Biarylalkyl Carboxylic Acid Derivatives as Novel Antischistosomal Agents

Article abstract of DOI:10.1002/cmdc.201600127

Parasitic platyhelminths are responsible for serious infectious diseases, such as schistosomiasis, which affect humans as well as animals across vast regions of the world. The drug arsenal available for the treatment of these diseases is limited; for example, praziquantel is the only drug currently used to treat ≥240 million people each year infected with Schistosoma spp., and there is justified concern about the emergence of drug resistance. In this study, we screened biarylalkyl carboxylic acid derivatives for their antischistosomal activity against S. mansoni. These compounds showed significant influence on egg production, pairing stability, and vitality. Tegumental lesions or gut dilatation was also observed. Substitution of the terminal phenyl residue in the biaryl scaffold with a 3-hydroxy moiety and derivatization of the terminal carboxylic acid scaffold with carboxamides yielded compounds that displayed significant antischistosomal activity at concentrations as low as 10 μm with satisfying cytotoxicity values. The present study provides detailed insight into the structure–activity relationships of biarylalkyl carboxylic acid derivatives and thereby paves the way for a new drug-hit moiety for fighting schistosomiasis.

Full text of DOI:10.1002/cmdc.201600127

DOI: 10.1002/cmdc.201600127
Full Papers
Biarylalkyl Carboxylic Acid Derivatives as Novel
Antischistosomal Agents
Patrick Mꢀder,[a] Ariane S. Blohm,[b] Thomas Quack,[b] Kerstin Lange-Grꢁnweller,[a]
Arnold Grꢁnweller,[a] Roland K. Hartmann,[a] Christoph G. Grevelding,*[b] and
Martin Schlitzer*[a]
Parasitic platyhelminths are responsible for serious infectious
diseases, such as schistosomiasis, which affect humans as well
as animals across vast regions of the world. The drug arsenal
available for the treatment of these diseases is limited; for ex-
ample, praziquantel is the only drug currently used to treat
ꢀ240 million people each year infected with Schistosoma spp.,
and there is justified concern about the emergence of drug re-
sistance. In this study, we screened biarylalkyl carboxylic acid
derivatives for their antischistosomal activity against S. manso-
ni. These compounds showed significant influence on egg pro-
duction, pairing stability, and vitality. Tegumental lesions or gut
dilatation was also observed. Substitution of the terminal
phenyl residue in the biaryl scaffold with a 3-hydroxy moiety
and derivatization of the terminal carboxylic acid scaffold with
carboxamides yielded compounds that displayed significant
antischistosomal activity at concentrations as low as 10 mm
with satisfying cytotoxicity values. The present study provides
detailed insight into the structure–activity relationships of biar-
ylalkyl carboxylic acid derivatives and thereby paves the way
for a new drug-hit moiety for fighting schistosomiasis.
Introduction
Schistosomiasis is one of the most prevalent parasitic infec-
tions worldwide, and it affects over 240 million people in the
tropics and subtropics, whereas over 780 million people are at
risk of infection.[1–3] The disease is usually caused by one of
three schistosome species that mainly affect humans: Schisto-
soma japonicum, Schistosoma mansoni, and Schistosoma hae-
matobium.
As the only member of the platyhelminths, schistosomes
live dioeciously. Since the 1980s, praziquantel (PZQ, 1;
Figure 1) has been the drug of choice for the treatment of
schistosomiasis, because it is orally effective against all schisto-
some species with a one-time treatment. PZQ (1) is significant-
ly more effective than oxamniquine (2) in the treatment of
S. mansoni infection,[4,5] and it is also effective in patients in-
fected with oxamniquine-resistant S. mansoni.[6] PZQ (1) is very
cheap (0.2 USD for a child) and is well tolerated at therapeutic
doses.[4] However, the long-term use of one drug may result in
drug-resistant parasites. Importantly, decreased susceptibility
of S. mansoni and S. haematobium to PZQ (1) has already been
observed.[7,8]
Figure 1. Structures of praziquantel (1) and oxamniquine (2).
Thus, there is an urgent need to develop novel antischisto-
somal compounds, and the identification of further drug tar-
gets is an important step toward this aim. Antioxidant defense
is an essential mechanism for schistosomes to cope with
damage from host immune-generated and self-generated reac-
tive oxygen species (ROS).[9] Many redox-associated proteins
such as thioredoxin glutathione reductase, peroxiredoxin, and
thioredoxin have been demonstrated in previous studies to be
involved in this regulatory defense system.[10–13] Although there
is no experimental evidence that shows that Schistosoma
aldose reductase (AR) participates in the antioxidant pathway
in other organisms, AR is believed to be an important antioxi-
dant component. Furthermore, the levels of AR expression as
well as its activity are increased during hyperglycemia and
other oxidative stress-induced diseases in humans.[14,15] Addi-
tionally, many by-products of oxidative stress, such as methyl-
glyoxal and 3-deoxyglucosone, have been shown to be excel-
lent substrates of AR.[16] Considering these facts and the antiox-
idant requirements of schistosomes living in a hostile environ-
ment within the vascular system of vertebrates, it is reasonable
to speculate that Schistosoma AR might also participate in anti-
[a] P. Mꢀder, Dr. K. Lange-Grꢁnweller, Dr. A. Grꢁnweller,
Prof. Dr. R. K. Hartmann, Prof. Dr. M. Schlitzer
Department of Pharmaceutical Chemistry, Philipps-Universitꢀt Marburg,
Marbacher Weg 6, 35032 Marburg (Germany)
E-mail: schlitzer@staff.uni-marburg.de
[b] A. S. Blohm, Dr. T. Quack, Prof. Dr. C. G. Grevelding
BFS, Institute for Parasitology, Justus-Liebig-Universitꢀt Gießen,
Schubertstraße 81, 35392 Gießen (Germany)
E-mail: christoph.grevelding@vetmed.uni-giessen.de
Supporting Information for this article can be found under http://
dx.doi.org/10.1002/cmdc.201600127.
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oxidant pathways and protect the worms from attack of host
ROS. Indeed, in the context of the genome project of S. manso-
ni, two AR orthologues have been identified (i.e., Smp_150700
and Smp_053220).[17–19] According to the relative gene expres-
sion data, one of these orthologues (i.e., Smp_150700) was
found to be exclusively expressed in larval and juvenile stages,
whereas the other (i.e., Smp_053220) was found to dominate
in adults. This expression pattern was independently confirmed
by RNA-seq analyses, which showed a dominant gene expres-
sion profile in adult S. mansoni for Smp_053220, whereas no
expression products of Smp_150700 occurred in adults.[20]
Moreover, ARs have also been demonstrated to play important
roles in aldehyde detoxification, steroid metabolism, energy
supply, cellular proliferation, apoptosis, and senescence.[21–24]
The potential functions of AR in schistosomes and the fact
that only one of its isoforms was found to be expressed in
adults suggest that this enzyme may fulfill a key role(s) in this
parasite. Therefore, we decided to investigate the in vitro po-
tential of some human AR inhibitors (see compounds 3–10)
available from one of our previous studies against S. mansoni
(Figure 2).[25]
pound 4 produced a different phenotype and showed a signifi-
cant decrease in egg production (20 eggs in 72 h, untreated
control: 2318 eggs in 72 h). Furthermore, the eggs produced
were highly deformed. Thus, compound 4 also had an influ-
ence on egg synthesis. Likewise, the pairing stability of the
worm couples was decreased (only five of ten couples were
paired relative to the control), whereas gut peristalsis and mo-
tility were normal. All other compounds tested showed abso-
lutely no effect on pairing stability, gut peristalsis, vitality, mo-
tility, or egg production, which suggests that electron-with-
drawing substituents on the phenyl ring lead to a loss of activi-
ty. On the basis of these results, we decided to synthesize addi-
tional derivatives of compound 4.
Results and Discussion
Chemistry
Scheme 1 illustrates the synthesis of aryl 4-oxobutanoic acids
12 and aryl 5-oxopentanoic acids 13 following a previously de-
scribed procedure.[25] Suzuki coupling in ethanol with the ap-
propriate boronic acid and 2-bromothiophene catalyzed by
palladium acetate and tetra-n-butylammonium bromide (TBAB)
yielded resulting biaryl precursors 11. Friedel–Crafts acylation
with succinic anhydride or glutaric anhydride and AlCl3 in di-
chloromethane yielded corresponding aryl 4-oxobutanoic acids
12 or aryl 5-oxopentanoic acids 13, respectively.
Scheme 1. Synthesis of 4-oxobutanoic acids 12 and 5-oxopentanoic acids
13. Reagents and conditions: a) K3PO4, (Bu)4NBr, Pd(OAc)2, EtOH, RT, 10 h;
b) succinic anhydride or glutaric anhydride, dichloromethane or 1,2-dichloro-
ethane, AlCl3, À58C to RT, overnight. See Table 1 for R groups.
Derivatization of 4-oxo-4-(5-phenyl-2-thienyl)butanoic acid
(4) and 5-oxo-5-(5-phenyl-2-thienyl)butanoic acid (13a) is
shown in Scheme 2. Wolff–Kishner reduction with potassium
hydroxide and hydrazine monohydrate in diethylene glycol
yielded corresponding butanoic acid 14a and pentanoic acid
14b. Esterification of 12a and 13a to give compounds 15a
and 15b was conducted in methanol with concentrated sulfu-
ric acid. Carboxamides 16a and 16b were prepared under
mild conditions: 12a and 13a were separately coupled with
diethylamine by using 1-ethyl-3-(3-dimethylaminopropyl)carbo-
diimide (EDC)/hydroxybenzotriazole (HOBt) in dichlorome-
thane.
Figure 2. Structures of the initially tested human aldose reductase inhibitors
against Schistosoma mansoni.
All compounds tested had a biaryl 4-oxobutanoic acid or
biaryl butanoic acid moiety and had, with the exception of
compound 4, an electron-withdrawing substituent in the 3- or
4-position of the terminal ring.
Because of the unavailability of recombinantly expressed
Schistosoma AR, we tested the compound series in vitro
against adult worms. As assay parameters, pairing stability, gut
peristalsis, vitality, motility, and egg production were initially
investigated at a concentration of 100 mm.[26,27] Whereas PZQ,
used as control, caused especially tegumental damage and pa-
ralysis of treated worms (up to a concentration of 5 mm), com-
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tron-withdrawing substituent, in line with our supposition.
