Synthesis and antischistosomal activity of linker‐ and thiophene‐modified biaryl alkyl carboxylic acid derivatives

Abstract

Schistosomiasis is a neglected tropical disease caused by blood flukes of the genus Schistosoma and causes severe morbidity in infected patients. In 2018, 290.8 million people required treatment, and 200,000 deaths are reported per year. Treatment of this disease depends on a single drug, praziquantel (PZQ). However, in the past few years, reduced sensitivity of the parasites toward PZQ has been reported. Therefore, there is an urgent need for new drugs against this disease. In the past few years, we have focused on a new substance class called biaryl alkyl carboxylic acid derivatives, which showed promising antischistosomal activity in vitro. Structure–activity relationship (SAR) studies of the carboxylic acid moiety led to three promising carboxylic amides (morpholine, thiomorpholine, and methyl sulfonyl piperazine) with an antischistosomal activity down to 10 µM (morpholine derivative) and no cytotoxicity up to 100 µM. Here, we show our continued work on this substance class. We investigated, in extended SAR studies, whether modification of the linker and the thiophene ring could improve the antischistosomal activity. We found that the exchange of the alkyl linker by a pentadienyl or benzyl linker was tolerated and led to similar antischistosomal effects, whereas the exchange of the thiophene ring was not tolerated. Our data suggest that the thiophene ring is important for the antischistosomal activity of this compound class. Biaryl alkyl carboxylic acid derivatives show antischistosomal activity in vitro. Extended structure–activity relationship studies were used to investigate the effects of modifications of the linker and the thiophene ring on the activity. It was found that replacement of the alkyl linker by more rigid structures is tolerated whereas replacement of the thiophene in the biaryl moiety leads to complete loss of the antischistosomal activity.

Full text

Received: 13 July 2021
|
Revised: 26 August 2021
|
Accepted: 27 August 2021
DOI: 10.1002/ardp.202100259
FULL PAPER
Synthesis and antischistosomal activity of linker‐and
thiophene‐modified biaryl alkyl carboxylic acid derivatives
Alejandra M. Peter Ventura
1
|Simone Haeberlein
2
|Leonie Konopka
1
|
Wiebke Obermann
1
|Arnold Grünweller
1
|Christoph G. Grevelding
2
|
Martin Schlitzer
1
1
Institute of Pharmaceutical Chemistry,
Philipps University Marburg, Marburg,
Germany
2
BFS, Institute of Parasitology, Justus Liebig
University Giessen, Giessen, Germany
Correspondence
Christoph G. Grevelding, BFS, Institute of
Parasitology, Justus Liebig University Giessen,
Schubertstraße 81, 35392 Giessen, Germany.
Email: Christoph.Grevelding@vetmed.uni-
giessen.de
Martin Schlitzer, Department of
Pharmaceutical Chemistry, Philipps
Universität Marburg, Marbacher Weg 6,
35032 Marburg, Germany.
Email: schlitzer@staff.uni-marburg.de
Funding information
Deutsche Forschungsgemeinschaft,
Grant/Award Number: SCHL 383/6‐1 and
GR1549/10‐1; LOEWE Zentrum DRUID
Abstract
Schistosomiasis is a neglected tropical disease caused by blood flukes of the genus
Schistosoma and causes severe morbidity in infected patients. In 2018, 290.8 million
people required treatment, and 200,000 deaths are reported per year. Treatment of
this disease depends on a single drug, praziquantel (PZQ). However, in the past few
years, reduced sensitivity of the parasites toward PZQ has been reported. Therefore,
there is an urgent need for new drugs against this disease. In the past few years, we
have focused on a new substance class called biaryl alkyl carboxylic acid derivatives,
which showed promising antischistosomal activity in vitro. Structure–activity re-
lationship (SAR) studies of the carboxylic acid moiety led to three promising car-
boxylic amides (morpholine, thiomorpholine, and methyl sulfonyl piperazine) with an
antischistosomal activity down to 10 µM (morpholine derivative) and no cytotoxicity
up to 100 µM. Here, we show our continued work on this substance class. We
investigated, in extended SAR studies, whether modification of the linker and the
thiophene ring could improve the antischistosomal activity. We found that the ex-
change of the alkyl linker by a pentadienyl or benzyl linker was tolerated and led to
similar antischistosomal effects, whereas the exchange of the thiophene ring was not
tolerated. Our data suggest that the thiophene ring is important for the anti-
schistosomal activity of this compound class.
KEYWORDS
biaryl alkyl carboxylic acid derivatives, inhibitors, schistosomiasis, structure–activity
relationship
1|INTRODUCTION
The parasitic disease schistosomiasis is caused by schistosome
parasites and triggers health problems of the host, such as liver
inflammation, periportal fibrosis, anemia, and/or hematuria.
[1]
In
2018, 290.8 million people required preventive treatment, and ap-
proximately 200,000 deaths can be linked to this infectious disease
each year.
[2–4]
These numbers illustrate the importance of research
concerning this disease. For decades, praziquantel (PZQ) is the only
drug used to treat schistosomiasis due to its high efficacy toward all
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schistosome species and its low cost.
[3,5]
The fear of upcoming re-
sistance against PZQ is increasing since cases of lower sensitivity
have been reported.
[6,7]
To overcome this problem, new drugs
against schistosomiasis are needed.
In the past few years, we have focused on a novel substance
class with antischistosomal activity called biaryl alkyl carboxylic acid
derivatives (BACADs).
[8–10]
Since the schistosomal aldose reductase
(SmAR) has been identified as an interesting target for potential
antischistosomal drugs,
[11,12]
inhibitors of the human aldose re-
ductase (hAR), available from previous studies, were tested in vitro
against adult worms of Schistosoma mansoni,
[8]
one of the medically
most important schistosome species. With this in vitro assay against
cultured worms, BACADs were found to possess antischistosomal
properties. Due to the unavailability of SmAR, no assays against this
enzyme have been performed in this or previous studies. Our
starting points were substances of the general structure 1(Figure 1).
Through first structure–activity relationships (SAR) we found that
antischistosomal activity can be increased by varying the R sub-
stituent of the terminal phenyl moiety. Specially electron‐donating
substituents like a hydroxyl group exhibited good antischistosomal
activity.
[8]
Modification of the carboxylic acid moiety revealed that
three carboxylic amides (morpholine‐3,thiomorpholine‐4, and methyl
sulfonyl piperazine derivative 5, as shown in Figure 1)weremore
active than the parent carboxylic acid 2. Based on this result, 82 car-
boxylic amides were synthesized and tested for their antischistosomal
activity. In course of these studies, we were able to identify the top six
carboxylic amides, which possessed an antischistosomal activity down
to 10 µM. These six compounds were subsequently tested for their
cytotoxicity showing that 3–5were found to be non‐cytotoxic at a
concentration up to 100 µM in HepG2 and LST174T cells.
[10]
These
results provide the basis for this study. By having identified the best
derivatives on the carboxylic acid moiety, we were now able to in-
vestigate other moieties of the BACAD compound 2. Here, we in-
vestigated whether the antischistosomal activity of the compounds
can be increased when the linker is rigidized by insertion of double
bonds or by a benzyl ring, or whether the thiophene ring can be ex-
changed by a furan, thiazole, or oxazole ring. A possible modification of
the linker by insertion of a triple bond was not part of this study.
FIGURE 1 Starting point of the derivatization of the BACADs were substances of the general structure 1.Am‐hydroxyl group (2) on the
phenyl moiety led to increased antischistosomal activity. Carboxylic amides were then synthesized and evaluated for their antischistosomal
activity. The top three derivatives (3–5) showed an antischistosomal activity down to 10 µM and no cytotoxicity up to 100 µM. BACAD, biaryl
alkyl carboxylic acid derivative; SAR, structure–activity relationship
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2|RESULTS AND DISCUSSION
2.1 |Chemistry
The biarylpentadiene amides were synthesized in four steps as shown in
Scheme 1.First,aSuzukireactionwith5‐bromo‐2‐thiophenecar-
boxaldehyde 6and 3‐hydroxyphenylboronic acid was performed to ob-
tain precursor 7.AHorner–Wadsworth–Emmons reaction followed by
alkaline hydrolysis provided the biarylpentadiene carboxylic acid 9in a
total yield of 65% over three steps. The desired carboxylic acid amides
were obtained by coupling the carboxylic acid 9with the corresponding
amines. The amines used were based on the results of our previously
published study.
[10]
All eight active piperazine derivatives were coupled
with the biarylpentadiene acid 9. With this approach, nine derivatives
could be synthesized for in vitro testing.
The biarylbenzoic acid amides were synthesized in four to five steps
starting with isophthalic acid monomethyl ester 18 (Scheme 2). In
contrast to the biarylpentadiene derivatives, the first step was a
Friedel–Crafts reaction with methyl 3‐(chlorocarbonyl)benzoate, which
was generated in situ out of isophthalic acid monomethyl ester 18 and
oxalyl chloride to obtain 19. Next, a Suzuki reaction followed by alkaline
hydrolysis was performed, which afforded the biarylbenzoic acid 20 in a
total yield of 30% over three steps. In our previous study, we described
biaryl alkyl carboxylic acid amides with and without the carbonyl group
in the linker. The biological data suggested that this group is not needed
for antischistosomal activity.
