Synthesis and pharmacological evaluation of novel N-alkyl/aryl substituted thiazolidinone arecoline analogues as muscarinic receptor 1 agonist in Alzheimer's dementia models

Article abstract of DOI:10.1016/j.ejmech.2009.07.026

Earlier we have reported the effect of arecoline thiazolidinone and morpholino arecoline analogues as muscarinic receptor 1 agonist in Alzheimer's dementia models. To elucidate further our SAR study on the chemistry and muscarinic receptor binding efficac

Full text of DOI:10.1016/j.ejmech.2009.07.026

European Journal of Medicinal Chemistry 44 (2009) 4848–4854
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and pharmacological evaluation of novel N-alkyl/aryl substituted
thiazolidinone arecoline analogues as muscarinic receptor 1 agonist in
Alzheimer’s dementia models
C.T. Sadashiva a, J.N. Narendra Sharath Chandra a, C.V. Kavitha a, A. Thimmegowda b,
,
M.N. Subhash c, Kanchugarakoppal S. Rangappa a
*
a Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, Karnataka, India
b Department of Studies in Chemistry, AVK College for Women, Hassan 573201, India
c Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bangalore 560029, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Earlier we have reported the effect of arecoline thiazolidinone and morpholino arecoline analogues as
muscarinic receptor 1 agonist in Alzheimer’s dementia models. To elucidate further our SAR study on the
chemistry and muscarinic receptor binding efficacy, a series of novel N-alkyl/aryl substituted thiazoli-
dinone arecoline analogues 6(a–m) were designed and synthesized from 3-pyridine carboxaldehyde by
Received 12 March 2009
Received in revised form
18 July 2009
Accepted 23 July 2009
Available online 6 August 2009
reacting with different amines in the presence of g-ferrite as catalyst and subjected to in vitro muscarinic
receptor binding studies using male Wistar rat brain membrane homogenate and extended to in vivo
pharmacological evaluation of memory and learning in male Wistar rats. Derivative 6j having diphe-
nylamine moiety attached to nitrogen of thiazolidinone showed significant affinity for the M1 receptor
binding.
Keywords:
M1 receptor binding
Alzheimer’s disease
Arecoline derivatives
Thiazolidinones
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
cholinergic function conducive to cognitive impairments. Musca-
rinic acetylcholine (mACh) receptor is a growing number of G
Degeneration of cortically projecting cholinergic neurons is
a pathological hallmark of Alzheimer’s disease (AD). The cholin-
ergic hypothesis of aging and of dementia suggests that the loss of
central forebrain cholinergic neurons contributes to the decline in
cognitive abilities associated with AD [1]. The presynaptic cholin-
ergic deficits in AD indicate that a cholinergic replacement therapy
might be beneficial in alleviating some of the cognitive dysfunc-
tions in this disorder. Thus, the discovery of cholinergic deficit in AD
patient’s brain has triggered research efforts to test cholinomimetic
approaches for their efficacy in AD therapy. It is also demonstrated
that the loss of presynaptic marker enzyme choline acetyl-
transferase and the muscarinic receptors of the M2 subtype are
mainly responsible in causing deficits in central cholinergic trans-
mission in Alzheimer’s patients [2–4].
protein-coupled receptors, each specifically regulates a different
physiological and biochemical function in the body. Four types of
muscarinic receptors are known, named M1–M4 [5] and five
subtypes of muscarinic receptors have been cloned and designated
m1–m5 [6,7]. Identifying M1 selective muscarinic agonists, which
are capable of crossing the blood–brain barrier is the subject of
active research for pharmacological application [8]. Most of the
potent muscarinic agonists, including those which were evaluated
in AD patients, show adverse central and peripheral side effects,
and are either non-selective or M2 > M1 selective. Thus, they may
also activate inhibitory M2 autoreceptors resulting in decreased
acetylcholine (ACh) release [9]. M1-type mAChRs are predominant
in cerebral cortex and hippocampus and might have important
roles in cognitive processes relevant to AD. To this end, the
following probes for mAChRs were suggested as a rational treat-
ment strategy in AD; (a) M1 agonists [10]; (b) M2 antagonists; (c)
mixed M1 agonist and M2 antagonist in the same compound [11].
However, clinical trials with some muscarinic agonists (e.g. areco-
line, oxotremorine, RS 86, pilocarpine and bathanechol) showed
the results that ranked from modest improvement to lack of
beneficial effects.
M1 muscarinic receptors play a role in an apparent linkage of
three major hallmarks of AD: b-amyloid (Ab) peptide; tau hyper-
phosphorylation and paired helical filaments (PHFs); and loss of
* Corresponding author. Tel.: þ91 821 2419661; fax: þ91 821 2412191.
E-mail address: rangappaks@chemistry.uni-mysore.ac.in (K.S. Rangappa).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.07.026

C.T. Sadashiva et al. / European Journal of Medicinal Chemistry 44 (2009) 4848–4854
4849
N-Methyl tetrahydropyridine embodying the muscarinic phar-
macophore in a framework of semirigid template is one such selec-
tive M1 agonist and at the same time, it is flexible enough to bring
about conformational change in M1 receptor during its activation. In
research, many structurally novel arecoline-based muscarinic
agonists have been synthesized which potentially may overcome the
limited oral activity, short duration of action, or lack of separation
between central and peripheral effects of classical agonists. Arecoline
oximes or oxadiazoles, arecoline thiadiazoles, arecoline oxazoles,
arecoline amides are the new generation muscarinic agonists [12].
Arecoline bioisosteres like Alvameline, Milameline, Sabcomeline,
Xanomeline, LY 593093 and YM 796 were in clinical trials and have
been discontinued during different phases of clinical trials due to
their low efficacy and high cholinergic side effects.
