Synthesis, pharmacophore modeling, and biological evaluation of novel 5h-thiazolo[3,2-A]pvrimidin-5-one derivatives as 5-HT2A receptor antagonists

Article abstract of DOI:10.3797/scipharm.0804-20

Novel 5H-thiazolo[3,2-a]pyrimidin-5-one derivatives linked through an ethylene bridge to various phenylpiperazine groups were prepared for evaluation as 5-HT_2A receptor antagonists. The target compounds 11a-p were prepared through the initial synthesis of the 2-chloroethyl intermediates 10a-d which were then reacted with the appropriate phenylpiperazines. All compounds were tested for their antagonistic activity on 5-HT_2a receptors using inhibition of 5-hydroxytryptophan(5-HTP)-induced head twitches in mice. Pharmacophore modeling study, based on a hypothetical pharmacophore template generated from a set of diverse known active ligands, revealed good fitting of the designed compounds to the generated hypothetical pharmacophore. Osterrechische Apotheker-Verlagsgedellschaft m.b.H.

Full text of DOI:10.3797/scipharm.0804-20

Sci Pharm. 2008; 76: 415–438
doi:10.3797/scipharm.0804-20
415
© Österreichische Apotheker-Verlagsgesellschaft m. b. H., Vienna, Austria
Reproduction is permitted for non-commercial purposes.
Synthesis, Pharmacophore Modeling, and Biological
Evaluation of Novel 5H-Thiazolo[3,2-a]pyrimidin-5-one
Derivatives as 5-HT2A Receptor Antagonists
Fadi M. AWADALLAH
Pharmaceutical Chemistry Department, Faculty of Pharmacy,
Cairo University, Kasr El-Eini street 11562 Cairo, Egypt
Abstract
Novel 5H-thiazolo[3,2-a]pyrimidin-5-one derivatives linked through an ethylene
bridge to various phenylpiperazine groups were prepared for evaluation as 5-HT2A
receptor antagonists. The target compounds 11a–p were prepared through the
initial synthesis of the 2-chloroethyl intermediates 10a–d which were then reacted
with the appropriate phenylpiperazines. All compounds were tested for their
antagonistic activity on 5-HT2A receptors using inhibition of 5-hydroxytryptophan(5-
HTP)-induced head twitches in mice. Pharmacophore modeling study, based on a
hypothetical pharmacophore template generated from a set of diverse known active
ligands, revealed good fitting of the designed compounds to the generated
hypothetical pharmacophore.
Keywords
Arylpiperazines • 5-HT2A antagonists • Thiazolo[3,2-a]pyrimidines • Inhibition of
5-HTP induced head twitches.
Introduction
Serotonin (5-hydroxytryptamine, 5-HT) has been recognized for more than 50
years as an effector on various smooth muscles and, subsequently, as an important
neurotransmitter in the brain [1]. The serotonin receptors represent a diverse family
* Corresponding author: Tel.: +002-02-26070436.
E-mail: fadi_mae@hotmail.com

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F. M. Awadallah:
of receptors that has been initially classified pharmacologically into multiple
subtypes [2]. The advent of molecular cloning provided additional discrimination
within the serotonin receptor family revealing the existence of seven subfamilies
containing a total of fourteen distinct receptors based on primary sequence,
pharmacology and signal transduction pathways [1]. Serotonin receptor dysfunction
has been implicated in many neuropsychiatric disorders including anxiety,
depression and schizophrenia [1]. Clinical use of therapeutics affecting serotonergic
function is exemplified by selective serotonin reuptake inhibitors for depression [2],
5-HT1A partial agonists for anxiety and depression, 5-HT1D agonists for acute
migraine [3], 5-HT2A and 5-HT2C antagonists for migraine prophylaxis, depression,
schizophrenia [4, 5], 5-HT3 antagonists for chemotherapy-induced emesis [6], and
5-HT4 agonists for gastrointestinal disorders [7].
With particular emphasis on the 5-HT2 receptor family, the three receptor
subtypes, 5-HT2A, 5-HT2B and 5-HT2C, are G-protein coupled receptors (GPCRs)
that couple through the Gq and G11 proteins eliciting their second messenger effects
through increases in activity of phospholipase C (diacylglycerol pathway) and/or
phospholipase A (arachidonic acid pathway). These subtypes share an overall
amino acid homology of approximately 50%. 5-HT2A receptors are broadly
distributed in the prefrontal, parietal, and somatosensory cortex, claustrum and in
platelets [8]. The 5-HT2A receptor has been implicated as a therapeutic target for
schizophrenia and depression. Representative 5-HT2A antagonists include
ketanserin 1 [8], the prototype of a large group of structurally related derivatives
such as risperidone 2 [9], and ritanserin 3 [10]. Other 5-HT2A antagonists, belonging
to different chemical classes, include the spiro compound, spiperone 4, the tricyclic
derivative, clozapine 5, the indole derivative, sertindole 6 [11], and the
arylpiperazine derivative, aripiprazole 7 [12] (Chart 1).

