The Effect of Carboxamide/Sulfonamide Replacement in Arylpiperazinylalkyl Derivatives on Activity to Serotonin and Dopamine Receptors

Article abstract of DOI:10.1002/ardp.201700090

A series of carboxamide and sulfonamide alkyl (p-xylyl and benzyl) 1-(2-methoxyphenyl)piperazine (o-OMe-PhP) and 1-(2,3-dichlorophenyl)piperazine (2,3-DCPP) analogs were prepared and tested for their affinity to bind to serotonin 5-HT_1A/5-HT₆/5-HT₇ and dopamine D₂ receptors. This chemical modification let us explore the impact of the replacement of the carboxamide by the sulfonamide group on the affinity changes. In both the o-OMe-PhP and 2,3-DCPP series, the relative activities of the carboxamides versus sulfonamides toward the 5-HT_1A/5-HT₆/5-HT₇ and D₂ receptors show similar trends. Varied or similar activities for particular receptors were found for the carboxamides/sulfonamides with p-xylyl spacer, while of the two classes of carboxamides and sulfonamides examined, benzyl derivatives of the sulfonamides displayed the highest serotoninergic affinity, in particular to the 5-HT₇ receptors (K_i 8–85 nM). The K_i values revealed that, irrespective of the carboxamide/sulfonamide zone, both p-xylyl and benzyl derivatives had the highest affinity for the dopamine D₂ receptor (i.e., 16 out of 24 compounds investigated have an affinity below 100 nM). A molecular modeling study of carboxamide 9a and sulfonamide 9b showed that their binding effects to each of 5-HT_1AR and D₂R created binding modes interaction with different conserved receptors residues. Structural similarities of carboxamide 9a in complexes with a 5-HT_1AR (9aI) and D₂R (9aII) are over 83%, while the respective similarities of sulfonamide 9b structures (9bI/9bII) are only about 40%.

Full text of DOI:10.1002/ardp.201700090

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Full Paper
The Effect of Carboxamide/Sulfonamide Replacement in
Arylpiperazinylalkyl Derivatives on Activity to Serotonin and
Dopamine Receptors
1
1, Grzegorz Satała2, Rafał Kurczab2, Ilona Bartos1, and Karol Zuchowicz1
ꢀ
Piotr Kowalski , Paweł Sliwa
1
ꢀ
Institute of Organic Chemistry and Technology, Cracow University of Technology, Krakow, Poland
2
ꢀ
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Krakow,
Poland
A series of carboxamide and sulfonamide alkyl (p-xylyl and benzyl) 1-(2-methoxyphenyl)piperazine
(o-OMe-PhP) and 1-(2,3-dichlorophenyl)piperazine (2,3-DCPP) analogs were prepared and tested for
their affinity to bind to serotonin 5-HT1A/5-HT6/5-HT7 and dopamine D2 receptors. This chemical
modification let us explore the impact of the replacement of the carboxamide by the sulfonamide group
on the affinity changes. In both the o-OMe-PhP and 2,3-DCPP series, the relative activities of the
carboxamides versus sulfonamides toward the 5-HT1A/5-HT6/5-HT7 and D2 receptors show similar trends.
Varied or similar activities for particular receptors were found for the carboxamides/sulfonamides with
p-xylyl spacer, while of the two classes of carboxamides and sulfonamides examined, benzyl derivatives
of the sulfonamides displayed the highest serotoninergic affinity, in particular to the 5-HT7 receptors (Ki
8–85nM). The Ki values revealed that, irrespective of the carboxamide/sulfonamide zone, both p-xylyl
and benzyl derivatives had the highest affinity for the dopamine D2 receptor (i.e., 16 out of 24
compounds investigated have an affinity below 100nM). A molecular modeling study of carboxamide
9a and sulfonamide 9b showed that their binding effects to each of 5-HT1AR and D2R created binding
modes interaction with different conserved receptors residues. Structural similarities of carboxamide 9a
in complexes with a 5-HT1AR (9aI) and D2R (9aII) are over 83%, while the respective similarities of
sulfonamide 9b structures (9bI/9bII) are only about 40%.
Keywords: Arylpiperazines / Carboxamides / Serotonin 5-HT1A/5-HT6/5-HT7 and D2 receptor ligands /
Structure–activity relationship (SAR) / Sulfonamides
Received: March 14, 2017; Revised: July 3, 2017; Accepted: July 29, 2017
DOI 10.1002/ardp.201700090
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
therapeutically attractive drug substances of different phar-
macological classes [1–4]. Replacement of carboxamide group
Introduction
Bioisosterism represents a successful strategy in rational
drug design, useful in molecular modification of new
with sulfonamide isoster is a common modification used in
medicinal chemistry. Although both come under the class of
amides, replacement of the carboxamide by a sulfonamide
strongly modifies physical properties and the spatial orienta-
tion of the molecules [5] and the success of this chemical
modification was varied in the literature [5–20].
In the case of arylpiperazines 1, both carboxy (1a) and
sulfonyl (1b) derivatives bond with high affinity to 5-HT1A
receptors (Ki values <10 nM) [16] (Fig. 1). Similarly, carbox-
amide 2a and sulfoamide 2b have excellent 5-HT1A, D2, and a1
ꢀ
Correspondence: Dr. Paweł Sliwa, Cracow University of
Technology, Institute of Organic Chemistry and Technology, 24
ꢀ
Warszawska Street, Krakow 31-155, Poland
E-mail: psliwa@indy.chemia.pk.edu.pl
Fax: þ48 (12) 6282037
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Figure 1. The activities of selected carboxa-
mides versus sulfonamide derivatives.
receptors affinities with Ki’s <10 nM [6, 7], but only 2a had in
vivo activity in the catalepsy test in rats [7].
(o-OMe-PhP) moiety as an amine pharmacophore (com-
pounds 9–14), while the other two sets comprised 1-(2,3-
dichlorophenyl)piperazine (2,3-DCPP) isostere (compounds
15–20). In the terminal part of the molecules studied phenyl,
2-naphthyl, or methyl group was introduced. In comparison
with the classic LCAP we replaced an alkylene spacer with
partly constrained p-xylyl (9–11, 15–17) and benzyl (12–14,
18–20) fragment, because the effect of the spacer structure
in LCAP ligands was the subject of our subsequent
research [22, 23].
The 5-HT1A receptor ligands 3–5 [14] (Fig. 1), however,
showed varied activity depending on the presence of
carboxamide or sulfonamide group at meta-position of the
phenyl ring attached to piperazine. The best Ki values were
obtained for MeCONH in 3a (Ki ¼ 6.8 nM), while MeSO2NH in
3b (Ki ¼ 46 nM) exhibits seven to eightfold lower 5-HT1A
binding affinity. Higher Ki values were measured for ethyl (4)
and isopropyl (5) analogs, but in these cases sulfonyl
derivatives 4b and 5b showed higher 5-HT1A binding affinity
compared to carboxy analog 4a and 5a, respectively.
Investigation of 3-arylcarboxyaminothiophene (6a and 7a)
and 3-arylsulfonylaminothiophene (6b and 7b) derivatives, as
a novel class of HCV NS5B polymerase inhibitors [12], proved
that the molecules with sulfonamide moieties (series b) had
higher activity than their carboxamide (series a) analogs
(Fig. 1).
Basak et al. [10] studied the DNA-cleavage activity of
monocyclic enediynyl carboxamides 8a versus sulfonamides
8b (Fig. 1). It was shown that only carboxamides 8a were able
to cleave the plasmid DNA at micromolar concentration. On
the contrary, the sulfonamides 8b did not show any DNA-
cleavage activity even at millimolar level.
While continuing the structure-activity studies described
in the literature (Fig. 1), in this paper we report the synthesis
of four long-chain arylpiperazine (LCAP) sets of the
carboxamide (9a–20a) and sulfonamide (9b–20b) derivatives,
investigated as serotonergic and dopaminergic receptor
ligands (Table 1). The first two sets of the investigated
Results and discussion
Chemistry
The synthesis of the compounds under study was carried out
according to Schemes 1 and 2. All the carboxamides (9a–20a)
and sulfonamides (9b–20b) were prepared by the reaction of
commercially available acyl or sulfonyl chlorides with the
amines 24, 25, 29, or 30 in the presence of
(Schemes 1–2).
a base
The synthesis of p-benzylmethylamines 24 and 25 was
carried out using N-[4-(chlorometyl)benzyl]phthalimide
(21) as the starting compound (Scheme 1). The intermediate
21 was obtained by reacting phthalimide with a,
a0-dichloro-p-xylene as described previously [22]. The
reaction of 21 with o-OMe-PhP or 2,3-DCPP, carried out
in DMF in the presence of K2CO3 at ambient temperature,
afforded N-alkylated phthalimides 22 and 23, respectively.
The latter compounds yielded amines 24 and 25 upon
cleavage in 40% aqueous solution of methylamine.
compounds
contained
1-(2-methoxyphenyl)piperazine
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Table 1. Structures of the compounds studied and their binding profile to 5-HT1A, 5-HT6, 5-HT7, and D2 receptors.