In our recent studies, we have reported arecoline thiazolidi-
nones [13], N-arylsulphonamide substituted 3-morpholino areco-
line analogues [14] and N-arylthiourea substituted 3-morpholino
arecoline analogues [15] as muscarinic receptor 1 agonist. Inspired
by the results of our earlier investigation, as a part of our continuing
effort aimed at the development of less toxic arecoline class of
muscarinic agonist and to further improve their selectivity and
potency, a series of N-alkyl/aryl substituted thiazolidinone areco-
line analogues 6(a–m) were designed and synthesized. All the
synthesized thiazolidinone arecolines were subjected to in vitro
muscarinic binding studies by using [3H]QNB with male Wistar rat
brain membrane homogenate and in vivo evaluation of memory
and learning in male Wistar rats.
learning [16]. It is reported that after infusion of 4 mg arecoline
administration, effects were not statistically significant when
compared to placebo treatment in patients with preside dementia
of Alzheimer’s type [17]. The low efficacy of arecoline can be
explained by its poor tolerability paired with a short biological half-
life. To overcome the limited oral activity and short duration of
action or lack of separation between central and peripheral effects
of arecoline and its bioisosteres previously tested for AD, many
structurally altered novel arecoline-based muscarinic agonists have
been synthesized. Both their affinity and efficacy are significantly
enhanced by tetrahydropyridine analogues to M1 receptor,
providing semirigid template, which has good affinity for the M1
receptor [18].
Many five-membered heterocyclic ring attached to arecoline
basic nuclei have been explored as M1 receptor agonist on AD
research. Sauerberg et al. developed a series of very potent
muscarinic agonists based on the 1,2,5-thiadiazole group, which
serve as an ester isostere [19]. A unique feature of this series of
compounds is that the extended amino groups can be accommo-
dated while agonist activity is retained. In our previous report we
have shown the efficacy of arecoline thiazolidinones [13], N-aryl-
sulphonamide substituted 3-morpholino arecoline derivatives [14]
and N-arylthiourea substituted 3-morpholino arecoline derivatives
[15] as muscarinic receptor 1 binding. In this regard, we were
interested in synthesizing similar five-membered systems, which
resemble thiazole (or thiadiazole). To probe the structural
requirement for the potent binding affinity, in the present study we
have synthesized N-alkyl/aryl substituted thiazolidinone arecoline
derivatives 6(a–m) and were subjected to in vitro competitive
muscarinic receptor studies and radiological (3H) quinuclidinyl
benzilate (QNB) using male Wistar rat brain membrane homoge-
nate (Table 2). We have extended in vitro findings to in vivo
pharmacological results involving evaluation of learning and
memory in male Wistar rats (Rodent memory evaluation and plus
maze studies) to ascertain their applicability in dementia (Table 3).
Structure–activity relationship (SAR) can be drawn from the in
vitro assay for the synthesized derivatives 6(a–m). Among all the
synthesized compounds 6(a–m), four derivatives 6f, 6i, 6j and 6k
showed greater affinity and potency towards the M1 receptor
(Table 2, Fig. 1), the potency of the molecules follows the order
6j > 6f > 6i > 6k. The remaining derivatives did not show any
2. Results and discussion
2.1. Chemistry
The N-alkyl/aryl substituted thiazolidinone arecoline analogues
6(a–m) were synthesized as depicted in Scheme 1. These analogues
were synthesized in three steps, starting with 3-pyridine carbox-
aldehyde, allowing it to react with different amines and thioglycolic
acid in the presence of g-ferrite as catalyst and tetrahydrofuran as
solvent. The successive thiazolidinone products were subjected to
N-methylation and sodium borohydride reduction to obtain desired
products. The physical characterization of the synthesized deriva-
tives is presented in Table 1.
agonistic activity. The most potent compound 6j (Ki ¼ 19 ꢀ 1.97
mM
and IC50 ¼ 48 ꢀ 6.23 M) is one which is having biphenyl amine
m
2.2. Pharmacological activity
attached to nitrogen of thiazolidinone arecoline. Among the
compounds with alkyl chain as substituent, 6c having ethyl group
did not show any agonistic activity. But replacement of the same
with isopropyl chain or n-butyl chain increases the activity. Inter-
estingly, when we further increase the length of the alkyl chain by
another two methylene groups (hexyl, 6e) activity decreases
drastically. This suggests that, alkyl group with four carbon atoms
may be the optimum length for the binding affinity. Among the
compounds with aryl group as substituents, different compounds
exhibited different affinity and binding potency towards M1
receptor based on the atoms/groups attached to the phenyl ring.
It has been demonstrated that the M1 receptor subtypes
predominate in the cerebral cortex and hippocampus areas in
which cholinergic transmission appears to be essential for learning
and memory [20,21]. The in vitro muscarinic receptor binding
studies formed a basis for extending correlation further to in vivo
pharmacological studies to ascertain applicability of the synthe-
sized N-aryl/alkyl thiazolidinone arecolines 6(a–m) in scopol-
amine-induced dementia models (male Wistar rats) using memory
and learning experiments (passive avoidance, plus maze tasks). In
accordance with the degree of affinity and potency of synthesized
arecoline analogues 6(a–m) in vitro binding experiments elicited
The effect of muscarinic agonist arecoline was investigated first
on human volunteers and found to improve performance in serial
S
H
O
O
OH
(a)
N
R
O
R-NH2
+
+
HS
N
N
4(a-m)
1
2(a-m)
3
(b)
S
S
O
(c)
N
R
O
N
+
N
R
-
N
I
CH3
CH3
6(a-m)
5(a-m)
Scheme 1. (a) Benzene, g
-ferrite, 60 ꢁC; (b) CH3I, acetone; (c) NaBH4, methanol.

4850
C.T. Sadashiva et al. / European Journal of Medicinal Chemistry 44 (2009) 4848–4854
Table 1
The physical characterization of the novel N-alkyl/aryl substituted thiazolidinone arecoline analogues 6(a–m).
