Synthesis of new praziquantel analogues: Potential candidates for the treatment of schistosomiasis

Article abstract of DOI:10.1016/j.bmcl.2011.11.108

An efficient synthesis of antischistosomal drug praziquantel and analogues was achieved and the synthetic route designed was to afford structurally diverse analogues for better structure-activity relationship understanding. Total of nineteen PZQ analogues with structural variations at amide, piperazine and aromatic moieties have been synthesized and fully characterized. Among all the new analogues tested for antischistosomal activity, one dimethoxy tetrahydroisoquinoline analogue and two tetrahydro-β-carboline analogues exhibited moderate activity against adult Schistosoma mansoni. Tetrahydro-β-carboline analogues showed moderate activity whereas the presence of p-trifluoromethylbenzoyl and p-toluenesulphonyl moieties resulted in complete suppression of antischistosomal activity.

Full text of DOI:10.1016/j.bmcl.2011.11.108

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1103–1106
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of new praziquantel analogues: Potential candidates for the treatment
of schistosomiasis
Partha Sarathi Sadhu a, Singam Naveen Kumar a, Malapaka Chandrasekharam b, , Livia Pica-Mattoccia c,
⇑
a,
Donato Cioli c, , Vaidya Jayathirtha Rao
⇑
⇑
a Organic Chemistry Division II, Indian Institute of Chemical Technology, Uppal Road Tarnaka, Hyderabad 500607, India
b Inorganic & Physical Chemistry Division, Indian Institute of Chemical Technology, Uppal Road Tarnaka, Hyderabad 500607, India
c Institute of Cell Biology and Neurobiology, National Research Council, 00015 Monterotondo, Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of antischistosomal drug praziquantel and analogues was achieved and the syn-
thetic route designed was to afford structurally diverse analogues for better structure–activity relation-
ship understanding. Total of nineteen PZQ analogues with structural variations at amide, piperazine and
aromatic moieties have been synthesized and fully characterized. Among all the new analogues tested for
antischistosomal activity, one dimethoxy tetrahydroisoquinoline analogue and two tetrahydro-b-carbo-
line analogues exhibited moderate activity against adult Schistosoma mansoni. Tetrahydro-b-carboline
analogues showed moderate activity whereas the presence of p-trifluoromethylbenzoyl and p-toluene-
sulphonyl moieties resulted in complete suppression of antischistosomal activity.
Received 26 September 2011
Revised 5 November 2011
Accepted 28 November 2011
Available online 13 December 2011
Keywords:
Praziquantel analogues
Schistosomiasis
Schistosoma mansoni
Antischistosomal
Ó 2011 Elsevier Ltd. All rights reserved.
Schistosomiasis is one of the most prevalent and harmful infec-
tious diseases among the ‘neglected tropical diseases’.1,2 It is only
second to malaria in terms of impact on human health caused by a
parasite. The disease is caused by a trematode flatworm of the genus
Schistosoma. Three species of the parasite, Schistosoma mansoni,
Schistosoma haematobium and Schistosoma japonicum are the major
agents of human schistosomiasis.3 Parasite larvae present in fresh
water enter the body by penetration of the skin and may affect sev-
eral organs. According to the World Health Organization, about 200
million people are infected, while 600 million people are at risk of
infection. The most affected areas are in Africa, West Asia, South
America, the Caribbean, Middle East, Southern China, parts of South-
east Asia, the Philippines and Laos. It has been estimated that