Synthesis, Pharmacophore Modeling, and Biological Evaluation of Novel …
417
O
N
O
O
N
O
F
N
N
N
N
F
CH3
N
H
O
2 (Risperidone)
1 (Ketanserin)
F
O
H
N
F
N
N
O
O
N
F
N
S
4 (Spiperone)
N
CH3
3 (Ritanserin)
F
H
N
N
Cl
N
Cl
N
N
N
6 (Sertindole)
CH3
O
N
5 (Clozapine)
HN
N
Cl
Cl
N
O
N
H
O
7 (Aripiprazole)
Chart 1.
Experimental structure activity data for 5-HT2A antagonists suggest that two
planar aromatic or heterocyclic ring systems separated by an aliphatic or alicyclic
chain, containing basic protonatable nitrogen, seem to constitute a potent 5-HT2A
ligand. Additional hydrophobic substituent in the heterocyclic ring, as demonstrated
by the 4-fluorophenyl group in sertindole 6 and the chlorophenyl ring in clozapine 5,
enhances the antagonistic potency [11, 13].

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F. M. Awadallah:
Inspired by this knowledge, the newly synthesized compounds were designed
as structural mimics of ketanserin 1 and its analogs 2 and 3. The new compounds
possessed an additional phenyl group on the thiazolopyrimidine nucleus, hoping to
enhance the 5-HT2A antagonistic activity. Moreover, the piperidine ring in the lead
compounds was replaced by the isosteric piperazine ring with the aromatic
substitution directly attached to it as in risperidone. The two carbon spacer (the
ethylene bridge) was retained to keep the distance between the heterocyclic
nucleus and the protonatable nitrogen (N1 of the piperazine ring) as supported by
the modeling study.
Results and Discussion
1. Chemistry
The target compounds 11a–p were prepared according to Scheme 1. The 2-
aminothiazole derivatives 9a–d were obtained through a cyclocondensation
reaction of the corresponding α-bromoacetophenones 8a–d [14] to thiourea
according the reported procedures [15, 16]. Reaction of the appropriate 2-
aminothiazole 9a–d, and 2-acetylbutyrolactone in phosphorous oxychloride
furnished the 2-chloroethyl intermediates 10a–d. This was followed by alkylation of
various phenylpiperazines with these intermediates in dry dimethylformamide in the
presence of triethylamine under nitrogen atmosphere to give the final compounds
11a–p.

