MCR Synthesis of Praziquantel Derivatives

Article abstract of DOI:10.1111/j.1747-0285.2011.01288.x

Schistosomiasis, a high volume neglected tropical disease affecting more than 200 million people worldwide, can only be effectively treated by the tetrahydroisoquinoline drug praziquantel (PZQ). Herein, we describe an efficient approach to access PZQ derivatives by the Ugi 4-component reaction followed by the Pictet-Spengler reaction in a two-step, one-pot procedure. 30 novel PZQ derivatives are described based on the Ugi 4-component reaction and an X-ray structure of a novel derivative revealing different conformation compared with PZQ is discussed. Several analogues comparable in activity to the drug PZQ have been identified based on an in vitro Schistosoma mansoni worm viability assay.

Full text of DOI:10.1111/j.1747-0285.2011.01288.x

ª 2011 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2011.01288.x
Chem Biol Drug Des 2012; 79: 470–477
Research Article
MCR Synthesis of Praziquantel Derivatives
Haixia Liu1, Samia William2, Eberhardt
and angiogenesis. Sandy patches occurring in the vagina owing to
Herdtweck3, Sanaa Botros2 and Alexander
FGS lead to bleeding and corrode the first HIV entrance barrier, the
intact vaginal lumen (4–6). Thus, it was recently proposed that an
effective and low-cost method to reduce HIV ⁄AIDS transmission could
be the preventative treatment of the endangered population with the
antischistosomal drug praziquantel (7). Praziquantel (PZQ, 1), a tetra-
hydroisoquinoline derivative, is the only commercially available treat-
ment against schistosomiasis. Currently, mass treatment of millions of
people in sub-Sahara Africa are carried out through the Schistosomia-
sis Control Initiative (SCI) with the long-term goal of eradicating this
debilitating disease (8). However, the dependency on one major drug
to treat schistosomiasis as well as the current large-scale drug admin-
istration could potentially lead into the development of drug
2resistance. Praziquantel itself is a rather simple molecule, and sev-
eral different synthetic routes (9–15) have already been reported,
from those detailed in the original patent (9) to a recent synthesis
based on a radical cyclization (15). The original medicinal chemistry
programme that identified PZQ at Merck ⁄ Bayer generated ꢀ400 PZQ
analogues. The great majority of these are variants in a single part of
the molecule (the exocyclic amide), and the compounds screened are
limited in diversity. Having recognized the key structural motive of the
Ugi multicomponent reaction in PZQ, we recently devised a short and
scalable new synthesis (16). Herein, we report our multicomponent
reaction approach to the synthesis of highly diverse PZQ derivatives
which are otherwise difficult to access.
1,4,
¨
Domling
*
1Departments of Pharmaceutical Sciences and Chemistry, University
of Pittsburgh, 3501 Fifth Avenue, BST3 11019, Pittsburgh, PA 1526,
USA
2Theodore Bilharz Institute, El-Nile St., Warrak El-Hader, Imbaba,
Giza, Egypt
3Department Chemie, Lehrstuhl fꢀr Anorganische Chemie,
Technische Universitꢁt Mꢀnchen, Lichtenbergstrasse 4, D-85747
Garching bei Mꢀnchen, Germany
4Drug Design, University of Groningen, A. Deusinglaan 1, 9713 AV
Groningen, Netherlands
*Corresponding author: Alexander Doemling, asd30@pitt.edu
Schistosomiasis, a high volume neglected tropical
disease affecting more than 200 million people
worldwide, can only be effectively treated by the
tetrahydroisoquinoline drug praziquantel (PZQ).
Herein, we describe an efficient approach to
access PZQ derivatives by the Ugi 4-component
reaction followed by the Pictet–Spengler reaction
in a two-step, one-pot procedure. 30 novel PZQ
derivatives are described based on the Ugi 4-com-
ponent reaction and an X-ray structure of a novel
derivative revealing different conformation com-
pared with PZQ is discussed. Several analogues
comparable in activity to the drug PZQ have been
identified based on an in vitro Schistosoma man-
soni worm viability assay.
Results and Discussion
The Ugi multicomponent reaction has proven to be a very powerful
and reliable reaction that involves a one-pot condensation of
Key words: isocyanide, multicomponent reaction, neglected tropical
disease, Pictet-Spengler, schistosomiasis, Ugi
R1
R1
HN
O
3
Received 4 October 2011, revised 21 October 2011 and accepted for
publication 20 November 2011
R2
H
Het(Ar)
H2N
Het(Ar)
O
NC
O
Ugi-4CR
2
+
O
N
R2
R3 CO2H
5
Schistosomiasis is a neglected tropical disease affecting more than
200 million people with more than 80% of cases occurring in sub-
Sahara Africa (1). Schistosomes have a complex life cycle involving
the alternate passage of the infection between the definitive host
(human) and an invertebrate intermediate host serving as a vector
(various species of freshwater snails depending on the schistosome
species) (2). The annual mortality rate as a result of schistosomiasis
in sub-Saharan Africa is as high as 280 000 (3). There has been
recent evidence to suggest a high correlation in women with schisto-
somiasis and increased susceptibility to HIV ⁄Aids. Women infected
with schistosomiasis have as high as a 75% likelihood of suffering
from female genital schistosomiasis (FGS) caused by egg deposits in
the uterus, cervix, vagina or vulva which lead to granulomas, fibrosis
O
O
O
R3
4
6
R1
N
O
Het(Ar)
Pictet-Spengler
cyclization
N
N
O
N
R2
O
O
7
R3
Praziquantel (1)
Scheme 1: Drug praziquantel (PZQ, 1) and general approach
for the multicomponent synthesis of its derivatives 7.
470

