Synthesis and structure-activity relationships of 2-(substituted phenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-thiazolidin-4-ones acting as H1-histamine antagonists

Article abstract of DOI:10.1016/S0014-827X(99)00064-6

2-(Substituted-phenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-thiazolidin-4-ones (1-15) showed dependence of the potency of the H₁-histamine antagonism on the m- and p-substituents suggesting that the aromatic moiety binds the receptor by a strong

Full text of DOI:10.1016/S0014-827X(99)00064-6

www.elsevier.nl/locate/farmac
Il Farmaco 54 (1999) 579–583
Synthesis and structure–activity relationships of 2-(substituted
phenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-thiazolidin-4-ones
acting as H1-histamine antagonists
M. Vittoria Diurno a,*, Orazio Mazzoni a, Gaetano Correale a,
Isabel Gomez Monterrey a, Antonio Calignano b, Giovanna La Rana b,
Adele Bolognese c
a Dipartimento di Chimica Farmaceutica e Tossicologica, Uni6ersita` di Napoli ‘Federico II’, Via D. Montesano 49, I-80131 Naples, Italy
b Dipartimento di Farmacologia Sperimentale, Uni6ersita` di Napoli ‘Federico II’, Via D. Montesano 49, I-80131 Naples, Italy
c Dipartimento di Chimica Organica e Biologica, Uni6ersita` di Napoli ‘Federico II’, Via Mezzocannone 16, I-80134 Naples, Italy
Received 18 January 1999; accepted 10 June 1999
Abstract
2-(Substituted-phenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-thiazolidin-4-ones (1–15) showed dependence of the potency of the
H1-histamine antagonism on the m- and p-substituents suggesting that the aromatic moiety binds the receptor by a strong
p-interaction. Electron-withdrawing substituents decrease the potency while the electron-donating alkyl substituents, enhancing
the aryl HOMO energy, increase the antihistamine activity. The m-substituents with the capability to form hydrogen bonds, seems
to share an extrainteraction with hydrogen accepting or donating groups of the histamine receptor and exhibits very high potency.
© 1999 Elsevier Science S.A. All rights reserved.
Keywords: 1,3-Thiazolidin-4-ones derivatives; H1-Antihistamine activity
[7–9] were reported. The dependence of the H1-antihis-
taminic potency on the aromatic substituents suggested
that the aryl group binds to the receptor by a strong
p-interaction.
In order to investigate this binding, a new series
of 2-(substituted-phenyl)-3-[3-(N,N-dimethylamino)-
propyl]-1,3-thiazolidin-4-ones (Fig. 1) was synthesized,
characterized and evaluated for its capacity to inhibit the
contraction induced by histamine on guinea pig ileum.
1. Introduction
The most important conclusion on the H1-histamine
antagonist model by QSAR and receptor mapping stud-
ies performed on both classical and non-classical H1-an-
tagonists suggests that there is a critical distance, around
,
6 A, between a basic tertiary nitrogen atom and an
aromatic ring [1–4]. The tertiary nitrogen and the
aromatic system have been proposed to interact respec-
tively, with the carboxy group of an aspartate (Asp311
)
and the phenyl group of two different phenylalanines
(Phe509 and Phe617) belonging to the H1-receptor protein
[5,6]. While the main interaction is electrostatic, the
phenyl–phenyl one is a p-stacking.
In a previous paper the synthesis and the H1-antihis-
taminic activity of some 2-(substituted-phenyl)-3-
[3-(N,N-dimethylamino)propyl]-1,3-thiazolidin-4-ones
* Corresponding author. Tel.: +39-081-748 6633; fax: +39-081-
748 6630.
E-mail address: diurno@unina.it (M.V. Diurno)
Fig. 1.
0014-827X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00064-6

580
M.V. Diurno et al. / Il Farmaco 54 (1999) 579–583
Scheme 1.
