Development of chiral praziquantel analogues as potential drug candidates with activity to juvenile Schistosoma japonicum

Article abstract of DOI:10.1016/j.bmcl.2014.07.039

A series of chiral praziquantel analogues were synthesized and evaluated against Schistosoma japonicum both in vitro and in vivo. All compounds exhibited low to considerable good activity in vivo. Remarkably, worm reduction rate of R-3 was 60.0% at a sing

Full text of DOI:10.1016/j.bmcl.2014.07.039

Bioorganic & Medicinal Chemistry Letters 24 (2014) 4223–4226
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Development of chiral praziquantel analogues as potential drug
candidates with activity to juvenile Schistosoma japonicum
Yang Zheng a, , LanLan Dong b, , Changyan Hu a, Bo Zhao b, Chunhua Yang a, Chaoming Xia b,
,
⇑
Dequn Sun a,
⇑
a Marine College, Shandong University at Weihai, No. 180, Wenhua West Road, Weihai 264209, PR China
b Department of Parasitology, Medical College of Soochow University, Jiangsu 215123, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chiral praziquantel analogues were synthesized and evaluated against Schistosoma japonicum
both in vitro and in vivo. All compounds exhibited low to considerable good activity in vivo. Remarkably,
worm reduction rate of R-3 was 60.0% at a single oral dose of 200 mg/kg against juvenile stage of
Schistosoma japonicum. The target compounds displayed in vivo antischistosomal activity against both
Schistosoma japonicum and Schistosoma mansoni. Furthermore, all R-isomers displayed stronger
antischistosomal activity than S-isomers in vivo, indicating R-isomers were the active enantiomers, while
S-isomers were less active ones. This structure activity relationship (SAR) could have important implica-
tions in further drug development for schistosomiasis.
Received 4 May 2014
Revised 17 June 2014
Accepted 14 July 2014
Available online 22 July 2014
Keywords:
Chiral praziquantel analogues
Antischistosomal
Ó 2014 Elsevier Ltd. All rights reserved.
Schistosoma japonicum
Nowadays, there is growing awareness of the huge public
health significance of the so-called neglected tropical diseases
(NTDs). The huge global burden due to NTDs is estimated to be
similar to human immunodeficiency virus/AIDS, malaria, and
tuberculosis.1,2 As an important member of NTDs,1,3 schistosomia-
sis is an ordinary chronic parasitic disease in the world, especially
in tropical and subtropical regions.4,5 About 200 million people are
infected with schistosomiasis, with 650 million people at a risk of
infection all over the world.6,7 In spite of this severe situation, the
most important drug in clinical use to control all forms of schisto-
somiasis is only praziquantel (PZQ). After the introduction since
1970s, PZQ is risking drug resistance or tolerance. Recently, schis-
tosome isolated with diminished sensitivity to PZQ continues to be
identified.8 It is very dangerous to lack of back-up drugs for the
treatment of schistosomiasis. PZQ is well known to have excellent
activity against adult schistosome. However, its annoying, even
fatal weakness is its low efficacy against juvenile stages of schisto-
somes,9 this is absolutely the exclusive reason for the endless
schistosomiasis and cause the unconditional necessity to find mol-
ecules with good activity against juvenile stages of schistosomes in
order to cease schistosomiasis completely. However, due to the
unclear action mechanism of PZQ, it is blind and difficult to design
the rational molecule with potential anti-schistosomal activity. So
far, several attempts have been made to find bioactive PZQ deriva-
tives,10–13 as well as other candidates for the treatment of
schistosomiasis.14,15
It has been reported that16 the PZQ metabolites (Fig. 1), includ-
ing the major trans-cyclohexanol metabolite, are less active than
the parent compound itself.
In order to impede the metabolism and increase metabolic
stability, racemate 3 (Fig. 2, Rac-3) with carbonyl group at meta-
bolic liable position was designed, its worm killing activity against
both juvenile and adult stages of S. mansoni in infected mice was
evaluated.10
It was interestingly found this compound showed significant
in vivo activity to S. mansoni even with no in vitro activity.