Moreover, bioisosteric substitution of the phenyl ring with
thiophene (e.g., to give compound 12p) revealed the same
result, and extension of the linker chain by one methylene unit
(e.g., to give compound 13a) led to an increase in activity. In-
troduction of more spacious, lipophilic residues such as naph-
thyl (e.g., to give compound 12m) led to inactive compounds.
Interestingly, compound 12k carrying a hydrophilic 3-hydroxy-
phenyl moiety caused an increase in activity and resulted in
additional phenotypes. In addition to a decline in egg produc-
tion within 72 h at 100 mm, the pairing stability decreased
within the same period. Furthermore, worms showed slowed
gut peristalsis, whereas the general motility seemed to be
normal. Some males showed slight tegumental damage. Given
that a polar residue with a negative induction effect and a posi-
tive mesomeric effect was expected to yield an inhibitor with
good activity, corresponding 3-aminophenyl derivative 12j was
also synthesized and tested. Unfortunately, compound 12j was
inactive. This finding suggests that deprotonatable groups are
tolerated, but not protonatable groups. All active compounds
were also tested at lower concentrations. The lowest active
concentrations and cytotoxicity values are given in Table 1.
Next, we wanted to verify whether the keto carbonyl group
was essential for activity. Wolff–Kishner reduction yielded cor-
responding butanoic acid 14a and pentanoic acid 14b. Where-
as the activity of compound 14b was improved relative to that
of compound 4 (no eggs produced within 72 h, only two of
ten couples were paired at 100 mm) and no cytotoxicity was
Scheme 2. Derivatization of 4 and 13a. Reagents and conditions:
a) NH2NH2·H2O, KOH, diethylene glycol, 1808C, 2 h; b) concentrated sulfuric
acid, MeOH, reflux, 6 h; c) HN(Et)2, EDC/HOBt, NEt3, dichloromethane, 08C to
RT, overnight.
Biological evaluation and structure–activity relationships
An established in vitro culture system for adult S. mansoni was
used to study the effects of all compounds.[26,27] Activity was
assessed on the basis of observable phenotypes such as pair-
ing stability, gut peristalsis, vitality, motility, tegumental dam-
ages, and egg production. DMSO-treated worms served as
negative control, whereas PZQ-treated worms as positive con-
trols provided the standard for qualitative comparisons. De-
tailed description of the phenotypes caused by this type of
compounds will be published in due course.[28] Cytotoxicity
values were determined in a cell proliferation assay (i.e., WST
assay) with HepG2 and LS174T cells based on decreased ab-
sorbance at l=450 nm and by using DMSO alone as negative
control. Antischistosomal activities and cytotoxicity values are
given in Tables 1–3.
Table 1. 4-Oxobutanoic acids 4 and 12 and 5-oxopentanoic acids 13.
Compd
R
n
Activity [mm][a]
Cytotoxicity [mm][b]
To identify preliminary structure–activity relationships, we
started with the replacement of the electron-withdrawing sub-
stituents by alkyl or alkoxy substituents. Another promising ap-
proach was the introduction of hydrophilic residues. We also
used other aryl residues such as naphthyl and thienyl instead
of the phenyl residue. For proof of concept, we synthesized 4-
[5-(3-nitrophenyl)-2-thienyl]-4-oxobutanoic acid (12i), which
should show no activity. Elongation of the chain length of the
linker was another strategy to increase the activity.
HepG2
LS174T
4
C6H5
4-MeC6H4
3-MeC6H4
2-MeC6H4
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
100
NA
100
NA
NA
100
NA
NA
NA
NA
NA
25
NA
NA
NA
NA
100
NA
100
NA
50
ꢀ100
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ꢁ50
ND
ND
ND
ND
ND
ND
ꢀ100
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ꢀ100
12a
12b
12c
12d
12e
12 f
12g
12h
12i
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
2,4-(MeO)2C6H3
4-MeO-3,5-Me2C6H2
3-O2NC6H4
3-H2NC6H4
3-HOC6H4
4-HO2CCH2C6H4
1-naphthyl
2-naphthyl
4-PhC6H4
Furthermore, a substituent was introduced in the 2-, 3-, or 4-
position of the phenyl ring. Only six compounds showed satis-
factory activity at 100 mm. Compounds 12b, 12e, and 12r with
an electron-donating moiety and, therefore, an electron-rich
phenyl ring showed activity very similar to that of compound
4. These compounds also resulted in a significant decrease in
egg production, and the remaining eggs were as deformed as
those in the case of compound 4. Likewise, the pairing stability
of the worm couples was decreased, and gut peristalsis and
motility were slightly decreased. This suggests that only meta-
substituted, electron-rich substituents were tolerated by the
putative target enzyme. Compound 12i, made for proof of
concept, was as inactive as any other compound with an elec-
12j
12k
12l
12m
12n
12o
12p
12q
12r
12s
13a
2-thienyl
4-BnOC6H4
3-BnOC6H4
2-BnOC6H4
C6H5
ND
ND
ꢀ100
[a] Values are the lowest concentrations required to observe inhibitory ef-
fects on Schistosoma mansoni; NA=not active. [b] All measurements
were performed at least three times; ND=not determined.
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observed up to the tested concentration of 100 mm, compound
14a was inactive. Two important conclusions can be inferred
from this finding: a carbonyl group does not seem to be es-
sential and elongation of the linker chain increases activity.
Subsequently, we tried a prodrug concept by using corre-
sponding carboxylic acid methyl esters 15a and 15b with the
aim to improve bioavailability as a result of the loss of the neg-
atively charged carboxylate and the resulting superior mem-
brane permeability. This approach yielded compounds with ac-
tivities and phenotypes similar to those of the oxocarboxylic
acid compounds. However, given that the free carboxylic acid
has been shown to be a potential interaction partner of the a-
1-acid glycoprotein and other serum proteins, derivatization of
the carboxylic acid to carboxamides 16a and 16b was the sub-
sequent step.[29–31] Surprisingly, we observed a massive increase
in activity. At 100 mm, both compounds completely inhibited
egg production and pairing stability (no eggs within 72 h,
complete loss of pairing stability of formerly 10 worms cou-
ples) and caused strongly decreased motility, vitality, and gut
peristalsis. Compound 16b was more active than 16a, as all
treated worms were already dead within 24 h at a concentra-
tion of 100 mm. Here, we were also able to observe new phe-
notypes, as in addition to the decrease in pairing stability and
egg production, tegumental damage and gut dilatation oc-
curred. All active compounds were also tested at a lower con-
centration (50 mm) with nearly the same results. The lowest
active concentrations and cytotoxicity values are given in
Table 2.
Figure 3. Combinatorial series considered to represent the best optimization
solutions.
pounds showed satisfying activity up to a concentration of
10 mm, although compound 17b was slightly less potent.
Again, tegumental damage including bubbles occurred as well
as strongly diminished pairing stability, motility, vitality, egg
production, and no gut peristalsis. The lowest active concen-
trations and cytotoxicity values are give in Table 3.
Table 3. Compounds 17a–d.
Compd
R
Activity [mm][a]
Cytotoxicity [mm][b]
HepG2
LS174T
Table 2. Derivatization of 4 and 13a.
17a
17b
17c
17d
PZQ
C(O)(CH2)3CO2H
(CH2)4CO2H
C(O)(CH2)3CON(CH2CH3)2
(CH2)4CON(CH2CH3)2
10
10
10
10
5
ꢀ100
ꢀ100
ꢀ100
ꢀ50
ꢀ50
ꢀ100
ꢀ100
ꢀ50
ꢀ100
ꢀ100
Compd
R
Activity [mm][a]
Cytotoxicity [mm][b]
[a] Values are the lowest concentrations required to observe inhibitory ef-
fects on Schistosoma mansoni; NA=not active. [b] All measurements
were performed at least three times; ND=not determined.
HepG2
LS174T
14a
14b
15a
15b
16a
16b
(CH2)3CO2H
(CH2)4CO2H
C(O)(CH2)2CO2Me
C(O)(CH2)3CO2Me
C(O)(CH2)2CON(CH2CH3)2
C(O)(CH2)3CON(CH2CH3)2
NA
50
100
50
50
50
ꢀ100
ꢀ100
ꢀ100
ꢀ100
ꢁ25
ꢀ100
ꢀ100
ꢀ100
ꢀ100
ND
Carboxamides 17c and 17d also showed an improvement
in activity, and no lethal effects were observed at any of the
tested concentrations. Phenotypic effects included loss of in-
ternal structure; anisocytosis; significant decreases in pairing
stability, motility, vitality, and egg production; as well as the
absence of any gut peristalsis.
ꢁ25
ND
[a] Values are the lowest concentrations required to observe inhibitory ef-
fects on Schistosoma mansoni; NA=not active. [b] All measurements
were performed at least three times; ND=not determined.
With this series of compounds, we identified the following
structure–activity relationships (Figure 4). As shown in the ini-
tial compound series tested, electron-withdrawing substituents
led to a loss of activity. Electron-donating, lipophilic, aromatic,
and hydrophilic residues were introduced, and variations in
the substitution pattern at all possible positions of the terminal
aromatic moiety were evaluated. Only compounds with sub-
stituents in the meta position were active; compounds with
substituents at other ring positions were inactive. Introduction
of a methyl (e.g., to give compound 12b) or an alkoxy sub-
stituent (e.g., to give compounds 12e and 12r) resulted in ac-
Finally, we decided to combine the most active residues by
synthesizing four additional compounds (i.e., compounds
17a–d) illustrated in Figure 3 to verify possible additive effects
on activity and to decrease cytotoxicity further.
Both carboxylic acid compounds 17a and 17b showed an
increase in activity. Lethal effects were observed up to concen-
trations of 25 mm (compound 17a caused lethality after 48 h,
compound 17b after 72 h). The phenotypes also included teg-
umental damage and loss of internal structure as well as a de-
crease in egg production and pairing stability. Both com-
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tion. The present study deepens our understanding of the
structure–activity relationships of this class of compounds and
thereby paves the way for further design efforts toward com-
batting schistosomiasis.
Experimental Section
Biological methods
Figure 4. Structure–activity relationships.