Receptor binding Ki (nM)
Comp. no
Set no
R
n
Z
5HT1A
5-HT6
5-HT7
D2
9a
9b
CO
SO2
52 ꢀ 6
56 ꢀ 5
2430 ꢀ 312
2779 ꢀ 251
178 ꢀ 67
226 ꢀ 36
25 ꢀ 3
32 ꢀ 2
1
1
10a
10b
CO
SO2
121 ꢀ 9
67 ꢀ 7
2521 ꢀ 342
2018 ꢀ 173
84 ꢀ 6
126a) ꢀ 14
137 ꢀ 19
1
1
2
1
1
0
106 ꢀ 9
11a
11b
CO
SO2
196 ꢀ 23
171 ꢀ 19
2309 ꢀ 281
3827 ꢀ 447
33 ꢀ 4
69 ꢀ 8
CH3
455 ꢀ 52
102 ꢀ 7
12a
12b
CO
SO2
140 ꢀ 12
55 ꢀ 8
4704 ꢀ 612
1767 ꢀ 249
635 ꢀ 48
32 ꢀ 5
12 ꢀ 2
10 ꢀ 3
13a
13b
CO
SO2
287 ꢀ 37
59 ꢀ 11
3719 ꢀ 232
657 ꢀ 85
505 ꢀ 43
12 ꢀ 2
68 ꢀ 5
98 ꢀ 4
2
2
3
0
0
1
14a
14b
CO
SO2
1408 ꢀ 162 7257 ꢀ 618
717 ꢀ 95
13 ꢀ 3
116 ꢀ 9
CH3
CH3
CH3
275 ꢀ 34
4138 ꢀ 577
187 ꢀ 27
15a
15b
CO
SO2
1007 ꢀ 71
794 ꢀ 81
680 ꢀ 79
188 ꢀ 26
213 ꢀ 18
66 ꢀ 7
1097 ꢀ 126
87 ꢀ 11
16a
16b
CO
SO2
5634 ꢀ 467
208 ꢀ 13
179 ꢀ 16
99 ꢀ 8
14690 ꢀ 1421
3
1
3925 ꢀ 527 1749 ꢀ 248
232 ꢀ 17
17a
17b
CO
SO2
906 ꢀ 139 1954 ꢀ 173
1610 ꢀ 267 1695 ꢀ 185
92 ꢀ 7
49 ꢀ 6
3
4
4
1
0
0
311 ꢀ 39
93 ꢀ 16
18a
18b
CO
2168 ꢀ 316 1602 ꢀ 94
1151 ꢀ 95
85 ꢀ 6
76 ꢀ 9
99 ꢀ 6
SO2
1982 ꢀ 164
525 ꢀ 61
19a
19b
CO
SO2
5665 ꢀ 429 4496 ꢀ 359
224 ꢀ 34
466 ꢀ 51
36950 ꢀ 2457
1147 ꢀ 79
939 ꢀ 132
52 ꢀ 4
20a
20b
CO
SO2
1140 ꢀ 183 1675 ꢀ 148
343 ꢀ 29 627 ꢀ 76
231 ꢀ 41
8 ꢀ 2
9 ꢀ 2
4
0
71 ꢀ 8
a Ki ¼ 200 ꢀ 14 nM according to Hackling et al. Ref. [21].
In the synthesis of p-benzylamines 29 and 30 commercially
available p-nitrobenzyl chloride (26) was applied (Scheme 2).
The reaction of 26 with arylpiperazines led to the nitro-
intermediates 27 and 28. Reduction of the nitro group in 27 to
the amine group in 29 was done using activated zinc and
ammonium formate [24], while the amine 30 was obtained by
reduction of 28 with stannous chloride under acidic
conditions [25].
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Scheme 1. Preparation of N-{[(4-arylpiperazin-1-
ylmethyl)phenyl]methyl}carboxamides 9a–11a,
15a–17a, and N-{[(4-arylpiperazin-1-ylmethyl)-
phenyl]methyl}sulfonamides 9b–11b, 15b–17b.
Reagents and conditions: (a) 1-(2Methoxy-
phenyl)piperazine hydrochloride or 1-(2,3-
dichlorophenyl)piperazine hydrochloride, DMF,
K2CO3, rt, 48 h, 72–80%; (b) methylamine 40% in
H2O, rt, 24–48 h, 90–93%; (c) acyl chlorides or
sulfonyl chlorides, TEA, DCM, rt, 24 h, 45–80%.
Biological evaluation
compounds investigated as estrogen receptor ligands [8] or
for dispiro-1,2,4-trioxolanes [9] with antimalarial activity.
In the series of benzyl derivatives of o-OMe-PhP and 2,3-
DCPP, all of the carboxamides 12a–14a and 18a–20a bind with
lower affinity to serotonin 5-HT1A, 5-HT6, 5-HT7 receptors than
their sulfonamide analogs 12b–14b and 18b–20b (Table 1).
This indicates that the activity of compounds with benzyl
spacer is strongly affected by the presence of carboxamide/
sulfonamide core in the molecule. The structural correlation
of the compounds containing benzyl spacer revealed that, for
the same substituents within the carboxamide (12a–14a,
18a–20a) and sulfonamide (12b–14b, 18b–20b) series, the
sulfonamides show significantly higher serotonin 5-HT1A/5-
HT6/5-HT7 activity. Moreover, the sulfonamides with benzyl
spacer (12b–14b, 18b–20b) exibit outstanding affinity toward
5-HT7R. Their Ki values in the range 8–85 nM (Table 1) are
affected to a lesser extent by the nature of the arylpiperazine
moiety and the type of sulfonamide group, which is in
contrast to the activity of arylpiperazinylpropylsulfona-
mides [28] and arenesulfonamides [29, 30] toward the same
receptor.
Ki values of the compounds studied, related to serotonin
5-HT1A, 5-HT6, 5-HT7, and dopamine D2 receptors (Table 1),
disclose that these compounds bind preferably to dopamine
receptor, as the largest number (i.e., 16 out of 24) of the
compounds tested showed the affinity below 100 nM, within
both the carboxamide (9 compounds) and the sulfonamide (7
compounds) series. Moreover, several of those compounds
have comparable D2R activity, and only amide 20a (Ki 9 nM)
showed explicitly greater activity than its sulfonyl analog 20b
(Ki 71 nM). In the face of the above, the affinity of examined
The affinity of the compounds studied toward serotonin
5-HT1A
, 5-HT6, 5-HT7, and dopamine D2 receptors was
evaluated in vitro by radioligand binding experiments
(Table 1), as described previously [26, 27]. This was accom-
plished by displacement of radioligands from cloned human
receptors, all stably expressed in HEK293 cells: [3H]-8-OH-
DPAT for 5-HT1AR, [3H]-LSD for 5-HT6R, [3H]-5-CT for 5-HT7R,
and [3H]-raclopride for D2R, respectively (other details are
shown in the Experimental part).
Activities of the phenylcarboxamides with p-xylyl spacer
(9a, 15a) toward all of the investigated serotonin and
dopamine receptors are very similar to the activities of the
corresponding phenylsulfonamides (9b, 15b). For example,
the activities (Ki) of 9a and 9b toward 5-HT1AR are 52 and
56 nM, respectively, while those of 15a and 15b are 1007 and
1097 nM, respectively. The same applies to the activity of
carboxamide 9a versus sulfonamide 9b, and 15a versus 15b
toward 5-HT6R, 5-HT7R, and D2R (Table 1). In the remaining
cases, (i.e., the 2-naphthyl and methylcarboxamides with p-
xylyl spacer 10a, 11a, 16a, and 17a, and the corresponding
sulfonamides 10b, 11b, 16b, and 17b), the relative activities
toward particular receptors vary, so in general it is difficult to
discern any universal rules. Different or similar activity of the
ligands with p-xylyl spacer indicates that their activity is
dependent both on the carboxamide/sulfonamide unit, as
well as on the nature of arylpiperazine moiety and the type of
substituent within the carboxamide/sulfonamide group.
Different activity of carboxamides compared to sulfonamides
toward receptors 5-HT1A and 5-HT7 was also found for other
compounds with serotonic activity [14, 11], as well for
Scheme 2. Preparation of N-[(4-arylpiperazin-1-
ylmethyl)phenyl]carboxamides 12a–14a, 18a–20a,
and N-[(4-arylpiperazin-1-ylmethyl)phenyl]sulfon-
amides 12b–14b, 18b–20b. Reagents and condi-
tions: (a) 1-(2-Methoxyphenyl)piperazine hydro-
chloride or 1-(2,3-dichlorophenyl)piperazine
hydrochloride, DMF, K2CO3, rt, 48 h, 80–88%; (b)
Zn, HCOONH4, THF/MeOH, rt, 30 min or SnCl2,
EtOH, HCl, reflux, 2 h, 60–68%; (c) acyl chlorides or
sulfonyl chlorides, pyridine, rt, 24 h, 35–60%.