[10]
To explore whether this observation can
also be made with a benzyl linker, the biarylbenzoic acid 20 was used in
two ways. On the one hand, we coupled this compound with the ap-
propriate amines to obtain the desired amides 21–26.Forthiscoupling,
only six of the eight active piperazine derivatives that we described in
our previous study
[10]
were used. On the other hand, the biarylbenzoic
acid 20 was used in a Wolff–Kishner reduction, which afforded the
corresponding biarylbenzoic acid 27 without the carbonyl group in the
linker. The latter compound was then coupled with the appropriate
amines to obtain amides 28–30.Becauseofunfavorablyhighcyto-
toxicity, only the best three amines, morpholine, thiomorpholine, and
methyl sulfonyl piperazine,
[10]
were used for the coupling. An overall of
11 derivatives of this series could be gained for further SAR studies.
To examine the importance of the thiophene ring for the anti-
schistosomal activity, the thiophene ring was replaced by a furan. Due to
better synthetic accessibility, farther‐reaching modifications were in-
troduced with the thiazole or oxazole derivatives also including mod-
ifications in the linker structure. The synthesis of the furan derivatives
was similar to the preparation of the original biaryl alkyl carboxylic acids
we published in our previous study.
[10]
The synthetic route is described in
Scheme 3.First,aFriedel–Crafts acylation was performed with
2‐bromofuran 31 obtaining the intermediate product 32.Asubsequent
Suzuki reaction led to the desired carboxylic acid 33. As mentioned for
the benzoic acid derivatives, we wanted to explore also for the furan
derivatives the importance of the carbonyl group for the antischistosomal
activity. Therefore, the target amides were synthesized with and without
the carbonyl group in the linker. For this, the carboxylic acid 33 was on
the one hand coupled with the appropriate amines, leading to the desired
amides 34–36. On the other hand, the carbonyl group of the carboxylic
acid 33 was removed by a Wolff–Kishner reduction. The subsequent
coupling with the appropriate amines led to the amide derivatives with-
out a carbonyl group in the linker 38–40. Three different amines were
chosen for the coupling: morpholine, thiomorpholine, and methyl sulfonyl
piperazine. In total, eight derivatives were synthesized in this series.
The synthesis of the thiazole and oxazole derivatives were identical
with two differences (Scheme 4). For the thiazole derivatives, an addi-
tional step at the beginning of the synthesis was required. The first step
consisted of the reaction of 2‐hydroxybenzoic acid 41 with ammonia,
leading to the carboxylic amide 42. For the oxazole derivatives, this
carboxylic amide could be used in the next reaction: the formation of
the oxazole ring. But for the thiazole derivatives, the carboxylic amide
42 had to be converted to a thioamide. This was achieved with Law-
esson's reagent. As mentioned above, the next reaction consisted of the
formation of the oxazole and thiazole ring. In the case of the thiazole,
the thioamide 43 could be heated with ethyl bromopyruvate without
the addition of a base. Since the carboxylic amide is less reactive toward
the ethyl bromopyruvate due to the lower nucleophilic properties in
SCHEME 1 Synthesis of the biarylpentadiene carboxylic amides. Reagents and conditions: (a) 3‐hydroxyphenylboronic acid, K
3
PO
4
,Pd
(OAc)
2
, EtOH, room temperature (rt), 19 h, quant.; (b) (I) ethyl‐4‐bromo‐but‐2‐enoate, P(OEt)
3
, 120°C, 2 h, (II) NaH, 0°C to rt, 2.5 h, 80%; (c) 2 M
NaOH, EtOH, 115°C, 3 h, 93%; (d) amine, HOBt, EDC·HCl, NEt
3
, dichloromethane (DCM), 0°C to rt, overnight, 23–92%
PETER VENTURA ET AL.
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comparison to the thioamide, an addition of NaHCO
3
as a base was
necessary. In both cases, the reaction with ethyl bromopyruvate led to
the ethyl esters 44 and 45. Alkaline hydrolysis, followed by coupling
with β‐alanine benzyl ester and subsequent hydrolysis led to carboxylic
acids 50 and 51. By coupling these compounds with the appropriate
amines, the desired amides could be obtained. With this, 13 additional
compounds for further biological testing were obtained.
SCHEME 2 Synthesis of the biarylbenzoic acid amides. Reagents and conditions: (a) (I) oxalyl chloride, dimethylformamide (DMF), room
temperature (rt), 3 h, (II) 2‐bromothiophene, AlCl
3
, dichloromethane (DCM), 0°C to rt, 16 h, 54%; (b) 3‐hydroxyphenylboronic acid, K
3
PO
4
,Pd
(OAc)
2
, EtOH, rt, 3 days; (c) 2 M NaOH, EtOH, 90°C, 3 h, 86%; (d) amine, HOBt, EDC·HCl, NEt
3
, DCM, 0°C to rt, overnight, 31–88%; (e)
N
2
H
4
·H
2
O, KOH, diethylene glycol, 180°C, overnight, 87%
SCHEME 3 Synthesis of the furan derivatives. Reagents and conditions: (a) glutaric anhydride, AlCl
3
in dichloromethane (DCM), 0°C to room
temperature (rt), overnight, 25%; (b) 3‐hydroxyphenylboronic acid, K
3
PO
4
, Pd(OAc)
2
, EtOH, rt, overnight, 52%; (c) amine, HOBt, EDC·HCl, NEt
3
,
DCM, 0°C to rt, overnight, 25–84%; (d) hydrazine monohydrate, KOH, diethylene glycol, 180°C, overnight, 73%
2.2 |Biological evaluation
The compounds were tested for their antischistosomal activity by an
established assay.
[8,9,13]
To this end, S. mansoni couples were cultured
in vitro with the respective compound (dissolved in dimethyl sulf-
oxide [DMSO]) at an initial concentration of 25 µM over a period of
72 h. Every 24 h, worms were analyzed by bright‐field microscopy,
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and motility, pairing stability and egg production of worms was
monitored as well as morphological phenotypes, like tegumental
damage and gut dilatation. DMSO‐treated worms were used as the
negative control, whereas PZQ‐treated worms (5 µM) were used as
the positive control.
Table 1shows the results of eight active biaryl carboxylic acid
amides
[10]
that served as our reference compounds.
First, the nine biarylpentadiene derivatives were tested for
their antischistosomal activity at an initial concentration of
25 µM (Table 2). We were able to classify these derivatives into
three different categories. Only three of the nine derivatives, the
free carboxylic acid (9), the methyl sulfonyl derivative (10), and
the phenylsulfonyl piperazine derivative (11) failed to show an-
tischistosomal activity at 25 µM representing the first category.
The second category included derivatives that only provoked a
strong reduction of egg number at 25 µM and detachment of
worms from the culture well. Therefore, these compounds were
rated with low antischistosomal activity. Three derivatives, the
methyl benzyl piperazine derivative 12, the thiomorpholine 13,
and the morpholine 14 derivative fell into this category. The first
two mentioned derivatives showed, in addition, an insignificant
separation of couples. The last category contained derivatives
that showed good antischistosomal activity at 25 µM. These
included the pentadiene derivatives: the Boc‐piperazine 15,the
unsubstituted piperazine 16, and the ethylpiperazine derivative
17. All three derivatives provoked a significant reduction in egg
numbers, a reduction of the worms' motility and vitality, and gut
dilatation (Figure 2). In the case of the unsubstituted piperazine
derivative 16, the internal structure of the gut was disrupted after
72 h of treatment (Figure 2c). The ethylpiperazine derivative 17
showed an antischistosomal activity even at 10 µM. Altogether,
these active derivatives showed similar phenotypes compared to
the analogue's derivatives with an alkyl chain (see Table 1).
However, it seems that the observed phenotypes were less pro-
nounced when the alkyl chain was replaced with a pentadiene
moiety.
Next, we evaluated the antischistosomal activity of the 11
biarylbenzoic acid derivatives. The phenotypic observations can be
seen in Table 3. Since the ethylpiperazine derivative 64b with an
alkyl linker was toxic at a concentration of 100 µM to HepG2 and
LST174T cells,
[10]
it was decided that the ethylpiperazine should not
be coupled with the biarylbenzoic acid 27. Furthermore, we did not
couple the p‐methylbenzylpiperazine since it was not among the six
most active piperazine compounds.