In vitro assay S. mansoni: All animal experiments have been ap-
proved by the Regional Council (Regierungspraesidium) Giessen
(V54-19 c 20/15 c GI 18/10) and were performed in accordance
with the European Convention for the Protection of Vertebrate Ani-
mals used for experimental and other scientific purposes (ETS
No 123; revised Appendix A).
tivities similar to that of parental compound 4. The activity
gained with the (3-hydroxy)phenyl moiety (e.g., as in com-
pound 12k) may be explained by putative H-bond donors pre-
sented in a possible specificity pocket of the target enzyme or
by formation of salt bridges (e.g., involving Lys, Arg, or His resi-
dues). Replacement of the hydroxy group with an amino
group (e.g., to give compound 12j) led to a loss of activity,
which is thus in line with this suggestion. Noteworthy, elonga-
tion of the alkyl spacer by introduction of one methylene unit
(e.g., compound 13a vs. 4) slightly improved the activity. This
provoked the question of whether the carbonyl group of the
alkyl spacer was essential for activity. Two derivatives lacking
this moiety were synthesized (i.e., compounds 14a and 14b),
but both exhibited slightly decreased activity. We attempted
to achieve higher bioavailability by converting the carboxylic
acid moiety into a carboxylic acid ester or into a carboxamide.
Ester derivatives 15a and 15b displayed activities similar to
those of the carboxylic acid compounds, whereas an improve-
ment in activity was observed for carboxamides 16a and 16b.
The carboxylic acid esters may not, or very slowly, be convert-
ed into their corresponding carboxylic acid by schistosomal es-
terases. The combination of the most active residues resulted
in a strong increase in activity and observation of new promis-
ing phenotypes. We assumed that effects on activity were ad-
ditive. Fortunately, 17b and 17c were nontoxic up to a concen-
tration of 100 mm. However, at the same concentration, com-
pound 17a was cytotoxic in LS174T cells and compound 17d
was cytotoxic in both cell lines.
Schistosoma mansoni couples were obtained from Syrian hamsters
(Mesocricetus auratus) by hepatoportal perfusion 46 days after in-
fection with cercariae. They were then maintained in groups of 20
couples at 378C with 5% CO2 in 60 mm diameter Petri dishes
(Greiner bio-one) with M199 medium (Gibco) supplemented with
10% newborn calf serum (NCS, Sigma), 1% HEPES, Roth; [1m]),
and 1% antibiotic antimycotic (ABAM, GE Healthcare; [10000 units
penicillin, 10 mg streptomycin, 25 mg amphotericin B per mL]).[17]
The inhibitor experiments took place in six-well plates (Greiner bio-
one) with ten couples per well and a volume of 5 mL (medium+
inhibitor). The inhibitor concentrations used were 5, 10, 25, 50, 75,
and 100 mm (n=3 for every concentration). The inhibitors were dis-
solved and diluted in dimethyl sulfoxide (DMSO, Sigma–Aldrich).
As the negative control, the same volume of DMSO was added as
in the test wells. Every 24 h, the medium and substance were re-
newed. For this purpose, the worms were transferred to newly pre-
pared six-well plates, and the eggs produced during the preceding
24 h were counted. An evaluation took place every 24 h by bright-
field microscopy. Pairing stability, gut peristalsis, vitality, motility,
and egg production were examined.
Cell culture: HepG2 (human hepatoma) and LS174T (colon carcino-
ma) cells were cultivated with Iscove’s modified Dulbecco medium
(IMDM) with 5 mm l-glutamine and 10% fetal calf serum (FCS) at
378C and 5% CO2 in a humidified atmosphere.
WST-1 assay in HepG2 and LS174T cells: Cells (7.5ꢃ103 cells in
200 mL IMDM, 10% FCS) were seeded in 96-well microplates and
incubated for 24 h (378C, 5% CO2). The medium was replaced with
fresh medium containing 50 or 100 mm of the respective com-
pound, followed by incubation for up to 144 h. DMSO controls
were included for every timepoint and concentration. Samples
were measured after 24, 72, 120, and 144 h (n=3 for every time-
point and concentration). The medium was aspirated and 110 mL
of 10% WST-1 reagent (Roche, Mannheim, Germany) in phosphate-
buffered saline (PBS) was added. Absorbance was measured after
2 h by using a Tecan Safire II (measurement wavelength: 450 nm;
reference wavelength: 600 nm).
Conclusions
Owing to a lack of antischistosomal compounds as alternatives
for praziquantel, the search for novel potent antihelminthics is
of utmost importance.[32] Starting from a modest hit, we devel-
oped a novel series of biaryl carboxylic acid derivatives. The ac-
tivities of these inhibitors were highly dependent on the pres-
ence of a 3-hydroxyphenyl moiety. Through structure–activity
relationship studies, we identified 5-oxopentanoic acid and
pentanoic acid as potent linkers for our inhibitor. We also
found that derivatization of the carboxylic acid into a carboxa-
mide was very useful, whereas derivatization into a carboxylic
acid ester did not improve the activity further. The efficacy
against S. mansoni in vitro and the absence of toxicity make 5-
[5-(3-hydroxyphenyl)-2-thienyl]pentanoic acid (17b) and N,N-
diethyl-5-[5-(3-hydroxyphenyl)-2-thienyl]-5-oxopentanamide
(17c) promising antischistosomal agents for future investiga-
Chemistry
General: 1H NMR and 13C NMR spectra were recorded with Jeol
ECA-500 and Jeol ECX-400 spectrometers; chemical shifts (d) are
reported in ppm relative to the central residual solvent signal.
Mass spectra were recorded with a Varian MAT CH7a and an S.I.S.
VG7070 (note that only the strongest peaks from the mass spectra
are reported). High-resolution mass spectra (ESI) were performed
with a Micromass VG-Autospec spectrometer. Melting points were
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obtained with a Barnstead Thermolyne MEL-TEMP-II microscope.
Reagents and solvents were purchased from abcr, Alfa Aesar, Fluo-
rochem, Matrix Scientific, Merck, Sigma–Aldrich, and Thermo Fisher
Scientific and were purified by distillation or recrystallization, if
necessary. Chromatography refers to flash chromatography with
the use of Macherey–Nagel silica gel (0.040–0.063 mm). Analytical
thin-layer chromatography (TLC) was performed on Merck silica
gel 60 F254 plates. The purities of the compounds were confirmed
by combustion analysis. Analytical data of the precursors can be
found in the Supporting Information.
elemental analysis calcd (%) for C14H12O3S (260.31): C 64.60, H 4.65,
N 0.00; found: C 64.64, H 4.54, N 0.18.
4-Oxo-4-[5-(p-tolyl)-2-thienyl]butanoic acid (12a): 2-(p-Tolyl)thio-
phene (530 mg, 3.04 mmol), succinic anhydride (304 mg,
3.04 mmol), and AlCl3 (892 mg, 6.69 mmol) according to proce-
dure 1 to give 12a as a pale-yellow solid (301 mg, 37%): mp:
1
3
1918C; H NMR (400 MHz, [D6]DMSO): d=2.30 (s, 3H), 2.54 (t, J=
3
3
5.5 Hz, 2H), 3.16 (t, J=5.5 Hz, 2H), 7.24 (d, J=7.6 Hz, 2H), 7.56 (d,
3J=3.2 Hz, 1H), 7.63 (d, 3J=7.6 Hz, 2H), 7.94 (d, 3J=3.4 Hz, 1H),
12.16 (s, 1H); 13C NMR (100 MHz, [D6]DMSO): d=21.4, 28.4, 33.6,
124.9, 126.5, 130.4, 130.5, 135.0, 139.5, 142.0, 151.9, 174.2,
191.9 ppm; MS (ESIÀ): m/z (%): 273 (100) [MÀH]À; HRMS (ESI+):
m/z: calcd for C15H14O3S: 274.0664; found: 274.0661; elemental
analysis calcd (%) for C15H14O3S (274.33): C 65.67, H 5.14, N 0.00;
found: C 65.44, H 5.22, N 0.23.
General procedure 1: Preparation of 4-oxobutanic acids 12 and
5-oxopentanic acids 13 by Friedel–Crafts acylation: The reaction
was performed under an inert atmosphere. The biaryl component
(1.0 equiv) and powdered succinic anhydride or glutaric anhydride
(1.0 equiv) were dissolved in 1,2-dichloroethane or dichlorome-
thane (5 mLmmolÀ1). The mixture was cooled to 08C and AlCl3
(2.2 equiv) was added. After stirring for 5 h at 08C, the mixture was
4-Oxo-4-[5-(m-tolyl)-2-thienyl]butanoic acid (12b): 2-(m-Tolyl)-
thiophene (526 mg, 3.02 mmol), succinic anhydride (302 mg,
3.02 mmol), and AlCl3 (886 mg, 6.64 mmol) according to proce-
dure 1 to give 12b as a pale-yellow solid (394 mg, 48%): mp:
warmed to RT overnight. A solution of aq HCl (10%, 25 mLmmolÀ1
)
was added, and the mixture was stirred for another 30 min. After
extracting with EtOAc (3ꢃ100 mL), the combined organic layer
was extracted with aq NaOH (10%, 5ꢃ100 mL). This layer was ad-
justed to pH 1 with aq HCl (10%). The resulting precipitate was fil-
tered off, washed with water, and dried.
1
3
1848C; H NMR (400 MHz, [D6]DMSO): d=2.32 (s, 3H), 2.55 (t, J=
3
3
6.0 Hz, 2H), 3.16 (t, J=6.0 Hz, 2H), 7.18 (d, J=7.3 Hz, 1H), 7.31 (t,
3J=7.6 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.55 (s, 1H), 7.58 (d, J=
3.3 Hz, 1H), 7.94 (d, 3J=3.9 Hz, 1H), 12.14 ppm (s, 1H); 13C NMR
(100 MHz, [D6]DMSO): d=21.4, 28.4, 33.6, 123.7, 125.4, 127.0, 129.7,
130.4, 133.1, 137.0, 134.9, 142.3, 151.6, 174.4, 192.0 ppm; MS
(ESIÀ): m/z (%): 273 (100) [MÀH]À; HRMS (ESI+): m/z: calcd for
C15H14O3S: 274.0664; found: 274.0658; elemental analysis calcd (%)
for C15H14O3S (274.33): C 65.67, H 5.14, N 0.00; found: C 65.66, H
5.00, N 0.16.