Synthesis, Pharmacophore Modeling, and Biological Evaluation of Novel …
419
R
R
O
O
S
R
O
N
CH3
H2N
NH2
O
Cl
N
N
Br
POCl3
NH2
S
S
O
CH3
8a R=H
8b R=Br
8c R=OCH3
9a R=H
9b R=Br
9c R=OCH3
10a R=H
10b R=Br
10c R=OCH3
8d R=CH3
9d R=CH3
10d R=CH3
N
R'
HN
R
O
N
N
R'
N
N
S
CH3
11a R=H R’=2-OCH3 11i R=OCH3 R’=2-OCH3
11bR=H R’=4-Cl
11c R=H R’=3-CF3
11dR=H R’=H
11j R=OCH3 R’=4-Cl
11k R=OCH3 R’=3-CF3
11l R=OCH3 R’=H
11e R=Br R’=2-OCH3 11mR=CH3 R’=2-OCH3
11f R=Br R’=4-Cl
11gR=Br R’=3-CF3
11hR=Br R’=H
11n R=CH3 R’=4-Cl
11o R=CH3 R’=3-CF3
11p R=CH3 R’=H
Sch. 1.
2. Pharmacology
The new compounds were evaluated, in vivo, for their 5-HT2A antagonistic
activity by measuring their ability to inhibit the 5-HTP induced head twitches in mice
[17, 18]. Risperidone was chosen as the standard drug. Risperidone was preferred
over ritanserin as the standard drug, although the latter is more closely related to
the tested compounds, because the former, unlike ritanserin, is widely marketed for
clinical treatment of psychosis. The observed data were summarized in Tab. 1
which showed the response percent calculated as the percent of mice showing no
head twitches to the total number of mice in each group. ED50 for all compounds
are shown in Tab. 2. The doses were calculated in mmol/kg and were administered

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F. M. Awadallah:
intraperitoneally (ip). From the obtained data (Tabs. 1,2 and Fig. 7), all compounds
were found to exhibit 5-HT2A receptor antagonistic activity with no significant
difference from the activity of risperidone, except for compounds 11n, 11o, and
11p. Compounds 11i and 11k possess an activity profile identical to that of
risperidone. The impact of the phenylpiperazine substituent (R’) viz. 2-OCH3, 4-Cl,
3-CF3, and H, upon activity is not absolute. However, the substituent (R) on the
phenyl ring at position 3 of the heterocyclic nucleus seems to play role in switching
the activity; so that compounds with R=CH3, especially compounds 11n, 11o, and
11p, are significantly less active than other derivatives with R= H, Br, or OCH3. On
the other hand, the series of compounds with R=OCH3 11i–l shows the highest
activity among other series; especially compounds 11i and 11k. Slightly lower
activity is exhibited by compounds with R=H 11a–d and R=Br 11e–h which have
almost similar activity profiles.
3. Pharmacophore modeling
A molecular modeling experiment was carried out to develop a hypothetical
pharmacophore model for the 5-HT2A receptor aiming to study the fitting of the
designed compounds to this pharmacophore. A ligand-based pharmacophore
model was developed using a training set of ten 5-HT2A antagonists of diverse
chemical structures including compounds 1–6 (Chart 1), in addition to, setoperone,
chlorpromazine, cyproheptadine, and tefludazine [11]. Fig. 1 shows the alignment
of the ten selected structures. The generated hypothetical pharmacophore (Fig. 2)
shows seven overlapping points with similar chemical properties in the training set,
F1: a hydrogen bond acceptor center; F2: an aromatic or hydrophobic center with
two parallel places F3 and F5 for Pi orbital accommodation; F4: an aromatic center
with a H-bond donor group; F6: a hydrophobic center; and F7: a second H-bond
acceptor center.
Fitting of the designed compounds 11a–d to the pharmacophore revealed the
presence of the appropriate chemical groups superimposed on the pharmacophoric
elements (Figs. 3–6). The phenylpiperazine tail represents the aromatic ring with its

Synthesis, Pharmacophore Modeling, and Biological Evaluation of Novel …
421
Pi orbitals properly oriented to fit to F2, F3 and F5. Also, N1 of the piperazine ring is
a H-bond acceptor corresponding to F1. The ethylene spacer is the hydrophobic
group fitting to F6; it is worth mentioned that this 2 carbon spacer was perfect in
adjusting the distance between other groups in the molecule. The thiazolo-
pyrimidine ring is a suitable aromatic group for F4 with the nitrogen atom, at
position 8, as a H-bond acceptor group for F7. Finally, it is interesting to note that,
according to the created model, the phenyl group at position 3 is not part of the
pharmacophore. Therefore, it will not be required to study the fitting of the rest of
the compounds 11e-p since variations in the substituents on the 3-phenyl group will
not affect the fitting results.
In conclusion, it could be assumed that the presence of the phenyl ring on the
heterocyclic nucleus, although seeming not essential for activity as suggested by
the molecular modeling study, yet the activity of the new compounds is in great part
dependent on it. The role of the 3-phenyl group is unclear but it can be assumed
that it fits into an accessory site of the receptor. Pharmacological data, supported
by the modeling study, showed that the phenylpiperazine moiety is a suitable
bioisostere of the arylpiperidine group present in ketanserin 1 and its analogs. In
addition, the ethylene bridge is the proper spacer that keeps other groups in the
molecule in the perfect position.