280,000 people are dying annually in sub-Saharan Africa alone.4 Pra-
ziquantel (PZQ) is the sole drug for the treatment of schistosomia-
sis.5 It is highly effective against all species of the parasite, it is
very safe and reasonably cheap.6 PZQ is being distributed to millions
of people every year through various mass chemotherapy pro-
grammes, chief among them the Schistosomiasis Control Initiative
funded by the Gates Foundation.7 Due to its widespread and inten-
sive use, there is serious concern that drug-resistant mutants of
the parasite may emerge. Although no conclusive report of clinically
relevant drug resistance or tolerance has appeared,8,9 various iso-
lates of S. mansoni and S. haematobium have shown different levels
of PZQ sensitivity.10,11 Therefore, it is a very precarious situation to
rely only on PZQ for the treatment of schistosomiasis, a disease
affecting millions of people, and there is an urgent need for the
development of new antischistosomal agents. In this direction Caf-
frey’s group has successfully tested a series of known leading drug
molecules for the development of new potential antischistosomal
agent.12–14
The synthesis of praziquantel (PZQ) has attracted the attention of
several groups as an efficient synthesis with reduction of steps or
increasing the over all yield would substantially reduce the cost
for mass distributionof the drug. Literature publishedon the synthe-
sis of PZQ and its derivatives reveals that its synthesis15–23 has been
studied extensively. A solid phase synthesis of PZQ was also
achieved by El-Fayyoumy et al.24 Despite the possibility of effecting
structural variations at five different positions of basic PZQ mole-
cule, not many new analogues have been synthesised since the last
review published in 1983.25 The effect of variation of substitution on
aromatic ring and on the amide group has been reported and Ronk-
etti et al. particularly substituted these two positions with amino
groups and their biological evaluation revealed that aminations of
the aromatic ring was tolerated.26 Subsequently Vennerstrom
et al. tested the antischistosomal activity of amide and urea deriva-
tives of PZQ.27 PZQ still remains the most potent drug among all the
reported analogues leaving space for further multiple structural
variations as a search for a PZQ derivative as non resistant potential
drug for the treatment of schistosomiasis. We therefore became
interested, as a part of our continued program on the development
⇑
Corresponding authors.
E-mail address: jrao@iict.res.in (V. Jayathirtha Rao).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.11.108

1104
P. S. Sadhu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1103–1106
sibility of variations on the amide group, piperazine ring as well as
on the aromatic moiety in all combinations. New analogues have
been synthesised by effecting structural variations at all three posi-
tions and the products obtained are fully characterised by IR, 1H
NMR, 13C NMR, HRMSand elemental analysis. It is interestingto note
that variation on the piperazine has been achieved by introducing
another keto functionality in the ring, the aromatic moiety has been
replaced by Indole and to our knowledge this is the first time this
kind of variations have been made in PZQ skeleton to study the bio-
logical activity against schistosomiasis. Analogues in which the
cyclohexyl ring of the PZQ replaced with p-toluenesulphonyl group
have also been synthesised (Fig. 1).
N
N
O
N
N
O
O
O
R
1 PZQ
2
Figure 1. Dotted lines indicate the centres where the possible structural modifi-
cations were carried out to synthesize the new PZQ analogues.