This interesting phenomenon impelled us to conjecture that
such kind of compounds might have similar bioactivity against S.
japonicum. Furthermore, PZQ used in clinic is a mixture of R-PZQ
N
N
N
O
N
O
OH
⇑
Corresponding authors.
E-mail addresses: xiachaoming@suda.edu.cn (C. Xia), dequn.sun@sdu.edu.cn
PZQ major metabolite
Praziquantel (PZQ)
(D. Sun).
These authors contribute equally.
Figure 1. Praziquantel (PZQ) and its major metabolite.
http://dx.doi.org/10.1016/j.bmcl.2014.07.039
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

4224
Y. Zheng et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4223–4226
N
N
O
N
N
O
O
N
N
O
N
N
O
O
N
N
O
H
H
H
H
H
H
H
O
O
O
O
O
O
O
O
Rac-2
R-2
O
O
Rac-1
S-1
R-1
N
N
N
O
N
N
O
N
H
H
N
N
O
O
O
O
O
R-3
S-3
Rac-3
S-2
O
O
O
RCOOH
EDCI
N
N
O
N
O
target compounds 1-3
N
H
O
R
PZQamine
Figure 2. PZQ analogues, their chiral isomers and preparation.
and S-PZQ, and the R-isomer is the eutomer, while the S-isomer is
the inactive enantiomer. The isomers have very different antis-
chistosomal activity.17 Chiral isomers of compound 3 and its ana-
logues have not been synthesized and evaluated for their activity
against S. japonicum. We further hypothesised that chiral isomers
of carbonyl compounds (1, 2, 3) would reveal similar activity
behaviour like PZQ and its chiral isomers regarding to S. japonicum.
Therefore, in order to study their SAR and to verify our hypothesis,
three carbonyl compounds and their corresponding chiral isomers
(Fig. 2) were prepared to estimate both in vitro and in vivo activity
against S. japonicum.
All nine test compounds were prepared by standard condensa-
tion reaction between PZQ amines and corresponding acids using
EDCI as coupling reagent. The nine target compounds were
obtained in 73–80% yield.18 The chiral PZQ amines used for prepa-
ration of chiral target compounds were obtained through the
reported resolution method reported.19 The ee value of chiral
PZQ amines was measured as over 99% by HPLC (DAICEL AD-H,
4.6 mm*250 mm, with hexane/ethanol/triethylamine = 80:20:0.1
as eluent, flow rate 1.0 ml/min).
All prepared compounds were evaluated for their activity
against adult and juvenile S. japonicum. Female ICR Kunming strain
mice (4–6 weeks, 20–22 g) were provided by the Experimental Ani-
mal Center of Soochow University, and S. japonicum cercariae
released from infected intermediate host snail Oncomelania hupen-
sis were purchased from the Institute of Schistosomiasis Control in
Jiangsu Province (Wuxi, China). In vitro and in vivo activity test was
conducted according to described method.20,21 Five adult male
worms (6 weeks post-infection) and nine juvenile worms (17 days
post-infection) were distributed in duplicate tissue culture dishes
(3.0 cm) in Dulbecco-modified Minimum Eagle’s Medium (bicar-
bonate buffered) supplemented with 20% newborn calf serum,
were dispensed from a stock solution in DMSO and diluted to the
concentration of 50–100 M. Compound activity was assessed by
l
worm survival rate and vitality reduction rate within 72 h. The
score of worm vitality is illustrated as: 3 scores: the highest score,
as observed in the control group during the observation period.
Worms moved more actively and softly, and the body was transpar-
ent. 2 scores: worms acted all over the body, but stiffly and slowly,
with the body translucent. 1 score: parasites moved partially with
opaque appearance. 0 score: the worm remained contracted, did
not resume movements, we could deem it ‘dead’. The total vitality
score and worm survival rate of adult and juvenile worms was sep-
arately counted for in vitro test and the data representative of
repeated experiments (5 adult worms or 9 juvenile worms each
group) was summarised in Tables 1 and 2.