MCR Synthesis
Table 1: Variations of isocyanides and praziquantel derivatives 8(a–e)
R1
NC
O
R1
O
Ar(Het)
N
i) MeOH, 0 oC - rt
H
H
2(a-h)
N
+
Ar(Het)
O
ii) MsOH, MgSO4,
DCE, 80 oC,
O
H2N
CO2H
O
8(a-e)
4
Entry
1
R1NC 2(a–h)
Product
8 (a–e)
Yield (%)
46a
O
N
8a
NC
MeO
N
2
8b
48a
MeO
O
MeO
MeO
NC
O
N
MeO
MeO
N
O
8c
34a
O
3
NC
N
S
S
N
O
8db
16a
45a
H
H
CO2Me
NC
CO2Me
O
4
5
6
N
8ec
N
O
H
H
CO2Me
O
NC
CO2Me
N
N
H
N
O
N
Boc
–
–
–
–
76d
73d
NC
CO2Me
F
NC
7
8
–
–
58d
NC
aOverall isolated yield for two steps.
bOnly trans-8d was identified.
cTwo diastereomers were isolated in a ratio of 2.4:1 (trans ⁄ cis).
dIsolated yield for the Ugi reaction.
Chem Biol Drug Des 2012; 79: 470–477
471

Liu et al.
Table 2: Variations of aldehydes and praziquantel derivatives 9(a–g)
O
O
NC
R2
O
R2
3(a-g)
H
N
i) MeOH, 0 oC - rt
N
+
O
ii) MsOH, MgSO4,
DCE, 80 oC,
H2N
CO2H
O
9(a-g)
Entry
1
R2CHO 3(a–g)
Producta
9 (a–g)
Yield (%)b
21
O
O
O
H
N
Me
O
9a
N
H
Me
CHO
CHO
H
9b
9c
9d
9e
9f
29
33
34
23
16
N
H
2
3
N
O
H
N
CHO
N
H
O
O
O
H
4
5
N
H
CHO
CHO
N
O
H
N
N
H
O
F
O
H
6
7
F
CHO
N
H
N
O
17
O
O
OH
O
H
HO
OH
9g
N
H
O
N
aRelative stereochemistry as drawn.
bOverall isolated yield for two steps.
isocyanide 2, carbonyl component 3, amine 4 and carboxylic acid 5
under mild conditions to produce a substituted acylaminocarbona-
mide product 6 (17–19). The PZQ skeleton 7 was then formed by a
Pictet–Spengler cyclization under acidic conditions (Scheme 1). As a
high degree of structural diversity can also be introduced by this
four-component reaction, we extended our research to investigate
the scope of this one-pot, two-step sequence. A great deal is
already known about the reliability of the Ugi reaction (20,21);
472
Chem Biol Drug Des 2012; 79: 470–477