2. Chemistry
3. Results and discussion
The thiazolidinones 1–15, reported in Scheme 1 and
Table 1, were synthesized by addition of mercaptoacetic
acid to N-(substituted-benzylidene)-N%,N%-dimethyl-1,3-
diaminopropane in refluxing benzene. Radziszewski oxi-
dation of 3 afforded 4, while 8 was obtained by treat-
ment of 5 with hydroxylamine. Compounds 7, 10 and
14 were obtained by reduction of the corresponding
nitro derivatives 6, 9 and 21, respectively. The substi-
tuted aldehydes used to prepare the compounds 6 and 9
were synthesized according to the procedures reported
in Section 4.
Thiazolidinones 1–15 as free bases were converted
into the corresponding hydrochlorides for the pharma-
cological assays. The H1-antihistaminic activity of the
synthesized compounds was evaluated in vitro by mea-
suring their ability to inhibit the histamine-induced
contractions of isolated guinea-pig ileum [10] and re-
ported, as pA2 values, in Table 3. The results were
Table 1
1,3-thiazolidin-4-ones (1–15)
Comp.
R
Formula
Yield
M.p. (°C)
The products were characterized by their spectro-
scopic properties (IR, 1H NMR) and elemental
analysis.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4-OH
4-N(Me)2
3-CN
3-CONH2
3-CHO
4-NO2, 3-Me
4-NH2, 3-Me
3-CHNOH
3-NO2, 4-Me
3-NH2, 4-Me
4-OC3H7
4-C2H5
4-NHCOMe
3-NH2
4-tBut
C
14H20N2O2S
45
58
40
70
32
42
60
57
48
65
68
62
65
62
70
208–9
168–9
227–8
224–5
275–6
200–1
230–1
200–1
218–9
248–9
173–4
156–7
226–7
170–1
253–4
C16H25N3OS
C15H19N3OS
C15H21N3O2S
C15H20N2O2S
C15H21N3O3S
C15H23N3OS
C15H21N3O2S
C15H21N3O3S
C15H23N3OS
C17H26N2O2S
C16H24N2OS
C16H23N3O2S
C14H21N3OS
C18H28N2O2S
1
The H NMR data of compounds 1–15, reported in
Table 2, and the NOESY experiments, in agreement
with the X-ray data, suggested that the chain lies in a
gauche (a–b CH2)-anti (b–g CH2) conformation. This
spatial arrangement reduces the distance between the
aromatic ring and the tertiary nitrogen compared with
the distance of an all-anti conformation. According to
the current reports, this conformation satisfies the re-
,
quirement of a 6 A distance that gives rise to good
electrostatic and p interaction of the basic nitrogen and
of the phenyl ring with the corresponding areas of
receptor.

M.V. Diurno et al. / Il Farmaco 54 (1999) 579–583
581
Table 2
1H NMR data of 1,3-thiazolidinones a
Comp.
2-Ph
2-H
AB system
R
b
b
c
5-CHA
5-CHB
a-CH2
b-CH2 g-CH2
N(CH3)2
1
2
3
7.13 (d)
7.15 (d)
7.65 (d)
7.53 (t)
7.80 (s)
7.46 (d)
7.78 (d)
7.51 (d)
7.99 (d)
7.26 (s)
6.97 (s)
6.92 (d)
7.48 (s)
7.37 (d)
7.91 (s)
7.38 (d)
7.02 (d)
6.57 (s)
7.02 (d)
7.21 (d)
7.35 (d)
6.91 (t)
6.23 (s)
7.37 (d)
6.66 (d)
6.64 (d)
7.58 (s)
7.51 (d)
7.79 (t)
7.45 (d)
7.75 (s)
7.49 (t)
7.27 (d)
5.58
5.57
5.68
3.79
3.76
3.81
3.69
3.64
3.70
3.58 2.79
3.55 2.74
3.67 2.71
1.64
1.56
1.62
2.28
2.16
2.24
2.21
2.11
2.14
2.93 (s)
4
5.69
5.68
5.73
5.53
5.58
5.70
5.54
3.83
3.75
3.81
3.78
3.78
3.82
3.79
3.69
3.63
3.72
3.67
3.64
3.71
3.67
3.61 2.78
3.58 2.64
3.71 2.68
3.56 2.73
3.61 2.77
3.67 2.73
3.66 2.66
1.57
1.53
1.83
1.59
1.61
1.68
1.61
2.17
2.12
2.39
2.17
2.12
2.19
2.19
2.10
2.05
2.29
2.12
1.99
2.14
2.15
6.80 (bs)
9.94 (s)
2.60 (s)
5
6
7
6.95 (d)
2.13(s)
1.94(bs)
8.02 (s)
8
7.47 (d)
7.28 (t)
7.46 (d)
9
2.61 (s)
10
6.59 (d)
2.14 (s)
1.90 (bs)
3.50(t) 1.53(m) 0.82(t)
2.63 (q) 1.21 (t)
7.68 (bs) 2.17 (s)
2.80 (bs)
11
12
13
14
6.72 (d)
7.18 (d)
7.25 (d)
6.47 (d)
6.18 (d)
7.22 (d)
5.38
5.63
5.64
5.33
3.69
3.79
3.78
3.77
3.52
3.68
3.66
3.51
3.38 2.78
3.58 2.77
3.59 2.71
3.65 2.78
1.47
1.64
1.59
1.50
2.01
2.33
2.20
2.17
1.93
2.25
2.13
1.94
15
5.64
3.79
3.68
3.58 2.78
1.62
2.33
2.23
1.29 (s)
a CDCl3, chemical shifts in ppm.
