Identification of novel phenyl butenonyl C-glycosides with ureidyl and sulfonamidyl moieties as antimalarial agents

Article abstract of DOI:10.1021/ml500211c

A new series of C-linked phenyl butenonyl glycosides bearing ureidyl(thioureidyl) and sulfonamidyl moieties in the phenyl rings were designed, synthesized, and evaluated for their in vitro antimalarial activities against Plasmodium falciparum 3D7 (CQ sensitive) and K1 (CQ resistant) strains. Among all the compounds screened the C-linked phenyl butenonyl glycosides bearing sulfonamidyl moiety (5a) and ureidyl moiety in the phenyl ring (7d and 8c) showed promising antimalarial activities against both 3D7 and K1 strains with IC₅₀ values in micromolar range and low cytotoxicity offering new HITS for further exploration.

Full text of DOI:10.1021/ml500211c

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Letter
Identification of novel phenyl butenonyl C-glycosides with
ureidyl and sulfonamidyl moieties as antimalarial agents
K. Kumar G. Ramakrishna, Sarika Gunjan, Akhilesh Kumar SHUKLA, Venkata Reddy
Pasam, Vishal M Balaramanvar, Abhisheak Sharma, Swati Jaiswal, Jawahar Lal, Renu
Tripathi, Anubhooti Srivastava, Ravishankar Ramchandran, and Rama Pati Tripathi
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/ml500211c • Publication Date (Web): 02 Jun 2014
Downloaded from http://pubs.acs.org on June 3, 2014
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Identification of novel phenyl butenonyl Cꢀglycosides with
ureidyl and sulfonamidyl moieties as antimalarial agents
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K. Kumar G. Ramakrishna†, Sarika Gunjanɸ, Akhilesh Kumar Shukla†, Venkata Reddy
Pasam†, Vishal M. Balaramnavar†, Abhisheak Sharma‡, Swati Jaiswal‡, Jawahar Lal‡,δ, Renu
Tripathi*,ɸ,δ, Anubhooti Srivastava# Ravishankar Ramachandranδ,#, Rama Pati Tripathi*,†,δ
,
†
ɸ
δAcademy of Innovative Science and Research, Medicinal and Process Chemistry Division, Parasitology
‡
#
Division, Pharmacokinetics & Metabolism Division, Molecular and Structural Biology Division, CSIRꢀCentral
Drug Research Institute (CSIRꢀCDRI), Sector 10, Jankipuram Extension, Sitapur Road, Lucknowꢀ226031, India.
Corresponding author: Tel.: +91 0522 2612411; Fax: +91 522 2623405/ 2623938/ 2629504.
Eꢀmail address: rpt.cdri@gmail.com (Dr.Rama P. Tripathi)
KEYWORDS: Antimalarial agent, phenyl sulfonamides, diarylureides, Plasmodium falciparum
ABSTRACT: A new series of Cꢀ linked phenyl butenonyl glycosides bearing ureidyl(thioureidyl) and sulfonamidyl
moieties in the phenyl rings were designed, synthesized and evaluated for their in vitro antimalarial activities against
Plasmodium falciparum 3D7 (CQ sensitive) and K1 (CQ resistant) strains. Among all the compounds screened the Cꢀ
linked phenyl butenonyl glycosides bearing sulfonamidyl moiety (5a) and ureidyl moiety in the phenyl ring (7d and 8c)
showed promising antimalarial activities against both 3D7 and K1 strains with IC50 values in µM range and low
cytotoxicity offering new HITS for further exploration.
Malaria, the most severe parasitic disease, infects more
than 500 million people and continues to kill around one
million children each year.1 Most of the malarial
infections and deaths are due to Plasmodium falciparum
and Plasmodium vivax species. Although an arsenal of
very effective antimalarial drugs have been used to
control this disease, the culprit P. falciparum has
developed resistance to nearly all available antimalarial
drugs.2 Artemisinin, the last line of defense against
multidrug resistant malaria parasites in some parts of the
parasites and they can undergo a metabolic shift in vivo,
switching from predominately glycolytic metabolism to
metabolism of alternative carbon sources through
induction of gene sets combined with function of
mitochondria and apicoplast.12 Glucose delivery,
however, is crucial for parasite survival and may also be
critical for metabolic diversion of this key substrate from
host tissues and thereby aggravating the disease
processes.13 Diphenyl propenones (chalcones), on the
14ꢀ22
other hand, also exhibit antimalrial activity7,
and
4
world, became resistance in present circumstance.3,
malaria trophozoite cysteine protease has been
The recent emergence of resistance necessitates the
search for new antimalarial drugs which overcome the
resistance and acting through novel mechanisms.