For the in vivo test, female ICR Kunming strain mice infected
with 60 2 bisexual S. japonicum cercariae were treated with
200 mg/kg of nine analogues suspended in corn oil once a day for
5 days beginning on day 14 after infection (juvenile stage). 21 days
post-treatment, mice were sacrificed and dissected to assess worm
reduction and the result of repeated experiments (5 mice each
group) was given in Table 3.
For the nine target compounds tested against adult S. japonicum
in vitro (Table 1), all of them displayed nearly no activity with the
exception of Rac-3 and R-3. Rac-3 reduced worm vitality by 66.7%
in 72 h at the concentration of 50 lM, which was totally different
from its activity against adult S. mansoni.10 And worm mortality
rate induced by R-3 was 40.0%in 72 h at the concentration of
100 lM.
Regarding activity to juvenile S. japonicum in vitro (Table 2),
more compounds exhibited activity at the concentration of
50 lM. Rac-2, Rac-3 and R-3 showed modest antischistosomal
activity and other compounds exhibited very low mortality rate.
45.8% of juvenile worms were killed by Rac-2within 72 h. Worm
mortality rate induced by Rac-3 was 30.8% within 72 h. Compound
with best antischistosomal activity was R-3, which reduced worm
survival rate to 44.1% after 72 h.
100 U/ml penicillin, 100 lg/ml streptomycin and 0.5 lg/ml ampho-
tericin B. Cultures were kept at 37 °C in an atmosphere of 5% CO2 in
air and were observed daily under a Leica MZ12.5 stereomicro-
scope. Cultures were exposed over-night to different PZQ analogues
and the next morning worms were washed thrice and transferred to
new dishes containing drug-free medium. PZQ and its analogues
However, all compounds displayed low to considerable good
antischistomal activity against juvenile S. japonicum in vivo

Y. Zheng et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4223–4226
4225
Table 1
Nine PZQ analogues activity against adult S. japonicum in vitro
Compound
Conc
M)
Worm number
24 h
48 h
72 h
(
l
bWorm survival%
cVitality total score/
Vitality reduction%
Worm survival%
Vitality total score/
Vitality reduction%
Worm survival%
Vitality total score/
Vitality reduction%
Control
aDMSO
5
5
100
100
15 0/0
14.7 0.6/2.2
100
100
15 0/0
15 0/0
100
100
15 0/0
15 0/0
Rac-1
50
100
50
100
50
100
5
5
5
5
5
5
100
100
100
100
100
100
13 0/13.3
100
100
100
100
100
100
15 0/0
100
100
100
100
100
100
15 0/0
14.5 0.6/6.7
12.3 0.6/17.8
11.3 0.6/24.5
14.3 0.6/4.5
14 0/6.7
13.5 0.6/10
12.7 0.6/15.5
11.7 0.6/22
15 0/0
13.5 0.6/10
12.7 1.2/15.3
11.6 0.6/22.7
15 0/0
R-1
S-1
13.7 0.6/8.7
13.7 0.6/8.9
Rac-2
50
80
100
50
100
50
100
5
5
5
5
5
5
5
100
100
100
100
100
100
100
15 0/0
100
100
100
100
100
100
100
15 0/0
100
100
100
100
100
100
100
15 0/0
15 0/0
13.7 0.6/8.7
14 0/6.7
13.3 1.1/11.1
15 0/0
11.5 0.6/23.3
12.3 0.6/17.8
12.7 0.6/15.5
13 1/13.3
14.3 0.6/4.5
12.6 0.5/16
13 0.8/13.3
13 1/13.3
15 0/0
13.3 1.1/11.1
15 0/0
R-2
S-2
12.7 0.6/15.5
12.7 0.6/15.3
Rac-3
R-3
50
80
100
50
80
100
50
5
5
5
5
5
5
5
5
100
100
100
60
60
40
9
0/40
100
100
100
80
100
60
5.3 0.6/64.5
5.3 0.6/64.5
100
100
100
100
100
60
5
0/66.7
7.7 0.7/48.9
8
4
5.33 0.5/64.5
6.7 0.6/55.3
6.7 0.6/55.5
0/46.7
0/73.3
6
6
0/60
0/60
2.7 0.5/82
0/86.7
4.6 0.6/69.3
2.7 0.6/82.2
15 0/0
6
0/60
2
3.3 0.6/77.8
15 0/0
12.7 0.6/15.5
S-3
100
100
15 0/0
13.7 0.6/8.7
100
100
100
100
100
12.7 0.6/15.3
a
3
l
L DMSO was added with no compound.
