Design, synthesis and antimalarial activity of benzene and isoquinoline sulfonamide derivatives

Article abstract of DOI:10.1016/j.bmcl.2007.11.038

A new series of benzene and isoquinoline sulfonamide derivatives were synthesized by nucleophilic displacement reaction on benzene and isoquinoline sulfonyl chlorides by substituted amines (primary and secondary). The title compounds were evaluated for an

Full text of DOI:10.1016/j.bmcl.2007.11.038

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 776–781
Design, synthesis and antimalarial activity of benzene
and isoquinoline sulfonamide derivativesq
Maloy Kumar Parai,a Gautam Panda,a,* Kumkum Srivastavab and Sunil Kumar Purib
aMedicinal & Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, UP, India
bParasitology Division, Central Drug Research Institute, Lucknow 226001, UP, India
Received 7 August 2007; revised 26 October 2007; accepted 12 November 2007
Available online 17 November 2007
Abstract—A new series of benzene and isoquinoline sulfonamide derivatives were synthesized by nucleophilic displacement reaction
on benzene and isoquinoline sulfonyl chlorides by substituted amines (primary and secondary). The title compounds were evaluated
for antimalarial activity against Plasmodium falciparum in vitro and showed MIC in the range of 2–50 lg/mL.
Ó 2007 Elsevier Ltd. All rights reserved.
Malaria remains major health problem in tropical and
O
H
N
R1
subtropical countries.1,2 The treatment of malaria de-
pends largely on chemotherapeutics and chemoprophy-
laxis due to the existence of limitations in vaccine
development and vector control. Malaria parasite, Plas-
modium falciparum, the most severe form of malaria, has
developed resistance against almost all the drugs avail-
able.3 The design and development of novel drugs for
the comprehensive treatment of malaria is highly neces-
sary, intensive research warrants to eradicate this deadly
disease.4
O
R2
s
HN
O2
S
O
O
Cl
N
H2N
N
H
N
H
H
Cl
1
R1= F, aryl
2
R2= Aryl
H
N
O2S
N
H
Br
3
N
H-89
O
S
NRR
O
O
R1
O
S
N
Sulfonamides represent an important class of medici-
nally important molecules and are known to possess
wide varieties of biological activities which include anti-
microbial drugs, saluretics, carbonic anhydrase inhibi-
tors, antithyroid agents, antitumour drugs, etc.5–14
Sulfonamides remain the most widely used antibacterial
agents in the world because of their low cost, low toxic-
ity and excellent activity against common bacterial dis-
eases. Moreover, antimalarial activity of several
benzene sulfonamides such as 1 and 2 is also re-
ported,15,16 Figure 1. Isoquinoline sulfonamide (H-89)
3 is a potent inhibitor of Pfmrk, one of the cyclin depen-
dent protein kinases (CDKs) from P. falciparum. Plas-
modial CDKs play an essential role in the growth and
NRR
5
4
R1= H, CH3, NO2
NRR = secondary, tertiary and cyclic amines
Figure 1.
development of the parasite. Functional conservation
among the CDKs suggests a role in cell cycle control
of the malaria parasite. Support for an essential role
of plasmodial CDKs comes from inhibitor studies in
which mammalian CDK inhibitors possessed anti-para-
sitic activity in vitro.17
These results promoted us to synthesize and evaluate a
new series of benzene and isoquinoline sulfonamide
derivatives for antimalarial efficacy. Our work focused
on the design and synthesis of benzene and isoquinoline
sulfonamide derivatives and in vitro activity of these
compounds against P. falciparum growth in culture
(Table 1).
Keywords: Benzene and isoquinoline sulfonamides; Antimalarial
activity.
q
CDRI communication No. 7326.
Corresponding author. Tel.: +91 522 2612411; fax: +91 522
2623938; e-mail: gautam.panda@gmail.com
*
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.038

M. Kumar Parai et al. / Bioorg. Med. Chem. Lett. 18 (2008) 776–781
777
Table 1. Synthesized sulfonamide derivatives with in vitro antimalarial activity21 against Plasmodium falciparum
Serial No.
Compound
R1
Structures of sulfonamides
Yielda (%)
MICb (lg/mL)
H2N
R2
n
5a-c
OCH3
OCH3
OCH3
1
8a
CH3
NO2
H
84
86
85
75
78
77
87
79
71
73
69
75
81
10
10
10
10
10
10
10
10
10
ND
10
ND
10
H2N
H2N
OCH3
H3C
O2N
S
N
H
O2
5a
5a
OCH3
OCH3
OCH3
OCH3
2
8b
S
N
O
2 H
OCH3
OCH3
OCH3
OCH3
3
8c
H2N
H2N
S
N
H
O2
5a
N
S
NH
H3C
N
4
8d
CH3
CH3
NO2
H
N
O2
N
5b
H2N
H2N
H2N
N
O
O
O
N
N
H3C
O2N
S
N
H
5
8e
O
O
O2
5c
N
N
S
N
H
6
8f
O2
5c
S
N
H
N
7
8g
O2
O
C
5c
HN
HN
HN
C
N
H2
O2N
H3C
N
N
S
N
N
8
10a
10b
10c
10d
10e
10f
NO2
CH3
H
O2
H2
7a
N
C
S
C
H2
9
O2
H2
7a
N
C
H2
S
N
C
N
10
11
12
13
O2
H2
7a
HN
HN
HN
N
Cl
H3C
H3C
S
N
Cl
N
N
CH3
CH3
H
O2
7b
N
S
N
N
N
O2
N
7c
N
S
N
N
O2
N
(continued on next page)
7c

