obtain parasitized cells harboring only the ring stage.
For carrying out the assay, an initial ring stage parasite-
mia of ꢀ1% at 3% haematocrit in a total volume of
200 lL of medium RPMI-1640 was uniformly main-
tained. The test compound in 20 lL volume at required
concentration (ranging between 0.25 and 50 lg/ml) in
duplicate wells was incubated with parasitized cell prep-
aration at 37 °C in a candle jar. After 36–40 h incuba-
tion, the blood smears from each well were prepared
and stained with Giemsa stain. The slides were micro-
scopically observed to record maturation of ring stage
parasites into trophozoites and schizonts in the presence
of different concentrations of compounds. The test con-
centration that inhibits the complete maturation into
COOCH3
COOCH3
Cl
O
H
N
NH
O
S
CH3
N
HN
N
n
N
H
N
H
a
O
n
N
Cl
R1
R2
R1
R2
3
R
R
23-45
5-22
b(ii)
d
nOH
HN
N
COOMe
NH2
Cl
N
n=2, 3
H
2
4a
c
b(i)
Cl
N
COOH
NH2
N
H
Cl
1
4
Scheme 1. Reagents and conditions: (a) DMF, 120 °C, high pressure; (b) i—SOCl2, MeOH, ii—aromatic aldehydes, reflux; (c) aminoethanol/
aminopropanol, Et3N, DMF, 120 °C; (d) methane sulphonylchloride, Pyridine, 0 °C.

3308
L. Gupta et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3306–3309
Table 1. Antimalarial in vitro activity against P. falciparum
Comp. No.
Isomer
n
R
R1
R2
MIC (lM)
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
L/cis
3
3
3
3
2
2
2
2
3
3
2
3
3
3
3
3
3
3
3
3
3
3
3
–CH(CH3)2
–CH(CH3)2
–CH(CH3)2
–CH(CH3)2
–CH(CH3)2
–CH(CH3)2
–CH(CH3)2
–CH(CH3)2
–CH3
H
H
0.22
0.22
L/trans
D/cis
H
H
H
H
0.22
0.05
D/trans
L/cis
H
H
H
H
18.12
18.12
18.12
18.12
0.46
L/trans
D/cis
H
H
H
H
D/trans
L/trans
D/trans
L/trans
D/cis
H
H
H
H
–CH3
–CH3
H
H
0.06
H
H
19.08
0.11
3.61
–CH2CH3
–OMe
–OMe
H
H
D/cis
H
H
D/trans
L/cis
H
H
3.61
3.61
–OMe
–OMe
H
H
L/trans
L/cis
H
H
18.05
16.28
16.28
16.58
3.58
–OMe
–OMe
–OMe
–OMe
H
–OMe
–OMe
H
L/trans
L/trans
L/cis
–Br
–Cl
H
H
L/trans
L/cis
–Cl
–SMe
–SMe
H
H
1.79
H
H
17.54
17.54
0.391
L/trans
H
H
Chloroquine (standard drug)
2. Sachs, J.; Malaney, P. Nature 2002, 415, 680.
having same substitution at para position of phenyl ring
but is prepared from L isomer showed MIC of 0.22 lM.
Similarly compound (32) which is obtained from D iso-
mer has MIC of 0.06 lM and compound (31) having
same substitution at para position of phenyl ring but ob-
tained from L isomer showed MIC of 0.46 lM. Similar
results can be seen in case of compounds 36 and 38. All
these results emphasize that compounds obtained from
D isomer of tryptophan, having alkylated phenyl ring
and propyl chain at 2-position of tetrahydro-b-carboline,
are more potent as compared to other molecules.
3. Sidhu, A. B.; Fidock, D. A. Science 2002, 298, 210.
4. Price, R. N.; Uhlemann, A.-C.; Brockman, A.; Mc
Gready, R.; Ashley, E.; Phaipun, L.; Patel, R.; Laing,
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11. Srivastava, S. K.; Agarwal, A.; Chauhan, P. M. S.;
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In conclusion, we have identified 2-[3-(7-Chloro-quino-
lin-4-ylamino)-alkyl]-1-(substituted phenyl)- 2,3,4,9-tet-
rahydro-1H-b-carbolines as a novel class of highly
potent antimalarial agents. Out of these 23 synthesized
compounds, three compounds have shown MIC of
0.22 lM and three have shown MIC in the range of
0.05–0.11 lM which is much more than that of stan-
dard drug chloroquine. Therefore these hybrid mole-
cules can be served as new lead in antimalarial
chemotherapy.
Acknowledgments
13. Ang, K. K. H.; Holmes, M. J.; Higa, T.; Hamann, M. T.;
Kara, U. A. K. Antimicrob. Agents Chemother. 2000, 44,
1645.
14. Winkler, J. D.; Londregan, A. T.; Ragains, J. R.;
Hamann, M. T. Org. Lett. 2006, 8, 3407.
L.G. thanks the University Grants Commission (India)
for providing financial support. We are also thankful
to S.A.I.F. Division, CDRI, Lucknow, for providing
spectroscopic data. CDRI Communication No. 7482.