3
3
General procedure 2: Preparation of butanoic acids and penta-
noic acids by Wolff–Kishner reduction: NH2NH2·H2O (4.0 equiv)
and KOH (4.0 equiv) were added to a stirred solution of the 4-oxo-
butanoic acid or 5-oxopentanoic acid (1.0 equiv) in diethylene
glycol (2 mLmmolacidÀ1). The mixture was heated at 1808C. After
cooling, the mixture was diluted with H2O (10 mLmmolacidÀ1). The
mixture was extracted once with EtOAc (200 mL) and adjusted to
pH 1 with aq HCl (10%) and again extracted with EtOAc (3ꢃ ꢃ
100 mL). The combined organic layer was extracted with aq KOH
(5%, 5ꢃ100 mL). The aqueous layer was adjusted to pH 1 with aq
HCl (10%). The precipitate was filtered off and washed with water
to give the butanoic or pentanoic acid derivative.
4-Oxo-4-[5-(o-tolyl)-2-thienyl]butanoic acid (12c): 2-(o-Tolyl)thio-
phene (296 mg, 1.70 mmol), succinic anhydride (170 mg,
1.70 mmol), and AlCl3 (499 mg, 3.74 mmol) according to proce-
dure 1 to give 12c as a pale-yellow solid (220 mg, 47%): mp:
1
3
1098C; H NMR (400 MHz, [D6]DMSO): d=2.37 (s, 3H), 2.56 (t, J=
3
3
5.7 Hz, 2H), 3.18 (t, J=5.7 Hz, 2H), 7.35–7.20 (m, 4H), 7.40 (d, J=
3.3 Hz, 1H), 7.96 (d, 3J=3.4 Hz, 1H), 12.13 ppm (s, 1H); 13C NMR
(100 MHz, [D6]DMSO): d=21.3, 28.3, 33.7, 128.7, 128.9, 129.5, 130.5,
131.5, 131.6, 133.1, 134.0, 136.0, 143.2, 150.9, 174.2, 192.1 ppm; MS
(ESIÀ): m/z (%): 273 (100) [MÀH]À; HRMS (ESI+): m/z: calcd for
C15H14O3S: 274.0664; found: 274.0652; elemental analysis calcd (%)
for C15H14O3S (274.33): C 65.67, H 5.14, N 0.00; found: C 65.58, H
5.07, N 0.32.
General procedure 3: Preparation of methyl carbonates 15: Con-
centrated sulfuric acid (0.5 mLmmolacidÀ1) was added to a stirred
solution of the 4-oxobutanoic acid or 5-oxopentanoic acid
(1.0 equiv) in MeOH (3 mLmmolacidÀ1). The mixture was heated at
reflux overnight followed by evaporation. Purification by flash
chromatography with silica gel gave the resulting product.
General procedure 4: Preparation of carboxamides 16 and 17:
HOBt (1.2 equiv) and EDC (1.2 equiv) were added to a stirred mix-
ture of diethylamine (1.0 equiv) and the carboxylic acid component
(1.0 equiv) in dichloromethane (10 mLmmolÀ1) at 08C under an
argon atmosphere. After 60 min, the solution was allowed to warm
to RT and was stirred for 36 h. It was then washed with 1 M HCl
(3ꢃ25 mL) and 1 M NaOH (3ꢃ25 mL). The organic layer was dried
(MgSO4), filtered, and evaporated. Purification by flash chromatog-
raphy with silica gel gave the resulting product.
4-[5-(4-Methoxyphenyl)-2-thienyl]-4-oxobutanoic acid (12d): 2-
(4-Methoxyphenyl)thiophene (560 mg, 2.95 mmol), succinic anhy-
dride (295 mg, 2.95 mmol), and AlCl3 (866 mg, 6.49 mmol) accord-
ing to procedure 1 to give 12d as a pale-yellow solid (485 mg,
57%): mp: 1658C; 1H NMR (400 MHz, [D6]DMSO): d=2.54 (t, 3J=
3
3
6.2 Hz, 2H), 3.15 (t, J=6.2 Hz, 2H), 3.77 (s, 3H), 6.99 (d, J=8.5 Hz,
3
3
3
2H), 7.48 (d, J=3.7 Hz, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.91 (d, J=
3.7 Hz, 1H), 12.12 ppm (s, 1H); 13C NMR (100 MHz, [D6]DMSO): d=
28.4, 33.5, 55.9, 115.2, 124.3, 125.9, 128.0, 135.1, 142.4, 151.9, 160.6,
174.2, 191.8 ppm; MS (ESIÀ): m/z (%): 289 (100) [MÀH]À; HRMS
(ESI+): m/z: calcd for C15H14O4S: 290.0613; found: 290.0616; ele-
mental analysis calcd (%) for C15H14O4S (290.33): C 62.05, H 4.86, N
0.00; found: C 62.39, H 4.55, N 0.01.
4-Oxo-4-(5-phenyl-2-thienyl)butanoic acid (4): 2-Phenylthiophene
(200 mg, 1.25 mmol), succinic anhydride (125 mg, 1.25 mmol), and
AlCl3 (367 mg, 2.75 mmol) according to procedure 1 to give 4 as
1
a pale-yellow solid (251 mg, 83%): mp: 2018C; H NMR (400 MHz,
[D6]DMSO): d=2.55 (t, 3J=6.4 Hz, 2H), 3.17 (t, 3J=6.4 Hz, 2H),
3
3
4-[5-(3-Methoxyphenyl)-2-thienyl]-4-oxobutanoic acid (12e): 2-
(3-Methoxyphenyl)thiophene (477 mg, 2.51 mmol), succinic anhy-
dride (251 mg, 2.51 mmol), and AlCl3 (736 mg, 5.52 mmol) accord-
ing to procedure 1 to give 12e as a pale-yellow solid (494 mg,
68%): mp: 1578C; 1H NMR (400 MHz, [D6]DMSO): d=2.55 (t, 3J=
7.47–7.36 (m, 3H), 7.61 (d, J=4.1 Hz, 1H), 7.74 (d, J=7.6 Hz, 2H),
7.96 (d, 3J=4.1 Hz, 1H), 12.12 ppm (s, 1H); 13C NMR (100 MHz,
[D6]DMSO): d=28.4, 33.7, 125.6, 126.6, 129.8, 133.2, 134.9, 142.6,
151.6, 174.2, 192.0 ppm; MS (ESIÀ): m/z (%): 259 (100) [MÀH]À;
HRMS (ESI+): m/z: calcd for C14H12O3S: 260.0507; found: 260.0508;
3
3
6.2 Hz, 2H), 3.19 (t, J=6.2 Hz, 2H), 3.79 (s, 3H), 6.95 (d, J=7.1 Hz,
&
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3
1H), 7.40–7.22 (m, 3H), 7.63 (d, J=3.7 Hz, 1H), 7.95 (d, J=3.9 Hz,
1H), 12.13 ppm (s, 1H); 13C NMR (100 MHz, [D6]DMSO): d=28.4,
33.6, 55.8, 111.7, 115.4, 119.0, 125.9, 131.0, 134.5, 134.9, 142.6,
151.4, 160.3, 174.2, 192.0 ppm; MS (ESIÀ): m/z (%): 289 (100)
[MÀH]À; HRMS (ESI+): m/z: calcd for C15H14O4S: 290.0613; found:
290.0625; elemental analysis calcd (%) for C15H14O4S (290.33): C
62.05, H 4.86, N 0.00; found: C 62.33, H 4.95, N 0.11.
305.0365; elemental analysis calcd (%) for C14H11NO5S (305.30): C
55.08, H 3.63, N 4.59; found: C 55.01, H 3.87, N 4.32.
4-[5-(3-Hydroxyphenyl)-2-thienyl]-4-oxobutanoic acid (12k): 3-(2-
Thienyl)phenol (633 mg, 3.59 mmol), succinic anhydride (359 mg,
3.59 mmol), and AlCl3 (1052 mg, 7.89 mmol) according to proce-
dure 1 to give 12k as a pale-yellow solid (326 mg, 33%): mp:
718C; 1H NMR (400 MHz, [D6]DMSO): d=2.52 (t, 3J=6.0 Hz, 2H),
3
4-[5-(2-Methoxyphenyl)-2-thienyl]-4-oxobutanoic acid (12 f): 2-(2-
Methoxyphenyl)thiophene (687 mg, 3.61 mmol), succinic anhydride
(361 mg, 3.61 mmol), and AlCl3 (1059 mg, 7.94 mmol) according to
procedure 1 to give 12 f as a pale-yellow solid (338 mg, 33%): mp:
1668C; 1H NMR (400 MHz, [D6]DMSO): d=2.55 (t, 3J=6.2 Hz, 2H),
3.14 (t, J=5.9 Hz, 2H), 6.73–6.66 (m, 1H), 7.20–7.03 (m, 3H), 7.54
(d, 3J=4.2 Hz, 1H), 7.76 (d, 3J=4.0 Hz, 1H), 12.15 ppm (s, 1H);
13C NMR (100 MHz, [D6]DMSO): d=28.2, 33.6, 112.7, 115.2, 116.8,
131.0, 135.5, 141.2, 144.1, 158.4, 174.3, 194.8 ppm; MS (ESIÀ): m/z
(%): 275 (100) [MÀH]À; HRMS (ESI+): m/z: calcd for C14H12O4S:
276.0456; found: 276.0461; elemental analysis calcd (%) for
C14H12O4S (276.31): C 60.86, H 4.38, N 0.00; found: C 60.77, H 4.35,
N 0.06.
3
3
3.17 (t, J=6.2 Hz, 2H), 3.91 (s, 3H), 7.03 (t, J=7.8 Hz, 1H), 7.16 (d,
3J=8.5 Hz, 1H), 7.37 (t, 3J=7.8 Hz, 1H), 7.67 (d, 3J=4.1 Hz, 1H),
3
3
7.81 (d, J=7.8 Hz, 1H), 7.91 (d, J=4.1 Hz, 1H), 12.12 ppm (s, 1H);
13C NMR (100 MHz, [D6]DMSO): d=28.4, 33.8, 56.3, 113.0, 121.6,
121.7, 126.7, 128.7, 133.2, 130.8, 142.5, 144.5, 156.1, 174.2,
192.3 ppm; MS (ESIÀ): m/z (%): 289 (100) [MÀH]À; HRMS (ESI+):
m/z: calcd for C15H14O4S: 290.0613; found: 290.0603; elemental
analysis calcd (%) for C15H14O4S (290.33): C 62.05, H 4.86, N 0.00;
found: C 62.15, H 4.66, N 0.16.