[10]
The derivatives in this series
could also be classified into three categories, that is, non‐active,
slightly active, and active at 25 µM. The three derivatives bearing a
SCHEME 4 Synthesis of the oxazole and thiazole derivatives. Reagents and conditions: (a) (I) thionyl chloride, toluol, 114°C, 5 h, (II) NH
3
,
tetrahydrofuran (THF), 0°C to room temperature (rt), overnight, only for Y = S:, (III) Lawesson's reagent, THF, rt, 3 h, Y = O: 62%, Y = S: 47%; (b)
ethyl bromopyruvate, for Y = O: NaHCO
3
, THF, 60°C, 2 days, 85%, for Y = S: EtOH, 87°C, 6 h, 78%; (c) KOH, MeOH, 35°C, overnight, Y = O:
50%, Y = S: 73%; (d) β‐alanine benzyl ester, NEt
3
, HOBt, EDC·HCl, dichloromethane (DCM), rt, 12 h, Y = O: 89%, Y = S: 78%; (e) Pd/C, H
2
, MeOH,
rt, 24 h, Y = O: 70%, Y = S: 54%; (f) amine, HOBt, EDC·HCl, NEt
3
, DCM, 0°C to rt, overnight, Y = O: 16–87%, Y = S: 53–78%
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carbonyl group in the linker, the free benzoic acid 20,thephe-
nylsulfonyl piperazine 22, and the morpholine derivative 24 failed to
show antischistosomal activity at a concentration of 25 µM after
72 h. The Boc‐substituted piperazine derivative with the carbonyl
group 25 was the only compound that showed low activity at
25 µM. Ninety‐seven percent reduction of egg number and 20% of
couple separation were observed after 72 h. All worms were not
attached in the culture well, which suggests a decreased vitality of
the worms. No other phenotypes were observed for this compound.
Interesting observations were made with the three remaining ben-
zoic acid derivatives with the carbonyl group. The methyl sulfonyl
piperazine derivative 21 showed a good antischistosomal activity
TABLE 1 Phenotypic results of the active biaryl alkyl carboxylic acid amides
[10]
Compound R Activity (µM)
a
Phenotypes
63a na ‐
63b 25 100% e.r., 100% c.s., teg. dam. ♀
64a 25 99% e.r., 90% c.s., gut dil. ♀and ♂
64b 25 85% e.r.
65a 25 100% e.r., 80% c.s., gut dil. ♀
65b 25 97% e.r., gut dil. ♀
66a na ‐
66b 25 100% e.r., 70% c.s., gut dil. ♀
67a na ‐
67b 25 100% e.r., 90% c.s., gut dil. ♀and ♂
68a na ‐
68b 25 100% e.r., 100% c.s., teg. dam.♀and ♂, gut dil. ♀
69a na ‐
69b 10 73% e.r., 50% c.s.
70a na ‐
70b 25 100% e.r., 100% c.s., teg. dam.
Note: Experiments were carried out in triplicate.
Abbreviations: c.s., couple separation; e.r., egg number reduction; gut dil., gut dilatation; na, not active at 25 µM; teg. dam., tegumental damage; ‐,no
damaging phenotype visible.
a
Values show the lowest concentration at which antischistosomal effect was observed.
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since complete couple separation, almost complete egg number
reduction, and tegumental damage of the male worms were ob-
served in parallel (Figure 3c). Furthermore, the motility and vitality
of the worms were clearly reduced. The thiomorpholine derivative
23 showed a slightly decreased couple separation and reduction of
egg numbers in comparison to the methyl sulfonyl piperazine deri-
vative 21. However, the remaining couples were not attached to the
culture well anymore, and tegumental damage was observed in both
TABLE 2 Phenotypic results for biarylpentadiene derivatives
[10]
Compound R Activity (µM)
a
Phenotypes
9na ‐
10 na ‐
11 na ‐
12 25 93% e.r., 10% c.s.
13 25 89% e.r. 20% c.s.
14 25 86% e.r.
15 25 100% e.r., 40% c.s., slight gut dil. ♀
16 25 99% e.r., 100% c.s., loss of internal gut
structure ♀
17 10 94% e.r., 30% c.s., slight gut dil. ♀
Note: Experiments were carried out in triplicate.
Abbreviations: c.s., couple separation; e.r., egg number reduction; gut dil., gut dilatation; na, not active at 25 µM; teg. dam., tegumental damage; ‐,no
damaging phenotype visible.
a
Values show the lowest concentration at which the antischistosomal effect was observed.
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female and male worms. In addition, female worms also displayed
gut dilatations (Figure 3d). The unsubstituted piperazine derivative
26 showed similar phenotypes as the methyl sulfonyl piperazine
derivative 21 (Figure 3a,b). All active derivatives failed to show
activity when decreasing the concentration to 10 µM. Un-
expectedly, none of the derivatives without the carbonyl group
(28–30) showed antischistosomal activity at 25 µM, which is in
contrast to the observations made with the alkyl linker.
[10]
All in all,
the active biarylbenzoic acid derivatives showed similar anti-
schistosomal activity as the derivatives with an alkyl linker
(see Table 1).
Interestingly, the replacement of the thiophene ring by an ox-
azole or a thiazole ring led to a complete loss of antischistosomal
activity. As seen in Table 4none of the 13 synthesized compounds
was active at 25 µM. Furthermore, in seven of eight examples, the
exchange of the same moiety with a furan ring (Table 4) led also to a
loss of antischistosomal activity with the only exception of compound
39. Cultivation of the parasites with the thiomorpholine derivative 39
without a carbonyl group in the linker led to complete inhibition of
egg production and worm separation. In addition, tegumental damage
and gut dilatation in both the female and male worms were observed.
This substance was similar in activity to the respective thiomorpho-
line derivative with a thiophene ring 70b. These data indicate that the
thiophene ring is the preferable substructure for antischistosomal
activity.
Out of all series, the best four derivatives were tested for their
cytotoxicity in HepG2 cells (Table 5)byaWST‐1 assay as de-
scribed previously.
[10]
Compound 21 showed no toxicity up to
100µM.Theotherthreecompoundsledtotoxiceffectsat100
and 50 µM. At 10 µM, none of the tested compounds led to any
cytotoxic effect. According to these results, the methyl sulfonyl
piperazine moiety seems to be the most promising derivatization
andshouldbemaintainedforfurtherSARstudies.Thisiscon-
sistent with our previous results, where the methyl sulfonyl pi-
perazine derivative showed good antischistosomal activity and no
cytotoxic effects on HepG2 cells.
[10]
3|CONCLUSION
This study summarizes our continued work on the investigation of
the antischistosomal potency of BACADs. Here, we explored the
importance of the alkyl linker andthethiopheneringbysynthe-
sizing a total of 41 derivatives. The linker was examined by ex-
changing the moiety with a pentadiene or a phenyl ring. The
importance of the thiophene ring was examined by synthesizing
FIGURE 2 Pictures of Schistosoma mansoni adult worms that were treated with the pentadienecarboxylic acid derivatives at a substance
concentration of 25 µM (a–c), 10 µM (d), and 5 µM (e). The pictures were made after 72 h (a–d) or 24 h (e) of treatment with the corresponding
substances. (a) Dimethyl sulfoxide (DMSO) control; (b) treatment with the Boc‐piperazine derivative 15, arrow shows gut dilatation; (c) treatment
with the unsubstituted piperazine derivative 16, internal structures of gut and ovary cannot be distinguished clearly in the anterior part (arrows);
(d) treatment with the ethylpiperazine derivative 17; arrow showed slight gut dilatation. (e) Treatment with praziquantel (PZQ) (5 µM); positive
control
[14]
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compounds with an oxazole, thiazole, or furan ring. We coupled
the respective carboxylic acid moieties with the most active pi-
perazine derivatives that we identified in our previous study.
[10]
Nine derivatives with a pentadiene linker were synthesized and
their biological activity against S. mansoni couples evaluated. Six of
these derivatives showed an antischistosomal activity at 25 µM. All
active derivatives induced a reduction of egg numbers and se-
paration of worm couples. Three of these compounds provoked
additional gut dilatation. Four out of 11 biarylbenzoic acid deri-
vatives showed antischistosomal activity at 25 µM. All active
derivatives caused a reduction of egg numbers and couple se-
paration. Three of these derivatives provoked additional pheno-
types like gut dilatation and tegumental damage. Interestingly, all
active compounds possessed a carbonyl group in the linker.
Without the carbonyl group, the antischistosomal activity seemed
tobelost.Thisisincontrasttotheobservationsmadewiththe
alkyl linker
[10]
where a carbonyl group lowered antischistosomal
activity. These investigations provided two significant clues for the
ongoing development of this class of potential antischistosomal
agents. First, the thiophene moiety appears as the preferred
TABLE 3 Phenotypic results for biarylbenzoic acid derivatives
[10]
Compound X R Activity (µM)
a
Phenotypes
20 CO na ‐
27 CH
2
na ‐
21 CO 25 97% e.r., 100% c.s., teg. dam. ♂
28 CH
2
na ‐
22 CO na ‐
23 CO 25 72% e.r., 60% c.s., teg. dam. ♀and ♂,
gut dil. ♀
29 CH
2
na ‐
24 CO na ‐
30 CH
2
na ‐
25 CO 25 97% e.r., 20% c.s.
26 CO 25 99% e.r., 100% c.s., gut dil. ♂, loss of
internal gut structure ♀
Note:n=3.
Abbreviations: c.s., couple separation; e.r., egg number reduction; gut dil., gut dilatation; na, not active at 25 µM; teg. dam., tegumental damage; ‐,no
damaging phenotype visible.
a
Values show the lowest concentration at which antischistosomal effect was observed.