proposed as possible target for this class of
18
compound.14,
Phenyl urenyl chalcones also exhibit
antimalrail activity via multiple mechanisms.7
The dihydropteroate synthase (DHPS), hemoglobin
degradation enzymes, and shikimate pathway enzymes
have been identified for the novel potential targets for
new antimalarial drugs in the last decade.5 Very recently
a
class of hemoglobin degradation enzymes,
plasmepsins has been discovered as a validated drug
target and diphenyl ureas are known to inhibit this
enzyme and display antimalarial activity.6 Several other
urea derivatives exhibit potent antimalarial activity.7ꢀ10
Plasmodium falciparum hexose transporter (PfHT) plays
very important role in malaria parasites as a critical
enzyme for glucose uptake and the survival of the
parasite.11 Simple 3ꢀOꢀalkyl/alkenyl glucosides were
shown to inhibit the PfHT and good antimalarial activity.
Indeed, glucose is an essential energy substrate in many
Figure 1.
derivatives.
Known antimalarials and targeted sugar
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IC50 ꢁM
Pf3D7
IC50 ꢁM
Pf3D7
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5
6
7
8
Compoun
Compoun
Inspired by the above facts we thought to design and
synthesize compounds based on sugars having Cꢀlinked
phenyl propenone moiety and diphenyl urea units
together to get hitherto unreported antimalarial agents
(Figure 1). In order to further analyze the feature
requirement of these molecules in 3D space, we
analyzed the common features through HipHop
algorithm.23 The HipHop algorithm finds the common
feature pharmacophore model among the set of the
highly active ligands and thus referred as qualitative
model without the use of the activity data representing
the 3D arrangement of the essential features important
for the specific activity. HypoGen on the converse deals
with the development of quantitative pharmacophore
model and requires biological activities with at least 3ꢀ4
orders of difference therefore in this work HipHop
module is preferred over HypoGen to explain the 3D
features of these compounds.
d
3a
d
4a
6.77
ND
14.05
ND
3b
3c
3d
4b
4c
4d
7.57
9.07
16.77
14.39
ND: Not done
9
Next, we have targeted the amino group to pursue our
investigation and further explore the SAR by carrying out
modifications. The functionalization of the amine group
into sulfonamides (5 and 6), ureides (7 and 8) was
thought of, using sulfonyl chloride, phenyl isocyanate
and isothiocynates by conventional methods. The
reaction of 3ꢀaminophenyl butenonyl glycopyranosides
4aꢀc with pꢀtoluene sulfonyl chloride in presence of Et3N
in CH2Cl2 at 0ꢀ30 °C led to the formation of respective
peracetylated Nꢀsulfonylaminophenyl glycopyranosides
5aꢀc in good yields (Scheme 2). Similarly reaction of
aminophenyl butenonyl glycopyranosides 4aꢀd with
different phenyl isocyanates and isothiocyanates
separately in presence of Et3N in CH2Cl2 at ambient
temperature resulted in respective peracetylated
ureidophenyl and thioureidophenyl glycopyronasides
(7aꢀk) in good yields (Scheme 2). The Zemplen
deacetylation of the above peracetylated compounds 5aꢀ
c and 7aꢀk with NaOMe/MeOH at room temperature led
to the formation of the deacetylated products 6aꢀc and
8aꢀk respectively in satisfactory yields (Scheme 2). All
the synthesized compounds were fully characterized by
their spectroscopic and HRMS data. In NMR (1H and
13C) spectral data of the compounds all the proton and
carbon signals were observed at their usual chemical
shift.
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The synthetic strategy of the compounds is very simple
and straight forward with no sophistication. The starting
aminophenyl glycoside derivatives 4aꢀd were obtained
via two step synthesis from the glycosylketones 1aꢀc.24
Thus reaction of preformed glycosylketones 1aꢀd with 3ꢀ
nitro and 4ꢀnitro benzaldehydes 2a and 2b in CH2Cl2 in
presence of pyrrolidine (20 mol %) at ambient
temperature afforded the respective glycosyl butenones
3aꢀd in good yields.25ꢀ27 The chemoselective reduction of
nitro group in the phenyl ring of the above nitrophenyl
butenonyl glycopyranosides 3aꢀd with SnCl2.2H2O (10.0
equiv.) in ethanol under ultrasonic vibration at 30 °C
afforded respective aminophenyl derivatives 4aꢀd in
good yields as reported earlier by us28 (Scheme 1).