b JA,B=15 Hz.
c Ja,b=13 Hz, Ja,b=7 Hz, Jb,g=7 Hz, J2,5A=between 1.5 and 2 Hz.
compared with the activity of mepyramine and with
previously synthesized thiazolidinones 16–22.
[11], could increase the electron availability of the aro-
matic system to share the p-interaction.
The electron-donating 4-substituents NH2 (17), OH
(1), N(Me)2 (2), OCH3 (20) would exert a detrimental
effect on activity, owing to their hydrophilic nature
[12]. In opposition to the potency of 15 the inactivity of
compound 11 is likely connected with the length of the
OC3H7 group, which could be repelled by the steric
The thiazolidinones 1–15 were also tested to investi-
gate the anticholinergic ability to inhibit the acetyl-
choline induced contractions on guinea-pig ileum. No
anticholinergic activity was detected for all compounds.
According to the previous pA2 data on the phenyl
substituent effect, the alkyl (Me [7], Et, i-Prop [7],
t-But) substituted thiazolidinones (19, 12, 16, 15)
showed high values of H1-antagonism (pA2\8). The
para-substituent effect was the most intensive (19 was
five times more active than 18). The pA2 values of the
alkyl derivatives (MeBEtBi-PropBt-But) suggested
that a hydrophobic interaction is involved, probably in
a lipophylic area.
On the contrary, the polar p-electron-donating
groups as OCH3 (20)BOC3H7 (11)BNH2 (17)#
N(Me)2 (2)#OH (1), with large mesomeric effects,
reduce the potency of the thiazolidinones as the elec-
tron-withdrawing halogens [7] and nitro group [7]
(pA257) do. Thiazolidinones 6 and 9 showed a low
potency, dramatically affected by the presence of the
strong electron-withdrawing nitro group, in spite of the
positive influence of the methyl group. Moreover, the
alkyl substituents, raising the energy of the HOMO
Table 3
H1-antagonistic activity on guinea-pig ileum a
b
b
Comp.
R
pA2
Comp.
R
pA2
1
2
3
4
5
6
7
8
9
4-OH
4-N(Me)2
3-CN
3-CONH2
3-CHO
4-NO2, 3-Me
4-NH2, 3-Me
3-CHNOH
3-NO2, 4-Me
3-NH2, 4-Me
4-OC3H7
6.4
6.3
5.7
11.4
11.7
5.7
9.3
11.2
6.4
11.3
5.5
12
13
14
15
4-C2H5
4-NHCOMe 7.2
8.8
3-NH2
4-tBut
4-iPro
4-NH2
3-Me
7.3
9.5
9.0
6.0
7.7
8.3
5.0
5.4
5.2
16 c
17 c
18 c
19 c
20 c
21 c
22 c
4-Me
4-OMe
3-NO2
4-NO2
10
11
a Mepyramine pA2=9.0.
b
90.2.
c Reported in Ref. [7].