b
number of survival worm
Worm survival% ¼
Vitality reduction% ¼
ꢀ 100%.
number of total worm
total score of worm vitality for control groupꢁtotal score of worm vitality for test group
c
ꢀ 100%.
total score of worm vitality for control group
Table 2
Nine PZQ analogues activity against juvenile S. japonicum in vitro
Compound
(50 M)
Worm
number
24 h
48 h
72 h
l
bWorm
survival%
cVitality total score/vitality
reduction%
Worm
survival%
Vitality total score/vitality
reduction%
Worm
survival%
Vitality total score/vitality
reduction%
aControl
Rac-1
R-1
9
9
9
9
100
82.5
100
88.3
27 0/0
100
82.5
100
88.3
27 0/0
100
82.5
100
88.3
27 0/0
17.3 1.2/35.8
18.3 3.8/32.1
18.7 0.6/30.9
17.3 1.2/35.8
17 4.6/37
18.7 2.1/30.9
17 1.7/37
16.7 4/38.3
17.7 1.2/34.6
S-1
Rac-2
R-2
S-2
9
9
9
54.2
100
100
12 0/55.6
16.7 2.9/38.3
14.7 3.1/45.7
54.2
100
100
12 0/55.6
16.7 2.9/38.3
14.7 3.1/45.7
54.2
88.3
85
12.3 0.6/54.3
13.3 1.3/50.6
12.7 1.2/53.1
Rac-3
R-3
S-3
9
9
9
69.2
51.6
88.3
17.3 5.7/35.8
10.7 5.5/60.5
19 1.7/29.6
69.2
48.3
88.3
17.7 5.1/34.6
9.7 5.5/64.2
19 1.7/29.6
69.2
44.1
88.3
17.7 5.1/34.6
9
4.4/66.7
19 1.7/29.6
a
3
l
L DMSO was added with no compound.
b
number of survival worm
Worm survival% ¼
Vitality reduction% ¼
ꢀ 100%.
number of total worm
c
total score of worm vitality for control groupꢁtotal score of worm vitality for test group
ꢀ 100%.
total score of worm vitality for control group
(Table 3) in spite of low activity in vitro, this result was in coinci-
dence with the report10 that Rac-3 exhibited modest activity
against S. mansoni in vivo even with no activity in vitro, which con-
firmed our hypothesis.
Remarkably, six compounds (R-1, Rac-2, R-2, S-2, Rac-3, R-3)
displayed stronger activity (24.6–60.0%) against juvenile S. japoni-
cum than PZQ (19.9%). Three compounds (R-1, R-2, R-3) showed
significant (P < 0.01) activity compared with control group. The
result of particular significance was for R-3, its worm reduction
rate was 60.0%, which might be a better drug candidate.
All three R-isomers exhibited better antischistosomal activity
than their corresponding S-isomers, which revealed consistency
with the activity of R-PZQ and S-PZQ. The activity of R-1 (41.0%)
was about 2.1 times of S-1 (19.0%); R-2 (44.1%) showed nearly
20% stronger activity than S-2 (24.6%); Of all the activity difference
between isomers, the greatest one was isomers of Rac-3,
Table 3
Nine PZQ analogues activity against juvenile S. japonicum in vivo. (oral dose 200 mg/
kg)
Compound
Worm number ðx þ sÞ
48.8 10.1
40.2 2.2
45 7.4
28.8 4.1
39.5 7.6
30.5 2.1
27.3 7.3
36.8 4.1
35.3 7.7
bWorm reduction%
aControl
PZQ
Rac-1
R-1
S-1
Rac-2
R-2
S-2
Rac-3
R-3
0
19.9
7.7
41.0
19.0
37.4
44.1
24.6
27.7
60.0
18.0
19.5
5
S-3
40 3.4
a
Mice were given equal volume of corn oil.