The scheme for the synthesis of PZQ and various analogues is
shown in Scheme 1. Initially the starting materials 3,4-dihydroiso-
quinoline 3, 6,7-dimethoxy-3,4-dihydroisoquinoline 4 and 3,4-
dihydro-b-carboline 38 as aromatic ring variants were prepared
of new bio-active heterocyclic molecules28, in the synthesis of new
PZQ analogues that could represent potential antischistosomal
agents. Our synthetic strategy reported in this paper allows the pos-
R1
R1
R1
(iii)
R1
R1
R1
R1
(ii)
(i)
(iv)
N
NBoc
NBoc
CN
NBoc
NH2
R1
3-4
NH
R
5-6
7-8
9-17
R1
R1
R1
R1
1
27
28
R
R
R
1 = H, R = -C6H11CO, X = H2
1 = H, R = -C5H9CO, X = H2
1 = H, R = -p-Me-C6H4SO2, X = H2
(v) or (vi)
N
NH
O
29 R = OMe, R = -C6H11CO, X = H2
N
R
X
NH
R
30 R1 = OMe, R = -C5H9CO, X = H2
18-26
31
32
33
R
R
R
1 = OMe, R = -p-Me-C6H4SO2, X = H2
1 = OMe, R = -p-CF3-C6H4CO, X = H2
1 = H, R = -C6H11CO, X = O
1, 27-37
34 R1 = H, R = -C5H9CO, X = O
35 R1 = H, R = -p-Me-C6H4SO2, X = O
R
R
1 = H, R = -p-CF3-C6H4CO, X = O
36
37
1 = H, R = -C6H11CH2CO, X = O
N
NBoc
CN
NBoc
NH2
NBoc
NH
(i)
(iii)
(ii)
N
N
H
N
H
N
H
R
H
39
40
38
41-44
O
O
NH
N
N
(iv)
(v)
(vii)
41, 43
N
N
NH
N
H
N
H
N
R
R
R2
R
45-46
47-48
49-50
R = -C6H11CO, R2 = Bn
49
47
R = -C6H11CO
48 R = -p-CF3-C6H4CO
R = -p-CF3-C6H4CO, R2 = Bn
50
O
NBoc
NH
NH
N
(vii)
(iv)
(vi)
O
41-44
N
N
NH
R
N
N
R2
R
R2
R2
R
51-54
55-58
59-62
59 R = -C6H11CO, R2 = Bn
R = -C5H9CO, R2 = Bn
60
61
R = -p-CF3-C6H4CO, R2 = Bn
62 R = -C6H11CH2CO, R2 = Bn
Scheme 1. Reagents and conditions: (i) (Boc)2O, DCM, 0 °C, 30 min. then TMSCN, rt, 24 h, 78–83%; (ii) Raney Ni, H2, MeOH, 12 h, 72–78%; (iii) C6H11COCl or C5H9COCl or p-
CF3C6H4COCl or C6H11CH2COCl or p-TsCl, Pyridine, 0 °C to rt, 1 h, 87–92%; (iv) TFA, DCM (1:4), rt, 1 h, 88–93%; (v) aq NaOH, ClCH2COCl, DCM, TEBAC, 2 h, 79–83%; (vi) Oxaloyl
chloride, Et3N, DCM, rt, 15 min, 62–69%; (vii) BnBr, KOH, acetone, 0 °C to rt, 1 h, 72–77%.

P. S. Sadhu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1103–1106
1105
Table 1
Effect of praziquantel analogs on adult S. mansoni
Serial no.
Compound no.
90% Lethal conc.
Serial no.
Compound no.
90% Lethal conc.
1
2
3
4
5
6
7
8
9
10
1 (PZQ)
27
28
29
30
31
32
33
34
3
10
>10
50
25
>100
>100
>100
>100
>100
11
12
13
14
15
16
17
18
19
20
36
37
47
48
49
50
59
60
61
62
>100
>100
25
50
25
>100
>100
>100
>100
>100
35
according to reported procedures.29–31 The Reissert compounds 5,
6 and 39 were prepared by reaction of the compounds 3, 4 and
38, with BOC anhydride, followed by the nucleophilic addition of
trimethylsilylcyanide (TMSCN) to the N-acylium intermediate in
one pot reaction. (Scheme 1). Further these substituted tetrahydro
derivatives 5, 6 and 39 were hydrogenated to the corresponding
primary amines 7, 8 and 40 using activated Raney nickel in meth-
anol in high yields (72–78%). The amines were then transformed
into corresponding amides/sulphonamides, 9–17 and 41–44, using
various acid chlorides/p-toluenesulphonyl chloride in excellent
yields (85–92%). Deprotection of N-Boc (DCM/TFA, 4:1) of the
amides/sulphonamides 9–17 and 41, 43 gave the BOC free amines
18–26 and 45–46. The amines, precursor to piperazine ring, were
subjected to ring closure by treating with chloroacetyl chloride un-
der Schotten Bauman conditions (DCM, 50% aq NaOH, TEBAc chlo-
ride)32 to give PZQ and its analogues 27–32, 47 and 48. The
tetrahydro-b-carboline intermediates 47 and 48 were further
derivatized to the corresponding N-benzylated derivatives 49 and
50 by treatment with benzyl bromide and KOH in acetone.