4-[5-[4-(Carboxymethyl)phenyl]-2-thienyl]-4-oxobutanoic
acid
(12l): Methyl-2-[4-(2-thienyl)phenyl]acetate (414 mg, 1.78 mmol),
succinic anhydride (178 mg, 1.78 mmol), and AlCl3 (523 mg,
3.92 mmol) according to procedure 1 to give 12l as a brown solid
1
(150 mg, 27%): mp: 2458C; H NMR (400 MHz, [D6]DMSO): d=2.55
3
3
3
(t, J=6.2 Hz, 2H), 3.16 (t, J=6.2 Hz, 2H), 3.59 (s, 2H), 7.31 (d, J=
3
3
4-[5-(2,4-Dimethoxyphenyl)-2-thienyl]-4-oxobutanoic acid (12g):
2-(2,4-Dimethoxyphenyl)thiophene (808 mg, 3.67 mmol), succinic
anhydride (367 mg, 3.67 mmol), and AlCl3 (1076 mg, 8.07 mmol) ac-
cording to procedure 1 to give 12g as a pale-yellow solid (660 mg,
56%): mp: 2038C; 1H NMR (400 MHz, [D6]DMSO): d=2.59 (t, 3J=
8.5 Hz, 2H), 7.58 (d, J=3.7 Hz, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.94
(d, 3J=3.7 Hz, 1H), 12.23 ppm (s, 2H); 13C NMR (100 MHz,
[D6]DMSO): d=28.4, 33.6, 40.0, 125.4, 126.4, 130.9, 131.6, 135.0,
136.8, 142.3, 151.3, 173.0, 174.2, 192.0 ppm; MS (ESIÀ): m/z (%):
317 (100) [MÀH]À; HRMS (ESI+): m/z: calcd for C16H14O5S:
318.0562; found: 318.0568; elemental analysis calcd (%) for
C16H14O5S (318.34): C 60.37, H 4.43, N 0.00; found: C 60.33, H 4.45,
N 0.11.
3
6.2 Hz, 2H), 3.21 (t, J=6.2 Hz, 2H), 3.85 (s, 3H), 3.89 (s, 3H), 6.71–
6.63 (m, 2H), 6.83 (s, 1H), 7.52 (d, 3J=4.0 Hz, 1H), 7.61 (d, 3J=
8.1 Hz, 1H), 7.95 (d, 3J=4.1 Hz, 1H), 12.21 ppm (s, 1H); 13C NMR
(100 MHz, [D6]DMSO): d=28.5, 33.2, 56.1, 57.3, 98.6, 108.4, 118.3,
125.7, 129.0, 134.0, 141.1, 150.0, 159.3, 160.7, 174.8, 192.4 ppm; MS
(ESIÀ): m/z (%): 319 (100) [MÀH]À; HRMS (ESI+): m/z: calcd for
C16H16O5S: 320.0718; found: 320.0729; elemental analysis calcd (%)
for C16H16O5S (320.36): C 59.99, H 4.82, N 0.00; found: C 60.01, H
4.82, N 0.36.
4-[5-(1-Naphthyl)-2-thienyl]-4-oxobutanoic acid (12m): 2-(1-
Naphthyl)thiophene (629 mg, 2.99 mmol), succinic anhydride
(299 mg, 2.99 mmol), and AlCl3 (877 mg, 6.58 mmol) according to
procedure 1 to give 12m as a pale-yellow solid (351 mg, 38%):
mp: 1708C; 1H NMR (400 MHz, [D6]DMSO): d=2.59 (t, 3J=6.2 Hz,
3
3
2H), 3.24 (t, J=6.2 Hz, 2H), 7.43 (d, J=3.9 Hz, 1H), 7.67–7.52 (m,
3
4-[5-(4-Methoxy-3,5-dimethylphenyl)-2-thienyl]-4-oxobutanoic
acid (12h): 2-(4-Methoxy-3,5-dimethylphenyl)thiophene (513 mg,
2.35 mmol), succinic anhydride (235 mg, 2.35 mmol), and AlCl3
(690 mg, 5.17 mmol) according to procedure 1 to give 12h as
4H), 8.05–7.95 (m, 2H), 8.06 (d, J=3.9 Hz, 1H), 8.15–8.07 (m, 1H),
12.16 ppm (s, 1H); 13C NMR (100 MHz, [D6]DMSO): d=28.4, 33.7,
125.2, 126.1, 127.0, 127.9, 128.8, 129.2, 129.8, 130.1, 130.9, 131.2,
134.0, 134.2, 143.8, 149.4, 174.3, 192.2 ppm; MS (ESIÀ): m/z (%):
309 (100) [MÀH]À; HRMS (ESI+): m/z: calcd for C18H14O3S:
310.0664; found: 310.0667; elemental analysis calcd (%) for
C18H14O3S: C 69.66, H 4.55, N 0.00; found: C 69.33, H 4.45, N 0.11.
1
a pale-yellow solid (265 mg, 36%): mp: 1498C; H NMR (400 MHz,
[D6]DMSO): d=2.23 (m, 6H), 2.54 (t, 3J=6.4 Hz, 2H), 3.15 (t, 3J=
3
6.4 Hz, 2H), 3.65 (s, 3H), 7.42 (s, 2H), 7.49 (d, J=3.7 Hz, 1H), 7.91
(d, 3J=3.9 Hz, 1H), 12.12 ppm (s, 1H); 13C NMR (100 MHz,
[D6]DMSO): d=16.3, 28.4, 33.5, 59.9, 124.9, 127.0, 128.7, 131.9,
135.0, 141.9, 151.7, 158.1, 174.2, 191.9 ppm; MS (ESIÀ): m/z (%):
317 (100) [MÀH]À; HRMS (ESI+): m/z: calcd for C17H18O4S:
318.0926; found: 318.0922; elemental analysis calcd (%) for
C17H18O4S (318.39): C 64.13, H 5.70, N 0.00; found: C 64.32, H 5.64,
N 0.36.
4-[5-(2-Naphthyl)-2-thienyl]-4-oxobutanoic acid (12n): 2-(2-Naph-
thyl)thiophene (540 mg, 2.57 mmol), succinic anhydride (257 mg,
2.57 mmol), and AlCl3 (754 mg, 5.65 mmol) according to proce-
dure 1 to give 12n as a pale-yellow solid (251 mg, 33%): mp:
2228C; 1H NMR (400 MHz, [D6]DMSO): d=2.57 (t, 3J=6.2 Hz, 2H),
3.19 (t, J=6.2 Hz, 2H), 7.44 (d, J=3.9 Hz, 1H), 7.80–7.62 (m, 4H),
8.01 (d, 3J=3.9 Hz, 1H), 8.0–7.92 (m, 2H), 8.35–8.28 (m, 1H),
12.17 ppm (s, 1H); 13C NMR (100 MHz, [D6]DMSO): d=28.4, 33.6,
124.4, 125.4, 126.0, 127.4, 127.5, 128.2, 128.8, 130.6, 133.5, 133.6,
135.1, 139.4, 142.7, 151.6, 174.0, 192.0 ppm; MS (ESIÀ): m/z (%):
309 (100) [MÀH]À; HRMS (ESI+): m/z: calcd for C18H14O3S:
310.0664; found: 310.0667; elemental analysis calcd (%) for
C18H14O3S: C 69.66, H 4.55, N 0.00; found: C 69.51, H 4.57, N 0.32.
3
3
4-[5-(3-Nitrophenyl)-2-thienyl]-4-oxobutanoic acid (12i): 2-(3-Ni-
trophenyl)thiophene (737 mg, 3.59 mmol), succinic anhydride
(359 mg, 3.59 mmol), and AlCl3 (1054 mg, 7.90 mmol) according to
procedure 1 to give 12i as a brown solid (675 mg, 62%): mp:
1868C; 1H NMR (400 MHz, [D6]DMSO): d=2.56 (t, 3J=6.0 Hz, 2H),
3
3
3
3.20 (t, J=6.0 Hz, 2H), 7.73 (t, J=8.0 Hz, 1H), 7.83 (d, J=3.2 Hz,
1H), 8.02 (d, 3J=3.2 Hz, 1H), 8.26–8.15 (m, 2H), 8.48 (s, 1H),
12.15 ppm (s, 1H); 13C NMR (100 MHz, [D6]DMSO): d=28.4, 33.8,
57.8, 120.7, 124.0, 127.6, 131.5, 132.8, 134.8, 134.9, 143.9, 148.4,
149.0, 174.1, 192.2 ppm; MS (ESIÀ): m/z (%): 304 (100) [MÀH]À;
HRMS (ESI+): m/z: calcd for C14H11NO5S: 305.0358; found:
4-Oxo-4-[5-(4-phenylphenyl)-2-thienyl]butanoic acid (12o): 2-(4-
Phenylphenyl)thiophene (1090 mg, 4.61 mmol), succinic anhydride
(461 mg, 4.61 mmol), and AlCl3 (1354 mg, 10.15 mmol) according
to procedure 1 to give 12o as a brown solid (467 mg, 34%): mp:
2458C; 1H NMR (400 MHz, [D6]DMSO): d=2.56 (t, 3J=6.4 Hz, 2H),
3
3
3
3.18 (t, J=6.4 Hz, 2H), 7.36 (t, J=7.8 Hz, 1H), 7.46 (t, J=7.6 Hz,
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2H), 7.76–7.64 (m, 4H), 7.90–7.81 (m, 3H), 7.98 (d, J=3.9 Hz, 1H),
366.0924; elemental analysis calcd (%) for C21H18O4S (366.43): C
68.83, H 4.95, N 0.00; found: C 68.72, H 4.64, N 0.26.
12.19 ppm (s, 1H); 13C NMR (100 MHz, [D6]DMSO): d=28.4, 33.6,
125.7, 127.0, 127.1, 127.4, 128.0, 129.6, 132.3, 135.1, 139.6, 141.2,
142.6, 151.2, 174.4, 192.0 ppm; MS (ESIÀ): m/z (%): 335 (100)
[MÀH]À; HRMS (ESI+): m/z: calcd for C20H16O3S: 336.0820; found:
336.0815; elemental analysis calcd (%) for C20H16O3S (336.40): C
71.41, H 4.79, N 0.00; found: C 71.76, H 4.79, N 0.09.