Worm reduction %¼
b
total worm number for control groupꢁtotal worm number for test group
total worm number for control group
ꢀ100%.

4226
Y. Zheng et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4223–4226
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antischistosomal activity of R-3 (60.0%) was over three times as
much as that of S-3 (18.0%).
The above results indicated that all R-isomers were the active
enantiomers in accordance with the report17 that R-PZQ was the
active enantiomer for PZQ. Furthermore, as the size of ring with
carbonyl group enlarged, antischistosomal activity of R-isomers
increased from 41.0% to 60.0%, while worm reduction induced by
S-isomers did not change obviously (from 18.0% to 24.6%). This
implied that the size of the ring with carbonyl group in PZQ ana-
logues had appreciable impact on the activity of R-isomers (active
enantiomers), but less impact on S-isomers (inactive enantiomers).
We have summarised the SAR of three racemic PZQ analogues
and their chiral isomers with activity against adult and juvenile
S. japonicum in vitro, and the in vivo activity to juvenile S. japoni-
cum. Even with no obvious activity in vitro, most compounds were
more effective against juvenile S. japonicum than PZQ in vivo. Espe-
cially, three R-isomers displayed considerably stronger activity
against juvenile S. japonicum in vivo than their corresponding S-
isomers, which suggested that R-isomer of PZQ analogues might
be a more valuable tool to probe the action mechanism of PZQ.
Notably, six compounds (R-1, Rac-2, R-2, S-2, Rac-3, R-3) showed
better antischistosomal activity than PZQ against juvenile S. japon-
icum, meanwhile, Rac-3 exhibited moderate activity to juvenile S.
mansoni,10 biological assay of these compounds against juvenile
Schistosoma haematobium and the cross drug resistance should be
further investigated in order to explore drug candidates with
broad-spectrum activity to cease schistosomiasis completely.
14. Sayed, A. A.; Simeonov, A.; Thomas, C. J.; Inglese, J.; Austin, C. P.; Williams, D. L.
Nat. Med. 2008, 14, 407.
15. Simeonov, A.; Jadhav, A.; Sayed, A. A.; Wang, Y.; Nelson, M. E.; Thomas, C. J.;
Inglese, J.; Williams, D. L.; Austin, C. P. PLoS Negl. Trop. Dis. 2008, 2, e127.
16. Andrews, P. Pharmacol. Ther. 1985, 29, 129.
17. Xiao, S.; You, J.; Mei, J.; Mei, J.; Hu, Y.; Zhou, D.; Catto, B. A. Chin. J. Parasitol.
Parasit. Dis. 1998, 16, 335.
18. Melting points (mp) of the products were determined in open capillary tubes
and are uncorrected. 1H and 13C NMR spectra were recorded on a 400 MHz
spectrometer in CDCl3 solvent. All chemical shifts are reported in parts per
million (ppm) and are relative to internal (CH3)4Si (0 ppm) for 1H NMR, and
CDCl3 (77.0 ppm) for 13C NMR. Mass spectra were recorded with a JEOL MS-D
300 mass spectrometer. Optical rotation values for each PZQ amine enantiomer
and PZQ analogue were determined in Jasco p-1030 Automatic Polarimeter
with CHCl3 as the solvent.
PZQ-amine: yield: 91.2%; mp: 115–117 °C (116–118°C12); 1H NMR: d: 7.12–
7.29 (m, 4H), 4.40–4.42 (t, 1H), 4.04–4.11 (m, 1H), 3.39(s, 4H), 3.26(s, 2H),
26.5
2.72–2.73(d, 1H), 2.63–2.67 (t, 2H). R-PZQ-amine:
[a]
ꢁ268.36 (c = 0.5,
D
26.5
CHCl3), S-PZQ-amine: [
a
]
+264.69 (c = 0.5, CHCl3).