MCR Synthesis
Table 3: Variations of carboxylic acids and praziquantel derivatives 10(a–h)
O
NC
O
i) MeOH, 0 oC - rt
H
H
N
N
R3
+
O
R3 CO2H
ii) MsOH, MgSO4,
DCE, 80 oC,
O
H2N
O
5(a-h)
10(a-h)
Entry
1
R3CO2H 5(a–h)
Product
10 (a–h)
Yield (%)a
58
O
10a
N
N
CO2H
O
O
2
10b
10c
42
44
N
N
CO2H
O
O
N
N
3
4
CO2H
CO2H
O
O2N
O
10d
10e
10f
25
29
10
19
25
F
N
F
N
NO2
O
N
CO2H
5
6
O
O
OMe
N
N
N
OMe
O
O
N
CO2H
N
N
N
O
O
O
10g
10h
N
N
S
CO2H
N
7
8
S
N
O
O
O
N
O
CO2H
N
O
aOverall isolated yield for two steps.
however, the Pictet–Spengler cyclization has its limitations as highly
electron-rich (hetero-)aromatic ethylamines and high reaction tem-
peratures are required (22,23).
As a large number of aldehydes (R2CHO) and carboxylic acids
(R3CO2H) are commercially available, we started our investigations
with the synthesis of several suitable (hetero)phenylethylamine-
Chem Biol Drug Des 2012; 79: 470–477
473

Liu et al.
Table 4: Late-stage modification of praziquantel derivative 8d and 10d
R5
O
R7
O
H
H
N
H
N
H
R4
N
R6
Condition A or B
N
O
O
8d, 10d
11(a-g)
a
Entry
1b
R4
R5
R6
R7
%
OMe
71
O
CO2Me
N
H
O
2b
CO2Me
46
98
N
O
NO2
H
H
NO2
F
3c
4c
N
H
NO2
F
NO2
H
H
H
H
97
81
N
H
OMe
5c
NO2
F
NO2
N
O
6c
7c
H
H
H
H
91
93
NO2
NO2
F
O
N
S
N
H
NMe2
NO2
F
NO2
O
O
N
H
N
H
2
aIsolated yield: TBD = 1,5,7-triazabicyclo[4.4.0]dec-5-ene.
bCondition A: Amine, 20% TBD, 60 ꢀC.
cCondition B: Amine, K2CO3, DMF, dimethylformamide; rt.
derived isocyanides (R1NC). Eight isocyanides 2(a–h) were prepared
either by a classical one-step 'Hoffmann procedure' or by an 'Ugi 2-
step method' (24–27). By mixing isocyanide, aminoacetaldehyde-dime-
thylacetale 4, formaldehyde and cyclohexanecarboxylic acid (in a ratio
of 1:1:1.2:1) in anhydrous methanol under ambient temperature, the
Ugi condensation product formed in very good to quantitative yield,
which was dried in vacuum and used directly in the next step of trans-
formation. Depending on the nature of the (hetero-)arylethylamine,
the yield of the Pictet–Spengler cyclization varied greatly.
carry out the Pictet–Spengler cyclization (28). Ugi products based
on electron-rich or electron-neutral (hetero)phenylethylamine-derived
isocyanides always reacted better and gave final PZQ derivatives in
good to excellent yields (Table 1, entries 1–3). The phenylalanine-
derived methyl ester isocyanide reacted rather sluggish in the Pic-
tet–Spengler step, and only small amount of cyclized product was
identified (Table 1, entry 4). In the case of tryptophan-derived isoc-
yanide, two diastereomers were isolated in a 2.4:1 ratio (trans ⁄ cis)
in good overall yield (Table 1, entry 5) (29). The relative stereochem-
istry was assigned on the basis of 2D NOESY experiments (see the
Appendix S1). The 4-fluoro phenylethylamine-derived isocyanide
was unreactive in the Pictet–Spengler step (Table 1, entry 6), owing
We utilized a modified cyclization condition (CH3SO3H, MgSO4, 1,2-
dichloroethane, 80 ꢀC) as published in an earlier PZQ synthesis to
474
Chem Biol Drug Des 2012; 79: 470–477