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F. M. Awadallah:
Tab. 1. Response % of the tested compounds (mmol/Kg) towards inhibition of
5-HTP induced head twitches
Response%a of the
tested animals towards
dose mmol/kg
Response%a of the
tested animals towards
dose mmol/kg
Compound
Compound
11i
12.2
24.4
48.8
12.2
66.67% 100%
50%
66.67% 100%
33.33% 83.33% 100%
24.4
48.8
Risperidone 66.67% 100%
100%
100%
11a
11b
11c
11d
11e
11f
0%
50%
83.33% 11j
83.33% 100%
100%
50%
66.67% 100%
11k
11l
33.33% 83.33% 100%
16.67% 100% 100%
16.67% 83.33% 100%
0% 83.33% 100%
11m
11n
11o
11p
0%
0%
50%
83.33%
16.67% 50%
16.67% 33.33% 83.33%
0% 33.33% 66.67%
11g
16.67% 100%
100%
11h
33.33% 100%
100%
a Response % of the tested animals showing no head twitches to the total number of mice
in each group.
Tab. 2. Potency (ED50) of the tested compounds in inhibition of 5-HTP induced
head twitches.
ED50
(mmol/kg)
Risperidone 3.58
ED50
(mmol/kg)
3.58
Compound
Compound
11i
11a
11b
11c
11d
11e
11f
29.43
9.78
11j
7.53
11k
3.58
10.27
10.7
11l
10.27
29.43
79.08a
30.53a
45.95a
11m
11n
13.24
16.45
10.7
11o
11g
11p
11h
8.11
a Significantly different from risperidone at p< 0.05.

Synthesis, Pharmacophore Modeling, and Biological Evaluation of Novel …
423
Fig. 1. Alignment of a training set of ten 5-
HT2A antagonists.
Fig. 2. The hypothetical pharmacophore
developed for the 5-HT2A receptor.
Fig. 3. Superimposition of the energy-
Fig. 4. Superimposition of the energy-
minimized structure of compound 11a on the minimized structure of compound 11b on
hypothetical 5-HT2A receptor
pharmacophore.
the hypothetical 5-HT2A receptor
pharmacophore.
Fig. 5. Superimposition of the energy-
minimized structure compound 11c on the
hypothetical 5-HT2A receptor
pharmacophore.
Fig. 6. Superimposition of the energy-
minimized structure of compound 11d on
the hypothetical 5-HT2A receptor
pharmacophore.
F1: Hydrogen bond acceptor center; F2: Aromatic or hydrophobic center; F3and F5:
Aromatic or Pi orbital place at the receptor site; F4: Aromatic center carrying a H-bond
donor; F6: Hydrophobic center; F7: H-bond acceptor place at the receptor site.