Scheme 1. Synthesis of the aminophenyl glycosyl
pyranosides
Scheme 2. Synthesis of the Nꢀsulfonylaminophenyl,
ureido and thioureido glycopyranosides
Reagents & Conditions: (a) Pyrrolidine (20 mol %),
CH2Cl2, RT; (b) SnCl2.2H2O (10eq), )))), 30 °C, EtOH
We initially preformed bioevalution of 3aꢀd and 4aꢀd
derivatives for their antimalarial activity against
Plasmodium falciparum 3D7 (CQ sensitive) strain. The
results depicts that the nitrophenyl and aminophenyl
glycosyl derivatives (3aꢀd and 4aꢀd) showed very poor
antimalarial activities with IC50 values more than 6.77 ꢁM
against Plasmodium falciparum 3D7 (CQ sensitive)
strain (Table 1).
Reagents
& Conditions: (a) pꢀtoulene sulfonyl
chloride, Et3N, CH2Cl2, 0ꢀ30 °C; (b) ArNCX (X = O/S),
Et3N, CH2Cl2, RT; (c) NaOMe, MeOH, 10ꢀ20 min, RT
For structureꢀactivity relationship (SAR) exploration and
to find out the role of sugars on antimalrial activity, we
next synthesized successively the analogues of
sulfonamide and ureido derivatives without sugar moiety.
The HornerꢀWadsworthꢀEmmons (HWE) olefination of 3ꢀ
nitrobenzaldehyde with triethyl phosphonoacetate in
presence of lithium hydroxide in THF at room
Table 1. In vitro antimalarial activity against the Pf
3D7 strain for 3aꢀd and 4aꢀd.
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temperature led to the formation of ethyl 3ꢀ(3ꢀ
synthesized simple phenyl sulfonamidyl (12), diaryl
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3
4
5
6
7
8
nitrophenyl)acrylate (9) in quantitative yield. The latter on
chemoselective reduction of nitro group with SnCl2.2H2O
(10.0 equiv.) as above the respective aminophenyl
derivative 10 in good yield. Compound 10 on reaction
with pꢀtoluene sulfonyl chlroide and phenyl isocyanates
separately as reported earlier led to the formation of the
desired sulfonamide (11a) and ureide (11bꢀc) derivatives
(Scheme A, S2) in good yields. On the other hand, we
ureidyl (13 and 14) and diaryl thioureidyl (15) moieties
from aniline (Scheme B, S2). All the synthesized
compounds were tested for their in vitro antimalarial
activity against Plasmodium falciparum 3D7 (CQ
sensitive) and K1 (CQ resistant). Subsequently
cytotoxicities of the desired compounds against
mammalian VERO cell line were also determined.
Table 2. In vitro antimalarial activity against the Pf 3D7 and Pf K1
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IC50 ꢁM
SI
Comp.
code
Compounds
CC50
ꢁM
Pf3D7
PfK1
Pf3D7
PfK1
5a
1.14
2.17
584.18
512.43
269.2
5b
5c
6a
3.96
1.39
2.20
5.19
3.00
3.87
123.25
268.23
380.92
31.12
192.97
173.14
23.73
89.41
98.42
6b
6c
7a
3.89
2.93
2.29
5.11
6.35
2.40
417.42
94.74
107.30
32.33
78.74
81.68
14.91
75.13
180.32
7b
7c
7d
1.91
0.94
0.55
4.48
4.23
0.42
336.58
729.92
559.20
176.21
776.51
75.12
172.5
1016.7
2
1331.42
7e
7f
5.27
5.55
819.67
155.53
147.68
1.83
2.30
663.25
362.43
288.36
7g
2.18
5.36
481.96
221.08
89.91
7h
7i
6.65
3.73
3.17
4.20
3.77
7.81
2.87
4.92
5.57
3.39
102.40
65.14
15.39
17.46
32.03
13.98
99.01
13.11
22.69
20.63
10.54
110.11
7j
101.54
58.73
7k
8a
8b
373.30
9.43
7.20
371.17
39.36
51.55
8c
8d
0.56
1.58
708.89
1265.8
7
448.66
3.35
2.47
202.62
60.48
82.03
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2
8e
7.51
7.66
1131.2
2
150.62
147.67
3
4
5
6
8f
11.85
5.91
13.79
5.28
274.45
23.16
19.90
8g
1016.2
6
171.95
192.47
7
8
8h
20
20
ND
ND
ND
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8i
8j
13.07
17.81
336.33
25.73
18.88
3.44
5.43
309.02
89.83
56.90
8k
6.89
16.12
8.80
8.69
16.12
13.41
289.32
77.12
41.99
4.78
33.29
4.78
11a
11b
292.96
33.26
21.83
11c
>20
>20
279.43
<13.97
<13.97
12
13
14
>20
13.79
>20
>20
>20
>20
221.32
351.62
434.52
<11.06
25.26
<11.06
<17.58
<21.72
<21.72
15
16
>20
18.01
1.16
355.73
684.68
<17.78
19.78
Chloroquine (CQ)
0.011
58833.