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compounds toward D2R is not dependent on the presence of
carboxamide or sulfonamide group.
arylpiperazine fragment of 9a and 9b interacts with the
aromatic residues of TMH6 and with nonpolar residue of
TMH3 (Val3.33) in both receptors, showing very similar poses.
(Fig. 2, Tables 2 and 3).
Molecular modeling
Intrigued by the same activity of both phenylcarboxamide 9a
and phenylsulfonamide 9b toward each of the serotonin
5-HT1A, 5-HT6, 5-HT7, and dopamine D2 receptors (Table 1), we
became interested in investigation of the effects of swapping
carboxamide with sulfonamide in these molecules. In order to
realize that goal, we performed molecular modeling studies
of 9a and 9b docked to the models of 5-HT1A and D2 receptors,
to which the compounds 9a and 9b displayed strongest
bonding affinity (Table 1).
The carboxamide/sulfonamide moieties of 9a and 9b are
placed in the second pocket, and their arrangement in the
ligand-receptor (L-R) complexes limits the diversity of amino
acid sequence between the 5-HT1A and D2 receptors. The
carboxamide moiety of 9a occupies the pocket located
between TMHs 7 and 2 for both the serotonin and the
dopamine receptors (Fig. 2). Despite, the orientation of the
amide moiety of 9a in 5-HT1AR, compared to that in D2R, is
determined by different interactions (Table 2; columns D and
E), similarity of 9aI and 9aII conformations in L-R complexes is
clearly higher (over 83%, see Fig. 3). In the case of 9b, the
sulfonamide moiety orientation in 5-HT1AR is determined by
strong two hydrogen bonds with Asp185 and Lys101, which
are not present in D2R (Table 3; columns C and E). Because of
the latter, as well as the absence of participation of the
sulfonamide unit in L-R complex stabilization, binding of 9b to
D2R is associated with a conformational change of 60%
compared to that in 5-HT1AR (see 9bI and 9bII in Fig. 3).
Analysis of the complexes between 5-HT1A receptor and the
carboxamide 9a (9aI) or sulfonamide 9b (9bI) ligands indicates
that their same binding effect (Ki for 9a and 9b to 5-HT1AR are
52 and 56 nM, respectively, Table 1) allows formation of
different attractive hydrogen bonds with three polar residues
Tyr7.41, Asp185, and Asn7.39 in the case of carboxamide 9a
The molecular modeling study was performed by ONIOM
procedure (details are shown in Experimental part).
The postulated binding sites of monoaminergic 5-HT1A and
D2 receptors to LCAPs are divided into two pockets that
extend to both sides of the main ligand-anchoring residue,
which is Asp3.32 [29, 31, 32]. The first pocket is situated
between TMHs 4 and 6, which consist of the conserved
aromatic amino acid residues, capable for binding ligands via
hydrophobic/aromatic interactions. The second pocket is
formed between TMHs 7 and 3, with the contribution of
residues that ensure both aromatic and H-bond interactions.
The ONIOM calculations showed that the anchoring points of
9a and 9b to both receptors involved a salt-bridge with
Asp3.32 and a weak H-bonding with Tyr7.41 in 5-HT1AR, or
with Tyr7.42 in D2R. The aromatic moiety (A) of the
Figure 2. Binding mode of the compounds 9a
and 9b to 5-HT1AR and D2R, respectively. Key
residues in the binding site are presented as
thick sticks. Distances between key amino
acid moieties and ligand structural elements
are shown in Tables 2 and 3. Dotted yellow
lines represent H-bonds with polar residues.
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Table 2. Distances (in A)a) between key amino acid residue and the structural elements of carboxamide 9a, measured in
ONIOM-optimized ligand-receptor (L-R) complexes; 9aI-5-HT1AR and 9aII-D2R.
̊
Structure 9a
in L-R
complexe
Receptor
A
B
C
D
E
F
5-HT1A
9aI
Phe6.52
(CH-p) 2.89
Asp3.32
(H-bond)
1.41
Phe6.51
(CH-p) 3.18
Asp185
(H-bond)
1.79
Asn7.39
(H-bond)
1.81
Leu6.58
(CH-p) 2.65
Val3.33
(CH-p) 3.43
Tyr7.41
(H-bond)
2.78
D2
9aII
Phe5.39
(CH-p) 3.82
Asp3.32
(H-bond)
1.64
–
–
Tyr7.34
(H-bond)
1.66
Tyr7.34
(CH-p) 3.13
Phe6.52
(CH-p) 4.12
Tyr7.42
(H-bond)
2.60
Leu2.63
(CH-p) 3.24
Val3.33
(CH-p) 3.09
Glu2.64
(CH-p) 3.83
a) H-bond distance measured between HBA (hydrogen bond acceptor) and the hydrogen. CH-p distances measured between
hydrogen and the center of aromatic ring.
(9aI) (Table 2), and Tyr7.41, Asp185, and Lys101, respectively,
for sulfonamide 9b (9bI) (Table 3). The same binding
interactions of 9a and 9b with D2R (Ki of 9a and 9b to
D2R are 25 and 32 nM, respectively, Table 1) balances
hydrogen bonds of both ligands with Tyr7.42 and Tyr7.34
of carboxamide 9a. Moreover, it is important to note that the
sulfonamide unit in 9b does not affect the L-D2R complex
stabilization (Tables 2 and 3).
benzyl spacer, the derivatives studied have the highest
affinity toward the dopamine D2 receptor.
The same Ki binding effect of carboxamide 9a and
sulfonamide 9b to each of the 5-HT1AR and D2R receptors
created interaction binding modes with different conserved
receptors residues. Structural similarity of carboxamide 9a in
the complexes with 5-HT1AR (9aI) and D2R (9aII) is over 83%,
while the corresponding similarity of sulfonamide structures
(9bI/9bII) is only about 40%.
Conclusions
Experimental
In conclusion, new o-OMe-PhP and 2,3-DCPP ligands have
been prepared to explore the effect of replacement of
carboxamide by a sulfonamide moiety in LCAP’s on their
binding affinity to serotonin 5-HT1A/5-HT6/5-HT7 and dopa-
mine D2 receptors. In both o-OMe-PhP and 2,3-DCPP series the
relative activities of the carboxamides versus sulfonamides
toward 5-HT1A/5-HT6/5-HT7 and D2 receptors show similar
trends. The carboxamides/sulfonamides with p-xylyl spacer
show varied or similar activities toward particular receptors,
while of the two classes of the amides examined, the
sulfonamides with benzyl spacer exhibit the highest seroto-
ninergic affinity, in particular toward the 5-HT7 receptor. On
the other hand, where receptor type is concerned, regardless
of the carboxamide/sulfonamide zone, and the p-xylyl or
Chemistry
General
€
Melting points were determined on a Boethius melting point
apparatus and are uncorrected. Elemental analyses were
performed on PerkinElmer 2400 analyzer and the results
are within ꢀ0.4% of the calculated values. Infrared spectra were
recorded in pressed KBr discs on a Bio-Rad FTS 175B spectrometer.
1H NMR spectra were taken on a Varian 300 MHz Mercury-VX
spectrometer in CDCl3, using TMS as an internal standard; the
chemical shifts are given in ppm (d). The mass spectra were
recorded on an Esquire 3000 mass spectrometer (Bruker Daltonik,
Bremen, Germany) equipped with an electrospray source. ESI-MS
spectra were registered in a positive-ion mode. The reactions and
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Table 3. Distances (in A)a) between key amino acid residue and the structural elements of sulfonamide 9b, measured in
ONIOM-optimized ligand-receptor complexes; 9bI-5-HT1AR and 9bII-D2R.
̊
Structure 9b
in L-R
complexe
Receptor
A
B
C
D
E
F
5-HT1A
9bI
Phe6.51
(CH-p) 2.98
Asp3.32
(H-bond)
1.59
Asp185
(H-bond)
1.09
Pro184
(polar
contact)
3.00
Lys101
(H-bond)
1.70
–
Val3.33
(CH-p) 4.30
Tyr7.41
(H-bond)
2.85
D2
9bII
Phe5.39
(CH-p) 3.16
Asp3.32
(H-bond)
1.14
–
–
–
Ile183
(CH-p) 3.37
Phe6.52
(CH-p) 4.63
Tyr7.42
(H-bond)
3.08
Val3.33
(CH-p) 2.78
a) H-bond distance measured between HBA (hydrogen bond acceptor) and the hydrogen. CH-p distances measured between
hydrogen and the center of aromatic ring.
purifications were monitored by TLC (UV detection) on aluminum
plates coated with silica gel 60 F254 (Merck), using chloroform/
methanol 9:1 mixture as eluent. All starting materials were
purchased from commercial sources (Sigma–Aldrich and Merck)
and were used without further purification.