15. Winkler, J. D.; Londregan, A. T.; Hamann, J. R. Org.
Lett. 2006, 8, 2591.
16. Cao, R.; Peng, W.; Chem, H.; Ma, Y.; Liu, X.; Hou, X.;
Xu, A. Biochem. Biophys. Res. Commun. 2005, 338, 1557.
17. Kumar, A.; Katiyar, S. B.; Gupta, S.; Chauhan, P. M. S.
Eur. J. Med. Chem. 2006, 41, 106.
References and notes
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C. V. J. Heterocycl. Chem. 2006, 43, 767.
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Lett. 2007, 48, 1379.
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J.; Riscoe, M. K.; Peyton, D. H. J. Med. Chem. 2006, 49,
5623.
23. Rieckmann, K. H.; Sax, L. J.; Campbell, G. H.; Mrema, J.
E. Lancet 1978, 1, 22.
164–167 °C; IR (KBr) 3265, 3199, 2930, 2875, 2730, 1784,
1615, 1580, 1491, 1450, 1392, 1364, 1135, 801, 743. 1H
NMR (CDCl3, 200 MHz): d (ppm) 8.57 (br s, 1H), 8.29 (d,
1H, J = 7.2 Hz), 8.02 (s, 1H), 7.60 (d, 1H, J = 3.0 Hz), 7.58
(br s, 1H), 7.13(d, 1H, J = 7.5 Hz), 7.01 to 6.98 (m, 4H),
6.82 (d, 2H, J = 6.7 Hz), 6.53 (d, 2H, J = 8.9 Hz), 6.33 (d,
1H, J = 4.0 Hz),5.40 (s, 1H), 4.09 (t, 2H, J = 6.8 Hz), 3.66
(s, 3H), 3.53 (dd, 1H, J = 4.5 and 4.8 Hz), 3.06 to 2.86 (m,
2H), 2.56 (s, 3H), 2.15 (t, 2H, J = 4.0 Hz), 1.63 to 1.59 (m,
2H). 13C (CDCl3, 50 MHz): 172.3, 151.2, 150.5, 138.6,
137.3, 137.0, 135.2, 133.4, 132.5, 129.9, 129.7, 127.1, 125.6,
126.9, 123.3, 122.6, 120.3, 119.9, 118.6, 117.3, 111.5, 108.6,
98.9, 60.5, 56.2, 52.3, 49.3, 43.5, 20.8, 21.7. Anal. Calcd for
C32H31ClN4O2: Calcd C: 71.30; H: 5.80; N: 10.39. Found:
C: 70.57; H: 5.65; N: 9.94.
Spectroscopic data for 34:. Yield 49%; MS: 553 (M+1);
mp 170–172 °C; IR (KBr) 3270, 3280, 2930, 2875, 2728,
1764, 1605, 1578, 1490, 1446, 1380, 1355, 1115, 801, 744.
1H NMR (CDCl3, 200 MHz): d (ppm) 8.67 (br s, 1H), 8.49
(d, 1H, J = 7.0 Hz), 8.12 (s, 1H), 7.63 (d, 1H, J = 3.1Hz),
7.50 (br s, 1H), 7.14 (d, 1H, J = 7.5 Hz), 7.05 to 6.89 (m,
4H), 6.72 (d, 2H, J = 6.3 Hz), 6.59 (d, 2H, J = 8.5 Hz),
6.40 (d, 1H, J = 3.6 Hz), 5.31 (s, 1H), 4.09 (t, 2H, J = 6.7
Hz), 3.76 (s, 3H), 3.45 (dd, 1H, J = 5.5, 6.8 Hz), 3.15 to
2.85 (m, 2H), 2.71 to 2.63 (m, 2H), 2.18 (t, 2H, J = 5.7 Hz),
1.75 to 1.53 (m, 2H), 1.31 (t, 3H, J = 5.7Hz). 13C (CDCl3,
50 MHz): 171.9, 152.1, 150.4, 149.5, 139.1, 138.2, 135.5,
132.1, 130.3, 128.9, 128.8, 127.5, 125.4, 122.9, 122.2, 122.6,
119.9, 118.5, 118.3, 116.5, 111.8, 101.6, 98.8, 61.2, 57.1,
53.2, 50.0, 43.5, 27.5, 25.9, 22.8, 17.2. Anal. Calcd for
C33H33ClN4O2: Calcd C: 71.66; H: 6.01; N: 10.13. Found:
C: 69.87; H: 6.15; N: 10.01.