Thiazolidinone arecolines 6(a–m)
R–NH2
Solvent
Reaction time (h)
10
Eluent used in separation
Yield (%)
60
6a
Benzene
Chloroform:methanol, 9.5:0.5
Cl
6b
Benzene
10
Chloroform:methanol, 9.5:0.5
60
6c
Benzene
Benzene
10
8
Chloroform:methanol, 9.5:0.5
Chloroform:methanol, 9.5:0.5
55
60
H3C
6d
6e
6f
Benzene
Benzene
8
8
Chloroform:methanol, 9.5:0.5
Chloroform:methanol, 9.5:0.5
60
55
H3C
H3C
6g
Benzene
9
Chloroform:methanol, 9.5:0.5
60
CH3
H3C
6h
6i
Benzene
Benzene
9
9
Chloroform:methanol, 9.5:0.5
Chloroform:methanol, 9.5:0.5
60
60
Br
O
OH
6j
Benzene
8
Chloroform:methanol, 9.5:0.5
55
N
H
6k
6l
Benzene
Benzene
9
Chloroform:methanol, 9.5:0.5
Chloroform:methanol, 9.5:0.5
55
60
NO2
NO2
10
CH3
6m
Benzene
8
Chloroform:methanol, 9.5:0.5
60
OH
almost anticipated level of pharmacological actions in reversing
scopolamine-induced dementia (Fig. 2). Our results obtained from
in vivo passive avoidance using Rodent memory evaluator in male
Wistar rats suggest that 6f, 6i and 6j reversed scopolamine-induced
dementia (Table 4, Fig. 2) by making rats commit less number of
mistakes [number of mistakes done in 12 (6f), 14 (6i) and 16 (6j)] as
compared to scopolamine-treated group (number of mistakes
done ¼ 35). On the other hand, 6b (30), 6d (32) and 6g (30) fail to
reverse scopolamine-induced mistakes in rats.
The in vivo plus maze for the synthesized N-alkyl/aryl thiazo-
lidinone arecoline analogues 6(a–m) in male Wistar rats measures
the transfer latency (TL) in seconds taken to reach from one
extreme end of open arm to one of the closed arms in a plus maze
(Fig. 3). Difference in TL in seconds between first day and second

C.T. Sadashiva et al. / European Journal of Medicinal Chemistry 44 (2009) 4848–4854
4851
Table 2
In vitro affinity and potency of N-alkyl/aryl substituted thiazolidinone arecoline
analogues 6(a–m) towards M1 receptor of male Wistar rat cortex homogenate.
Compounds
Ki (
mM)
IC50 (mM)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
Arecoline
200 ꢀ 14.76
149 ꢀ 9.56
230 ꢀ 15.95
105 ꢀ 6.98
110 ꢀ 7.35
32 ꢀ 4.27
653 ꢀ 37.65
789 ꢀ 46.98
670 ꢀ 38.54
886 ꢀ 42.65
632 ꢀ 37.25
68 ꢀ 6.35
97 ꢀ 6.98
579 ꢀ 32.92
536 ꢀ 30.13
74 ꢀ 7.85
122 ꢀ 8.01
37 ꢀ 4.97
19 ꢀ 1.97
48 ꢀ 6.23
43 ꢀ 5.35
158 ꢀ 9.75
626 ꢀ 36.35
563 ꢀ 30.89
469 ꢀ 28.83
125 ꢀ 14.12
102 ꢀ 6.23
86 ꢀ 4.86
Results are expressed as mean (ꢀS.E.M.). Bold values represent the potent
molecules.
day for scopolamine-treated group and test compound along with
scopolamine-treated groups was compared to evaluate learning
(TL1) and memory (TL2). Derivatives 6f, 6i, 6j and 6k reversed acute
memory loss and learning impairment in male Wistar rats. 6j
produced lesser TL for first day (TL1 ¼16 s) compared to scopol-
amine-treated group (TL1 ¼62 s), but on second day (TL2 ¼12 s) TL
was lesser than first day, indicating how 6j is helpful in reversing
learning impairment as compared to rest of the derivatives. Overall
difference between TL2 and TL1 was lesser for 6j. However other
derivatives showed moderate efficiency in reversing acute memory
loss and learning impairment in male Wistar rats. TL for all the
synthesized molecules is given in Table 4.
Fig. 1. Displacement studies were done with 0.2 nM [3H] QNB for different derivatives
(showing considerable activity) among N-alkyl/aryl substituted thiazolidinone areco-
lines 6(a–m) and arecoline at varying concentrations. The mean values of percentage
bound are plotted against log of displacer concentration IC50 and Ki values are obtained
from Ligand-Drug programme.
nitrogen of thiazolidinone moiety determines the potency of the
compound for the M1 receptor affinity. Derivatives 6f, 6i, 6j and 6k
displayed significant activity in in vitro and in vivo experiments
tested. Among these four derivatives 6j, having diphenylamine is
found to be the most potent molecule for M1 receptor binding.
However, structural modifications of this molecule and more in-
depth studies both at in vitro and in vivo levels are required for
strengthening our findings. N-Alkyl substituted derivatives showed
weak, moderate and strong activity. All the synthesized N-alkyl/aryl
substituted thiazolidinone arecolines 6(a–m) showed no visible
cholinergic toxicity at the dose tested.
3. Conclusion
In summary, in vitro competitive M1 receptor affinity assay and
in vivo pharmacological experiments conducted for the synthe-
sized compounds 6(a–m) to test the relation between affinity of
these molecules to M1 receptor, their ability to reverse scopol-
amine-induced memory loss and learning impairment in male
Wistar rats, have ascertained their applicability in dementia. Our
results emphasize that the nature of the substituent attached to the
4. Experimental protocols
The melting points were determined on a SELCO-650 hot stage
apparatus and are uncorrected. All the synthesized compounds
were characterized by IR, 1H NMR and CHNS analysis. Infrared (IR)
spectra were recorded using Nujol on JASCO-FTIR, 4100 series.