5-Oxo-5-(5-phenyl-2-thienyl)pentanoic acid (13a): 2-Phenylthio-
phene (2.020 g, 12.61 mmol), glutaric anhydride (1.439 g,
12.61 mmol), and AlCl3 (3.699 g, 27.74 mmol) according to proce-
dure 1 to give 13a as a pale-yellow solid, yield (2.099 g, 61%): mp:
1408C; 1H NMR (400 MHz, [D6]DMSO): d=1.81 (quint, 3J=7.3 Hz,
3
3
4-Oxo-4-[5-(2-thienyl)-2-thienyl]butanoic acid (12p): 2-(2-Thie-
nyl)thiophene (382 mg, 2.30 mmol), succinic anhydride (230 mg,
2.30 mmol), and AlCl3 (674 mg, 5.05 mmol) according to proce-
dure 1 to give 12p as a pale-yellow solid (258 mg, 42%): mp:
1708C; 1H NMR (400 MHz, [D6]DMSO): d=2.54 (t, 3J=6.2 Hz, 2H),
2H), 2.28 (t, J=6.4 Hz, 2H), 2.96 (t, J=7.3 Hz, 2H), 7.47–7.35 (m,
3
3
3
3H), 7.60 (d, J=3.9 Hz, 1H), 7.73 (d, J=7.6 Hz, 2H), 7.90 (d, J=
4.1 Hz, 1H), 12.06 ppm (s, 1H); 13C NMR (100 MHz, [D6]DMSO): d=
20.1, 33.3, 37.7, 125.6, 126.5, 129.9, 133.2, 134.9, 142.9, 151.7, 174.7,
193.2 ppm; MS (ESIÀ): m/z (%): 273 (100) [MÀH]À; HRMS (ESI+):
m/z: calcd for C15H14O3S: 274.0664; found: 274.0669; elemental
analysis calcd (%) for C15H14O3S (274.33): C 65.67, H 5.14, N 0.00;
found: C 65.60, H 5.14, N 0.09.
3
3
3
3.15 (t, J=6.2 Hz, 2H), 7.11 (t, J=3.5 Hz, 1H), 7.39 (d, J=3.8 Hz,
3
3
3
1H), 7.45 (d, J=3.7 Hz, 1H), 7.61 (d, J=3.8 Hz, 1H), 7.92 (d, J=
3.9 Hz, 1H), 12.14 ppm (s, 1H); 13C NMR (100 MHz, [D6]DMSO): d=
28.4, 33.6, 125.5, 126.5, 126.9, 129.3, 134.9, 137.1, 142.7, 151.6,
173.4, 191.0 ppm; MS (ESIÀ): m/z (%): 265 (100) [MÀH]À; HRMS
(ESI+): m/z: calcd for C12H10O3S2: 266.0071; found: 266.0079; ele-
mental analysis calcd (%) for C12H10O3S2 (266.34): C 54.12, H 3.78, N
0.00; found: C 54.15, H 3.66, N 0.16.
5-[5-(3-Hydroxyphenyl)-2-thienyl]-5-oxopentanoic acid (17a): 3-
(2-Thienyl)phenol (3.377 g, 19.16 mmol), glutaric anhydride
(2.186 g, 19.16 mmol), and AlCl3 (5.620 g, 42.15 mmol) according to
procedure 1 to give 17a as a brown solid (4.553 g, 82%): mp:
1688C; 1H NMR (400 MHz, [D6]DMSO): d=1.81 (quint, 3J=7.3 Hz,
3
3
4-[5-(4-Benzyloxyphenyl)-2-thienyl]-4-oxobutanoic acid (12q): 2-
(4-Benzyloxyphenyl)thiophene (935 mg, 3.51 mmol), succinic anhy-
dride (351 mg, 3.51 mmol), and AlCl3 (1030 mg, 7.72 mmol) accord-
ing to procedure 1 to give 12q as a brown solid (576 mg, 33%):
mp: 1788C; 1H NMR (400 MHz, [D6]DMSO): d=2.44 (t, 3J=6.2 Hz,
2H), 2.28 (t, J=6.4 Hz, 2H), 2.96 (t, J=7.3 Hz, 2H), 6.73–6.66 (m,
3
3
1H), 7.20–7.03 (m, 3H), 7.54 (d, J=4.2 Hz, 1H), 7.76 (d, J=4.0 Hz,
1H), 12.15 ppm (s, 1H); 13C NMR (100 MHz, [D6]DMSO): d=20.1,
33.3, 37.7, 112.7, 115.2, 116.8, 128.9, 131.0, 135.5, 141.2, 144.1,
158.4, 174.3, 194.8 ppm; MS (ESIÀ): m/z (%): 289 (100) [MÀH]À;
HRMS (ESI+): m/z: calcd for C15H14O4S: 290.0613; found: 290.0618;
elemental analysis calcd (%) for C15H14O4S (290.33): C 62.05, H 4.86,
N 0.00; found: C 62.31, H 4.83, N 0.07.
3
2H), 3.19 (t, J=6.2 Hz, 2H), 5.14 (s, 2H), 7.48–7.32 (m, 5H), 7.06 (d,
3J=8.1 Hz, 2H), 7.54 (d, 3J=4.1 Hz, 1H), 7.69 (d, 3J=8.1 Hz, 2H),
7.93 (d, 3J=3.9 Hz, 1H), 12.16 ppm (s, 1H); 13C NMR (100 MHz,
[D6]DMSO): d=28.2, 33.5, 70.8, 114.6, 114.8, 125.1, 126.7, 127.1,
127.6, 128.5, 128.6, 128.9, 129.0, 134.6, 135.4, 137.7, 141.1, 151.0,
158.6, 174.4, 192.6 ppm; MS (ESIÀ): m/z (%): 365 (100) [MÀH]À;
HRMS (ESI+): m/z: calcd for C21H18O4S: 366.0926; found: 366.0902;
elemental analysis calcd (%) for C21H18O4S (366.43): C 68.83, H 4.95,
N 0.00; found: C 68.84, H 4.84, N 0.06.
4-[5-(3-Aminophenyl)-2-thienyl]-4-oxobutanoic acid (12j): 4-[5-(3-
Nitrophenyl)-2-thienyl]-4-oxobutanoic
acid
(12i,
580 mg,
1.90 mmol, 1.0 equiv) was dissolved in MeOH (25 mL). Hydrogena-
tion was performed under an atmosphere of H2 (101.3 kPa) at RT.
The progress of the reaction was followed by the consumption of
H2. Upon completion of the reaction, the mixture was filtered
through a mixture of silica gel and Celite, which was followed by
evaporation. Purification by flash chromatography with silica gel
gave 12j as a brown solid (515 mg, 97%): mp: 1828C; 1H NMR
(400 MHz, [D6]DMSO): d=2.54 (t, 3J=6.2 Hz, 2H), 3.15 (t, 3J=
4-[5-(3-Benzyloxyphenyl)-2-thienyl]-4-oxobutanoic acid (12r): 2-
(3-Benzyloxyphenyl)thiophene (578 mg, 2.17 mmol), succinic anhy-
dride (217 mg, 2.17 mmol), and AlCl3 (637 mg, 4.77 mmol) accord-
ing to procedure 1 to give 12r as a brown solid (301 mg, 38%):
mp: 1838C; 1H NMR (400 MHz, [D6]DMSO): d=2.51 (t, 3J=6.1 Hz,
3
6.1 Hz, 2H), 5.25 (s, 2H), 7.10–6.78 (m, 4H), 7.43 (d, J=4.3 Hz, 1H),
3
2H), 3.24 (t, J=6.0 Hz, 2H), 5.23 (s, 2H), 7.41–7.30 (m, 8H), 7.06–
7.91 (d, 3J=4.1 Hz, 1H), 12.15 ppm (s, 1H); 13C NMR (100 MHz,
[D6]DMSO): d=28.1, 33.6, 114.2, 116.4, 118.7, 127.6, 130.0, 134.0,
134.1, 144.9, 148.1, 149.9, 173.2, 192.4 ppm; MS (ESIÀ): m/z (%):
276 (100) [M+H]+; HRMS (ESI+): m/z: calcd for C14H13NO3S:
275.0616; found: 275.0635; elemental analysis calcd (%) for
C14H13NO3S (275.32): C 61.07, H 4.76, N 5.09; found: C 61.31, H 4.94,
N 5.03.
6.92 (m, 1H), 7.49 (d, 3J=4.1 Hz, 1H), 7.91 (d, 3J=3.9 Hz, 1H),
12.14 ppm (s, 1H); 13C NMR (100 MHz, [D6]DMSO): d=28.2, 33.5,
71.1, 111.3, 114.3, 118.7, 126.6, 127.1, 127.2, 127.6, 128.8, 129.0,
130.2, 134.0, 134.4, 136.9, 140.0, 151.4, 157.2, 175.3, 191.1 ppm; MS
(ESIÀ): m/z (%): 365 (100) [MÀH]À; HRMS (ESI+): m/z: calcd for
C21H18O4S: 366.0926; found: 366.0934; elemental analysis calcd (%)
for C21H18O4S (366.43): C 68.83, H 4.95, N 0.00; found: C 68.59, H
4.72, N 0.25.
4-(5-Phenyl-2-thienyl)butanoic acid (14a): 4-Oxo-4-(5-phenyl-2-
thienyl)butanoic acid (4, 400 mg, 1.54 mmol), hydrazine hydrate
(0.30 mL, 6.16 mmol), and KOH (345 mg, 6.16 mmol) according to
procedure 2 to give 14a as a brown solid (283 mg, 75%): mp:
4-[5-(2-Benzyloxyphenyl)-2-thienyl]-4-oxobutanoic acid (12s): 2-
(2-Benzyloxyphenyl)thiophene (475 mg, 1.79 mmol), succinic anhy-
dride (179 mg, 1.79 mmol), and AlCl3 (524 mg, 3.92 mmol) accord-
ing to procedure 1 to give 12s as a brown solid (290 mg, 44%):
mp: 1918C; 1H NMR (400 MHz, [D6]DMSO): d=2.50 (t, 3J=6.1 Hz,
1
338C; H NMR (400 MHz, [D6]acetone): d=2.00–1.92 (m, 2H), 2.38
3
3
3
(t, J=7.3 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 6.83 (d, J=3.9 Hz, 1H),
7.44–7.33 (m, 3H), 7.58–7.51 (m, 2H), 7.59 (d, 3J=4.1 Hz, 1H),
10.63 ppm (s, 1H); 13C NMR (100 MHz, [D6]acetone): d=26.8, 33.3,
31.9, 123.1, 125.2, 129.0, 133.6, 134.7, 141.8, 144.4, 173.6 ppm; MS
(ESIÀ): m/z (%): 245 (100) [MÀH]À; HRMS (ESI+): m/z: calcd for
C14H14O2S: 246.0715; found: 246.0724; elemental analysis calcd (%)
for C14H14O2S (246.32): C 68.26, H 5.73, N 0.00; found: C 68.31, H
5.71, N 0.09.