Spectroscopic data for 43: Yield 37%; MS: 559 (M+1); mp
179–182 °C; IR (KBr) 3190, 3250, 2928, 2869, 2638, 1759,
1615, 1498, 1490, 1437, 1380, 1367, 1095, 798, 756. 1H
NMR (CDCl3, 200 MHz): d (ppm) 8.52 (br s, 1H), 8.30 (d,
1H, J = 6.9 Hz), 8.05 (s, 1H), 7.75 (d, 1H, J = 2.7Hz), 7.38
(br s, 1H), 7.10 (d, 1H, J = 8.0Hz), 7.15 to 7.11 ( m, 4H),
6.99 (d, 2H, J = 7.6 Hz), 6.72 (d, 2H, J = 7.8 Hz), 6.45 (d,
1H, J = 3.5 Hz), 5.39 (s, 1H), 4.13 (t, 2H, J = 6.8 Hz), 3.72
(s, 3H), 3.65 (dd, 1H, J = 4.0, 4.3 Hz), 3.10 to 2.99 (m,
2H), 2.12 (t, 2H, J = 5.2 Hz), 1.72 to 1.65 (m, 2H). 13C
(CDCl3, 50 MHz): 172.52, 150.9, 150.4, 148.2, 137.2,
137.0, 135.5, 131.2, 128.8, 127.5, 127.2, 126.8, 124.6,
123.3, 122.6, 121.1, 121.0, 118.7, 116.9, 110.3, 108.6, 98.6,
61.2, 57.1, 50.9, 50.1, 43.2, 26.2, 21.7. Anal. Calcd for
C31H28Cl2N4O2: Calcd C: 66.55; H: 5.04; N: 10.01. Found:
C: 69.87; H: 5.15; N: 9.08.
24. Trager, C.; Vanderberg, J. P. J. Parasitol. 1979, 193, 673.
25. Spectroscopic data for 24: Yield 40%; MS: 567 (M+1); mp
161–163 °C; IR (KBr) 3258, 3133, 2910, 2857, 2729, 1752,
1612, 1582, 1491, 1449, 1365, 1329, 1135, 802, 744. 1H
NMR (CDCl3, 200 MHz): d (ppm) 8.43 (br s, 1H), 8.35 (d,
1H, J = 7.2 Hz), 8.09 (s, 1H), 7.83 (d, 1H, J = 2.3 Hz), 7.56
(br s, 1H), 7.25 (d, 1H, J = 8.5 Hz), 7.19 to 7.11 ( m, 4H),
6.99 (d, 2H, J = 7.6 Hz), 6.85 (d, 2H, J = 8.0 Hz), 6.50 (d,
1H, J = 5.2 Hz), 5.30 (s, 1H), 4.28 (t, 2H, J = 7.0 Hz), 3.65
(s, 3H), 3.58 (dd, 1H, J = 5.0, 5.6 Hz), 3.43 to 3.19 (m,
1H), 2.86 to 2.76(m, 2H), 2.12 (t, 2H, J = 6.2 Hz), 1.73 to
1.59 (m, 2H), 1.31 (d, 6H, J = 7.6 Hz). 13C (CDCl3,
50 MHz): 172.5, 151.8, 150.8, 148.5, 138.1, 137.9, 135.9,
131.2, 128.6, 127.3, 127.0, 125.1, 125.7, 123.8, 121.9, 119.1,
120.0, 118.5, 117.5, 109.5, 108.5, 98.5, 62.7, 56.9, 51.8,
50.4, 43.4, 37.2, 25.5, 24.8, 21.9. Anal. Calcd for
C34H35ClN4O2: Calcd. C: 72.01; H: 6.22; N: 9.88. Found:
C: 71.93; H: 6.57; N: 9.74. Spectroscopic data for 26:
Yield 45%; MS: 567 (M+1); mp 163–165 °C; IR (KBr)
3267, 3023, 2925, 2857, 2729, 1744, 1612, 1582, 1491, 1449,
1
1365, 1329, 1137, 805, 740. H NMR (CDCl3, 200 MHz):
d (ppm) 8.41 (br s, 1H), 8.36 (d, 1H, J = 6.4 Hz), 8.12 (s,
1H), 7.90 (d, 1H, J = 1.72 Hz), 7.34 (br s, 1H), 7.28 (d, 1H,
J = 8.3 Hz), 7.17 to 7.13 (m, 4H), 7.04 (d, 2H, J = 7.8 Hz),
6.83 (d, 2H, J = 8.8 Hz), 6.32 (d, 1H, J = 4.5 Hz), 5.27
(s,1H), 4.18 ( t, 2H, J = 7.0 Hz), 3.67 (s, 3H), 3.47 (dd, 1H,
J = 5.2, 4.8 Hz), 3.23 to 3.05 (m, 1H), 2.98 to 2.80 (m, 2H),
2.05 (t, 2H, J = 5.3 Hz), 1.64 to 1.58 (m, 2H), 1.23 (d, 6H,
J = 8.4 Hz). 13C (CDCl3, 50 MHz): 173.5, 151.8, 150.4,
149.5, 138.1, 137.0, 135.9, 132.5, 129.8, 127.3, 127.1, 126.8,
125.4, 123.3, 122.5, 120.1, 120.0, 118.7, 117.4, 111.5, 108.5,
98.5, 60.7, 56.9, 52.2, 49.4, 43.4, 34.2, 25.7, 24.3, 21.6.
Anal. Calcd for C34H35ClN4O2: Calcd C: 72.01; H: 6.22;
N: 9.88. Found: C: 71.58; H: 6.65; N: 8.74.
Spectroscopic data for 32: Yield 38%; MS: 539 (M+1); mp