Table 3
Acute studies of N-alkyl/aryl substituted thiazolidinone arecoline analogues 6(a–m)
on learning and memory against scopolamine-induced memory loss and learning
impairment on elevated plus maze in male Wistar rats.
Sl. no. Treatment group
Treatment Transfer
Average difference
transfer latency (TL)
(dose)
latency (TL)
(mg/kg ip)
TL1
TL2
1
2
Control group
Scopolamine-treated 0.4
group
–
12
62
10
56
11
59
3
4
5
6
7
8
9
10
11
12
13
14
15
6a-Treated group
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
46
20
48
46
34
19
38
40
20
16
26
45
28
38
18
42
42
26
15
32
36
16
12
16
35
16
42
19
45
44
30
17
35
38
18
14
21
40
22
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
Results are expressed as mean (ꢀ S.E.M.), n ¼ 6. Bold values represent the potent
Fig. 2. Antiamnesic effect of N-alkyl/aryl substituted thiazolidinone arecoline
analogues 6(a–m) against scopolamine-induced memory loss.
molecules.

4852
C.T. Sadashiva et al. / European Journal of Medicinal Chemistry 44 (2009) 4848–4854
acetone at 0 ꢁC afforded 3-(thiazolidin-4-one)-N-methyl pyr-
idinium iodides 5(a–m). Finally, title compounds 6(a–m) were
achieved by reduction of compounds 5(a–m) with sodium boro-
hydride (1.2 equiv.) in methanol at ꢂ15 ꢁC using acetone and dry ice
as freezing mixture (Table 1 and Scheme 1).
Table 4
Antiamnesic effect of N-alkyl/aryl substituted thiazolidinone arecoline analogues
6(a–m) against scopolamine-induced memory loss.
Sl. Experimental
no. groups
Treatment Basal latency (s)
Memory parameters
(dose)
of rat to reach SFS
(mg/kg ip)
I
II
III
Latency (s) No. of
mistakes
4.1.1. Synthesis of 3-(4-chlorophenyl)-2-(1,2,5,6-tetrahydro-1-
methylpyridin-3-yl)-thiazolidin-4-one (6a)
The product 6a was obtained by the reaction of 3-pyridine
carboxaldehyde (1) (0.100 g, 0.00093 mol), p-chloroaniline (2a)
(0.118 g, 0.00093 mol), anhydrous g-ferrite (1 g), thioglycolic acid
(3) (0.129 g, 0.0014 mol), methyl iodide (0.265 g, 0.00187 mol) and
1
2
Control groups
Scopolamine-treated 0.4
groups
–
18
36
3
10
0.8
8
1
4
8 ꢀ 1.3
35 ꢀ 2.6
3
4
5
6
7
8
9
6a-Treated groups
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
30
33
20
34
28
20
34
25
27
22
28
24
22
6
9
8
9
8
7
9
8
8
6
9
7
8
3
7
4
8
7
5
8
7
6
5
7
5
6
3
4
2
4
4
4
3
3
4
3
4
3
3
28 ꢀ 1.8
30 ꢀ 2.1
21 ꢀ 1.3
32 ꢀ 2.4
21 ꢀ 1.2
12 ꢀ 1.1
30 ꢀ 1.9
29 ꢀ 1.6
14 ꢀ 1.4
16 ꢀ 1.2
25 ꢀ 1.9
25 ꢀ 1.5
23 ꢀ 1.8
6b
6c
6d
6e
6f
sodium borohydride (0.042 g, 0.0011 mol) as a semisolid: mp 186–
188 ꢁC. 1H NMR (400 MHz, CDCl3)
d: 2.0 (m, 2H, tetrahydropyridine
C5), 2.25 (s, 3H, N–CH3), 2.45 (t, 2H, tetrahydropyridine C6), 2.83
(s, 2H, tetrahydropyridine C2), 3.43 (s, 2H, thiazolidin-4-one ring
CH2), 5.32 (s, 1H, thiazolidin-4-one ring CH), 5.62 (t, 1H, tetrahy-
dropyridine C4), 7.1 (dd, 2H, J ¼ 1.9 Hz, Ar–H), 7.3 (dd, 2H,
J ¼ 1.9 Hz). IR nmax (KBr): 1692 (C]O), 1160 (C–N) cmꢂ1. Anal. calcd
for C15H17ClN2OS (in %): C, 58.34; H, 5.55; Cl, 11.48; N, 9.07; S, 10.38.
Found: C, 58.24; H, 5.45; Cl, 11.40; N, 9.25; S, 10.42.
6g
10 6h
11 6i
12 6j
13 6k
14 6l
15 6m
Bold values represent the potent molecules.
Nuclear magnetic resonance (1H NMR) spectra were recorded on
Shimadzu AMX 400-Bruker, 400 MHz spectrometer using DMSO as
4.1.2. Synthesis of 3-benzyl-2-(1-methyl-1,2,5,6-tetrahydropyridin-
3-yl)-thiazolidin-4-one (6b)
The product 6b was obtained by the reaction of 3-pyridine
carboxaldehyde (1) (0.100 g, 0.00093 mol), benzylamine (2b) (0.1 g,
a solvent and TMS as internal standard (chemical shift in
d ppm).
Spin multiplets are given as s (singlet), d (doublet), t (triplet) and m
(multiplet). Elemental (CHNS) analyses were obtained on Vario EL
III Elementar. Silica gel column chromatography was performed
using Merck 7734 silica gel (60–120 mesh) and Merck made TLC
plates. All chemicals and reagents were obtained from Aldrich
(USA), Spectrochem Pvt. Ltd. (India) and Rankem Pvt. Ltd. (India),
and were used without further purification.