3
578.68
IC50: 50% inhibitory concentration against parasite, SI: CC50/IC50, ND: Not done
0.55 to 3.77 ꢁM against Pf3D7 and 0.42 to 5.43 ꢁM
against PfK1 respectively. In this series, acetylated
As evident from Table 2, all of the phenyl sulfonamides
and most of the urea and thiourea derivatives of
glycopyranosides showed better in vitro antimalarial
activity as compared to the sulfonamido and ureido
derivatives without sugar moiety. The phenyl
sulfonamides with glycopyranoside moieties 5aꢀc and
6aꢀc displayed IC50 values in the range of 1.14 to 3.96
ꢁM and 2.17 to 6.35 ꢁM against the Pf3D7 and PfK1
strains respectively. Among the glycosides, the
acetylated glucosides and xylosides bearing phenyl
sulfonamides (5a and 5c) displayed promising
antimalarial activity with IC50 values of 1.14 ꢁM and 1.39
ꢁM (Pf3D7) and 2.17 ꢁM and 3.00 ꢁM (PfK1)
respectively. The deacetylated glucosides and xylosides
with phenyl sulfonamides (6a and 6c) did also display
significant antimalarial activity with IC50 values 2.20 ꢁM
and 2.93 ꢁM (Pf3D7) and 3.87 ꢁM and 6.35 ꢁM (PfK1)
respectively. By observing the results it is concluded that
by changing the sugar with mannopyaranose in the
glycopyranoside series (both peracetylated and
deacetylated) having phenyl sulfonamidyl moieties 5b
and 6b resulted in loss of antimalarial activity with IC50
values 3.96 ꢁM and 3.89 ꢁM (Pf3D7) and 5.19 ꢁM and
5.11 ꢁM (PfK1) respectively.
thioureido glucoside (7d, 0.55 ꢁM & 0.42 ꢁM) exhibited
most promising activity when compared to deacetylated
ureido glucoside (8c, 0.56 ꢁM & 1.58 ꢁM) and both have
methoxy and nitro substituents in different positions on
the phenyl ring. Another methoxy and nitro substituted
acetylated ureido glucoside (7c, 0.94 ꢁM & 4.23 ꢁM) and
deacetylated thioureido glucoside (8d, 3.35 ꢁM & 2.47
ꢁM) showed moderate activity as compared to 7d and
8c. Unsubstituted glucosides 7a, 7b, 7f and 8a were
showed good antimalarial activity with IC50 values
varying from 1.83 to 3.77 ꢁM and 2.30 to 4.48 ꢁM
against Pf3D7 and PfK1 respectively. The alteration of
the glucose moiety with mannose and xylose as
represented by 7i, 7j and 8j were found less active with
IC50 values in the range of 3.17 to 3.73 ꢁM and 2.87 to
5.43 ꢁM against Pf3D7 and PfK1 respectively. Therefore
it is concluded that, out of all these compounds most of
the glucoside moieties were displayed significant
antimalarial activities as compared to the mannoside and
xyloside moieties. Among this series the acetylated
thiureido glucoside 7d and deactylated ureido glucoside
8c are very promising compounds for further
optimization. All these active compounds showing low
cytotoxicity against VERO cell line (Monkey kidney cell
line). Based on IC50 and CC50 values, selective index (SI)
In the case of ureide and thioureide glycoside moieties,
total 22 compounds evaluated 11 compounds (7a, 7b,
7c, 7d, 7f, 7i, 7j, 8a, 8c, 8d and 8j) showed promising
antimalarial activities with IC50 values in the range of
of all the compounds were calculated and the most
active compounds in these series found to be good
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selective index (Figure A&B, S3). The two most
promising antimalarial active compounds 7d and 8c
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7
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found to be high selective index in this series.
Furthermore we have also screened in-vitro antimalarial
activity of phenyl sulfonamidyl (12), diary ureidyl (13 and
14) and diaryl thioureidyl (15) derivatives without sugar
and buetenone moieties which resulted in loss of activity
as compared to their glycoside counterparts with
sulfonamidyl and ureidyl derivatives.
9
We have investigated to the inhibition of haem
polymerization to the 17 most active compounds of this
series. Among the all the active compounds, the
compound 7c exhibited most inhibition 92.72 % and
three compounds 7a, 7d, and 7j were exhibited the
similar inhibition of the values 72.47 %, 72.13 % and
76.86 % respectively. Other compounds are exhibited
less inhibition compared to above compounds (Table A,
S3).