D
2-(3-Oxocyclobutanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquino
lin-4(11bH)-one (Rac-1): yield: 73.4%; mp 150–152 °C; 1H NMR d 7.25–7.30 (m,
4H), 5.13–5.17 (m, 1H), 4.81–4.88 (m, 2H), 4.10–4.42 (dd, 2H, J = 17.2), 3.50–
3.51 (t, 3H), 3.29–3.35 (m, 4H), 2.91–2.97 (m, 2H), 2.79–2.83 (d, 1H, J = 16.0);
13C NMR d 203.05, 171.20, 63.61, 134.73, 132.29, 129.36, 127.61, 127.04,
125.41, 54.83, 50.99, 48.81, 45.73, 39.13, 28.65, 25.82. HR-MS (ESI) calcd. for
Acknowledgment
C
17H18N2O3 (M+1), 299.1396; found, 299.1397. 1H NMR of R-1 and S-1 were
26.6 26.6
the same as those of Rac-1. R-1: [
+126.07 (c = 0.5, CHCl3).
a
]
D
ꢁ154.46 (c = 0.5, CHCl3), S-1: [a]
D
The project was supported by the National High-Tech Program
of China (863 Project No. 2012AA020306).
2-(3-Oxocyclopentanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquin
olin-4(11bH)-one (Rac-2): yield: 83.7%, mp 154–156 °C, 1H NMR d 7.19–7.28(m,
4H), 5.15(t, 1H), 4.83(m, 3H), 4.46(m, 1H), 4.153(m, 2H), 3.357(m, 1H),
2.895(m, 4H), 2.684(m, 2H), 2.437(m, 2H), 2.270(m, 4H); 13C NMR d 216.26,
172.26, 163.72, 135.44, 134.67, 132.33, 131.62, 129.43, 127.33, 54.77, 48.83,
45.48, 41.38, 39.11, 38.25, 37.09, 28.63. HR-MS (ESI) calcd. for C18H20N2O3
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.07.
039.
(M+1), 313.1552; found, 313.1553. 1H NMR of R-2 and S-2 were the same as
26.7
those of Rac-2. R-2: [
CHCl3).
a
]
ꢁ151.35 (c = 0.5, CHCl3), S-2: [a]
26.7 +148.25 (c = 0.5,
D
D
2-(4-Oxocyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquin
olin-4(11bH)-one (Rac-3): yield: 76.8%, mp 176–179 °C, 1H NMR d 7.29(m, 4H),
5.14(m, 1H), 4.81(m, 2H), 4.53(d, 1H),4.19(d, 1H), 2.94(m, 4H), 2.81(m, 1H),
References and notes
2.54(m,2H), 2.39(m,2H), 2.08(m,4H); 13C NMR
d 209.36, 172.73, 163.85,
1. Hotez, P. J.; Molyneux, D. H.; Fenwick, A.; Ottesen, E.; Sachs, S. E.; Sachs, J. D.
PLoS Med. 2006, 3, e102.
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McManus, D. P. N. Eng. J. Med. 2002, 346, 1212.
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6, 411.
135.05, 131.98, 129.43, 127.33, 125.47, 54.81, 49.10, 45.33, 39.77, 39.12,
38.21, 28.73, 28.64. HR-MS (ESI) calcd. for C19H22N2O3 (M+1), 327.1709; found,
327.1715. 1H NMR of R-3 and S-3 were the same as those of Rac-3. R-3: [
a]
D
26.8
26.8
ꢁ138.18 (c = 0.5, CHCl3), S-3: [
a]
D
+130.33 (c = 0.5, CHCl3).
19. Woelfle, M.; Seerden, J.; Gooijer, J.; Pouwer, K.; Olliaro, P.; Tood, M. H. PLoS
Negl. Trop. Dis. 2011, 5, e1260.
20. Keiser, J. Parasitol 2010, 137, 589.
21. Pica-Mattoccia, L.; Valle, C.; Basso, A.; Troiain, A. R.; Vigorosi, F.; Liberti, P.;
Festucci, A.; Cioli, D. Exp. Parasitol. 2007, 115, 344.