General procedure for the synthesis of 22 and 23
A mixture of 0.01 mol of the N-[4-(chlorometyl)benzyl]-
phthalimide (21), 0.01 mol of the 1-(2-methoxyphenyl)-
piperazine (o-OMe-PhP), or 1-(2,3-dichlorophenyl)arylpi-
perazine (2,3-DCPP) in the hydrochloride forms, 0.03 mol of
The InChI codes of the investigated compounds together
with some biological activity data are provided as Supporting
Information.
anhydrous potassium carbonate, and a few crystals
(ꢁ0.01 g) of potassium iodide in 20 mL of dimethylforma-
mide, were stirred with a magnetic stirrer at a room
Figure 3. ONIOM optimized structures of the
carboxamide derivative 9a bound to 5-
HT1AR (9aI) and D2R (9aII) and the sulfon-
amide derivative 9b bound to 5-HT1AR (9bI)
and D2R (9bII) receptors. For clarity, nonpolar
hydrogens have been removed. The calcu-
lated overlay similarity 9aI/9aII is 0.837, and
9bI/9bII is 0.395.
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temperature for 48 h. Then, the reaction mixture was
poured into 100–150 mL of water, and the precipitate was
collected by filtration. The solid products were purified by
crystallization.
dissolved in 10 mL of methylene chloride and washed
subsequently with 5% solution of sodium hydrogen carbonate
(2 ꢃ 10 mL) and water (10 mL). Organic layer was dried over
anhydrous magnesium sulfate, and the solvent was evapo-
rated. Crude amides were purified by crystallization, and some
of them by silica gel column chromatography, using chloro-
form/methanol 9:1 as eluent. For biological experiments, free
bases of carboxamides 9a–11a, 15a–17a, and sulfonamides 9b–
11b, 15b–17b were converted into hydrochloride salts, using
ethanol saturated with HCl, and their molecular weights were
established on the basis of elemental analysis.
N-{4-([4-(2-Methoxyphenyl)piperazin-1-yl]methyl)benzyl}-
phthalimide (22)
m.p.: 124–126°C (DMF/methanol); (Ref. [22]; m.p.: 124–126°C);
yield 62%. 1H NMR, IR and MS-ESIþ spectra are consistent
with the original sample [22].
N-{4-([4-(2,3-Dichlorophenyl)piperazin-1-yl]methyl)-
benzyl}phthalimide (23)
N-{4-([4-(2-Methoxyphenyl)piperazin-1-yl]methyl)benzyl}-
benzamide (9a)
m.p.: 164–166°C (DMF/methanol); yield 70%; 1H NMR (d):
2.55–2.65 (4H, m, 2xCH2), 2.99–3.09 (4H, m, 2xCH2), 3.53 (2H, s,
CH2-Npiper), 4.84 (2H, s, CH2-Nimide), 7.10–7.46 (7H, m, H-Ar),
7.55–7.67 (2H, m, H-Ar), 7.75–7.81 (2H, m, H-Ar); IR (cmꢂ1):
2936, 2816, 1767, 1714, 1450, 1392, 1245, 808, 743; ESI-MSþ:
m/z 480 (MH)þ.
Base: m.p.:125–126°C(acetone);yield 59%;1HNMR(d):2.59–2.70
(4H, m, 2xCH2), 3.03–3.15 (4H, m, 2xCH2), 3.58 (2H, s, CH2-Npiper),
3.84 (3H, s, OCH3), 4.63 (2H, d, J ¼ 5.60 Hz, CH2NH), 6.48 (1H, br s,
NHCO), 6.90–6.95 (4H, m, H-Ar), 7.26–7.52 (7H, m, H-Ar),
7.74–7.86 (2H, m, H-Ar); IR (cmꢂ1): 3279, 3050, 2941, 2805,
1624, 1549, 1499, 1239, 1181, 1029, 701; ESI-MSþ:m/z 416 (MH)þ.
Hydrochloride: m.p.: 221–223°C; Anal. calcd. for
General procedure for the synthesis of amines 24 and 25 by
removal of the phthalimide group
C
26H29N3O2 ꢄ HCl (451.99): C, 69.09; H, 6.69; N, 9.30. Found:
A mixture of 6 mmol of 22 or 23 and 30 mL of 40% aqueous
solution of methylamine was stirred at room temperature for
2 days. To the resulting solution 30 mL of 20% aqueous
sodium hydroxide was added and the mixture was stirred for
1.5 h. Then 4 g of sodium chloride was added and the solution
was extracted with methylene chloride (2 ꢃ 30 mL). Organic
layer was washed with water (30 mL), and then dried over
anhydrous magnesium sulfate. The product was obtained by
evaporation of methylene chloride. Where necessary, the
product was purified on silica gel column, using chloroform/
methanol 9:1 as eluent.
C, 69.17; H, 6.79; N, 9.22.
N-{4-([4-(2-Methoxyphenyl)piperazin-1-yl]methyl)benzyl}-
2-naphthalenecarboxamide (10a)
Base: m.p.: 193–195°C (CHCl3/n-hexane); yield 75%; 1H NMR
(d): 2.63–2.70 (4H, m, 2xCH2), 3.04–3.13 (4H, m, 2xCH2), 3.59
(2H, s, CH2-Npiper), 3.85 (3H, s, OCH3), 4.70 (2H, d, J ¼ 5.61 Hz,
CH2NH), 6.58 (1H, br s, NHCO), 6.83–6.95 (3H, m, H-Ar),
7.34–7.37 (4H, m, H-Ar), 7.53–7.57 (3H, m, H-Ar), 7.85–7.90
(4H, m, H-Ar), 8.31–8.32 (1H, m, H-Ar); IR (cmꢂ1): 3279, 3055,
2940, 2803, 1622, 1498, 1238, 1142, 1024, 751; ESI-MSþ: m/z
466 (MH)þ.
4-{[4-(2-Methoxyphenyl)piperazin-1-yl]methyl}-
benzylamine (24)
Hydrochloride: m.p.: 225–229°C; Anal. calcd. for
C
30H31N3O2 ꢄ 2HCl ꢄ H2O (556.52): C, 64.75; H, 6.34; N, 7.55.
Oil; yield 90%; 1H NMR spectrum is consistent with the
original sample [21]; IR (cmꢂ1): 3358, 3276, 2935, 2817, 1499,
1237, 1115, 1021, 755; ESI-MSþ: m/z 312 (MH)þ.
Found: C, 64.86; H, 6.19; N, 7.32.
N-{4-([4-(2-Methoxyphenyl)piperazin-1-yl]methyl)benzyl}-
acetamide (11a)
4-{[4-(2,3-Dichlorophenyl)piperazin-1-yl]methyl}-
benzylamine (25)
Base: oil; yield 47%; 1H NMR (d): 2.02 (3H, s, COCH3),
2.57–2.64 (4H, m, 2xCH2), 3.00–3.11 (4H, m, 2xCH2), 3.59
(2H, s, CH2-Npiper), 3.84 (3H, s, OCH3), 4.41 (2H, d, J ¼ 5.60 Hz,
CH2NH), 6.83–7.02 (4H, m, H-Ar), 7.23–7.26 (2H, m, H-Ar),
7.32–7.34 (2H, m, H-Ar), invisible NHCO; IR (cmꢂ1): 3288,
3060, 2933, 2818, 1652, 1500, 1241, 1141, 1027, 732; ESI-MSþ:
m/z 354 (MH)þ.
m.p.: 88–91°C (ethanol/n-hexane); yield 93%; 1H NMR (d): 1.80
(2H, s, NH2), 2.57–2.68 (4H, m, 2xCH2), 2.99–3.12 (4H, m,
2xCH2), 3.57 (2H, s, CH2-Npiper), 3.86 (2H, s, CH2-NH2), 7.10–7.46
(7H, m, H-Ar); IR (cmꢂ1): 3353, 3288, 2957, 2816, 1446, 1236,
798, 772; ESI-MSþ: m/z 350 (MH)þ.
Hydrochloride: m.p.: 218–221°C; Anal. calcd. for
General procedure for the preparation of carboxamides
9a–11a, 15a–17a, and sulfonamides 9b–11b, 15b–17b
Amixtureoftheamine24or25(1 mmol),1 mLoftriethylamine,
and10 mLofmethylenechloridewasstirredfor5 min. Thenthe
corresponding acyl chloride or sulfonyl chloride (1.1 mmol) in
2 mL of methylene chloride was added at 10°C. The reaction
mixture was left at room temperature for 24 h. The solvent and
excess of triethylamine were evaporated. The residue was
C
21H27N3O2 ꢄ HCl (389.92): C, 64.69; H, 7.24; N, 10.78. Found:
C, 64.70; H, 7.01; N, 10.59.