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Figure 2. A) The pharmacophore model developed using
the training set compounds. B) & C) The mapping of the
most active compounds (7d & 8c) from the training set. D)
& E) The mapping of the most active compounds from the
test set (8a & 7g).F) & G) The mapping of the moderately
and least active compounds from the test set (11a & 14).
In order to find the common structural features required
for these set of compounds and to further validate the
SAR studies a pharmacophore modeling was carried out
using 16 training set compounds (Figure C, S5) and
validated on 19 test set of compounds (Table C, S6).
The HipHop module was used for pharmacophore
modeling using reported protocol.23 The ten hypotheses
generated had the scores ranging from 208.706ꢀ206.689
and four features viz. hydrogen bond acceptor lipid
feature (H, 3), hydrogen bond donor features (D, 1)
common for all hypotheses (Table B, S5). Out of ten
hypotheses Hypoꢀ3 (Figure 2A) was selected for further
study as it map all the training set compounds correctly
and maps all essential features of the most active
compound 7d (Figure 2B). The one NꢀH functionality
from thioureido maps well with the centroid alignment of
one D feature of Hypoꢀ3 while the one carbonyl
functionality of the (E)ꢀ4ꢀphenylbutꢀ3ꢀenꢀ2ꢀone part of
the compound 7d fulfills the requirement of one H
functionality. The remaining two H features were
supported by the C=O functionalities of 3,4ꢀdiyl
diacetate. The Hypoꢀ3 also mapped well the second
most active compound 8c satisfactorily (Figure 2C),
which predicted well in the test set compounds (Table C,
S5) and confirms the applicability of this hypothesis. The
Hypoꢀ3 maps well the most active compounds from the
test set 8a and 7g respectively in to their highly active
As a representative compound, the most promising
glycoside with ureido phenyl butenonyl moiety (8c) was
studied for its pharmacokinetic parameters in male
Sprague Dawley rats through intravenous administration
(5 mg/kg) (Figure 3). It was quickly distributed and
eliminated from the serum with terminal elimination halfꢀ
life (t1/2) of 7.1±0.3 h. The volume of distribution (2.8
L/kg) is higher than the total blood volume (0.054 L/kg)29
of the rat and systemic clearance (1.02 L/h/Kg) is lower
than the total hepatic blood flow in rats (2.9 L/h/kg)29
indicating extravascular distribution with negligible
extrahepatic elimination (S7ꢀS8).
Figure 3. Concentrationꢀtime profile of 8c after intravenous
(5 mg/kg) administration in male Sprague Dawley rats
(n=3). Bar represents SEM.
In conclusion, we have identified hitherto unreported
novel phenyl butenonyl Cꢀglycosides with ureidyl,
thioureidyl and sulfonamidyl moieties as promising
antimalrials against both the 3D7 and K1 strains of
Plasmodium falciparum with high selectivity index and
low cytotoxicity. The synthesis, structureꢀactivity
relationship and systematic bioevaluation of compounds
are discussed. Compounds 7d and 8c exhibited most
promising activities within the series. The ureidyl and
thioureidyl derivatives of the glycosides showed haem
polymerization inhibition significantly. This class of
compounds with good inꢀvitro antimalarial activity offers
a new direction to explore new antimalarials.
class (Figure 2D
& 2E). The moderately active
compound 11a from this series maps well the three H
features, while unable to map one D function of Hypoꢀ3
(Figure 2F). The compound 14, least active compound
from this series lacks the 2H features and one D feature
(Figure 2G) therefore predicted as inactive and also
observed poorly active in in-vitro studies.
ASSOCIATED CONTENT
Supporting information. Details for synthesis and
characterization of all compounds together with protocols
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12. Daily, J. P.; Scanfeld, D.; Pochet, N.; Le Roch, K.; Plouffe,
for biological assays, pharmacokinetic parameters and
pharmacophore development are available free of charge
via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
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C.; Tewari, R.; Krishna, S. Life cycle studies of the hexose
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Email: rpt.cdri@gmail.com; rp_tripathi@cdri.res.in
Authors Contribution: All authors have contributed in this
study and have given their permission for communication
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ACKNOWLEDGMENT
GRK and SG are thankful to CSIR, New Delhi for
fellowships. We thank to Dr. Brijesh Kumar and SAIF
division, CSIRꢀCDRI for the analytical facilities and Mrs
Shashi Rastogi for technical assistance. It is a CDRI
communication No:
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