778
M. Kumar Parai et al. / Bioorg. Med. Chem. Lett. 18 (2008) 776–781
Table 1 (continued)
Serial No.
Compound
R1
Structures of sulfonamides
Yielda (%)
MICb (lg/mL)
H2N
R2
n
5a-c
HN
HN
HN
HN
N
N
N
H3C
O2N
S
N
N
N
N
14
15
16
17
10g
10h
10i
10j
CH3
NO2
H
76
83
76
73
10
10
10
10
OH
OH
OH
O2
OH
OH
7d
7d
7d
S
O2
S
N
N
O2
OH
N
O2N
S
N
N
N
NO2
O2
Cl
Cl
7e
HN
HN
N
O2N
S
N
18
19
10k
10l
NO2
79
80
10
10
N
O2
N
7c
Cl
N
Cl
S
N
N
H
O2
7b
HN
HN
HN
HN
CH3
N
H3C
O2N
S
CH3
N
N
20
21
22
23
24
25
26
10m
10n
10o
12a
12b
16a
16b
CH3
NO2
H
83
79
82
88
84
69
71
10
10
10
50
10
50
10
O2
7f
7f
7f
7d
CH3
CH3
N
N
S
CH3
N
N
O2
S
CH3
N
N
N
O2
S
N
N
O2
OH
H
OH
N
N
S
N
N
O2
HN
N
NH2
H
NH2
CH3
CH2CH(OH)CH2NH
OH
S
N
O2
H
HN
HN
OH
N
N
CH3
CH2CH(OH)CH2NH
Cl
S
N
O2
H
Cl

M. Kumar Parai et al. / Bioorg. Med. Chem. Lett. 18 (2008) 776–781
779
Table 1 (continued)
Serial No.
Compound
R1
Structures of sulfonamides
Yielda (%)
MICb (lg/mL)
H2N
R2
n
5a-c
Cl
CH3
Cl
S
N
CH2CH(OH)CH2NH
O2
27
28
29
30
31
32
33
34
35
16c
16d
16e
16f
16g
16h
16i
H
H
H
H
H
H
H
H
H
66
65
72
67
64
74
69
62
67
10
10
50
10
10
2
HN
N
N
CH3
OCH3
OCH3
S
CH2CH(OH)CH2NH
OCH3
OCH3
N
O2
HN
HN
CH3
N
S
N
CH2CH(OH)CH2NH
N
O2
N
N
N
CH3
S
N
CH2CH(OH)CH2NH
O2
HN
N
N
CH3
S
N
CH2CH(OH)CH2NH
OCH3
O2
HN
HN
OCH3
Cl
Cl
CH3
Cl
Cl
S
N
CH2CH(OH)CH2NH
O2
N
CH3
Cl
Cl
S
N
CH2CH(OH)CH2NH
Cl
O2
2
HN
HN
Cl
N
N
CH3
S
CH2CH(OH)CH2NH
N
O2
16j
10
10
N
N
H
H
CH3
S
N CH2CH(OH)CH2NH
O2
O
16k
HN
O
N
a Reported yields are optimized.
b Standard drug, pyrimethamine; MIC 10 lg/mL.
The structures of the target molecules 4 and 5 are given.
Benzene and isoquinoline sulfonyls are attached to sec-
ondary, tertiary and cyclic amines. Substitution of
benzene and isoquinoline sulfonyl chlorides with vari-
ous amines is expected to give the target molecule
(Scheme 1).
respectively. To synthesize the b-amino alcohol deriva-
tives 16a–k of isoquinoline sulfonamide, 11 was reacted
with methylamine hydrochloride 13 to furnish 14. The
hydrogen atom attached to nitrogen in 14 is acidic and
thus reaction of 14 with NaH/DMF followed by epi-
chlorohydrin furnished the epoxide 15. Nucleophilic
addition reaction of 15 with primary amines in MeOH
gave a series of b-amino alcohol derivatives 16a–k
regioselectively.
Reaction of commercially available benzene sulfonyl
chlorides 6a–c with primary amine 7a–c in the presence
of triethylamine and chloroform at room temperature
furnished 8a–g in 75–87% yield. Similarly 6a–c and iso-
quinoline sulfonyl chloride 11 with secondary amine 9a–
f under similar reaction condition gave 10a–p and 12a–b,
All sulfonamide derivatives displayed activity against P.
falciparum with minimum inhibitory concentrations
(MIC) ranging from 2 to 50 lg/mL. The analysis of