MCR Synthesis
Table 5: 50% effective concentration of Schistosoma mansoni
worm killing for different praziquantel (PZQ) derivatives.
inhibitors (31). The substrate scope in the carboxylic acid part is
amazingly broad with the possibility of generating more complicated
PZQ derivatives with unprecedented structural complexity.
Compound
EC50 [lM]a
Compound
EC50 [lM]a
Currently, the molecular target(s), the detailed mode-of-action, and
the mechanism of possible resistance to PZQ remain unknown despite
many reported mechanistic studies (32,33). The synthesis of radio- or
fluorescent-labelled PZQ derivatives, coupled with modern proteo-
mics, might be helpful to perform affinity and target fishing studies.
With this general access to multiple functionalized PZQ derivatives,
there are many different choices for site-specific labelling (Table 4).
For example, as for derivative 10d, the dansyl fluorescent label was
introduced via an aromatic nucleophilic amine substitution (11g).
Derivatives 11(a–g), on the other hand, showed increased water sol-
ubility and might show different pharmacodynamic properties as
opposed to the highly hydrophobic PZQ derivatives.
S. mansoni PZQ
PZQ (synthetic)
0.18
10b
10c
10d
10e
10f
3.9ab
46.8ab
9.9ab
>100ab
>100ab
NE
0.37c
9.7ab
NE
8a
8b
8c
8d
8e
9a
9b
9c
9d
9e
9f
0.9ab
>100ab
>100ab
1.3ab
>100ab
NE
10g
10h
11a
11b
11c
11d
11e
11f
NE
NE
>100ab
NE
43.7ab
>100ab
>100ab
NE
NE
NE
NE
NE
10a
11g
With these representative PZQ derivatives in hand, the antischist-
osomal activities were assessed by performing schistosome worm
viability assays as a primary screen. Schistosoma mansoni cerca-
riae shed from Biomphalariae alexandrina snails were used to
infect hamsters to obtain adult schistosomes as previously
described (34–37). The PZQ derivatives and the analytical standard
PZQ were prepared in stock solutions of 5 mM and were then
serially diluted using complete media and were added to Petri
dishes containing the freshly harvested schistosomes. On the day
5, the number of living ⁄ dead worms was recorded and compared
with parallel values in negative control Petri dishes containing
pure medium alone or medium with DMSO and positive control
media containing comparable concentrations from the mother PZQ.
The percentages of Schistosoma mansoni worm death in vitro
under the influences of different PZQ derivatives in different con-
centrations versus untreated and DMSO negative controls and
positive controls treated with the mother drug PZQ were deter-
mined. Different EC50's (the concentration at which 50% of worms
was recorded to be dead) and the significance between different
EC50 values were calculated using computerized program
'Pharm ⁄ PCS' version 4.2 (Pharmacologic calculation system) by a
plot of the per cent of worm mortality (versus living worms)
against the concentration of the drug.
NE, no effect.
aSignificant difference from the mother brand of PZQ at p < 0.05.
bSignificant difference from the synthetic PZQ at p < 0.05.
ccomparable sensitivity to mother PZQ with no statistically significant differ-
ence.
to the electron-deficient nature of the aromatic ring. Attempts to
prepare a five or seven-membered ring homologue of PZQ failed
(Table 1, entry 7–8). This is consistent with the literature that no
cyclization of N-acyiminium ion yielding 5-membered product or 7-
membered product has been reported (30).
Next, we investigated different aldehydes to produce structurally
diversified PZQ derivatives. All aldehydes including acyclic, cyclic
aldehyde as well as aryl aldehydes reacted very well in the Ugi-
4CR reaction, and the subsequent Pictet-Spengler in most cases led
to the final PZQ derivatives 9(a–g) in acceptable overall yields
(Table 2, entries 1–7).
It should be noted that the Pictet–Spengler cyclization occurs with
remarkably high diastereoselectivity and only one diastereomer was
formed according to NMR experiments. The relative stereochemistry
was assigned on the basis of 2D NOESY experiments (see the
Appendix S1). In addition, the structure and relative stereochemistry
of compound 9e were unequivocally determined by X-ray diffraction
analysis (see the Appendix S1). In almost all of the cases, only
trans-fused product was formed (Table 2, entries 1–6), while the
relative configuration of the final product 9g from glycolaldehyde
dimer is opposite to the others (Table 2, entry 7). This could be
interpreted by an intramolecular H-bond binding between the hydro-
xyl group and the carbonyl group through a six-membered ring in
the Pictet–Spengler cyclization precursor, which favours the forma-
tion of the cis-fused cycloproduct 9g (see the Appendix S1).
Selected EC50 values were shown in Table 5. Untreated and DMSO-
treated controls had no observed mortality. The mother drug PZQ
was the most effective compound studied, with 100% of the worms
dying with concentrations from 0.8, 1.5, 3.0, 6.0, 12.5, 25, 50, 75
and 100 lM. The 50% effective concentrations (EC50) of promising
PZQ derivatives ranged from 0.37 to 9.9 lM. Not surprisingly, the
herein synthesized PZQ revealed an EC50 value of 0.37 lM which is
not significantly different from that of the analytical standard PZQ
(0.18 lM). The EC50 for compounds 8c, 9a, 10b, 8a and 10d
were 0.9, 1.3, 3.9, 9.7 and 9.9 lM, respectively. PZQ derivatives
8d, 8e, 9d, 9e, 9f, 10c, 10f, 11b and 10e showed weak
schistosoma mansoni worm death (EC50 from 30 to 100 lM) respec-
tively. Compounds 8b, 9c, 10g, 10h and 11a–g did not reveal
any antischistosomal activity.
Finally, the scope and limitations of the carboxylic acid component
(R3CO2H) were also investigated. Aromatic and aliphatic acids as
well as functionalized acids reacted nicely in the Ugi-4CR (Table 3,
entries 1–7). We also prepared conjugates of known antibiotic of
the quinolinone type, such as 4-methoxyquinoline antibiotics
(Table 3, entry 4) and nalidixic acid (Table 3, entry 5), a gyrase
We aligned the solid-state structure of compound 9e with PZQ
based on the common phenyl group (Figure 1). Interestingly, it can
Chem Biol Drug Des 2012; 79: 470–477
475