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substructure since any modification with the sole exception of the
furan derivative 39 resulted in the complete loss of activity. Since
the target(s) of our compounds are unknown, any attempt to ex-
plain the preference of the thiophene moiety would be purely
speculative. Second, the alkyl linker can be replaced by the more
rigid pentadiene and benzyl linkers; however, this modification
does not lead to increased antischistosomal activity. Therefore, the
original alkyl linker will be preserved in the follow‐up development
of this class of potential drugs. Furthermore, the best four com-
pounds were tested for their cytotoxicity in HepG2 cells. The re-
sults showed that the methyl sulfonyl piperazine derivative 21 was
non‐cytotoxic at a concentration up to 100 µM. Although the
identification of aldose reductase in S. mansoni was the initial
reason for testing inhibitors of human aldose reductase against
cultured schistosoma worms, subsequent development has led to
compounds structurally significantly different from the initial in-
hibitors of hAR. Currently, we do not have any clue about the
schistosomal targets of the compounds presented here and espe-
cially whether they still display any activity against aldose re-
ductases, whether from human or schistosomes. This issue will be
addressed in a separate study.
4|EXPERIMENTAL
4.1 |Chemistry
4.1.1 |General
Nuclear magnetic resonance (NMR) spectra (
1
Hand
13
C) were measured
with JEOL ECA‐400 or ECX‐500 spectrometers and the chemical shifts
(δ) are shown in ppm relative to the central residual solvent signal. Mass
spectra were measured with a Q‐Trap 2000 (Applied Biosystems) and
high‐resolution mass spectra were recorded with a Micromass VG‐
Autospec spectrometer. Melting points were identified with a type Mel‐
Temp® II (Laboratory Devices Inc.) device. Reagents and solvents were
purchased from abcr, Alfa Aesar, Merck, Sigma‐Aldrich, and Thermo
Fisher Scientific. Flash chromatography was performed with the use of
Macherey‐Nagel silica gel (0.040–0.063 mm) and for analytical thin‐layer
chromatography (TLC) Merck silica gel 60 F254 plates were used.
The InChI codes of the investigated compounds, together with
some biological activity data, are provided as Supporting Information.
The spectroscopic data of more compounds are also provided as
Supporting Information.
FIGURE 3 Pictures of Schistosoma mansoni adult worms treated with the biarylbenzoic acid derivatives at a substance concentration of
25 µM (a–d). The pictures were made after 72 h of treatment with the corresponding substances. (a,b) Treatment with the unsubstituted
piperazine derivative 26, arrow shows gut dilatation; (c) treatment with the methyl sulfonyl piperazine derivative 21, arrow shows tegumental
damage; (d) treatment with the thiomorpholin derivative 23, arrow shows gut dilatation
[14]
10 of 17
|
PETER VENTURA ET AL.

5‐(3‐Hydroxyphenyl)thiophene‐2‐carbaldehyde (7) (modified from
Ref. [8])
Under an argon atmosphere, 5‐bromothiophene‐2‐carbaldehyde
(10.5 mmol, 1.0 eq), 3‐hydroxyphenylboronic acid (12.6 mmol, 1.2 eq),
and K
3
PO
4
(21.0 mmol, 2.0 eq) were suspended in EtOH (5 ml/mmol)
at room temperature (rt). After 5 min, Pd(OAc)
2
(0.21 mmol, 2 mol%)
was added and the reaction mixture was stirred at rt overnight. The
insoluble particles were removed by filtration through celite and the
solvent was evaporated under reduced pressure. The crude product
was purified via column chromatography (cyclohexane/EtOAc 3:1).
2.14 g (10.5 mmol, quant.) of the desired product 7was obtained as a
yellow solid. R
f
= 0.41 (cyclohexane/EtOAc 2:1).
1
HNMR:(DMSO‐d
6
,
400 MHz), δ(ppm) = 9.90 (s, 1H), 9.74 (s, 1H), 8.02 (d,
3
J= 4.0 Hz, 1H),
7.66 (d,
3
J= 4.0 Hz, 1H), 7.28 (t,
3
J= 7.8 Hz, 1H), 7.22 (dt,
3
J= 7.7 Hz,
4
J= 1.4 Hz), 7.14 (t,
4
J= 2.0 Hz, 1H), 6.84 (ddd,
3
J= 7.9 Hz,
4
J= 2.4 Hz,
4
J= 1.2 Hz, 1H).
13
CNMR:(DMSO‐d
6
, 100 MHz), δ(ppm) = 184.0,
158.0, 152.8, 141.7, 139.1, 133.6, 130.5, 125.1, 117.0, 116.7, 112.7.
Mass spectrometry (MS) (electrospray ionization [ESI+]): m/z(%) = 205
(100, [M+H]
+
), 222 (19, [M+NH
4
]
+
). High‐resolution mass spectro-
metry (HRMS) (ESI+): m/zcalcd. for C
11
H
9
O
2
S: 205.0318; found:
205.0320 and calcd. for C
11
H
8
NaO
2
S: 227.0137; found: 227.0128.
Ethyl (2E,4E)‐5‐[5‐(3‐hydroxyphenyl)thiophen‐2‐yl]penta‐2,4‐
dienoate (8) (modified from Refs. [15,16])
Triethylphosphite (2.37 ml, 13.6 mmol, 2.8 eq) was heated at
130°C and ethyl‐4‐brombut‐2‐enoate (1.35 ml, 9.79 mmol, 2.0 eq)
was added. The reaction mixture was heated for 2 h at 130°C. The
volatiles were removed under reduced pressure and the obtained
phosphonate was used without further purification. Under an ar-
gon atmosphere, NaH (0.41 g, 12.3 mmol, 2.5 eq) was suspended in
absolute dimethylformamide (DMF) (7 ml/mmol) and cooled down
to 0°C. A solution of the phosphonate in DMF (1 ml/mmol) was
added dropwise over 20 min. Afterward, the solution was stirred
for another 20 min at rt. A solution of the aldehyde 7(1.00 g,
4.00 mmol, 1.0 eq) in DMF (1 ml/mmol) was added dropwise and
thereactionmixturewasstirredfor45minatrt.OnemolarHCl
(20 ml) was added and the reaction mixture was extracted three
times with EtOAc (3×20ml). The combined organic phases were
washed with brine, dried over MgSO
4
, and the solvent evaporated
under reduced pressure. The crude product was purified via col-
umn chromatography (cyclohexane/EtOAc 6:1) to afford 8as or-
ange solid (1.18 g, 3.92 mmol, 80%). An E/Zratio of 8:1 was
achieved that was increased by additional column chromatography
to 22:1. This time the first product fractions were not collected.
R
f
= 0.51 (cyclohexane/EtOAc 2:1).
1
HNMR:(DMSO‐d
6
,
400 MHz), δ(ppm) = 9.62 (s, 1H), 7.43 (d,
3
J= 3.7 Hz, 1H), 7.38
TABLE 4 Phenotypic observation for furan derivatives
[1]
Compound X R
Activity
(µM)
a
Phenotypes
33 CO na ‐
37 CH
2
na ‐
34 CO na ‐
38 CH
2
na ‐
35 CO na ‐
39 CH
2
25 100% e.r.,
100% c.s., teg.
dam. ♀and ♂,
gut dil. ♀and ♂
36 CO na ‐
40 CH
2
na ‐
Note:n=3.
Abbreviations: c.s., couple separation; e.r., egg number reduction; gut dil.,
gut dilatation; na, not active at 25 µM; teg. dam., tegumental damage; ‐,
no damaging phenotype visible.
a
Activity measured at 25 µM, values show the lowest concentration at
which antischistosomal effect was observed.
TABLE 5 Phenotypic observation for furan derivatives
[1]
Compound Activity
a
(µM) Cytotoxicity in HepG2 cells (µM)
17 10 <50
16 25 <50
21 25 ≥100
26 25 <50
a
Activity measured at 25 µM, values show the lowest concentration at
which antischistosomal effect was observed.
PETER VENTURA ET AL.
|
11 of 17

(d,
3
J=15.1Hz, 1H), 7.20–7.30(m,3H),7.11(d,
3
J=7.9Hz, 1H),
7.03 (t,
4
J=2.0Hz,1H),6.82(d,
3
J=15.3Hz, 1H), 6.76–6.74 (m,
1H), 6.09 (d,
3
J= 15.2 Hz, 1H), 4.12 (q,
3
J= 8.1 Hz, 2H), 1.23 (t,
3
J=8.2Hz, 3H).
13
CNMR:(DMSO‐d
6
,100MHz),δ(ppm) = 166.2,
157.9, 144.7, 144.3, 140.1, 134.3, 133.2, 130.7, 130.3, 125.7,
124.7, 120.6, 116.3, 115.4, 112.1, 59.8, 14.2. MS (ESI+): m/z
(%) = 301 (100, [M+H]
+
), 318 (16, [M+NH
4
]
+
). HRMS (ESI+): calcd.
for C
17
H
17
O
3
S: 301.0893; found: 301.0888 and calcd. for
C
17
H
16
NaO
3
S: 323.0712; found: 323.0712.