0.00093 mol), anhydrous
g-ferrite (1 g), thioglycolic acid (3)
(0.129 g, 0.0014 mol), methyl iodide (0.265 g, 0.00187 mol) and
sodium borohydride (0.042 g, 0.0011 mol) as a semisolid: mp 195–
198 ꢁC. 1H NMR (400 MHz, CDCl3)
d: 2.1 (m, 2H, tetrahydropyridine
C5), 2.3 (s, 3H, N–CH3), 2.5 (t, 2H, tetrahydropyridine C6), 2.9 (s, 2H,
tetrahydropyridine C2), 3.1 (t, 2H, N–CH2), 3.6 (s, 2H, thiazolidin-4-
one ring CH2), 4.46 (s, 2H, CH2), 5.4 (s, 1H, thiazolidin-4-one ring
CH), 5.7 (t,1H, tetrahydropyridine C4), 7.0–7.5 (m, 5H, Ar–H). IR nmax
(KBr): 1695 (C]O), 1190 (C–N) cmꢂ1. Anal. calcd for C16H20N2OS
(in %): C, 66.63; H, 6.99; N, 9.71; S, 11.12. Found: C, 66.55; H, 6.81;
N, 9.64; S, 11.0.
4.1. General procedure for the synthesis of N-alkyl/aryl substituted
thiazolidinone arecoline derivatives 6(a–m)
To an equimolar mixture of 3-pyridine carboxaldehyde (1) and
amines 2(a–m), anhydrous g-ferrite (Fe2O3; 2 equiv.) was added and
4.1.3. Synthesis of 3-ethyl-2-(1-methyl-1,2,5,6-tetrahydropyridin-
3-yl)-thiazolidin-4-one (6c)
The product 6c was obtained by the reaction of 3-pyridine car-
boxaldehyde (1) (0.100 g, 0.00093 mol), ethylamine (2c) (0.042 g,
the reaction mixture was refluxed with constant stirring in dry
benzene (20 ml) for 1/2 h, followed by the addition of thioglycolic
acid (3). The refluxing and stirring were continued for another 6 h.
The reaction was monitored by TLC. After the completion of the
reaction, a reddish brown amorphous solid Fe2O3$2H2O/FeO(OH)
was removed by filtration, filtrate was concentrated to dryness
under reduced pressure to achieve compounds 4(a–m). Compounds
4(a–m) on stirring for 3 h with methyl iodide (2 equiv.) in dry
0.00093 mol), anhydrous
g-ferrite (1 g), thioglycolic acid (3)
(0.129 g, 0.0014 mol), methyl iodide (0.265 g, 0.00187 mol) and
sodium borohydride (0.042 g, 0.0011 mol) as a semisolid: mp
188–190 ꢁC. 1H NMR (400 MHz, CDCl3)
d: 1.20 (t, 3H, CH3), 2.15 (m,
2H, tetrahydropyridine C5), 2.25 (s, 3H, N–CH3), 2.49 (t, 2H, tetra-
hydropyridine C6), 2.8 (s, 2H, tetrahydropyridine C2), 3.2 (t, 2H,
N–CH2), 3.3 (q, 2H, CH2), 3.58 (s, 2H, thiazolidin-4-one ring CH2),
5.42 (s, 1H, thiazolidin-4-one ring CH), 5.66 (t, 1H, tetrahydropyr-
idine C4). IR nmax (KBr): 1698 (C]O), 1130 (C–N) cmꢂ1. Anal. calcd
for C11H18N2OS (in %): C, 58.37; H, 8.02; N, 12.38; S, 14.17. Found:
C, 58.22; H, 8.19; N, 12.15; S, 14.22.
4.1.4. Synthesis of 2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-3-
phenyl-thiazolidin-4-one (6d)
The product 6d was obtained by the reaction of 3-pyridine car-
boxaldehyde (1) (0.100 g, 0.00093 mol), aniline (2d) (0.0869 g,
0.00093 mol), anhydrous g-ferrite (1 g), thioglycolic acid (3) (0.129 g,
0.0014 mol), methyl iodide (0.265 g, 0.00187 mol) and sodium
borohydride (0.042 g, 0.0011 mol) as a semisolid: mp 190–193 ꢁC. 1H
NMR (400 MHz, CDCl3) d: 2.1 (m, 2H, tetrahydropyridine C5), 2.21 (s,
3H, N–CH3), 2.42 (t, 2H, tetrahydropyridine C6), 2.79 (s, 2H, tetrahy-
dropyridineC2), 3.21(t, 2H, N–CH2), 3.56(s, 2H, thiazolidin-4-onering
CH2), 5.41 (s, 1H, thiazolidin-4-one ring CH), 5.65 (t, 1H,
Fig. 3. Effect of N-alkyl/aryl substituted thiazolidinone arecoline derivatives 6(a–m) on
memory and learning against scopolamine-induced memory loss and learning
impairment on elevated plus maze in male Wistar rats.

C.T. Sadashiva et al. / European Journal of Medicinal Chemistry 44 (2009) 4848–4854
4853
tetrahydropyridine C4), 6.96–7.4 (m, 5H, Ar–H). IR nmax (KBr): 1696
(C]O), 1105 (C–N) cmꢂ1. Anal. calcd for C15H18N2OS (in %): C, 65.66;
H, 6.61; N, 10.21; S, 11.69. Found: C, 65.55; H, 6.5; N, 10.1; S, 11.51.
Anal. calcd for C15H17BrN2OS (in %): C, 51.00; H, 4.85; Br, 22.62;
N, 7.93; S, 9.08. Found: C, 51.24; H, 4.79; Br, 22.54; N, 7.8; S, 9.2.