582
M.V. Diurno et al. / Il Farmaco 54 (1999) 579–583
boundaries of the lipophilic area which probably has
the feature of a restricted cleft.
spectrometer. The purity of the compounds was
checked by ascending TLC on F254 Merck precoated
silica-gel plates (0.25 mm) with fluorescent backing.
IR spectra were taken on a Perkin–Elmer 399 spec-
trophotometer in KBr. The CꢀO stretching occurs at
1705–1710 cm−1 for the thiazolidinones 1–15. The
CONH2 stretching of the compound 4 lies at 3350–
The strong H1-antihistaminic activity (pA2\11)
showed by 4, 5 and 8, expected to be less active, needs
a different interpretation. In fact, the electron-with-
drawing substituents CONH2, CHO and CHNOH
make the thiazolidinones more active than the other
electron-withdrawing substituted derivatives and more
active also than the alkyl substituted ones.
This behavior might depend on the capability of the
CONH2, CHO and CHNOH groups to be involved in
hydrogen-bond interactions in the binding site.
Actually, the above quoted mapping receptor studies
of H1 - receptor suggest that Asn508 is present in prox-
imity of the Phe509 and could promote the binding by
interaction with the 3-substituents CONH2, CHO and
CHNOH as hydrogen bond accepting/donating group
[5].
In fact, the 3,4-disubstituted thiazolidinones 7 and 10
showed higher potency than the corresponding mono-
substituted methyl or amino thiazolidinones. The 100
times increase in activity observed going from 7 (4-
NH2, 3-Me) to its positional isomer 10 (3-NH2, 4-Me),
may reflect favorable interactions involving the 3-NH2
(hydrogen bond) and the 4-Me (HOMO energy en-
hancement) groups.
In conclusion, whenever the phenyl moiety of the
thiazolidinones interacts with a complementary area of
the H1 - receptor, this p interaction is enhanced by not
hydrophilic substituents increasing the HOMO energy
and is affected by the size of the 4 - alkyl substituent.
The 3 - arylsubstituent capable of hydrogen - bonding,
probably lying at suitable distance from Asn508, seems
to produce a strong additional interaction, thus enhanc-
ing the potency. In this perspective, the hypothesis of
an additional hydrogen bond between the electronega-
tive atom of the 3-substituent and a neighboring site of
the H1-histamine receptor, could explain the high H1-
antihistaminic activity of 4, 5 and 8. Moreover, this
result highlights another aspect of the H1-histamine
receptor and supports the early hypothesis of Nauta et
al. on the possibility of hydrogen bonding between a
hydrophilic aminoacidic residue and some antihis-
taminic drugs [2].
3170 and 1646 cm−1
.
1H NMR data reported in Table 2 were recorded in
CDCl3 on a Bruker 500 MHz spectrometer with Me4Si
as internal reference. Chemical shifts are given in ppm
and coupling constants in Hz.
4.1.1. 2-(Substituted-phenyl)-3-[3-(N,N-dimethylamino)-
propyl]-1,3-thiazolidin-4-one (1–3, 5, 6, 9, 11–15)
General procedure. An equimolar mixture (10 mmol)
of substituted benzaldehydes and 3-(N,N-dimethyl
amino)-1-propylamine (10 mmol) in dry benzene (50
ml) was refluxed until no more water was collected in a
Dean–Stark water separator. Mercaptoacetic acid (0.01
mol) was added, dropwise, to this crude mixture, and
the reaction was carried out at reflux temperature until
stoichiometric water was collected.
The mixtures, cooled and evaporated in vacuo, af-
forded, as pale yellow oils, the free bases of 1–3, 5, 6,
9, 11–15, which were dissolved in anhydrous ethanol
(20 ml). Diethyl ether (20 ml), saturated with HCl, was
added to these solutions. White powders were collected
and, recrystallized by absolute ethanol, yielded the thia-
zolidin-4-one hydrochlorides.
4.1.2. 3-Methyl-4-nitro- and 4-methyl-3-nitrobenzal-
dehydes (23, 24)
General procedure. The benzaldehydes 23 and 24
were synthesized to prepare thiazolidinones 6 and 9 by
oxidation of the corresponding benzyl alcohols. To the
yellow complex, formed by mixing CrO3 (3.2 g) to
pyridine (60 ml) at 0°C, the 3-nitro, 4-methyl or 3-
methyl, 4-nitro benzylalcohol (20 mmol) was added.