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F. M. Awadallah:
Experimental
1. Chemistry
Unless otherwise noted, all materials were obtained from commercial suppliers
and used without further purification. Dimethylformamide (DMF) was dried over
molecular sieve 4Ǻ. TLC was monitored on FLUKA silica gel TLC aluminium cards
(0.2mm thickness) with fluorescent indicator 254 nm using chloroform:methanol
(9:1) as eluent. Melting points were performed on Stuart SMP3 version 5 digital
melting point apparatus and were uncorrected. Elemental microanalyses were
performed at the microanalytical center, Faculty of Science, Cairo University. NMR
1
1
spectra were recorded on 200 MHz H NMR Varian Gemini 200, and 300 MHz H
13
and 75.45 MHz C NMR Varian mercury 300BB. Chemical shift values (δ) were
given in ppm. Mass spectra were performed on Fennigan MAT, SSQ 7000 mass
spectrophotometer at 70eV. IR spectra were recorded on Bruker FT-IR
spectrophotometer as potassium bromide disc. Compounds 8a–d [14], and 9a [15],
and 9b–d [16] were prepared according to the published procedures.
1.1. General procedure for the preparation of 6-(2-chloroethyl)-7-methyl-3-
(un)substituted- phenyl-5H-thiazolo[3,2-a]pyrimidin-5-ones 10a–d:
A mixture of 9a–d (6 mmol) and 2-acetylbutyrolactone (0.65 ml, 6 mmol) in
phosphorous oxychloride (15 ml) was heated under reflux for 2h. Excess
phosphorous oxychloride was distilled under reduced pressure. The residue was
triturated with ice-water and the suspension was neutralized with 2M ammonium
hydroxide solution. The crude product was filtered, dried and crystallized from
DMF-ethanol.
1.1.1. 6-(2-Chloroethyl)-7-methyl-3-phenyl-5H-thiazolo[3,2-a]pyrimidin-5-one
(10a):
1
Yield 43%; mp. 120-122o. H-NMR (200 MHz, CDCl3) δ 2.49 (s, 3H, -CH3),
3.04 (t, 2H, J= 6.6 Hz, -CH2CH2Cl), 3.68 (t, 2H, J= 6.6 Hz, -CH2CH2Cl), 6.55-7.68

Synthesis, Pharmacophore Modeling, and Biological Evaluation of Novel …
425
(m, 6H, aromatic H). MS m/z (%): M+ 304 (12.08), [M+2]+ 306 (4.78), 176 (100).
Analysis calculated for C15H13ClN2OS (304.80): C, 59.11; H, 4.30; N, 9.19. Found:
C, 59.26; H, 4.19; N, 9.33.
1.1.2. 3-(4-Bromophenyl)-6-(2-chloroethyl)-7-methyl-5H-thiazolo[3,2-
a]pyrimidin-5-one (10b):
1
Yield 38%; mp. 176-179o. H-NMR (200 MHz, CDCl3) δ 2.45 (s, 3H, -CH3),
2.77 (t, 2H, J= 6 Hz, -CH2CH2Cl), 3.66 (t, 2H, J= 6 Hz, -CH2CH2Cl), 6.67-7.67 (m,
5H, aromatic H). MS m/z (%): M+ 384.15 (0.36). Analysis calculated for
C15H12BrClN2OS (383.53): C, 46.98; H, 3.15; N, 7.30. Found: C, 46.40; H, 3.50; N,
6.98.
1.1.3. 6-(2-Chloroethyl)-3-(4-methoxyphenyl)-7-methyl-5H-thiazolo[3,2-
a]pyrimidin-5-one (10c):
Yield 52%; mp. 152-155o. 1H-NMR (200 MHz, DMSO-d6) δ 2.49 (s, 3H, -CH3),
2.89 (t, 2H, J= 8 Hz, -CH2CH2Cl), 3.66 (t, 2H, J= 8 Hz, -CH2CH2Cl), 3.80 (s, 3H, -
OCH3), 6.9-7.35 (m, 5H, aromatic H). MS m/z (%): M+ 334 (13.48), [M+2]+ 336
(5.39), 149 (100). Analysis calculated for C16H15ClN2O2S (334.83): C, 57.40; H,
4.52; N, 8.37. Found: C, 57.17; H, 4.48; N, 8.06.
1.1.4. 6-(2-Chloroethyl)-7-methyl-3-(4-methylphenyl)-5H-thiazolo[3,2-
a]pyrimidin-5-one (10d):
Yield 48%; mp.196-200o. 1H-NMR (200 MHz, CDCl3) δ 2.41 (s, 3H, -CH3 tolyl),
2.47 (s, 3H, -CH3), 3.008 (t, 2H, J= 6.4 Hz, -CH2CH2Cl), 3.69 (t, 2H, J= 6.4 Hz, -
CH2CH2Cl), 6.66-7.31 (m, 5H, aromatic H). MS m/z (%): M+ 318 (36.54), [M+2]+ 320
(12.03), 269 (100). Analysis calculated for C16H15ClN2OS.2H2O (354.86): C, 54.16;
H, 5.39; N, 7.89. Found: C, 54.04; H, 5.40; N, 8.21.
1.2. General procedure for the preparation of 7-methyl-3-
(un)substitutedphenyl-6-{2-[4-((un)substitutedphenyl)piperazin-1-yl]ethyl}-5H-
thiazolo[3,2-a]pyrimidin-5-ones 11a–p:

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F. M. Awadallah:
A solution of compound 10a–d (2 mmol), the appropriate phenylpiperazine
(2.1 mmol), and triethylamine (5 ml) in dry DMF (10 ml) was heated in a boiling
water bath under nitrogen atmosphere for 10h. The solvent was removed under
vacuum, and the residue was triturated with ice-water. The crude product was
filtered, dried, and crystallized from the appropriate solvent.
1.2.1. 6-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}-7-methyl-3-phenyl-5H-
thiazolo[3,2-a]pyrimidin-5-one (11a):
1
Yield 33%; mp. 116-118o (isopropanol). H-NMR (200 MHz, CDCl3) δ 2.44 (s,
3H, -CH3), 2.65 (t, 2H, J= 6 Hz, CH2CH2N-), 2.79 (br s, 4H, (CH2)2N1 piperazinyl),
3.11 (t, 2H, J= 6 Hz, -CH2CH2N-), 3.25 (br s, 4H, (CH2)2N4 piperazinyl), 3.844 (s,
3H, -OCH3), 6.65-7.91 (m, 10H, aromatic H). MS m/z (%): M+ 460.75 (1.23), 335
(100). Analysis calculated for C26H28N4O2S (460.60): C, 67.80; H, 6.13; N, 12.16.
Found: C, 67.30; H, 6.30; N, 12.46.
1.2.2. 6-{2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl}-7-methyl-3-phenyl-5H-
thiazolo[3,2-a]pyrimidin-5-one (11b):
1
Yield 42%; mp. 170-171o (isopropanol). H-NMR (300 MHz, DMSO-d6) δ 2.34
(s, 3H, -CH3), 2.64 (t, 2H, J= 7.2 Hz, CH2CH2N-), 3.06 (br s, 4H, (CH2)2N1
piperazinyl), 3.13 (t, 2H, J= 7.2 Hz, -CH2CH2N-), 3.48 (br s, 4H, (CH2)2N4
piperazinyl), 6.95-8.06 (m, 10H, aromatic H). 13C-NMR (75.45 MHz, CDCl3) δ 21.39
(CH3), 23.08 (CH2CH2N), 49.14 ((CH2)2N4 piperazinyl), 52.40 (CH2CH2N), 56.08
((CH2)2N1 piperazinyl), 101.42, 110.88, 114.25, 116.62, 117.60, 120.70 , 122.99,
126.99, 127.08, 128.50, 129.09 (aromatic C), 137.12 (aromatic C-1 of
phenylpiperazine), 149.82 (C-7 of thiazolopyrimidine ring), 160.76 (C=O), 168.13 (-
S-C(N)=N- of thiazolopyrimidine ring). MS m/z (%): M+ 464 (3.99). IR, Cm-1: 3058
(aromatic CH), 2920 (aliphatic CH), 1660 (CO). Analysis calculated for
C25H25ClN4OS (465.02): C, 64.57; H, 5.42; N, 12.05. Found: C, 64.51; H, 5.88; N,
12.02.