N-{4-([4-(2-Methoxyphenyl)piperazin-1-yl]methyl)benzyl}-
benzenesulfonamide (9b)
Base: m.p.: 61–63°C (methanol); yield 52%; 1H NMR (d):
2.55–2.67 (4H, m, 2xCH2), 3.02–3.14 (4H, m, 2xCH2), 3.54 (2H, s,
CH2-Npiper), 3.85 (3H, s, OCH3), 4.15 (2H, d, J ¼ 5.85 Hz, CH2NH),
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4.71 (1H, t, J ¼ 5.95 Hz, NHSO2), 6.90–7.08 (4H, m, H-Ar),
7.18–7.33 (4H, m, H-Ar), 7.48–7.60 (3H, m, H-Ar), 7.83–7.93
(2H, m, H-Ar); IR (cmꢂ1): 3284, 3058, 2936, 2818, 1499, 1325,
1236, 1140, 1022, 748; ESI-MSþ: m/z 452 (MH)þ.
3057, 2942, 2817, 1615, 1448, 1300, 772; ESI-MSþ: m/z 504
(MH)þ.
Hydrochloride: m.p.: >250°C (decomp.); Anal. calcd. for
C
29H27Cl2N3O ꢄ 2HCl (577.37): C, 60.33; H, 5.06; N, 7.28. Found:
Hydrochloride: m.p.: 246–248°C; Anal. calcd. for
C, 60.60; H, 5.31; N, 7.01.
C
25H29N3O3S ꢄ 2HCl ꢄ H2O (542.52): C, 55.35; H, 6.13; N,
7.75. Found: C, 55.59; H, 6.00; N, 7.82.
N-{4-([4-(2,3-Dichlorophenyl)piperazin-1-yl]methyl)-
benzyl}acetamide (17a)
N-{4-([4-(2-Methoxyphenyl)piperazin-1-yl]methyl)benzyl}-
2-naphthalenesulfonamide (10b)
Base: oil; yield 49%; 1H NMR (d): 2.02 (3H, s, COCH3), 2.60–2.67
(4H, m, 2xCH2), 3.03–3.09 (4H, m, 2xCH2), 3.58(2H, s, CH2-Npiper),
4.41 (2H, d, J ¼ 5.62Hz, CH2NH), 6.90–6.97 (1H, m, H-Ar),
7.11–7.15(2H, m, H-Ar), 7.22–7.35(4H, m, H-Ar), invisible NHCO;
IR (cmꢂ1): 3288, 3064, 2932, 2820, 1652, 1577, 1448, 1370, 1246,
957, 733; ESI-MSþ: m/z 392 (MH)þ.
Base: m.p.: 120–122°C (methanol); yield 80%; 1H NMR (d):
2.50–2.62 (4H, m, 2xCH2), 3.00–3.11 (4H, m, 2xCH2), 3.46
(2H, s, CH2-Npiper), 3.84 (3H, s, OCH3), 4.16 (2H, d, J ¼ 6.16 Hz,
CH2NH), 4.79 (1H, t, J ¼ 6.10 Hz, NHSO2), 6.80–6.98 (4H, m,
H-Ar), 7.18–7.31 (4H, m, H-Ar), 7.57–7.74 (2H, m, H-Ar),
7.85–8.03 (4H, m, H-Ar), 8.44 (1H, s, H-Ar); IR (cmꢂ1): 3289,
3053, 2854, 1497, 1333, 1235, 1156, 1062, 740; ESI-MSþ: m/z
502 (MH)þ.
Hydrochloride: m.p.: >250°C (>225°C sublim.); Anal. calcd.
for C20H23Cl2N3O ꢄ HCl (428.78): C, 56.02; H, 5.64; N, 9.80.
Found: C, 56.18; H, 5.56; N, 9.70.
Hydrochloride: m.p.: 182–185°C; Anal. calcd. for
N-{4-([4-(2,3-Dichlorophenyl)piperazin-1-yl]methyl)-
benzyl}benzenesulfonamide (15b)
C
29H31N3O3S ꢄ 2HCl (574.56): C, 60.62; H, 5.79; N, 7.31. Found:
C, 60.80; H, 5.59; N, 7.54.
Base: oil; yield 80%; 1H NMR (d): 2.50–2.68 (4H, m, 2xCH2),
2.96–3.08 (4H, m, 2xCH2), 3.46 (2H, s, CH2-Npiper), 4.07 (2H, s,
CH2NH), 5.29 (1H, s, NHSO2), 6.85–7.28 (5H, m, H-Ar), 7.50–7.74
(3H, m, H-Ar), 7.88–8.72 (4H, m, H-Ar); IR (cmꢂ1): 3272, 3059,
2938, 2819, 1576, 1447, 1324, 1156, 977, 733; ESI-MSþ: m/z 490
(MH)þ.
N-{4-([4-(2-Methoxyphenyl)piperazin-1-yl]methyl)benzyl}-
methanesulfonamide (11b)
Base oil; yield 45%; 1H NMR (d): 2.61–2.68 (4H, m, 2xCH2)),
2.88 (3H, s, SO2CH3), 2.95–3.12 (4H, m, 2xCH2), 3.58 (2H, s,
CH2-Npiper), 3.85 (3H, s, OCH3), 4.31 (2H, d, J ¼ 5.68 Hz,
CH2NH), 6.83–7.01 (4H, m, Ar-H) 7.28–7.34 (4H, m, Ar-H),
invisible NHSO2; IR (cmꢂ1): 3288, 2934, 2820, 1500, 1451,
1320, 1241, 1146, 1010, 913, 750; ESI-MSþ: m/z 390 (MH)þ.
Hydrochloride: m.p.: 214–216°C; Anal. calcd. for
Hydrochloride: m.p.: 215–218°C (at >150°C a change of
crystalline form); Anal. calcd. for
H2O (581.38): C, 49.58; H, 5.03; N, 7.23. Found: C, 49.88; H,
5.31; N, 7.20.
C
24H25Cl2N3O2S ꢄ 2HCl ꢄ
C
20H27N3O3S ꢄ 2HCl (462.43): C, 51.95; H, 6.32; N, 9.09. Found:
N-{4-([4-(2,3-Dichlorophenyl)piperazin-1-yl]methyl)-
benzyl}2-naphthalenesulfonamide (16b)
C, 52.12; H, 6.39; N, 9.21.
Base: oil; yield 51%; 1H NMR (d): 2.48–2.66 (4H, m, 2xCH2),
2.95–3.06 (4H, m, 2xCH2), 3.46 (2H, s, CH2-Npiper), 4.16 (2H, s,
CH2NH), 5.28 (1H, s, NHSO2), 6.91–7.27 (7H, m, H-Ar), 7.55–7.66
(2H, m, H-Ar), 7.83–8.00 (4H, m, H-Ar), 8.41 (1H, s, H-Ar); IR
(cmꢂ1): 3272, 3055, 2963, 2818, 1576, 1447, 1346, 1199, 1154,
961, 735; ESI-MSþ: m/z 540 (MH)þ.
N-{4-([4-(2,3-Dichlorophenyl)piperazin-1-yl]methyl)-
benzyl}benzamide (15a)
Base: m.p.: 162–164°C (methanol/H2O); yield 63%; 1H NMR
(d): 2.57–2.68 (4H, m, 2xCH2), 3.00–3.12 (4H, m, 2xCH2), 3.57
(2H, s, CH2-Npiper), 4.63 (2H, d, J ¼ 5.66 Hz, CH2NH), 6.49 (1H,
br s, NHCO), 6.92–7.17 (2H, m, H-Ar), 7.26–7.38 (5H, m, H-Ar),
7.38–7.48 (3H, m, H-Ar), 7.74–7.86 (2H, m, H-Ar); IR (cmꢂ1):
3291, 3057, 2942, 2817, 1633, 1451, 1245, 970, 696; ESI-MSþ:
m/z 454 (MH)þ.
Hydrochloride: m.p.: >250°C (at >190°C a change of
crystalline form); Anal. calcd. for
C
28H27Cl2N3O2S ꢄ 2HCl ꢄ
H2O (631.44): C, 53.26; H, 4.95; N, 6.65. Found: C, 53.56; H,
5.11; N, 6.51.
Hydrochloride: m.p.: >250°C (decomp.); Anal. calcd. for
C
25H25Cl2N3O ꢄ 2HCl ꢄ H2O (545.33): C, 55.06; H, 5.36; N, 7.71.
N-{4-([4-(2,3-Dichlorophenyl)piperazin-1-yl]methyl)-
benzyl}methanesulfonamide (17b)
Found: C, 55.09; H, 5.39; N, 7.89.
Base: oil; yield 51%; 1H NMR (d): 2.60–2.66 (4H, m, 2xCH2), 2.89
(3H, s,SO2CH3),3.05–3.09(4H,m, 2xCH2), 3.60(2H, s, CH2-Npiper),
4.32 (2H, d, J ¼ 5.71Hz, CH2NH), 6.93–6.96 (1H, m, Ar-H),
7.13–7.16 (2H, m, Ar-H), 7.29–7.39 (4H, m, Ar-H), invisible
NHSO2; IR (cmꢂ1): 3285, 2930, 2822, 1578, 1449, 1320, 1150, 958,
735; ESI-MSþ: m/z 428 (MH)þ.