4.1.2 |General procedure 1 for the alkaline
hydrolysis (from Ref. [10])
At rt, the ester (1.00 eq) was dissolved in EtOH and an aqueous
solution of 2 M NaOH (2 ml/mmol) was added. The reaction mix-
ture was heated to 100°C and stirred until the reaction was
complete (TLC). H
2
O(10ml/mmol)wasadded,theaqueousphase
was extracted with EtOAc (3 × 10 ml) and then acidified with
concentrated HCl until the aqueous phase had a pH of 1. The
precipitate was filtered, washed with H
2
O, and dried under a
vacuum.
(2E,4E)‐5‐[5‐(3‐Hydroxyphenyl)thiophen‐2‐yl]penta‐2,4‐dienoic
acid (9)
Following general procedure 1, 8(0.93 g, 3.10 mmol, 1.00 eq) and
2 M NaOH (5.50 ml) were dissolved in EtOH (5.50 ml). 783 mg
(2.88 mmol, 93%) of the desired product 9was afforded as yellow
solid with an E/Zratio of 18:1. R
f
= 0.33 (cyclohexane/EtOAc
1:1 + 1% formic acid). Mp: 204°C.
1
H NMR: (DMSO‐d
6
, 400 MHz), δ
(ppm) = 12.21 (s, 1H), 9.62 (s, 1H), 7.42 (d,
3
J= 3.9 Hz, 1H), 7.31 (d,
3
J= 15.2 Hz, 1H), 7.28–7.20 (m, 3H), 7.11 (d,
3
J= 7.9 Hz, 1H), 7.03 (t,
4
J= 2.1 Hz, 1H), 6.80 (d,
3
J= 15.3 Hz, 1H), 6.75 (dd,
3
J= 8.1 Hz,
4
J= 2.5 Hz, 1H), 6.01 (d,
3
J= 15.2 Hz, 1H).
13
C NMR: (DMSO‐d
6
,
100 MHz), δ(ppm) = 167.6, 157.9, 144.5, 143.9, 140.2, 134.4, 133.6,
130.4, 130.3, 125.9, 124.7, 121.8, 116.3, 115.4, 112.0. Infrared (IR): ν
(cm
−1
) = 3250 (w), 3050 (w), 2550 (w), 1673 (s), 1611 (vs), 1592 (vs),
1559 (m), 1454 (s), 1434 (m), 1417 (m), 1375 (w), 1328 (m), 1310 (s),
1278 (vs), 1254 (m), 1227 (s), 1174 (m), 1159 (m), 1105 (w), 1080 (w),
1035 (m), 987 (vs), 942 (s), 878 (m), 856 (m), 845 (m), 823 (w), 800
(vs), 773 (vs), 732 (w), 706 (m), 674 (s), 613 (m), 570 (m), 560 (m), 550
(m), 533 (m), 503 (m), 442 (m). MS (ESI−): m/z (%) = 271 (100, [M
−H
+
]
−
). HRMS (ESI+): calcd. for C
15
H
11
O
3
S: 271.0434; found:
271.0425.
4.1.3 |General procedure 2 for the synthesis of the
carboxylic amides (from Ref. [8])
In a flask, the carboxylic acid (1.0 eq), the respective amine
(1.0–1.5 eq), and NEt
3
(3.0 eq) were dissolved at rt in di-
chloromethane (DCM) and stirred at this temperature for 5 min.
Subsequently, the mixture was cooled to 0°C and HOBt (1.5 eq) and
EDC·HCl (1.5 eq) were added. The mixture was stirred at rt overnight.
The volatiles were removed under reduced pressure and the crude
product was purified via column chromatography.
4.1.4 |General procedure 3 for the removal of the
Boc protecting group (from Ref. [10])
The Boc‐piperazine derivative was dissolved at rt in 4 M HCl in 1,4‐
dioxane (7.6 ml/mmol) and 1,4‐dioxane (5 ml/mmol) and stirred for
3 h. The precipitate was filtered, washed with 1,4‐dioxane, and dried
under a vacuum.
Methyl 3‐(5‐bromothiophene‐2‐carbonyl)benzoate (19)
Methyl hydrogen isophthalate (18) (3.00 g, 16.7 mmol, 1.0 eq)
was dissolved in DCM (50 ml). Oxalyl chloride (2.10 ml,
25.0 mmol, 1.5 eq) and DMF (two drops) were added and the
mixture was stirred for 2 h at rt. The volatile compounds were
removed under vacuum and the residue dissolved in dry DCM
(80 ml). 2‐Bromothiophene (1.60 ml, 16.7 mmol, 1.0 eq) was ad-
ded and the solution cooled to 0°C. After 5 min, AlCl
3
(4.90 g,
36.7 mmol, 2.2 eq) was added and the reaction mixture was stir-
red at 0°C for 5 h and at room temperature overnight. The re-
action was stopped with 10% aqueous HCl (80 ml) and stirred for
1 h. The aqueous phase was extracted three times with DCM
(3 × 30 ml) and the combined organic phases were washed with
1 M NaOH (30 ml). The aqueous phase was acidified with con-
centrated HCl and the precipitate was collected and washed with
H
2
O.Thecrudeproductwaspurified via column chromatography
(cyclohexane/EtOAc 9:1) to afford 2.92 g (8.97 mmol, 54%) of the
desired product 19 as an orange solid. R
f
=0.37 (cyclohexane/
EtOAc 9:1).
1
HNMR:(DMSO‐d
6
,400MHz),δ(ppm) = 8.31
(t,
4
J= 1.5 Hz, 1H), 8.24 (dt,
3
J=7.8Hz,
4
J= 1.4 Hz, 1H), 8.10 (dt,
3
J=7.7Hz,
4
J= 1.5 Hz, 1H), 7.74 (t,
3
J= 7.8 Hz, 1H), 7.58 (d,
3
J= 4.1 Hz, 1H), 7.46 (d,
3
J= 4.1 Hz, 1H), 3.90 (s, 3H).
13
CNMR:
(DMSO‐d
6
,100MHz),δ(ppm) = 185.4, 165.4, 144.0, 137.0,
136.6, 133.3, 132.9, 132.6, 130.1, 129.5, 129.2, 123.0, 52.5. MS
(ESI+): m/z(%) = 326 (100, [M+H]
+
), 343 (10, [M+NH
4
]
+
). HRMS
(ESI+) calcd. for C
13
H
9
BrNaO
3
S: 346.9348; found: 346.9358.
12 of 17
|
PETER VENTURA ET AL.

Methyl 3‐[5‐(3‐hydroxyphenyl)thiophene‐2‐carbonyl]benzoate (71)
Compound 19 (2.92 g, 8.97 mmol, 1.0 eq), 3‐hydroxyphenylboronic
acid (1.96g, 13.5mmol, 1.5eq),and K
3
PO
4
(3.80g,17.94mmol,2.0eq)
were suspended in EtOH (45 ml) at rt. After 5 min Pd(OAc)
2
(40 mg,
0.18 mmol, 2 mol%) was added and 1,4‐dioxane was added until all
compounds were completely dissolved. The mixture was stirred over-
night. The mixture was filtered through celite and the solvent evaporated
under vacuum. The crude product was purified via column chromato-
graphy (cyclohexane/EtOAc 4:1 →1:1) to afford 2.61 g (7.72 mmol, 86%)
of the desired product 71 as orange solid. R
f
= 0.16 (cyclohexane/EtOAc
4:1).
1
HNMR:(DMSO‐d
6
,400MHz),δ(ppm) = 9.74 (s, 1H), 8.34 (s, 1H),
8.23 (d,
3
J= 7.7 Hz, 1H), 8.12 (d,
3
J= 7.7 Hz, 1H), 7.77–7.71 (m, 2H), 7.62
(d,
3
J= 3.6 Hz, 1H), 7.31–7.23 (m, 2H), 7.16 (s, 1H), 6.85 (d,
3
J=7.8Hz),
3.91 (s, 3H).
13
CNMR:(DMSO‐d
6
, 100 MHz), δ(ppm) = 186.2, 165.6,
158.0, 152.9, 140.1, 137.7, 137.2, 133.6, 133.4, 132.7, 130.5, 130.1,
129.5, 129.2, 125.2, 117.0, 116.7, 112.7, 52.5. MS (ESI+): m/z(%) = 339
(100, [M+H]
+
), 356 (33, [M+NH
4
]
+
). HRMS (ESI+): calcd. for C
19
H
15
O
4
S:
339.0686; found: 339.0693.
3‐[5‐(3‐Hydroxyphenyl)thiophene‐2‐carbonyl]benzoic acid (20)
Following general procedure 1, 71 (2.61 g, 8.97 mmol, 1.0 eq) and
2 M NaOH (35 ml) were dissolved in EtOH (35 ml). 2.01 g (5.69 mmol,
77%) of the desired product 20 was obtained as yellow solid. R
f
=
0.44 (cyclohexane/EtOAc 1:1 + 0.1% formic acid). Mp: 265°C.
1
H
NMR: (DMSO‐d
6
, 400 MHz), δ(ppm) = 13.30 (s, 1H), 9.75 (s, 1H), 8.34
(s, 1H), 8.22 (d,
3
J= 7.9 Hz, 1H), 8.10 (d,
3
J= 7.9 Hz, 1H), 7.74–7.70
(m, 2H), 7.62 (d,
3
J= 3.9 Hz, 1H), 7.31–7.23 (m, 2H), 7.17 (s, 1H), 6.85
(d,
3
J= 8.9 Hz).