Liu et al.
O
O
N
N
N
N
H
O
O
Praziquantel (1)
9e
Figure 1: X-ray structure of praziquantel 1 (green sticks, CCDC 286150) aligned with derivative 9e (cyan sticks, CCDC 768130) based on
the phenyl rings.
be seen that the bulky neopentyl group in 9e induces a dramatic
conformational change in the diketopiperazine (DKP) moiety and
especially the cyclohexylcarbonyl moiety. The DKP in PZQ is almost
planar whereas the DKP ring in 9e adopts a boat-like conformation.
Additionally, the cyclohexylcarbonyl moiety in PZQ exits the DKP
ring in-plane and is almost coplanar with the DKP, and the cyclo-
hexylcarbonyl moiety in 9e, however, is turned by 180ꢀ and resides
on the top of the phenyl ring. The dramatically decreased activities
of 9(a–f), where various R2 groups (mainly hydrophobic alkyl sub-
stituents) were introduced, together with the conformation change,
may indicate that this part of the structure may not be a good
choice for variation in the development of new PZQ alternatives.
Modification of derivatives 8d and 10d also resulted in a total
loss of activities. Variation of aromatic ring (R1) and cyclohexyl ring
part (R3) led to slightly decreased activity. Analogue 8c that bears
a smaller heteroaromatic ring displayed less activity was still com-
parable with mother PZQ. The results from 10b and 10d are also
interesting, where the nature of the substituent's on the aromatic
ring plays an important role in their activity.
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Supporting Information
Additional Supporting Information may be found in the online ver-
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Appendix S1. MCR Synthesis and Biological Evaluation of Novel
Praziquantel Derivatives.
Please note: Wiley-Blackwell is not responsible for the contents or
functionality of any supporting materials supplied by the authors.
Any queries (other than missing material) should be directed to the
corresponding author of the article.
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