3
2H), 3.23 (t, J=6.0 Hz, 2H), 5.19 (s, 2H), 7.06–6.92 (m, 1H), 7.40–
7.29 (m, 4H), 7.44 (d, J=3.9 Hz, 1H), 7.52–7.49 (m, 2H), 7.71–7.66
3
(m, 1H), 7.89 (d, 3J=3.7 Hz, 1H), 12.11 ppm (s, 1H); 13C NMR
(100 MHz, [D6]DMSO): d=28.2, 33.5, 71.1, 116.6, 121.5, 126.6, 127.1,
127.5, 127.6, 128.5, 128.9, 129.0, 129.7, 134.0, 134.4, 136.9, 140.0,
151.4, 157.2, 175.3, 191.1 ppm; MS (ESIÀ): m/z (%): 365 (100)
[MÀH]À; HRMS (ESI+): m/z: calcd for C21H18O4S: 366.0926; found:
5-(5-Phenyl-2-thienyl)pentanoic acid (14b): 5-Oxo-5-(5-phenyl-2-
thienyl)pentanoic acid (13a, 400 mg, 1.46 mmol), hydrazine hy-
&
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drate (0.28 mL, 5.83 mmol), and KOH (327 mg, 5.83 mmol) accord-
192.3 ppm; MS (ESI+): m/z (%): 316 (100) [M+H]+; HRMS (ESI+):
m/z: calcd for C18H21NO2S: 315.1293; found: 315.1287; elemental
analysis calcd (%) for C18H21NO2S (315.43): C 68.54, H 6.71, N 4.44;
found: C 68.45, H 6.76, N 4.41.
ing to procedure 2 to give 14b as a brown solid (256 mg, 67%):
1
mp: 1048C; H NMR (400 MHz, [D6]acetone): d=1.77–1.62 (m, 2H),
3
3
2.08–1.99 (m, 2H), 2.33 (t, J=7.1 Hz, 2H), 2.85 (t, J=7.0 Hz, 2H),
3
6.83 (d, J=3.9 Hz, 1H), 7.44–7.33 (m, 3H), 7.58–7.51 (m, 2H), 7.59
N,N-Diethyl-5-oxo-5-(5-phenyl-2-thienyl)pentanamide (16b): 5-
(d, 3J=4.1 Hz, 1H), 10.55 ppm (s, 1H); 13C NMR (100 MHz,
[D6]acetone), d=24.2, 28.7, 31.0, 33.0, 123.0, 125.2, 129.0, 133.6,
134.7, 141.6, 145.0, 173.7 ppm; MS (ESIÀ): m/z (%): 259 (100)
[MÀH]À; HRMS (ESI+): m/z: calcd for C15H16O2S: 260.0871; found:
260.0874; elemental analysis calcd (%) for C15H16O2S (260.35): C
69.20, H 6.19, N 0.00; found: C 68.97, H 6.06, N 0.09.
Oxo-5-(5-phenyl-2-thienyl)pentanoic
acid
(13a,
400 mg,
1.46 mmol), diethylamine (0.15 mL, 1.46 mmol), NEt3 (0.68 mL,
2.92 mmol), EDC (418 mg, 2.19 mmol), and HOBt (295 mg,
2.19 mmol) according to procedure 4 to give 16b as a yellow solid
(293 mg, 60%): Rf =0.16 (cyclohexane/EtOAc 1:1); mp: 648C; 1H
(400 MHz, CDCl3): d=1.11 (t, 3J=7.1 Hz, 3H), 1.14 (t, 3J=7.1 Hz,
3H), 2.10 (quint, 3J=7.1 Hz, 2H), 2.43 (t, 3J=7.1 Hz, 2H), 3.01 (t,
3J=6.9 Hz, 2H), 3.30 (q, 3J=7.1 Hz, 2H), 3.37 (q, 3J=7.1 Hz, 2H),
7.30 (d, 3J=3.9 Hz, 1H), 7.45–7.31 (m, 3H), 7.66–7.60 (m, 2H),
7.72 ppm (d, 3J=3.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=13.2,
14.4, 20.6, 32.0, 38.2, 40.2, 42.0, 124.1, 126.4, 129.2, 133.3, 133.5,
142.9, 152.6, 171.6, 193.3 ppm; MS (ESI+): m/z (%): 330 (100) [M+
H]+; HRMS (ESI+): m/z: calcd for C19H23NO2S: 329.1450; found:
329.1467; elemental analysis calcd (%) for C19H23NO2S (329.46): C
69.27, H 7.04, N 4.25; found: C 69.38, H 7.16, N 4.33.
5-[5-(3-Hydroxyphenyl)-2-thienyl]pentanoic acid (17b): 5-[5-(3-
Hydroxyphenyl)-2-thienyl]-5-oxopentanoic acid (17a, 1000 mg,
3.44 mmol), hydrazine hydrate (0.67 mL, 13.76 mmol), and KOH
(772 mg, 13.76 mmol) according to procedure 2 to give 17b as
a brown solid (586 mg, 62%): mp: 1398C; 1H NMR (400 MHz,
[D6]DMSO): d=1.73–1.60 (m, 2H), 2.00–1.91 (m, 2H), 2.31 (t, 3J=
3
3
7.0 Hz, 2H), 2.81 (t, J=7.2 Hz, 2H), 6.80 (d, J=4.1 Hz, 1H), 7.48–
6.91 (m, 4H), 7.60 (d, J=4.2 Hz, 1H), 10.61 ppm (s, 1H); 13C NMR
3
(100 MHz, [D6]DMSO): d=24.5, 29.7, 31.0, 33.9, 112.4, 114.9, 116.5,
128.1, 130.8, 135.7, 141.4, 144.9, 158.3, 174.9 ppm; MS (ESIÀ): m/z
(%): 275 (100) [MÀH]À; HRMS (ESI+): m/z: calcd for C15H16O3S:
276.0820; found: 276.0834; elemental analysis calcd (%) for
C15H16O3S (276.35): C 65.19, H 5.84, N 0.00; found: C 65.06, H 5.89,
N 0.24.
N,N-Diethyl-5-[5-(3-hydroxyphenyl)-2-thienyl]-5-oxopentanamide
(17c): 5-[5-(3-Hydroxyphenyl)-2-thienyl]-5-oxopentanoic acid (17a,
435 mg, 1.50 mmol), diethylamine (0.16 mL, 1.50 mmol), NEt3
(0.71 mL, 3.00 mmol), EDC (479 mg, 2.25 mmol), and HOBt
(338 mg, 2.25 mmol) according to procedure 4 to give 17c as
a pale-yellow solid (219 mg, 42%): Rf =0.23 (cyclohexane/EtOAc
Methyl 4-oxo-4-(5-phenyl-2-thienyl)butanoate (15a): 4-Oxo-4-(5-
phenyl-2-thienyl)butanoic acid (4, 400 mg, 1.54 mmol) according to
procedure 3 to give 15a as a yellow solid (288 mg, 69%): Rf =0.30
(cyclohexane/EtOAc 3:1); mp: 1138C; 1H NMR (400 MHz, CDCl3):
d=2.77 (t, 3J=6.6 Hz, 2H), 3.25 (t, 3J=6.8 Hz, 2H), 3.70 (s, 3H),
7.31 (d, 3J=3.9 Hz, 1H), 7.44–7.33 (m, 3H), 7.67–7.60 (m, 2H),
7.71 ppm (d, 3J=3.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=28.2,
33.7, 52.0, 124.1, 126.4, 129.2, 133.1, 133.4, 142.2, 152.8, 173.3,
190.9 ppm; MS (ESI+): m/z (%): 275 (100) [M+H]+; HRMS (ESI+):
m/z: calcd for C15H14O3S: 274.0664; found: 274.0658; elemental
analysis calcd (%) for C15H14O3S (274.33): C 65.67, H 5.14, N 0.00;
found: C 65.54, H 5.14, N 0.09.
1
3
1:3); mp: 1258C; H NMR (400 MHz, CDCl3): d=1.13 (t, J=7.1 Hz,
3H), 1.17 (t, 3J=7.1 Hz, 3H), 2.11 (quint, 3J=6.1 Hz, 2H), 2.46 (t,
3J=6.4 Hz, 2H), 2.98 (t, 3J=6.4 Hz, 2H), 3.32 (q, 3J=7.1 Hz, 2H),
3
3.40 (q, J=6.9 Hz, 2H), 6.73–6.66 (m, 1H), 7.20–7.03 (m, 3H), 7.54
(d, 3J=4.2 Hz, 1H), 7.60 (d, 3J=3.4 Hz, 1H), 8.36 ppm (s, 1H);
13C NMR (100 MHz, CDCl3): d=13.2, 14.3, 20.6, 32.2, 38.1, 40.6, 42.4,
113.4, 116.6, 117.8, 130.3, 133.6, 134.5, 142.3, 144.1, 157.5, 172.4,
193.4 ppm; MS (ESI+): m/z (%): 346 (100) [M+H]+; HRMS (ESI+):
m/z: calcd for C19H23NO3S: 345.1399; found: 345.1413; elemental
analysis calcd (%) for C19H23NO3S (345.46): C 66.05, H 6.71, N 4.05;
found: C 66.08, H 6.72, N 3.99.
Methyl 5-oxo-5-(5-phenyl-2-thienyl)pentanoate (15b): 5-Oxo-5-
(5-phenyl-2-thienyl)pentanoic acid (13a, 400 mg, 1.46 mmol) ac-
cording to procedure 3 to give 15b as a brown solid (243 mg,
58%): Rf =0.38 (cyclohexane/EtOAc 3:1); mp: 1278C; 1H NMR
(400 MHz, CDCl3): d=2.08 (quint, 3J=7.2 Hz, 2H), 2.45 (t, 3J=
N,N-Diethyl-5-[5-(3-hydroxyphenyl)-2-thienyl]pentanamide
(17d): 5-[5-(3-Hydroxyphenyl)-2-thienyl]pentanoic acid (17b,
471 mg, 1.70 mmol), diethylamine (0.18 mL, 1.70 mmol), NEt3
(0.79 mL, 3.40 mmol), EDC (487 mg, 2.55 mmol), and HOBt
(345 mg, 2.55 mmol) according to procedure 4 to give 17d as
a pale-yellow solid (277 mg, 51%): Rf =0.20 (cyclohexane/EtOAc
3
3
7.1 Hz, 2H), 2.98 (t, J=7.2 Hz, 2H), 3.68 (s, 3H), 7.31 (d, J=3.9 Hz,
3
3
1
3
1H), 7.44–7.33 (m, 3H), 7.65 (d, J=7.6 Hz, 2H), 7.69 ppm (d, J=
3.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=19.9, 33.2, 37.9, 51.7,
124.0, 126.4, 129.2, 133.0, 133.4, 142.8, 152.7, 173.7, 192.4 ppm; MS
(ESI+): m/z (%): 289 (100) [M+H]+; HRMS (ESI+): m/z: calcd for
C16H16O3S: 288.0820; found: 288.0824; elemental analysis calcd (%)
for C16H16O3S (288.36): C 66.64, H 5.59, N 0.00; found: C 66.94, H
5.70, N 0.01.