13
C NMR: (DMSO‐d
6
, 100 MHz), δ(ppm) = 186.3,
166.6, 158.0, 152.8, 140.8, 137.6, 137.1, 133.7, 133.0, 132.9, 131.3,
130.6, 129.4, 129.3, 125.2, 117.0, 116.7, 112.7. IR: ν(cm
−1
) = 3309
(w), 3024 (w), 2977 (w), 2825 (w), 2556 (w), 1703 (m), 1619 (s), 1597
(s), 1456 (m), 1438 (s), 1413 (m), 1377 (w), 1330 (s), 1296 (m), 1283
(m), 1263 (m), 1243 (m), 1224 (m), 1190 (m), 1161 (m), 1107 (w), 1085
(w), 1067 (m), 997 (w), 929 (w), 915 (w), 901 (w), 867 (m), 833 (m),
813 (m), 768 (m), 728 (s), 719 (vs), 693 (w), 675 (m), 642 (m), 588 (w),
565 (m), 539 (w), 489 (w), 452 (w), 434 (m), 412 (w). MS (ESI+): m/z
(%) = 325 (100, [M+H]
+
), 347 (30, [M+Na]
+
). HRMS (ESI+): calcd. for
C
18
H
13
O
4
S: 325.0529; found: 325.0533.
3‐{[5‐(3‐Hydroxyphenyl)thiophen‐2‐yl]methyl}benzoic acid (27)
In a flask, the carboxylic acid 20 (800 mg, 2.47 mmol, 1.0 eq), KOH
(554 mg, 9.87 mmol, 4.0 eq), and N
2
H
4
·H
2
O (0.48 ml, 9.87 mmol, 4.0 eq)
were dissolved in diethylene glycol (10 ml). The mixture was heated to
180°C and stirred for 7 h. The reaction mixture was cooled to rt and
H
2
O (50 ml) was added. The aqueous phase was extracted three times
with EtOAc (3 × 30 ml) and the combined organic phases were washed
with 1 M NaOH (30 ml). The aqueous phase was acidified with conc.
HCl until pH = 1. The precipitate was filtered and washed with H
2
O. The
crude product was recrystallized from toluene. 663 mg (2.14 mmol,
87%) of the desired product 27 wasobtainedasred‐brown solid. Mp:
145°C.
1
HNMR:(DMSO‐d
6
, 400 MHz), δ(ppm) = 12.93 (s, 1H), 9.49 (s,
1H), 7.87 (t,
4
J= 1.5 Hz, 1H), 7.82 (dt,
3
J=7.6Hz,
4
J= 1.4 Hz, 1H), 7.56
(dt,
3
J=7.6Hz,
4
J= 1.5 Hz, 1H), 7.46 (t,
3
J=7.6Hz,1H),7.25(d,
3
J= 3.6 Hz, 1H), 7.16 (t,
3
J= 7.9 Hz, 1H), 6.99 (ddd,
3
J=7.7Hz,
4
J=1.7Hz,
4
J=1.0Hz,1H),6.94(t,
4
J= 1.9 Hz, 1H), 6.91 (d,
3
J=3.6Hz,
1H), 6.67 (ddd,
3
J=8.1Hz,
4
J=2.4Hz,
4
J= 0.9 Hz), 4.23 (s, 2H).
13
C
NMR: (DMSO‐d
6
,100MHz),δ(ppm) = 167.3, 158.0, 143.1, 142.1,
140.9, 135.0, 133.0, 131.0, 130.1, 129.3, 128.5, 127.5, 126.8, 123.2,
115.9, 114.5, 111.7, 35.5. IR: ν(cm
−1
) = 3328 (w), 3024 (w), 2823 (w),
2674 (w), 2563 (w), 1685 (vs), 1606 (m), 1581 (s), 1501 (m), 1454 (m),
1423 (m), 1366 (w), 1303 (m), 1259 (m), 1229 (m), 1204 (m), 1181 (m),
1165 (m), 1123 (w), 1084 (w), 990 (m), 933 (m), 922 (m), 852 (m), 840
(w), 822 (w), 801 (m), 776 (s), 758 (m), 741 (m), 700 (s), 677 (s), 663 (m),
630 (m), 578 (w), 561 (w), 538 (m), 443 (m). MS (ESI−): m/z(%) = 309 (10,
[M−H]
−
). HRMS (ESI+): m/zcalcd. for C
18
H
14
O
3
S: 311.0736; found:
311.0731 and calcd. for C
18
H
14
NaO
3
S: 333.0553; found: 333.0557.
3‐Hydroxybenzamide
[17]
(42)
In a flask, the carboxylic acid 41 (3.00g, 21.7mmol, 1.0eq) was
suspended in toluene (24 ml). Then, thionyl chloride (4.6 ml, 65.2 mmol,
3.0 eq) was added. The reaction mixture was heated for 5 h at 114°C.
PETER VENTURA ET AL.
|
13 of 17

Afterward, the reaction mixture was cooled to rt and the volatile
compounds were removed under vacuum. The residue was dissolved in
tetrahydrofuran (THF) (9 ml) and cooled to 0°C. Then, conc. NH
3
(8.4 ml)
was added dropwise, and the reaction mixture was stirred overnight at
rt. The solvent was removed under vacuum. Water (30 ml) was added to
the residue. The resulting precipitate was filtered and washed with
water. 1.68 g (12.3 mmol, 56%) of the desired product 42 was obtained
as colorless solid.
1
HNMR:(DMSO‐d
6
, 400 MHz), δ(ppm) = 9.57 (s, 1H),
7.83 (s, 1H), 7.29–7.20 (m, 4H), 6.91–6.88 (m, 1H).
13
CNMR:(DMSO‐
d
6
, 100 MHz), δ(ppm) = 168.0, 157.2, 135.8, 129.1, 118.1, 118.0, 114.5.
MS (ESI+): m/z(%) = 138 (25, [M+H]
+
), 155 (100, [M+Na]
+
), 275 (30, [2M
+H]
+
). HRMS (ESI+) calcd. for C
7
H
8
NO
2
: 138.0550; found: 138.0546.
Ethyl 2‐(3‐hydroxyphenyl)oxazole‐4‐carboxylate
[18]
(44)
In a flask, the carboxylic amide 42 (100 mg, 0.73 mmol, 1.0 eq),
NaHCO
3
(245 mg, 2.92 mmol, 4.0 eq), and ethyl bromopyruvate (0.1 ml,
0.80 mmol, 1.1 eq) were dissolved in THF (3 ml). The reaction mixture
was stirred at 60°C until the reaction was completed (TLC control: cy-
clohexane/EtOAc 3:1). The suspension was filtered through celite and
the solvent was removed under vacuum. The residue was taken up with
THF (10 ml) and cooled to 0°C. Trifluoroacetic anhydride (0.73 ml) was
added slowly, and the reaction mixture was stirred overnight at rt. The
reaction was stopped with a solution of NaHCO
3
(20 ml), and the aqu-
eous phase was extracted three times with EtOAc (3 × 20 ml). The
combined organic phases were dried over MgSO
4
and the solvent was
removed under vacuum. The crude product was purified via column
chromatography (cyclohexane/EtOAc 3:1). 144 mg (0.62 mmol, 85%) of
the desired product 44 was obtained as colorless solid. R
f
=0.25 (cy-
clohexane/EtOAc 3:1).
1
HNMR:(DMSO‐d
6
,500MHz),δ(ppm) = 9.84 (s,
1H), 8.54 (s, 1H), 7.42–7.40(m,1H),7.38–7.37 (m, 1H), 7.33 (t,
3
J= 7.9 Hz, 1H), 6.94–6.92 (m, 1H), 4.28 (q,
3
J= 7.2 Hz, 2H), 1.28 (t,
3
J= 7.0 Hz, 3H).
13
CNMR:(DMSO‐d
6
,125MHz),δ(ppm) = 161.3, 160.6,
157.8, 145.5, 133.6, 130.4, 127.0, 118.5, 117.0, 112.7, 60.6, 14.1. MS
(ESI+): m/z(%) = 234 (30, [M+H]
+
), 251 (100, [M+NH
4
]
+
), 256 (15, [M
+Na]
+
). HRMS (ESI+) calcd. for C
12
H
12
NO
4
: 234.0761; found: 234.0769.
2‐(3‐Hydroxyphenyl)oxazole‐4‐carboxylic acid
[19]
(46)
44 (128 mg, 0.55 mmol, 1.0 eq) and KOH (93.0 mg, 1.65 mmol,
3.0 eq) were suspended in 5.0 ml MeOH. The reaction mixture was
heated for 24 h at 35°C. The reaction was stopped with H
2
O(20ml)
and the aqueous phase extracted three times with EtOAc
(3×10ml). The aqueous phase was acidified with HCl (pH 4) and
extracted with EtOAc (3 × 20 ml). The combined organic phases
were dried over MgSO
4
and the volatile compounds were removed
under vacuum. The compound was used without further purifica-
tion. 59 mg (0.29 mmol, 52%) of the desired product 46 was ob-
tained as colorless solid.