4.1.9. Synthesis of 4-[2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-
4-oxo-thiazolidin-3-yl]-benzoic acid (6i)
The product 6i was obtained by the reaction of 3-pyridine
carboxaldehyde (1) (0.100 g, 0.00093 mol), 4-amino benzoic acid
4.1.5. Synthesis of 3-hexyl-2-(1-methyl-1,2,5,6-tetrahydropyridin-
3-yl)-thiazolidin-4-one (6e)
The product 6e was obtained by the reaction of 3-pyridine
carboxaldehyde (1) (0.100 g, 0.00093 mol), hexylamine (2e)
(2i) (0.128 g, 0.00093 mol), anhydrous g-ferrite (1 g), thioglycolic
(0.0945 g, 0.00093 mol), anhydrous
g-ferrite (1 g), thioglycolic acid
acid (3) (0.129 g, 0.0014 mol), methyl iodide (0.265 g,
(3) (0.129 g, 0.0014 mol), methyl iodide (0.265 g, 0.00187 mol) and
0.00187 mol) and sodium borohydride (0.042 g, 0.0011 mol) as
sodium borohydride (0.042 g, 0.0011 mol) as a semisolid: mp
a solid: mp 220–222 ꢁC. 1H NMR (400 MHz, CDCl3)
d: 2.15 (m, 2H,
191–194 ꢁC. 1H NMR (400 MHz, CDCl3)
d
: 0.96 (t, 3H, CH3),1.29–1.55
tetrahydropyridine C5), 2.25 (s, 3H, N–CH3), 2.49 (t, 2H, tetrahy-
dropyridine C6), 2.8 (s, 2H, tetrahydropyridine C2), 3.2 (t, 2H,
N–CH2), 3.58 (s, 2H, thiazolidin-4-one ring CH2), 5.42 (s, 1H,
thiazolidin-4-one ring CH), 5.66 (t, 1H, tetrahydropyridine C4), 7.3
(dd, 2H, J ¼ 1.9 Hz, Ar–H), 8.1 (dd, 2H, J ¼ 1.9 Hz), 10 (s, 1H, COOH).
IR nmax (KBr): 1683 (C]O), 1144 (C–N) cmꢂ1. Anal. calcd for
C16H18N2O3S (in %): C, 60.36; H, 5.70; N, 8.80; S, 10.07. Found:
C, 60.15; H, 5.58; N, 8.71; S, 10.22.
(m, 8H, hexyl CH2), 2.1 (m, 2H, tetrahydropyridine C5), 2.3 (s, 3H,
N–CH3), 2.5 (t, 2H, tetrahydropyridine C6), 2.9 (s, 2H, tetrahy-
dropyridine C2), 3.1 (t, 2H, N–CH2), 3.6 (s, 2H, thiazolidin-4-one ring
CH2), 5.4 (s, 1H, thiazolidin-4-one ring CH), 5.7 (t, 1H, tetrahy-
dropyridine C4). IR nmax (KBr): 1706 (C]O), 1180 (C–N) cmꢂ1. Anal.
calcd for C15H26N2OS (in %): C, 63.61; H, 9.15; N, 9.8; S, 11.2. Found:
C, 63.6; H, 9.3; N, 9.6; S, 11.4.
4.1.6. Synthesis of 3-(4-amino-butyl)-2-(1-methyl-1,2,5,6-
tetrahydropyridin-3-yl)-thiazolidin-4-one (6f)
4.1.10. Synthesis of 2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-3-
(4-phenylamino-phenyl)-thiazolidin-4-one (6j)
The product 6f was obtained by the reaction of 3-pyridine car-
boxaldehyde (1) (0.100 g, 0.00093 mol), butylamine (2f) (0.0682 g,
The product 6j was obtained by the reaction of 3-pyridine
carboxaldehyde (1) (0.100 g, 0.00093 mol), 4-amino diphenyl-
0.00093 mol), anhydrous
g
-ferrite (1 g), thioglycolic acid (3)
amine (2j) (0.1719 g, 0.00093 mol), anhydrous g-ferrite (1 g), thio-
(0.129 g, 0.0014 mol), methyl iodide (0.265 g, 0.00187 mol) and
sodium borohydride (0.042 g, 0.0011 mol) as a semisolid: mp
glycolic acid (3) (0.129 g, 0.0014 mol), methyl iodide (0.265 g,
0.00187 mol) and sodium borohydride (0.042 g, 0.0011 mol) as
181–183 ꢁC. 1H NMR (400 MHz, CDCl3)
d: 0.96 (t, 3H, CH3), 1.25–1.5
a solid: mp 246–248 ꢁC. 1H NMR (400 MHz, CDCl3)
d: 2.01 (m, 2H,
(m, 4H, 2CH2), 2.22 (m, 2H, tetrahydropyridine C5), 2.39 (s, 3H,
N–CH3), 2.46 (t, 2H, tetrahydropyridine C6), 2.84 (s, 2H, tetrahy-
dropyridine C2), 3.20 (t, 2H, CH2), 3.28 (t, 2H, N–CH2), 3.59 (s, 2H,
thiazolidin-4-one ring CH2), 5.46 (s, 1H, thiazolidin-4-one ring CH),
5.71 (t, 1H, tetrahydropyridine C4). IR nmax (KBr): 1690 (C]O), 1115
(C–N) cmꢂ1. Anal. calcd for C13H22N2OS (in %): C, 61.38; H, 8.72;
N, 11.01; S, 12.60. Found: C, 61.5; H, 8.8; N, 11.2; S, 12.69.
tetrahydropyridine C5), 2.27 (s, 3H, N–CH3), 2.47 (t, 2H, tetra-
hydropyridine C6), 2.85 (s, 2H, tetrahydropyridine C2), 3.5 (s, 2H,
thiazolidin-4-one ring CH2), 5.38 (s, 1H, thiazolidin-4-one ring CH),
5.66 (t, 1H, tetrahydropyridine C4), 6.5–7.3 (m, 9H, Ar–H). IR nmax
(KBr): 1698 (C]O), 1165 (C–N) cmꢂ1. Anal. calcd for C21H23N3OS (in
%): C, 69.01; H, 6.34; N, 11.50; S, 8.77. Found: C, 69.11; H, 6.15;
N, 11.40; S, 8.6.