Another new set of PZQ analogues 33–37 were obtained by
affecting ring closure of the amines using oxaloyl chloride.36
Oxaloyl chloride induced cyclisation could not be effected in case
of tetrahydro-b-carboline PZQ analogues, probably due to the pres-
ence of a free N-H of the indole ring. However the compounds
41–44 were first converted into their corresponding N-benzyl
derivatives 51–54 and were then treated with DCM/TFA to depro-
tect the NBoc group to get the desired tetrahydro-b-carboline
amides 55–58. Finally the ring closure was successfully effected
with oxalolyl chloride to get the target compounds 59–62. A total
of 19 PZQ analogues with broad structural variations were
prepared. PZQ analogues 28–36, 47–50 and 59–62 are new com-
pounds. Antischistosomal activity of 27 was reported by Andrews
et. al.25 Synthesis of PZQ analogue 47 was previously reported by
Haixia et. al.33 without mentioning of any antischistosomal
activity.
sulphonamide group respectively did not show satisfactory
activity. Among tetrahydro-b-carboline modified PZQ analogues
(47–50), compound 47 and 49 showed moderate activity against
the schistosome where R is cyclohexanecarbonyl group. The com-
pounds 48 and 50 where R is p-trifluoromethylbenzoyl group
found to be inactive. So it can be concluded that the presence of
p-trifluoromethylbenzoyl group and p-toluenesulphonamide
group results in complete suppression of activity. PZQ analogues,
33–37, 59–62, obtained by modification of the piperazine ring
(piperazine 2-one to piperazine 2, 3-dione system) showed no
activity. These novel piperazine ring modified PZQ analogues, com-
bined with variation at R group (33–37) or modification of the aro-
matic ring (59–62) did not provide any encouraging activity.
In summary, we have synthesized praziquantel (PZQ) and a ser-
ies of PZQ analogues employing a new and efficient synthetic
route. Among all the derivatives synthesized, three of the ana-
logues showed moderate activity. The p-tosyl and trifluoromethyl-
benzoyl groups were found to be not a suitable replacement for
cyclohexyl group in the PZQ molecule for their activity against
schistisomiasis. The piperazine ring modification too did not exhi-
bit satisfactory activity. The tetrahydro-b-carboline modified ana-
logues with selective substituents showed good activity. The
study on all these structurally diverse compounds will definitely
provide meaningful information for the design of further new
PZQ analogues. Obviously, after the initial in vitro screening,
in vivo activity and toxicity will have to be tested. Design and syn-
thesis of more potent antischistosomal agents are currently under-
way in our laboratory.
Acknowledgments
The authors thank the Director, IICT and Head, Organic Divi-
sion-II for support. PSS and SNK thank CSIR-New Delhi, for the fel-
lowships. This is main lab project (MLP) of IICT.
The PZQ analogues were tested in vitro (Table 1) on cultures34,35
of adult S. mansoni. Briefly, 10–12 male adult parasites were left in
contact overnight with the compound at 37 °C in Dulbecco-modi-
fied Eagle’s medium containing 20% newborn calf serum, antibiot-
ics and antimycotic. Parasites were then washed, resuspended in
drug-free medium and observed for the subsequent 7 days. End
point was survival at day 7 after wash, when live and dead para-
sites were recorded.
Among the analogues synthesized by varying only R group (27
and 28) compound 27 showed a good degree of activity, as also re-
ported by Andrews et. al.25 whereas 28 showed no activity. Among
compounds 29–32, prepared by variation in R group and with 3,4-
dimethoxy substitution on the aromatic ring, 30 displayed moder-
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.11.108.
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