1
HNMR:(DMSO‐d
6
, 500 MHz), δ
(ppm) = 13.07 (s, 1H), 9.88 (s, 1H), 8.79 (s, 1H), 7.44–7.34 (m, 3H),
6.93 (dd,
3
J=8.0Hz,
4
J= 2.0 Hz, 1H).
13
CNMR:(DMSO‐d
6
,
125 MHz), δ(ppm)=162.0,161.1,157.8,145.1,134.5,130.4,
127.3, 118.3, 116.9, 112.7. MS (ESI+): m/z(%) = 206 (100, [M+H]
+
),
223 (80, [M+NH
4
]
+
). HRMS (ESI+) calcd. for C
10
H
8
NO
4
: 206.0448;
found: 206.0450 and calcd. for C
10
H
7
NO
4
Na: 228.0267; found:
228.0267.
Benzyl 3‐[2‐(3‐hydroxyphenyl)oxazole‐4‐carboxamido]-
propanoate (48)
Following general procedure 2, the carboxylic acid 46
(479 mg, 2.32 mmol, 1.0 eq), β‐alanine benzyl ester (814 mg,
2.32 mmol, 1.0 eq), NEt
3
(0.5 ml, 3.48 mmol, 3.0 eq.), EDC·HCl
(667 mg, 3.48 mmol, 1.5 eq), and HOBt (470 mg, 3.48 mmol,
1.5 eq) in DCM (75 ml) were used. The crude product was purified
via column chromatography (cyclohexane/EtOAc 1:1). 734 mg
(2.00 mmol, 86%) of the desired product 48 wasobtainedascol-
orless solid. R
f
= 0.27 (cyclohexane/EtOAc 1:1). Mp: 159°C.
1
H
NMR: (DMSO‐d
6
,500MHz),δ(ppm) = 9.88 (s, 1H), 8.65 (s, 1H),
8.30 (t,
3
J= 5.9 Hz, 1H), 7.46–7.28 (m, 8H), 6.97–6.95 (m, 1H),
5.11 (s, 2H), 3.56–3.52 (m, 2H), 2.67 (t,
3
J= 6.9 Hz, 2H).
13
CNMR:
(DMSO‐d
6
,125MHz),δ(ppm) = 171.2, 160.6, 159.9, 157.8, 141.8,
137.0, 136.0, 130.4, 128.3, 127.92, 127.89, 127.3, 118.3, 117.0,
112.8, 65.6, 34.7, 33.7. IR: ν(cm
−1
) = 3406 (m), 3165 (m), 3115 (w),
1720 (vs), 1655 (vs), 1605 (m), 1590 (s), 1561 (m), 1525 (m), 1474
(s), 1446 (m), 1421 (m), 1389 (m), 1369 (s), 1311 (s), 1276 (m),
1253(w),1214(s),1193(s),1176(vs),1118(s),1092(m),1080
(m), 1055 (m), 1037 (m), 995 (w), 978 (m), 963 (m), 934 (m), 873
(m), 842 (m), 832 (m), 792 (s), 756 (vs), 725 (vs), 703 (s), 682 (m),
609 (m), 585 (s), 566 (m), 531 (m), 514 (w), 497 (m), 473 (m), 450
(m). MS (ESI+): m/z(%) = 367 (100, [M+H]
+
), 384 (80, [M+NH
4
]
+
),
389 (20, [M+Na]
+
). HRMS (ESI+) calcd. for C
20
H
19
N
2
O
5
:
367.1288; found: 367.1280.
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PETER VENTURA ET AL.

3‐[2‐(3‐Hydroxyphenyl)oxazole‐4‐carboxamido]propanoic acid (50)
In a flask, 48 (400 mg, 1.09 mmol, 1.0 eq) and Pd/C (33.0 mg,
0.11 mmol, 10 mol%) were suspended in MeOH (100 ml). The re-
actionmixturewasstirredatrtunderaH
2
atmosphere. The solid
compounds were filtered and the solvent evaporated under va-
cuum. The crude product was recrystallized from EtOAc/cyclo-
hexane (as much EtOAc given until it dissolved; then heated to
reflux and then cyclohexane was added dropwise until the pre-
cipitate took long time to get dissolved. Then the solution was
cooled down slowly overnight and the precipitated compound
filtered). 211 mg (0.76 mmol, 70%) of the desired product 50 was
obtained as colorless solid. Mp: 177°C.
1
HNMR:(DMSO‐d
6
,
400 MHz), δ(ppm) = 8.64 (s, 1H), 8.26 (t,
3
J= 5.8 Hz, 1H),
7.45–7.40 (m, 2H), 7.35 (t,
3
J=7.9Hz,1H),6.96(dd,
3
J=8.0Hz,
4
J= 1.5 Hz, 1H), 3.49–3.44 (m, 4H).
13
CNMR:(DMSO‐d
6
,
100 MHz), δ(ppm) = 173.3, 160.7, 159.9, 150.0, 141.9, 137.1,
130.5, 127.3, 118.4, 117.0, 112.8, 34.8, 34.1. IR: ν(cm
−1
) = 3363
(w), 3062 (m), 2974 (m), 2846 (w), 2719 (w), 2638 (w), 1713 (vs),
1649 (vs), 1593 (vs), 1564 (s), 1527 (m), 1527 (s), 1476 (s), 1446
(m), 1427 (m), 1411 (m), 1383 (s), 1313 (m), 1277 (m), 1221 (s),
1195 (s), 1176 (vs), 1114 (s), 1089 (w), 1069 (w), 1032 (w), 997 (w),
966 (w), 933 (w), 909 (m), 875 (m), 838 (m), 791 (s), 759 (w), 726 (s),
681 (vs), 673 (vs), 601 (w), 580 (m), 567 (m), 534 (m), 520 (m), 471
(m), 451 (m). MS (ESI+): m/z(%) = 277 (100, [M+H]
+
), 294 (60, [M
+NH
4
]
+
), 299 (20, [M+Na]
+
). HRMS (ESI+) calcd. for C
13
H
13
N
2
O
5
:
277.0819; found: 277.0818.
3‐Hydroxybenzothioamide
[20]
(43)
Under an argon atmosphere, 3‐hydroxybenzamide (42,
200 mg, 1.46 mmol, 1.0 eq) and Lawesson's reagent (708 mg,
1.75 mmol, 1.2 eq) were dissolved in THF (22 ml) at rt. The reaction
mixture was stirred overnight. The volatile compounds were re-
movedundervacuumandthecrudeproductwaspurifiedvia
column chromatography (cyclohexane/EtOAc 1:1). 105 mg
(0.67 mmol, 47%) of the desired product 43 wasobtainedasyel-
low solid. R
f
= 0.38 (cyclohexane/EtOAc 1:1).
1
HNMR:(DMSO‐d
6
,
400 MHz), δ(ppm) = 9.75 (s, 1H), 9.61 (s, 1H), 9.36 (s, 1H),
7.32–7.17 (m, 3H), 6.89–6.87 (m, 1H).
13
CNMR:(DMSO‐d
6
,
100 MHz), δ(ppm) = 200.3, 156.8, 141.0, 128.9, 118.1, 117.4,
114.9. MS (ESI+): m/z(%) = 154 (100, [M+H]
+
). HRMS (ESI+) calcd.
for C
7
H
8
NOS: 154.0321; found: 154.0329.
Ethyl 2‐(3‐hydroxyphenyl)thiazole‐4‐carboxylate
[21]
(45)
The thioamide 43 (100 mg, 0.65 mmol, 1.0 eq) and ethyl bro-
mopyruvate (0.1 ml, 0.72 mmol, 1.1 eq) were dissolved in EtOH (5 ml).
The reaction mixture was stirred for 6 h at 87°C. Then, the solvent
was removed under vacuum. The crude product was purified
via column chromatography (cyclohexane/EtOAc 3:1). 127 mg
(0.51 mmol, 78%) of the desired product 45 was obtained as colorless
solid. R
f
= 0.29 (cyclohexane/EtOAc 3:1).
1
H NMR: (DMSO‐d
6
,
400 MHz), δ(ppm = 9.81 (s, 1H), 8.54 (s, 1H), 7.41–7.31 (m, 3H),
6.93–6.90 (m, 1H), 4.34 (q,
3
J= 7.1 Hz, 2H), 1.33 (t,
3
J= 7.1 Hz, 3H).
13
C NMR: (DMSO‐d
6
, 100 MHz), δ(ppm) = 167.3, 160.7, 158.0,
146.8, 133.5, 130.5, 129.0, 118.0, 117.3, 112.6, 60.8, 14.2. MS (ESI
+): m/z(%) = 250 (100, [M+H]
+
). HRMS (ESI+) calcd. for C
12
H
12
NO
3
S:
250.0532; found: 250.0527 and calcd. for C
12
H
11
NNaO
3
S:
272.0352; found: 272.0349.
2‐(3‐Hydroxyphenyl)thiazole‐4‐carboxylic acid
[19]
(47)
45 (320 mg, 1.28 mmol, 1.0 eq) and KOH (216 mg, 3.85 mmol,
3.0 eq) were suspended in 5.0 ml MeOH. The reaction mixture was
heated for 24 h at 35°C. The reaction was stopped with H
2
O (20 ml)
and the aqueous phase extracted three times with EtOAc (3 × 20 ml).