The mixture, stirred for 30 min at 0°C and heated at
50°C for 2 h, was filtered and the solution was evapo-
rated in vacuo and chromatographed on a silica gel
column using chloroform as eluent. The fraction con-
taining the aldehydes recovered and evaporated in
vacuo yielded 23 and 24, respectively, both as pale-yel-
low crystals.
4. Experimental
1
4.1. Chemistry
23: H NMR (CDCl3): 10.09 (1H, s), 8.46 (1H, d,
J=8.0), 7.87 (1H, d, J=1.3), 7.86 (1H, dd, J=8.0,
1.3), 2.67 (3H, s). M.p. 65–66°C. MS, m/z: 165 (M+).
Anal. C8H7NO3: (C, H, N). Yield 38%.
Melting points of thiazolidinones hydrochlorides re-
ported in Table 1 were determined with a Kofler ap-
paratus and are uncorrected. The elemental analyses
(C, H and N) of the reported compounds are within
90.4% of theoretical values. Electron impact (EI) mass
spectra were obtained at 70 eV on a VG ZAB 2F mass
24: 1H NMR (CDCl3): 9.59 (1H, s), 8.46 (1H, d,
J=1.6), 8.03 (1H, dd, J=7.8, 1.6), 7.55 (1H, d, J=
7.8), 2.70 (3H, s). M.p. 94–95°C. MS, m/z: 165 (M+).
Anal. C8H7NO3: (C, H, N). Yield 45%.

M.V. Diurno et al. / Il Farmaco 54 (1999) 579–583
583
4.1.3. 2-(4-Amino-3-methyl-phenyl)-3-[3-(N,N-
Acknowledgements
dimethylamino)propyl]-1,3-thiazolidin-4-one (7), 2-(3-
amino-4-methyl-phenyl)-3-[3-(N,N-dimethylamino)-
propyl]-1,3-thiazolidin-4-one (10) and 2-(3-amino-
phenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-
We thank the Centro di Ricerca Interdipartimentale
di Analisi Strumentale and the Centro di Metodologie
Chimico-fisiche dell’Universita` di Napoli ‘Federico II’
for the NMR spectra. This work was supported by a
grant of Progetto Operativo Plurifondo POP94/99 of
Regione Campania.
thiazolidin-4-one (14)
To a solution of 6, 9 or 2-(3-nitrophenyl)-3-[3-(N,N-
dimethylamino)propyl]-1,3-thiazolidin-4-one (21) (10
mmol) in ethanol (15 ml), glacial acetic acid (5 ml) and
Fe filings (4 g) were added. The reaction mixture, after
stirring at reflux temperature for 4 h, was diluted with
HCl 2 N and extracted with chloroform. The aqueous
layer, alkalinized with NaOH 2 N and extracted with
diethyl ether, afforded 7, 10 and 14, respectively.
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4.1.4. 2-(3-Carbamoyl-phenyl-3-[3-(N,N-dimethyl-
amino)-propyl]-1,3-thiazolidin-4-one (4)
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reaction mixture was filtered and the filtrate evaporated
in vacuo yielded the crude 4, that was purified by TLC
(0.50 mm) on silica gel using triethylamine:n-hex-
ane:ethanol 3:10:2 v/v.
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separator. When no more water was separated, the
mixture was evaporated in vacuo to yield the crude 8
that was purified as indicated in the general procedure.
4.2. Pharmacology
4.2.1. Guinea-pig ileum in 6itro assay for H1-receptor
histamine antagonism
The assays were performed on ileum of either sex
guinea-pigs weighing ꢀ250 g [10]. The dissociation
constants (KB) for pA2 value calculations were evalu-
ated, according to Schild [13], from the equation KB=
[10] J.C. Emmet, G.J. Durant, C.R. Ganellin, A.M. Roe, J.L.
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x
is the respective ratio of
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(1991) 165–195.
concentrations of histamine needed to produce half-
maximal responses in the presence and absence of
different concentrations (B) of antagonists; pA2=
−log KB. The pA2 values, reported in Table 3, are the
average of six measurements.
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(1957) 242.