N-{4-([4-(2,3-dichlorophenyl)piperazin-1-yl]methyl)-
benzyl}2-naphthalenecarboxamide (16a)
Base: m.p.: 172–173°C (CHCl3/n-hexane); yield 79%;
1H NMR (d): 2.61–2.67 (4H, m, 2xCH2), 3.03–3.08 (4H, m,
2xCH2), 3.58 (2H, s, CH2-Npiper), 4.70 (2H, d, J ¼ 5.67 Hz,
CH2NH), 6.54 (1H, br s, NHCO), 6.92–7.14 (3H, m, H-Ar),
7.34–7.38 (4H, m, H-Ar), 7.50–7.58 (2H, m, H-Ar), 7.82–7.95
(4H, m, H-Ar), 8.30–8.32 (1H, m, H-Ar); IR (cmꢂ1): 3260,
Hydrochloride:
m.p.:
>250°C;
Anal.
calcd.
for
C
19H23Cl2N3O2S ꢄ 2HCl ꢄ H2O (519.31): C, 43.94; H, 5.24; N,
8.09. Found: C, 43.71; H, 5.01; N, 8.05.
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General procedure for the synthesis of 27 and 28
Procedure for the preparation of 4-{[4-(2,3-
A mixture of 0.01 mol of the 4-nitrobenzyl chloride (26),
0.01 mol of the 1-(2-methoxyphenyl)piperazine (o-OMe-PhP)
or 1-(2,3-dichlorophenyl)arylpiperazine (2,3-DCPP) in the
hydrochloride forms, 0.03 mol of anhydrous potassium
carbonate, and a few crystals (ꢁ0.01 g) of potassium iodide
in 20 mL of dimethylformamide, were stirred with a magnetic
stirrer at a room temperature for 48 h. Then, the reaction
mixture was poured into 100–150 mL of water, and the
precipitate was collected by filtration. The solid products 27
and 28 were purified by crystallization.
dichlorophenyl)piperazin-1-yl]methyl}aniline (30)
The mixture of 2.7 g (12 mmol) of tin(II) chloride dihydrate,
8 mL of ethanol, and 1.6 mL of concentrated HCl was stirred at
70°C until it became clear (about 2 h). To this hot solution 1.1 g
(3 mmol) of 1-(4-nitrobenzyl)-4-(2,3-dichlorophenyl)pipera-
zine (28) was added portionwise for 30 min. Next, the mixture
was gently refluxed until the reaction was complete, as
indicated by TLC analysis (about 1 h). After addition of water
(20 mL), the resulting solution was alkalized with KOH and
allowed to cool to room temperature. The aqueous layer was
extracted with ethyl acetate (3 ꢃ 25 mL) and the combined
organic extracts were washed with brine (2 ꢃ 25 mL) and
water (3 ꢃ 50 mL), dried with MgSO4, and concentrated under
reduced pressure. The crude amine 30 was purified on a silica
gel column, using chloroform/methanol 9:1 as eluent.
1-(4-Nitrobenzyl)-4-(2-methoxyphenyl)piperazine (27)
m.p.: 110–111°C (DMF/methanol); yield 88%; 1H NMR (d):
2.60–2.73 (4H, m, 2xCH2), 3.04–3.17 (4H, m, 2xCH2), 3.67 (2H, s,
CH2-Npiper), 3.86 (3H, s, OCH3), 6.91–7.00 (4H, m, H-Ar), 7.54
(2H, d, J ¼ 8.80 Hz, H-Ar), 8.20 (2H, d, J ¼ 8.82 Hz, H-Ar); IR
(cmꢂ1): 3071, 2808, 1517, 1453, 1346, 1230, 1014, 740; ESI-
MSþ: m/z 328 (MH)þ.
4-{[4-(2,3-Dichlorophenyl)piperazin-1-yl]methyl}aniline
(30)
Oil; yield 68%; 1H NMR (d): 2.60–2.67 (4H, m, 2xCH2)), 3.00–3.10
(4H, m, 2xCH2), 3.48 (2H, s, CH2-Npiper), 3.58–3.71 (2H, br. s, NH2),
6.59–6.70 (2H, m, Ar-H), 6.84–6.99 (1H, m, Ar-H), 7.06–7.22
(4H, m, Ar-H); IR (cmꢂ1): 3447, 3358, 3001, 2814, 1619, 1447,
1245, 1133, 955, 777; ESI-MSþ: m/z 336 (MH)þ.
1-(4-Nitrobenzyl)-4-(2,3-dichlorophenyl)piperazine (28)
m.p.: 135–136°C (petroleum ether); yield 80%; 1H NMR (d):
2.55–2.72 (4H, m, 2xCH2), 2.97–3.14 (4H, m, 2xCH2), 3.67 (2H, s,
CH2-Npiper), 6.89–7.00 (1H, m, Ar-H), 7.09–7.22 (2H, m, Ar-H),
7.51–7.61 (2H, m, Ar-H), 8.15–8.24 (2H, m, Ar-H); IR (cmꢂ1):
3070, 2823, 1517, 1448, 1341, 1231, 954, 781; ESI-MSþ: m/z 366
(MH)þ.
General procedure for the preparation of carboxamides
12a–14a, 18a–20a, and sulfonamides 12b–14b, 18b–20b
A mixture of the amine 29 or 30 (1 mmol) and 10 mL of
pyridine was stirred for 5 min. Then, the corresponding acyl
chloride or sulfonyl chloride (1.1 mmol) in 2 mL of pyridine
was added at 10°C. The reaction mixture was left at room
temperature for 24 h. Next, the pyridine was evaporated, and
the resulting solid was dissolved in 10 mL of methylene
chloride and washed subsequently with 5% solution of
sodium hydrogen carbonate (2 ꢃ 10 mL) and water (10 mL).
Organic layer was dried over anhydrous magnesium sulfate,
and the solvent was evaporated. Crude amides were purified
by crystallization, or by chromatography on a silica gel
column, using chloroform/methanol 9:1 as eluent.
For biological experiments, free bases of amides 12a–14a,
18a–20a, and sulfonamides 12b–14b, 18b–20b were converted
into hydrochlorides, using ethanol saturated with HCl, and
their molecular weights were established on the basis of an
elemental analysis.
Procedure for the preparation of 4-{[4-(2-methoxyphenyl)-
piperazin-1-yl]methyl}aniline (29)
1-(4-Nitrobenzyl)-4-(2-methoxyphenyl)piperazine (27) (1.64 g,
5 mmol) was dissolved in a mixture of THF (10 mL) and
methanol (10 mL), containing 1.63 g (25 mmol) of zinc powder
(activated by stirring with 15 mL 5% ag. HCl for 5 min, then
washed well with water and finally with 20 mL of methanol).
To the stirred mixture, at ambient temperature 1.58 g
(25 mmol) of ammonium formate was added in one portion.
After 3 min the mixture became warm, and after the
following 30 min the reaction was over, as indicated by
TLC. The mixture was filtered and the solvents were
evaporated. The residue was extracted with 20 mL of ethyl
acetate. The extract was washed twice with 15 mL of
saturated sodium chloride solution and then with 10 mL of
water. The organic layer was dried over sodium sulfate and
then concentrated to obtain the crude amine 29, which was
purified by silica gel column chromatography, using chloro-
form/methanol 9:1 as eluent.
N-{4-([4-(2-Methoxyphenyl)piperazin-1-yl]methyl)phenyl}-
benzamide (12a)
Base:m.p.:146–148°C(propan-2-ol);yield51%;1HNMR(d):2.66
(4H, br s, 2xCH2), 3.08 (4H, br s, 2xCH2), 3.57 (2H, s, CH2-Npiper),
3.86 (3H, s, OCH3), 6.83–7.02 (4H, m, H-Ar), 7.34–7.40 (2H, m,
H-Ar), 7.46–7.63 (5H, m, H-Ar), 7.29 (1H, br s, NHCO), 7.85–7.90
(2H, m, H-Ar); IR (cmꢂ1): 3344, 3056, 2939, 2813, 1654, 1525,
1501, 1243, 746; ESI-MSþ: m/z 402 (MH)þ.
4-{[4-(2-Methoxyphenyl)piperazin-1-yl]methyl}aniline (29)
Oil; yield 60%; 1H NMR (d): 2.58–2.70 (4H, m, 2xCH2), 3.04–3.16
(4H, m, 2xCH2), 3.48 (2H, s, CH2-Npiper), 3.56 (2H, br s, NH2), 3.85
(3H, s, OCH3), 6.65 (2H, d, J ¼ 8.32Hz, H-Ar), 6.89–6.99 (4H, m,
H-Ar), 7.14(2H, d, J ¼ 8.24 Hz, H-Ar); IR (cmꢂ1): 3444, 3350, 3049,
2815, 1451, 1238, 1128, 1030, 758; ESI-MSþ: m/z 298 (MH)þ.
Hydrochloride: m.p.: 215–218°C (decomp.); Anal. calcd. for
C
25H27N3O2 ꢄ 2HCl (474.42): C, 63.29; H, 6.16; N, 8.86. Found: C,
63.51; H, 6.01; N, 8.75.