The aqueous phase was acidified with HCl (pH 4) and extracted with
EtOAc (3 × 20 ml). The combined organic phases were dried over
MgSO
4
and the volatile compounds were removed under vacuum.
The compound was used without further purification. 205 mg
(0.93 mmol, 73%) of the desired product 47 was obtained as colorless
solid.
1
H NMR: (DMSO‐d
6
, 400 MHz), δ(ppm) = 13.07 (s, 1H), 9.79 (s,
1H), 8.46 (s, 1H), 7.40–7.30 (m, 3H), 6.91 (d,
3
J= 8.9 Hz, 1H).
13
C
NMR: (DMSO‐d
6
, 125 MHz), δ(ppm) = 167.4, 162.0, 157.9, 148.0,
133.6, 130.4, 128.5, 117.8, 117.2, 112.7. MS (ESI+): m/z(%) = 222
(100, [M+H]
+
), 239 (30, [M+NH
4
]
+
). HRMS (ESI+) calcd. for
C
10
H
8
NO
3
S: 222.0219; found: 222.0219.
PETER VENTURA ET AL.
|
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Benzyl 3‐[2‐(3‐hydroxyphenyl)thiazole‐4‐carboxamido]-
propanoate (49)
Following general procedure 2, the carboxylic acid 47 (201 mg,
0.91 mmol, 1.0 eq), β‐alanine benzyl ester (319 mg, 0.91 mmol,
1.0 eq), NEt
3
(0.4 ml, 2.37 mmol, 3.0 eq), EDC·HCl (263 mg,
1.37 mmol, 1.5 eq), and HOBt (185 mg, 1.37 mmol, 1.5 eq) in DCM
(25 ml) were used. The crude product was purified via column chro-
matography (cyclohexane/EtOAc 1:1). 272 mg (0.71 mmol, 78%) of
the desired product 49 was obtained as colorless solid. R
f
= 0.32
(cyclohexane/EtOAc 1:1). Mp: 111°C.
1
H NMR: (DMSO‐d
6
,
400 MHz), δ(ppm) = 9.80 (s, 1H), 8.53 (t,
3
J= 6.0 Hz, 1H), 8.26 (s, 1H),
7.45–7.27 (m, 8H), 6.94–6.91 (m, 1H), 5.11 (s, 2H), 3.60–3.55 (m,
2H), 2.69 (t,
3
J= 6.9 Hz, 2H).
13
C NMR: (DMSO‐d
6
, 100 MHz), δ
(ppm) = 171.3, 167.3, 160.4, 157.9, 150.4, 136.0, 133.6, 130.3,
128.3, 127.9, 127.9, 123.8, 117.8, 117.3, 112.9, 65.6, 35.0, 33.8. IR: ν
(cm
−1
) = 3391 (w), 3150 (w), 3120 (w), 1720 (vs), 1643 (s), 1595 (s),
1552 (s), 1490 (m), 1470 (m), 1448 (s), 1416 (vs), 1394 (m), 1370 (m),
1321 (m), 1277 (s), 1241 (s), 1208 (m), 1182 (vs), 1154 (s), 1121 (m),
1078 (w), 1041 (w), 1027 (m), 987 (m), 938 (m), 892 (s), 864 (w), 841
(s), 769 (s), 730 (vs), 693 (s), 683 (s), 639 (w), 607 (s), 588 (vs), 544 (m),
526 (m), 475 (w), 451 (m), 441 (m). MS (ESI+): m/z(%) = 383 (100, [M
+H]
+
), 400 (90, [M+NH
4
]
+
), 404 (30, [M+Na]
+
). HRMS (ESI+) calcd. for
C
20
H
19
N
2
O
4
S: 383.1060; found: 383.1064.
3‐[2‐(3‐Hydroxyphenyl)thiazole‐4‐carboxamido]propanoic acid (51)
In a flask, 49 (100 mg, 0.26 mmol, 1.0 eq) and Pd/C (3.00 mg,
0.03 mmol, 10 mol%) were suspended in MeOH (12 ml). The reaction
mixture was stirred at rt under a H
2
atmosphere. The solid com-
pounds were filtered, and the solvent evaporated under vacuum. The
crude product was recrystallized from EtOAc/cyclohexane (as much
EtOAc given until it dissolved; then heated to reflux and then cy-
clohexane was added dropwise until the precipitate took long time to
get dissolved. Then the solution was cooled down slowly overnight
and the precipitated compound filtered). 41 mg (0.14 mmol, 54%) of
the desired product 51 was obtained as colorless solid. Mp: 174°C.
1
H NMR: (DMSO‐d
6
, 500 MHz), δ(ppm) = 12.15 (s, 1H), 9.79 (s, 1H),
8.46 (t,
3
J= 5.7 Hz, 1H), 8.26 (s, 1H), 7.45–7.42 (m, 2H), 7.32 (t,
3
J= 7.9 Hz, 1H), 6.93–6.91 (m, 1H), 3.53–3.49 (m, 2H), 2.55 (t,
3
J= 7.0 Hz, 2H).
13
C NMR: (DMSO‐d
6
, 125 MHz), δ(ppm) = 173.0,
167.3, 160.3, 157.9, 150.5, 133.6, 130.3, 123.7, 117.8, 117.2, 112.9,
34.9, 33.8. IR: ν(cm
−1
) = 3402 (w), 3338 (m), 3087 (m), 2490 (w),
1702 (s), 1619 (s), 1592 (s), 1548 (vs), 1482 (m), 1446 (vs), 1410 (m),
1361 (w), 1332 (w), 1279 (m), 1264 (vs), 1250 (s), 1209 (s), 1160 (m),
1135 (w), 1080 (m), 1040 (w), 1027 (w), 992 (m), 967 (m), 942 (m),
889 (m), 878 (m), 845 (s), 820 (m), 773 (m), 761 (s), 684 (s), 669 (m),
612 (s), 590 (vs), 539 (m), 525 (s), 467 (m), 440 (w), 417 (m). MS (ESI+):
m/z(%) = 293 (60, [M+H]
+
). HRMS (ESI+) calcd. for C
13
H
13
N
2
O
4
S:
293.0591; found: 293.0587.
4.2 |Pharmacological/biological assays
In vitro assay on S. mansoni couples: Animal experiments have been ap-
proved by the Regional Council (Regierungspräsidium) Giessen (V54‐19
c20/15 cGI18/10) and were performed in accordance with the European
Convention for the Protection of Vertebrate Animals used for Experi-
mental and Other Scientific Purposes (ETS No 123; revised appendix A).
Forty‐six days after infection of Syrian hamsters (Mesocricetus
auratus)withcercariae,
[22]
S. mansoni couples were obtained by hepa-
toportal perfusion and incubated in M199 medium (Gibco) supple-
mented with 10% newborn calf serum (Sigma‐Aldrich),1%HEPES(1M;
Carl Roth), and 1% antibiotic antimycotic (10,000 units penicillin, 10 mg
streptomycin, 25 mg amphotericin Bperml;ABAM,GEHealthcare)at
37°C with 5% CO
2
.Twenty‐four after the perfusion, in vitro culture
experiments were started. Six‐well plates (Greiner Bio‐One) were filled
with 10 couples per well and a total volume of 5 ml (medium +
compound). All substances were dissolved as 10 mM stock solutions in
DMSO. The substances were initially tested at 25 µM. When a positive
result was achieved with a substance, a new experiment was performed
at a lower concentration (10 µM). DMSO (25 µM) was used in every
experiment as the negative control, whereas PZQ (5µM) served as a
positive control. Every 24 h in the total of 72 h of culture, the worms
were evaluated for their pairing stability and phenotypes (such as gut
dilatation, vitality, and motility) under bright‐field microscopy and then
transferred to new plates containing fresh medium and substance. Eggs
produced during each 24 h period were counted. Compounds showing a
reduction in egg production only werenotregardedasactivecom-
pounds. Compounds showing at least one phenotype in addition to a
reduction in egg numbers were regarded as active and retested two
times with different worm batches. For active compounds, three in-
dependent test experiments were performed.
ACKNOWLEDGMENTS
This project was funded by the LOEWE centre DRUID within the
Hessian Excellence Initiative (Martin Schlitzer, Christoph G.
Grevelding, Arnold Grünweller, and Simone Haeberlein) and the DFG
16 of 17
|
PETER VENTURA ET AL.

(SCHL 383/6‐1 and GR1549/10‐1). Open Access funding enabled
and organized by Projekt DEAL.
CONFLICTS OF INTERESTS
The authors declare that there are no conflicts of interests.
ORCID
Martin Schlitzer http://orcid.org/0000-0002-3334-6273
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SUPPORTING INFORMATION
Additional Supporting Information may be found online in the
supporting information tab for this article.
How to cite this article: A. M. Peter Ventura, S. Haeberlein, L.
Konopka, W. Obermann, A. Grünweller, C. G. Grevelding, M.
Schlitzer, Arch. Pharm.2021, e2100259.
https://doi.org/10.1002/ardp.202100259
PETER VENTURA ET AL.
|
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