1:1); mp: 1038C; H NMR (400 MHz, CDCl3): d=1.12 (t, J=7.2 Hz,
3 3
3H), 1.16 (t, J=7.3 Hz, 3H), 1.80–1.65 (m, 4H), 2.35 (t, J=7.0 Hz,
3
3
3
2H), 2.79 (t, J=7.0 Hz, 2H), 3.29 (q, J=7.1 Hz, 2H), 3.38 (q, J=
7.1 Hz, 2H), 6.73–6.66 (m, 1H), 7.20–7.03 (m, 3H), 7.54 (d, 3J=
4.2 Hz, 1H), 7.60 (d, 3J=3.4 Hz, 1H), 8.36 ppm (s, 1H); 13C NMR
(100 MHz, CDCl3): d=13.2, 14.4, 24.5, 30.1, 31.5, 33.0, 40.6, 42.4,
112.7, 114.4, 117.4, 125.2, 130.0, 136.0, 141.8, 144.8, 157.0,
172.8 ppm; MS (ESI+): m/z (%): 332 (100) [M+H]+; HRMS (ESI+):
m/z: calcd for C19H25NO2S: 331.1606; found: 331.1607; elemental
analysis calcd (%) for C19H25NO2S (331.47): C 68.85, H 7.60, N 4.23;
found: C 68.74, H 7.55, N 4.13.
N,N-Diethyl-4-oxo-4-(5-phenyl-2-thienyl)butanamide (16a): 4-
Oxo-4-(5-phenyl-2-thienyl)butanoic acid (4, 400 mg, 1.54 mmol), di-
ethylamine (0.16 mL, 1.54 mmol), NEt3 (0.73 mL, 3.08 mmol), EDC
(443 mg, 2.31 mmol), and HOBt (312 mg, 2.31 mmol) according to
procedure 4 to give 16a as a yellow solid (252 mg, 53%): Rf =0.23
1
(cyclohexane/EtOAc 1:1); mp: 838C; H NMR (400 MHz, CDCl3): d=
Keywords: biaryls · carboxylic acids · inhibitors · parasites ·
structure–activity relationships
3
3
3
1.10 (t, J=7.1 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H), 2.77 (t, J=6.7 Hz,
3
3
3
2H), 3.29 (t, J=6.7 Hz, 2H), 3.39 (q, J=7.1 Hz, 4H), 7.31 (d, J=
3.9 Hz, 1H), 7.44–7.33 (m, 3H), 7.66–7.61 (m, 2H), 7.76 ppm (d, J=
4.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=13.2, 14.3, 27.3, 34.1,
3
[1] A. G. P. Ross, P. B. Bartley, A. C. Sleigh, G. R. Olds, Y. Li, G. M. Williams,
D. P. McManus, N. Engl. J. Med. 2002, 346, 1212–1220.
[2] P. Steinmann, J. Keiser, R. Bos, M. Tanner, J. Utzinger, Lancet Infect. Dis.
2006, 6, 411–425.
40.4, 42.0, 124.1, 126.4, 129.2, 133.2, 133.5, 142.7, 152.5, 170.7,
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[3] Schistosomiasis Fact Sheet N115, World Health Organization: http://
www.who.int/mediacentre/factsheets/fs115/en/, 2014 (last accessed:
April 2015).
[4] J. B. Thꢄtiot-Laurent, A. Robert, B. Meunier, Angew. Chem. Int. Ed. 2013,
52, 7936–7956; Angew. Chem. 2013, 125, 8092–8114.
[5] M. L. A. Ferrari, P. M. Z. Coelho, C. M. F. Antunes, C. A. P. Tavares, A. S. da
Cunha, Bull. W. H. O. 2003, 81, 190–196.
[6] L. C. de Souza Dias, P. de Jesus, E. R. Deberaldini, Trans. R. Soc. Trop.
Med. Hyg. 1982, 76, 652–659.
[7] D. Alonso, J. MuÇoz, J. Gascꢅn, M. E. Valls, M. Corachan, Am. J. Trop.
Med. Hyg. 2006, 74, 342–344.
[18] Gene DB: http://www.genedb.org/gene/Smp_150700 (last accessed:
January 2016).
[19] Gene DB: http://www.genedb.org/gene/Smp_053220 (last accessed:
January 2016).
[20] Z. Lu, F. Sessler, N. Holroyd, S. Hahnel, T. Quack, M. Berryman, C. G. Gre-
velding, unpublished results.
[21] A. Colciago, P. Negri-Cesi, F. Celotti, Exp. Clin. Endocrinol. Diabetes 2002,
110, 22–26.
[22] E. S. Kang, K. Iwata, K. Ikami, S. A. Ham, H. J. Kim, K. C. Chang, J. H. Lee,
J.-H. Kim, S.-B. Park, J.-H. Kim, C. Yabe-Nishimura, H. Geuk Seo, Free
Radic. Biol. Med. 2011, 50, 680–688.
[8] S. D. Melman, M. L. Steinauer, C. Cunningham, L. S. Kubatko, I. N.
Mwangi, N. Barker Wynn, M. W. Mutuku, D. M. S. Karanja, D. G. Colley,
C. L. Black, W. E. Secor, G. M. Mkoji, E. S. Loker, PLoS Negl. Trop. Dis.
2009, 3, e504.
[23] J. Rath, V. S. Gowri, S. C. Chauhan, P. K. Padmanabhan, N. Srinivasan, R.
Madhubala, Gene 2009, 429, 1–9.
[24] R. Tammali, A. Saxena, S. K. Srivastava, K. V. Ramana, Endocrinology
2010, 151, 2140–2150.
[9] H. M. Alger, D. L. Williams, Mol. Biochem. Parasitol. 2002, 121, 129–139.
[10] G. Boumis, F. Angelucci, A. Bellelli, M. Brunori, D. Dimastrogiovanni, A. E.
Miele, Protein Sci. 2011, 20, 1069–1076.
[11] A. N. Kuntz, E. Davioud-Charvet, A. A. Sayed, L. L. Califf, J. Dessolin,
E. S. J. Arnꢄr, D. L. Williams, PLoS Med. 2007, 4, e206.
[12] S. G. Rhee, H. Z. Chae, K. Kim, Free Radical Biol. Med. 2005, 38, 1543–
1552.
[25] M. Eisenmann, H. Steuber, M. Zentgraf, M. Altenkꢀmper, R. Ortmann, J.
Perruchon, G. Klebe, M. Schlitzer, ChemMedChem 2009, 4, 809–819.
[26] S. Beckmann, G. C. Grevelding, Int. J. Parasitol. 2010, 40, 521–526.
[27] S. Beckmann, S. Leutner, N. Gouignard, C. Dissous, G. C. Grevelding,
Curr. Pharm. Des. 2012, 18, 3579–3594.
[28] A. S. Blohm, P. Mꢀder, T. Quack, Z. Lu, S. Hahnel, M. Schlitzer, C. G. Gre-
velding, unpublished results.
[13] A. A. Sayed, S. K. Cook, D. L. Williams, J. Biol. Chem. 2006, 281, 17001–
17010.
[29] J. Min, X. Meng-Xia, Z. Dong, L. Yuan, L. Xiao-Yu, C. Xing, J. Mol. Struct.
2004, 692, 71–80.
[14] S. K. Srivastava, U. C. Yadav, A. B. Reddy, A. Saxena, R. Tammali, M.
Shoeb, N. H. Ansari, A. Bhatnagar, M. J. Petrash, S. Srivastava, K. V.
Ramana, Chem. Biol. Interact. 2011, 191, 330–338.
[15] U. C. S. Yadav, S. K. Srivastava, K. V. Ramana, Curr. Mol. Med. 2010, 10,
540–549.
[30] G. Sudlow, D. J. Birkett, D. N. Wade, Mol. Pharmacol. 1975, 11, 824–832.
[31] Z. H. Israili, P. G. Dayton, Drug Metab. Rev. 2001, 33, 161–235.
[32] S. Lustigman, R. K. Prichard, A. Gazzinelli, W. N. Grant, B. A. Boatin, J. S.
McCarthy, M. G. BasꢆÇez, PLoS Neglected Trop. Dis. 2012, 6, e1582.
[16] D. L. Vander Jagt, L. A. Hunsaker, Chem.-Biol. Interact. 2003, 143–144,
341–351.
Received: March 2, 2016
[17] M. Berriman, B. J. Haas, P. T. LoVerde, R. A. Wilson, G. P. Dillon, G. C. Cer-
queira, S. T. Mashiyama, B. Al-Lazikani, L. F. Andrade, P. D. Ashton et al.,
Nature 2009, 460, 352–358.
Revised: April 6, 2016
Published online on && &&, 0000
&
ChemMedChem 2016, 11, 1 – 11
www.chemmedchem.org
10
ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

FULL PAPERS
Mind your PZQs: Over 240 million
people worldwide are infected by schis-
tosomiasis. Since the 1980s, praziquan-
tel (PZQ) has been the drug of choice
for the treatment of schistosomiasis.
However, long-term use of one drug
may result in drug-resistant parasites.
Therefore, we investigated the in vitro
potential of biarylalkyl carboxylic acid
derivatives against Schistosoma manso-
ni. The present study provides deep in-
sight into structure–activity relation-
ships.
P. Mꢀder, A. S. Blohm, T. Quack,
K. Lange-Grꢁnweller, A. Grꢁnweller,
R. K. Hartmann, C. G. Grevelding,*
M. Schlitzer*
&& – &&
Biarylalkyl Carboxylic Acid Derivatives
as Novel Antischistosomal Agents
ChemMedChem 2016, 11, 1 – 11
www.chemmedchem.org
11
ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