780
M. Kumar Parai et al. / Bioorg. Med. Chem. Lett. 18 (2008) 776–781
Et3N
O
S
O
S
R1
H2N
R2
O
O
+
R1
n
CHCl3, r.t, 2-3 hr
R2
N
H
n
Cl
6a-c
7a-c
8a-g
O
S
O
Et3N
R2
R1
+
R1
N
R2
HN
N
Cl
S
N
n
CHCl3, r.t,2 hr
n
O
O
10a-p
9a-f
6a-c
O
O
Cl
S
S
N
N
R2
S
O
O
Et3N
HN
N
R2
+
n
CHCl3
N
N
9a-b
11
12a-b
O
Cl
CH3
N
CH3 OH
N
H
N
S
O
NHR2
O
O
O
O
O
S
S
CH3
O
O
NH2R2
MeOH
Epichlorohydrin
DMF, NaH
Et3N
N
11
+
N
N
CHCl3
N
14
16a-k
15
NH2Me.HCl
13
Scheme 1.
the structures and antimalarial activity reveals that sub-
stitution in the benzene ring among the series of benzene
sulfonamides did not have any effect on activity. How-
ever, isoquinoline derivatives showed better activity. Be-
tween 12a and 12b, compound containing amino group
is more active than the hydroxyl group.
References and notes
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Isoquinoline sulfonamides with 2-hydroxy-propyl
amines exhibited lower inhibitory activity than benzene
sulfonamides. The analysis reveals that isoquinoline sul-
fonamide derivatives with disubstituted phenyl ring
showed better inhibitory activity than other mono-
substituted phenyl derivatives. Increasing hydrophilic
moiety on propyl amine did not exhibit better activity.
Isoquinoline sulfonamides 12a, 16a, 16e containing
piperazine, 4-(2-amino-ethyl)-phenol and 3-imidazol-1-
yl-propylamine group, respectively, did not show good
activity. Thus, 2-hydroxy propyl amines with isoquino-
line on one side and dichloro phenyl ring on another
side showed better antimalarial activity.
In conclusion, a series of benzene and isoquinoline sul-
fonamides were synthesized from corresponding sulfo-
nyl chlorides using nucleophilic addition reaction.
While benzene sulfonamides did not exhibit good activ-
ity, some of the isoquinoline derivatives showed good
activity in vitro. Further optimization on the lead ob-
tained might result into potent antimalarial agents.
13. Joshi, S.; Khosla, N.; Tiwari, P. Bioorg. Med. Chem. 2004,
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¨
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M.K.P. thanks CSIR for providing fellowship (NET-
SRF). The DST, New Delhi, India, supported this
project.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2007.11.038.
´
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serum.19 The asynchronous parasite of P. falciparum was
synchronized after 5% D-sorbitol treatment to obtain
parasitized cells harbouring only the ring stage.20 For
carrying out the assay, an initial ring-stage parasitaemia of
ꢀ1% at 3% haematocrit in total volume of 200 lL of
RPMI-1640 medium was uniformly maintained. The test
compound in 20 lL volume at required concentration
(ranging between 1.0 and 10 lg/mL) in duplicate wells was
incubated with parasitized cell preparation at 37 °C in
candle jar. After 36–40 h of incubation, the blood smears
from each well were prepared and stained with Giemsa
stain. The slides were microscopically observed to record
maturation of ring-stage parasites into trophozoites and
schizonts in the presence of different concentrations of
compounds. The test concentration, which inhibits the
complete maturation into schizonts, was recorded as the
minimum inhibitory concentration (MIC). Pyrimethamine
was used as the standard reference drug. Activity of all the
tested compounds is given in Table 1.
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Gerena, L.; Lopez-Sanchez, M.; Kyle, D. E.; Bhattachar-
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21. Procedure for in vitro antimalarial activity evaluation: the
in vitro antimalarial assay was carried out in 96-well
microtitre plates according to the micro assay of Rieck-
mann et al.18 The culture of P. falciparum NF-54 strain is
routinely being maintained in the RPMI-1640 medium
supplemented with 25 mM Hepes, 1% D-glucose, 0.23%
sodium bicarbonate and 10% heat-inactivated human