4.1.7. Synthesis of 3-isopropyl-2-(1-methyl-1,2,5,6-
tetrahydropyridin-3-yl)-thiazolidin-4-one (6g)
4.1.11. Synthesis of 2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-3-
(4-nitrophenyl)-thiazolidin-4-one (6k)
The product 6g was obtained by the reaction of 3-pyridine
carboxaldehyde (1) (0.100 g, 0.00093 mol), isopropylamine (2g)
The product 6k was obtained by the reaction of 3-pyridine
carboxaldehyde (1) (0.100 g, 0.00093 mol), 4-nitroaniline (2k)
(0.0542 g, 0.00093 mol), anhydrous
g-ferrite (1 g), thioglycolic acid
(0.13 g, 0.00093 mol), anhydrous g-ferrite (1 g), thioglycolic acid (3)
(3) (0.129 g, 0.0014 mol), methyl iodide (0.265 g, 0.00187 mol) and
(0.129 g, 0.0014 mol), methyl iodide (0.265 g, 0.00187 mol) and
sodium borohydride (0.042 g, 0.0011 mol) as a semisolid: mp
sodium borohydride (0.042 g, 0.0011 mol) as a semisolid: mp
192–195 ꢁC. 1H NMR (400 MHz, CDCl3)
d
: 1.25 (d, 6H, 2CH3), 2.1 (m,
219–222 ꢁC. 1H NMR (400 MHz, CDCl3)
d: 2.15 (m, 2H, tetrahydro-
2H, tetrahydropyridine C5), 2.21 (s, 3H, N–CH3), 2.42 (t, 2H, tetra-
hydropyridine C6), 2.79 (s, 2H, tetrahydropyridine C2), 3.21 (t, 2H,
N–CH2), 3.56 (s, 2H, thiazolidin-4-one ring CH2), 3.94 (m, 1H, CH),
5.41 (s, 1H, thiazolidin-4-one ring CH), 5.65 (t, 1H, tetra-
hydropyridine C4), 6.96–7.4 (m, 5H, Ar–H). IR nmax (KBr): 1695
(C]O), 1115 (C–N) cmꢂ1. Anal. calcd for C12H20N2OS (in %): C, 59.96;
H, 8.39; N, 11.65; S, 13.34. Found: C, 59.8; H, 8.23; N, 11.77; S, 13.45.
pyridine C5), 2.25 (s, 3H, N–CH3), 2.49 (t, 2H, tetrahydropyridine
C6), 2.8 (s, 2H, tetrahydropyridine C2), 3.2 (t, 2H, N–CH2), 3.58 (s, 2H,
thiazolidin-4-one ring CH2), 5.42 (s, 1H, thiazolidin-4-one ring CH),
5.66 (t, 1H, tetrahydropyridine C4), 6.9–7.45 (m, 4H, Ar–H). IR nmax
(KBr): 1705 (C]O),1115 (C–N) cmꢂ1. Anal. calcd for C15H17N3O3S (in
%): C, 56.41; H, 5.37; N, 13.16; S, 10.04. Found: C, 56.35; H, 5.3;
N, 13.25; S, 10.11.
4.1.8. Synthesis of 3-(4-bromophenyl)-2-(1-methyl-1,2,5,6-
tetrahydropyridin-3-yl)-thiazolidin-4-one (6h)
4.1.12. Synthesis of 3-(4-methyl-2-nitro-phenyl)-2-(1-methyl-
1,2,5,6-tetrahydropyridin-3-yl)-thiazolidin-4-one (6l)
The product 6h was obtained by the reaction of 3-pyridine car-
boxaldehyde (1) (0.100 g, 0.00093 mol), 4-bromoaniline (2h)
The product 6l was obtained by the reaction of 3-pyridine car-
boxaldehyde (1) (0.100 g, 0.00093 mol), 4-amino-3-nitrotoluene
(0.160 g, 0.00093 mol), anhydrous
g-ferrite (1 g), thioglycolic acid
(2l) (0.142 g, 0.00093 mol), anhydrous g-ferrite (1 g), thioglycolic
(3) (0.129 g, 0.0014 mol), methyl iodide (0.265 g, 0.00187 mol) and
acid (3) (0.129 g, 0.0014 mol), methyl iodide (0.265 g, 0.00187 mol)
sodium borohydride (0.042 g, 0.0011 mol) as a semisolid: mp 198–
and sodium borohydride (0.042 g, 0.0011 mol) as a semisolid: mp
200 ꢁC. 1H NMR (400 MHz, CDCl3)
d
: 2.2 (m, 2H, tetrahydropyridine
252–254 ꢁC. 1H NMR (400 MHz, CDCl3)
d: 2.2 (m, 2H, tetra-
C5), 2.4 (s, 3H, N–CH3), 2.45 (t, 2H, tetrahydropyridine C6), 2.8 (s,
2H, tetrahydropyridine C2), 3.25 (t, 2H, N–CH2), 3.58 (s, 2H, thiazo-
lidin-4-one ring CH2), 5.45 (s, 1H, thiazolidin-4-one ring CH), 5.7 (t,
1H, tetrahydropyridine C4), 6.9 (dd, J ¼ 1.9 Hz, 2H, Ar–H), 7.2 (dd,
hydropyridine C5), 2.3 (s, 3H, N–CH3), 2.35 (s, 3H, CH3), 2.45 (t, 2H,
tetrahydropyridine C6), 2.81 (s, 2H, tetrahydropyridine C2), 3.21 (t,
2H, CH2), 3.27 (t, 2H, N–CH2), 3.58 (s, 2H, thiazolidin-4-one ring
CH2), 5.45 (s, 1H, thiazolidin-4-one ring CH), 5.72 (t, 1H, tetrahy-
dropyridine C4), 6.9–7.5 (m, 4H, Ar–H). IR nmax (KBr): 1696 (C]O),
J ¼ 1.9 Hz, 2H, Ar–H). IR nmax (KBr): 1698 (C]O), 1120 (C–N) cmꢂ1
.