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Carboxamides versus Sulfonamides
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N-{4-([4-(2-Methoxyphenyl)piperazin-1-yl]methyl)phenyl}-
2-naphthalenecarboxamide (13a)
2936, 2818, 1499, 1452, 1323, 1239, 1148, 1024, 748; ESI-MSþ:
m/z 376 (MH)þ.
Base: m.p.: 153–155°C (propan-2-ol); yield 55%; 1H NMR (d):
2.63–2.71 (4H, m, 2xCH2), 3.10 (4H, br s, 2xCH2), 3.58 (2H, s,
CH2-Npiper), 3.86 (3H, s, OCH3), 6.84–7.02 (4H, m, Ar-H),
7.35–7.42 (2H, m, Ar-H), 7.55–7.68 (4H, m, Ar-H), 7.87–7.96
(4H, m, Ar-H), 7.99 (1H, br s, NHCO), 8.36–8.39 (1H, m, Ar-H); IR
(cmꢂ1): 3325, 3055, 2952, 2804, 1653, 1501, 1452, 1315, 1243,
746; ESI-MSþ: m/z 452 (MH)þ.
Hydrochloride: m.p.: >250°C (decomp.); Anal. calcd. for
C
19H25N3O3S ꢄ 2HCl (448.41): C, 50.89; H, 6.07; N, 9.37. Found:
C, 50.69; H, 5.95; N, 9.61.
N-{4-([4-(2,3-Dichlorophenyl)piperazin-1-yl]methyl)-
phenyl}benzamide (18a)
Base: m.p.: 176–178°C (ethanol); yield 59%; 1H NMR (d): 2.61–
2.68 (4H, m, 2xCH2), 3.03–3.10 (4H, m, 2xCH2), 3.57 (2H, s, CH2-
Hydrochloride: m.p.: >250°C (decomp.); Anal. calcd. for
C
29H29N3O2 ꢄ 2HCl (524.48): C, 66.41; H, 5.96; N, 8.01. Found: C,
Npiper ), 6.91–6.99 (1H, m, Ar-H), 7.10–7.17 (2H, m, Ar-H), 7.33–
66.67; H, 6.11; N, 8.25.
7.39 (2H, m, Ar-H), 7.46–7.63 (5H, m, Ar-H), 7.82 (1H, br s,
NHCO), 7.85–7.90 (2H, m, Ar-H); IR (cmꢂ1): 3310, 2946, 2808,
1647, 1595, 1510, 1488, 1448, 1312, 1246, 957, 775; ESI-MSþ:
m/z 440 (MH)þ.
N-{4-([4-(2-Methoxyphenyl)piperazin-1-yl]methyl)phenyl}-
acetamide (14a)
Base: oil; yield 35%; 1H NMR (d): 2.17 (3H, s, COCH3), 2.59–2.68
(4H, m, 2xCH2), 3.02–3.12 (4H, m, 2xCH2), 3.53 (2H, s, CH2-Npiper),
3.84 (3H, s, OCH3), 6.82–7.03 (4H, m, Ar-H), 7.27–7.34 (3H, m, Ar-
Hþ NHCO), 7.41–7.50 (m, 2H, Ar-H); IR (cmꢂ1): 3307, 3058, 2940,
2810, 1659, 1499, 1367, 1312, 1240, 747; ESI-MSþ:m/z 340 (MH)þ.
Hydrochloride: m.p.: 244–248°C (decomp., at >190°C
a change of crystalline form); Anal. calcd. for C20H25N3O2 ꢄ
2HCl ꢄ H2O (430.37): C, 55.82; H, 6.79; N, 9.76. Found: C, 55.88; H,
6.59; N, 9.65.
Hydrochloride: m.p.: >250°C (decomp.); Anal. calcd. for
C
24H23Cl2N3O ꢄ 2HCl (513.29): C, 56.16; H, 4.91; N, 8.19. Found:
C, 56.36; H, 4.92; N, 8.21.
N-{4-([4-(2,3-Dichlorophenyl)piperazin-1-yl]methyl)-
phenyl}2-naphthalenecarboxamide (19a)
Base: m.p.: 173–174°C (methanol); yield 56%; 1H NMR (d):
2.62–2.70 (4H, m, 2xCH2), 3.04–3.11 (4H, m, 2xCH2), 3.60 (2H, s,
CH2-Npiper), 6.93–7.16 (3H, m, Ar-H), 7.36–7.41 (2H, m, Ar-H),
7.54–7.70 (4H, m, Ar-H), 7.89 (1H, br s, NHCO), 7.90–8.00
(4H, m, Ar-H), 8.37–8.40 (1H, m, Ar-H); IR (cmꢂ1): 3361, 3054,
2965, 1655, 1578, 1451, 963, 761; MSþ: m/z 490 (MH)þ.
Hydrochloride: m.p.:>250°C (decomp.); Anal. calcd. for
N-{4-([4-(2-Methoxyphenyl)piperazin-1-yl]methyl)phenyl}-
benzenesulfonamide (12b)
Base: m.p.: 68–71°C (methanol/H2O); yield 37%; 1H NMR (d):
2.52–2.64 (4H, m, 2xCH2), 3.00–3.12 (4H, m, 2xCH2), 3.48 (2H, s,
CH2-Npiper),3.84(3H,s,OCH3),6.88–6.98(4H,m,H-Ar),7.06–7.28
(4H, m, H-Ar), 7.39–7.56 (3H, m, H-Ar), 7.71–7.84 (2H, m, H-Ar),
invisible NHSO2; IR (cmꢂ1): 3276, 3056, 2809, 1499, 1452, 1333,
1237, 1153, 1127, 752; ESI-MSþ: m/z 438 (MH)þ.
C
28H25Cl2N3O ꢄ 2HCl (563.35): C, 59.70; H, 4.83; N, 7.46. Found:
C, 59.92; H, 4.94; N, 7.33.
N-{4-([4-(2,3-Dichlorophenyl)piperazin-1-yl]methyl)-
phenyl}acetamide (20a)
Hydrochloride: m.p.: 158–160°C; Anal. calcd. for
Base: m.p.: 202–204°C (methanol); yield 58%; 1H NMR (d): 2.17
(3H, s, COCH3), 2.58–2.65 (4H, m, 2xCH2), 3.02–3.08 (4H, m,
2xCH2),3.54(2H,s,CH2-Npiper), 6.91–6.98(1H,m, Ar-H),7.09–7.17
(3H, m, Ar-H þ NHCO), 7.27–7.33 (2H, m, Ar-H), 7.42–7.48 (2H, m,
Ar-H); IR (cmꢂ1): 3292, 3125, 2812, 1662, 1600, 1510, 1447, 1367,
1314, 1247, 954, 805; MSþ: m/z 378 (MH)þ.
C
24H27N3O3S ꢄ 2HCl ꢄ 0.5H2O (519.48): C, 55.49; H, 5.82; N,
8.09. Found: C, 55.27; H, 5.98; N, 8.00.
N-{4-([4-(2-Methoxyphenyl)piperazin-1-yl]methyl)phenyl}-
2-naphthalenesulfonamide (13b)
Base: m.p.: 153–155°C (methanol/H2O); yield 60%; 1H NMR (d):
2.50–2.62 (4H, m, 2xCH2), 2.98–3.10 (4H, m, 2xCH2), 3.47 (2H, s,
CH2-Npiper),3.84(3H,s,OCH3),6.88–6.97(4H,m,H-Ar),7.08–7.26
(4H, m, H-Ar), 7.50 (1H, br s, NHSO2), 7.58–7.98 (6H, m, H-Ar),
8.34–8.37 (1H, m, H-Ar); IR (cmꢂ1): 3274, 3058, 2804, 1499, 1447,
1328, 1235, 1153, 1130, 753; ESI-MSþ: m/z 488 (MH)þ.
Hydrochloride: m.p.: 208–210°C; Anal. calcd. for
Hydrochloride: m.p.: >250°C (>230°C sublim.); Anal. calcd.
for C19H21Cl2N3O ꢄ 2HCl (451.22): C, 50.58; H, 5.14; N, 9.31.
Found: C, 50.59; H, 4.92; N, 9.13.
N-{4-([4-(2,3-Dichlorophenyl)piperazin-1-yl]methyl)-
phenyl}benzenesulfonamide (18b)
Base: m.p.: 150–152°C (methanol); yield 49%; 1H NMR (d):
2.60–2.67 (4H, m, 2xCH2), 3.04–3.10 (4H, m, 2xCH2), 3.53 (2H, s,
CH2-Npiper), 6.90–6.95 (1H, m, Ar-H), 7.00–7.07 (2H, m, Ar-H),
7.09–7.18 (2H, m, Ar-H), 7.20–7.30 (2H, m, Ar-H), 7.40–7.48
(2H, m, Ar-H), 7.50–7.57 (1H, m, Ar-H), 7.75–7.80 (2H, m, Ar-H),
invisible NHSO2; IR (cmꢂ1): 3384, 3049, 2834, 1581, 1455, 1336,
1156, 1090, 924, 688; MSþ: m/z 476 (MH)þ.