4854
C.T. Sadashiva et al. / European Journal of Medicinal Chemistry 44 (2009) 4848–4854
1115 (C–N) cmꢂ1. Anal. calcd for C16H19N3O3S (in %): C, 57.64; H, 5.74;
N, 12.60; S, 9.62. Found: C, 57.78; H, 5.58; N, 12.51; S, 9.72.
at the end of one arm facing away from the central platform and
time they take to move from open arm to either of the enclosed
arms (TL) was measured. On the first day male Wistar rats were
allowed to explore the plus maze for 90 s with scopolamine and
test compounds along with scopolamine treatment to respective
animal groups 30 min before the plus maze exploration. Control
group animals were treated with distilled water. Second day TL was
measured in the similar way on the same animals. The resultant
data were subjected to statistical analysis. p < 0.005 was considered
statistically significant [27].
4.1.13. Synthesis of 3-(3-hydroxy-phenyl)-2-(1-methyl-1,2,5,6-
tetrahydropyridin-3-yl)-thiazolidin-4-one (6m)
The product 6m was obtained by the reaction of 3-pyridine
carboxaldehyde (1) (0.100 g, 0.00093 mol), 3-aminophenol (2m)
(0.1018 g, 0.00093 mol), anhydrous g-ferrite (1 g), thioglycolic acid
(3) (0.129 g, 0.0014 mol), methyl iodide (0.265 g, 0.00187 mol) and
sodium borohydride (0.042 g, 0.0011 mol) as a semisolid: mp
210–212 ꢁC. 1H NMR (400 MHz, CDCl3)
d: 2.18 (m, 2H, tetrahydro-
pyridine C5), 2.27 (s, 3H, N–CH3), 2.31 (s, 3H, CH3), 2.41 (t, 2H, tetra-
hydropyridine C6), 2.81 (s, 2H, tetrahydropyridine C2), 3.21 (t, 2H,
CH2), 3.25 (t, 2H, N–CH2), 3.55 (s, 2H, thiazolidin-4-one ring CH2),
5.45 (s, 1H, thiazolidin-4-one ring CH), 5.71 (t, 1H, tetrahydro-
pyridine C4), 6.8–7.5 (m, 4H, Ar–H),10 (s,1H, OH). IR nmax (KBr): 1703
(C]O),1180 (C–N) cmꢂ1. Anal. calcd for C15H18N2O2S (in %): C, 62.04;
H, 6.25; N, 9.65; S, 11.04. Found: C, 62.25; H, 6.35; N, 9.75; S, 11.12.
4.2.4. Acute toxicity
Rats (six per group), which had fasted 16 h were treated orally
with various doses of the compounds and observed for 1 week after
treatment, deaths were recorded daily. None of the rats died within
1 week after administration under test dose.
Acknowledgements
4.2. Pharmacology
Dr. A.T. thanks the UGC for the grant of minor research project
and the authors JNNSC and CVK are grateful to the Department of
Science and Technology, New Delhi for financial support under the
project SR/SO/HS-58/2003. The CHNS and IR data obtained from
the instruments granted by DST-FIST and UGC-SAP respectively are
greatly acknowledged.
4.2.1. Displacement study
The competitive inhibition study was done using all newly
synthesized N-alkyl/aryl substituted thiazolidinone arecoline
compounds 6(a–m) to find out their affinity towards cortical M1
receptor. Male Wistar rat brain cortex was taken out and used for
membrane preparation. Crude membrane pellet was obtained from
brain tissue, homogenized in 20 volumes of Tris–HCl buffer
(50 mmol/l, pH 7.4) containing 0.32 mol/l sucrose, following the
procedure described by Creese and Snyder [22]. The tissue homo-
genate was centrifuged at a speed of 1000 ꢃ g for 10 min at 4 ꢁC, to
remove cellular debris. The supernatant obtained was centrifuged
at 32,000 ꢃ g for 20 min at 4 ꢁC. Pellet obtained was resuspended
in 50 mmol/l phosphate assay buffer (pH 7.4) containing 1 mmol
MgCl2. The protein concentration was estimated by method
described by Lowry et al. [23]. The affinity of various compounds
towards M1 receptor was estimated by using [3H]QNB (0.2 nM,
specific activity 48 Ci/mmol, Amersham, Little Chalfont, Bucks, UK)
essentially following the procedure described by Hyttel et al. [24].
For the displacement studies, an aliquot of membrane proteins
obtained from the cortex (50
concentrations of compounds as a displacer and [3H]QNB (0.2 nM)
and reaction volume was made up to 200 l with assay buffer and
incubated for 2 h at 37 ꢁC. The reaction for all displacement assays
was stopped by adding ice-cold assay buffer and reaction mixtures
were rapidly filtered through GF/B filters under vacuum. The
filtrates were transferred to vials containing scintillation fluid
(5 ml) and allowed to equilibrate overnight. Radioactivity was
measured in a liquid scintillation counter (Tris-Carb 2100TR,
Packard, US) at 65% efficiency.
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percentage bound are plotted against log of displacer concentration
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4.2.2. Antiamnesic activity assay
Antiamnesic activity assay was carried out for synthesized
N-alkyl/aryl thiazolidinone arecoline derivatives 6(a–m) against
scopolamine-induced memory loss using passive avoidance step
down task paradigm in male Wistar rats (weight: 200–250 g)
according to the method described by Sharma and Kulkarni [26,27].
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4.2.3. Elevated plus maze
This was employed for the measurement of transfer latency (TL).
The male Wistar rats (weight: 200–250 g) were placed individually