C
28H29N3O3S ꢄ 2HCl (560.54): C, 60.00; H, 5.57; N, 7.50. Found:
C, 60.09; H, 5.35; N, 7.67.
N-{4-([4-(2-Methoxyphenyl)piperazin-1-yl]methyl)phenyl}-
methanesulfonamide (14b)
Base: oil; yield 45%; 1H NMR (d): 2.60–2.67 (4H, m, 2xCH2), 3.02
(3H, s,SO2CH3),2.97–3.14(4H,m, 2xCH2), 3.56(2H, s, CH2-Npiper),
3.85 (3H, s, OCH3), 6.80–7.02 (4H, m, Ar-H), 7.16–7.23 (2H, m,
Ar-H), 7.30–7.38 (2H, m, Ar-H), invisible NHSO2; IR (cmꢂ1): 3252,
Hydrochloride: m.p.: 161–163°C; Anal. calcd. for
C
23H23Cl2N3O2S ꢄ 2HCl ꢄ 0.5H2O (558.35): C, 49.48; H, 4.69; N,
7.53. Found: C, 49.65; H, 4.49; N, 7.62.
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Arch. Pharm. Chem. Life Sci. 2017, 350, e1700090
P. Kowalski et al.
Archiv der Pharmazie
N-{4-([4-(2,3-Dichlorophenyl)piperazin-1-yl]methyl)-
phenyl}-2-naphthalenesulfonamide (19b)
120 mM NaCl, 5 mM KCl, 1.5 mM CaCl2 and 0.1% ascorbate. All
assays were incubated in a total volume of 200mL in 96-well
microtitre plates for 1 h at 37°C, except for 5-HT1AR which were
incubated at room temperature for 1 h. The process of
equilibration was terminated by rapid filtration through
Unifilter plates with a 96-well cell harvester and radioactivity
retained on the filters was quantified on a Microbeta plate
reader (PerkinElmer, USA). For displacement studies the assay
samples contained as radioligands (PerkinElmer, USA): 2.5 nM
[3H]-8-OH-DPAT (135.2 Ci/mmol) for 5-HT1AR; 2 nM [3H]-LSD
(83.6 Ci/mmol)for 5-HT6R; 0.6 nM [3H]-5-CT (39.2 Ci/mmol) for 5-
HT7R or [3H]-raclopride (76.0 Ci/mmol) for D2LR. Non-specific
binding was defined with 10 mM of 5-HT in 5-HT1AR and 5-
HT7R binding experiments, whereas 10mM of methiothepine or
1 mM of (þ)butaclamol were used in 5-HT6R and D2L assays,
respectively. Each compound was tested in triplicate at 7–8
concentrations (10ꢂ11–10ꢂ4 M). The inhibition constants (Ki)
were calculated from the Cheng–Prusoff equation [33]. Results
were expressed as means of atleast three separate experiments.
Base: m.p.: 194–196°C (methanol/H2O); yield 60%; 1H NMR (d):
2.50–2.56 (4H, m, 2xCH2), 2.97–3.04 (4H, m, 2xCH2), 3.47 (2H, s,
CH2-Npiper), 6.89–6.96 (1H, m, Ar-H), 7.01–7.07 (2H, m, Ar-H),
7.09–7.23 (4H, m, Ar-H), 7.56–7.65 (2H, m, Ar-H), 7.71–7.77
(1H, m, Ar-H), 7.84–7.92 (3H, m, Ar-H), 8.32–8.35 (1H, m, Ar-H),
invisible NHSO2; IR (cmꢂ1): 3224, 3055, 2811, 1507, 1439, 1334,
1156, 1133, 953, 692; MSþ: m/z 526 (MH)þ.
Hydrochloride: m.p.: 225–228°C (decomp.); Anal. calcd. for
C
27H25Cl2N3O2S ꢄ 2HCl (599.40): C, 54.10, 4.54; N, 7.01. Found:
C, 54.22; H, 4.41; N, 7.33.
N-{4-([4-(2,3-Dichlorophenyl)piperazin-1-yl]methyl)-
phenyl}methanesulfonamide (20b)
Base: m.p.: 180–182°C (methanol); yield 50%; 1H NMR (d):
2.59–2.67 (4H, m, 2xCH2), 3.02 (3H, s, SO2CH3), 3.01–3.10
(4H, m, 2xCH2), 3.56 (2H, s, CH2-Npiper), 6.91–6.98 (1H, m, Ar-H),
7.10–7.21 (4H, m, Ar-H), 7.31–7.38 (2H, m, Ar-H), invisible
NHSO2; IR (cmꢂ1): 3287, 3093, 2933, 1615, 1515, 1423, 1333,
1315, 1147, 922, 783; MSþ: m/z 414 (MH)þ.
Computational details
Molecular docking
Hydrochloride: m.p.: >250°C (decomp.); Anal. calcd. for
C
18H21Cl2N3O2S ꢄ 2HCl (487.27): C, 44.37, 4.76; N, 8.62. Found:
The 3-dimensional structures of the compounds studied were
prepared using LigPrep ver. 3.7 [34], while the appropriate
ionization states at pH ¼ 7.4 were assigned using Epik version
3.5 [35]. The Protein Preparation Wizard was used to assign
the bond orders, appropriate amino acid ionization states and
to check the steric clashes. The receptor grids were generated
(the OPLS_2005 force field) by centering the grid box of the
C, 44.29; H, 4.94; N, 8.88.
In vitro pharmacology
Cell culture
All receptor cDNAs were obtained from the Missouri S&T
cDNA Resource Center (www.cdna.org). HEK293 cells with
stable expression of human serotonin 5-HT1AR, 5-HT6R,
5-HT7bR, or dopamine D2LR were obtained with the use of
Lipofectamine 2000 (Invitrogen). Cells were maintained at
37°C in a humidified atmosphere with 5% CO2 and were
grown in Dulbecco’s modified Eagle’s Medium containing
10% dialyzed fetal bovine serum under selective conditions
(500 mg/mL G418). For membranes preparations, cells
were subcultured into 150 cm2 cell culture flasks, grown
to 90% confluence, washed twice with pre-warmed to
37°C phosphate buffered saline (PBS) and were pelleted by
centrifugation (200 ꢃ g) in PBS containing 0.1 mM EDTA and
1 mM dithiothreitol, and stored at ꢂ80°C.
̊
size of 15 A on the Asp3.32. Automated docking was
performed by using Glide version 7.0 at SP level with the
flexible docking option turned on [36]. The spatial constrain
was imposed on creation of an ionic interaction between the
protonated amine group of the ligand and Asp3.32 side chain.
ONIOM optimization protocol
Full optimization of the systems studied (4618–4387 atoms
depending on the receptor) was performed using QM/MM:
ONIOM protocol, implemented in the Gaussian09 [37] soft-
ware. The high level QM, including ligands and all amino acid
̊
residues, whose atoms were less than 4 A from the ligand was
applied. A dividing boundary was established at the Csp3–Csp3
bonds, which gave 242–271 atoms for the QM level. The
remaining parts of the receptor were assigned to the MM
region, described by the AMBER [38] force field. The
optimization of the binding site was performed using DFT
and B3LYP methods [39, 40], in combination with split-valence
basis set 6-31Gꢅ [41–46]. For each structure, MM fragment was
removed and replaced by hydrogen, and then harmonic
vibrational frequencies were calculated to confirm the
potential energy minimum (T ¼ 298.15 K, p ¼ 1 atm).
5-HT1A/5-HT6/5-HT7/D2 receptors radioligand binding
assays
Membrane preparation and general assay procedures for
cloned receptors were adjusted to 96-microwell format based
on protocols was described by us previously [26, 27]. Cell pellets
were thawed and homogenized in 20 volumes of assay buffer
using anUltra Turraxtissue homogenizer and centrifuged twice
at35000 gfor20minat4°C,withincubationfor15minat37°Cin
between. The composition of the assay buffers was as follows:
for 5-HT1AR: 50 mM Tris-HCl, 0.1 mM EDTA, 4 mM MgCl2, 10 mM
pargyline, and 0.1% ascorbate; for 5-HT6R: 50mM Tris-HCl,
0.5 mM EDTA and 4 mM MgCl2, for 5-HT7bR: 50mM Tris-HCl,
4 mM MgCl2, 10mM pargyline and 0.1% ascorbate; for
dopamine D2LR: 50mM Tris-HCl, 1 mM EDTA, 4 mM MgCl2,
We are grateful to Prof. Andrzej J. Bojarski for research
support.
The authors have declared no conflict of interest.
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Arch. Pharm. Chem. Life Sci. 2017, 350, e1700090
Carboxamides versus Sulfonamides
Archiv der Pharmazie
ꢁ
[18] M. Boukraa, M. Sabbah, L. Soulere, M. L. El Efrit,
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