Synthesis, Pharmacophore Modeling, and Biological Evaluation of Novel …
427
1.2.3. 7-Methyl-3-phenyl-6-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-
yl}ethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (11c):
1
Yield 37%; mp. 139-142o (ethanol-water). H-NMR (200 MHz, DMSO-d6) δ
2.36 (s, 3H, -CH3), 2.65 (t, 2H, J= 7 Hz, CH2CH2N-), 2.95 (br s, 4H, (CH2)2N1
piperazinyl), 3.11 (t, 2H, J= 7 Hz, -CH2CH2N-), 3.41 (br s, 4H, (CH2)2N4 piperazinyl),
6.99-7.93 (m, 10H, aromatic). IR, Cm-1: 3057 (aromatic CH), 2925 (aliphatic CH),
1663 (CO). MS m/z (%): M+ 498.5 (4.95), 176 (100). Analysis calculated for
C26H25F3N4OS (498.57): C, 62.64; H, 5.05; N, 11.24. Found: C, 63.12; H, 5.25; N,
11.55.
1.2.4. 7-Methyl-3-phenyl-6-[2-(4-phenylpiperazin-1-yl)ethyl]-5H-thiazolo[3,2-
a]pyrimidin-5-one (11d):
1
Yield 37%; mp. 152-154o (ethanol). H-NMR (200 MHz, DMSO-d6) δ 2.36 (s,
3H, -CH3), 2.66 (t, 2H, J= 6.6 Hz, CH2CH2N-), 2.99 (br s, 4H, (CH2)2N1 piperazinyl),
3.15 (t, 2H, J= 6.6 Hz, -CH2CH2N-), 3.44 (br s, 4H, (CH2)2N4 piperazinyl), 6.95-8.01
(m, 11H, aromatic H). MS m/z (%): M+ 430.25 (2.92), 207 (100). Analysis calculated
for C25H26N4OS.2H2O (466.61): C, 64.35; H, 6.48; N, 12.01. Found: C, 64.70; H,
6.90; N, 12.46.
1.2.5. 3-(4-Bromophenyl)-6-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-7-
methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (11e):
Yield 35%; mp. 132-3o (isopropanol). 1H-NMR (300 MHz, CDCl3) δ 2.44 (s, 3H,
-CH3), 2.54 (t, 2H, J= 8 Hz, CH2CH2N-), 2.74 (br s, 4H, (CH2)2N1 piperazinyl),
3.01(t, 2H, J= 8 Hz, -CH2CH2N-), 3.10 (br s, 4H, (CH2)2N4 piperazinyl), 3.85 (s, 3H,
13
-OCH3), 6.66-7.66 (m, 9H, aromatic H). C-NMR (75.45 MHz, CDCl3) δ 21.82
(CH3), 23.34 (CH2CH2N), 50.52 ((CH2)2N4 piperazinyl), 53.23 (CH2CH2N), 55.33
((CH2)2N1 piperazinyl), 56.60 (OCH3), 103.21, 109.89, 111.28, 115.37, 118.17,
120.96, 121.51, 123.32, 127.51, 130.67, 131.60 (aromatic C), 137.37 (aromatic C-1
of phenylpiperazine), 152.24 (C-7 of thiazolopyrimidine ring), 160.10 (C=O), 167.31
(-S-C(N)=N- of thiazolopyrimidine ring). MS m/z (%): M+ 538.25 (0.82), [M+2]+

428
F. M. Awadallah:
540.25 (0.79), 205 (100). Analysis calculated for C26H27BrN4O2S. 1.5H2O (566.52):
C, 55.12; H, 5.16; N, 9.89. Found: C, 55.30; H, 5.10; N, 10.22.
1.2.6. 3-(4-Bromophenyl)-6-{2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}-7-
methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (11f):
1
Yield 43%; mp. 182-185o (isopropanol). H-NMR (200 MHz, CDCl3) δ 2.44 (s,
3H, -CH3), 2.55 (t, 2H, J= 8 Hz, CH2CH2N-), 2.66 (br s, 4H, (CH2)2N1 piperazinyl),
2.74 (t, 2H, J= 8 Hz, -CH2CH2N-), 3.13 (br s, 4H, (CH2)2N4 piperazinyl), 6.67-7.66
(m, 9H, aromatic H). IR, Cm-1: 3058 (aromatic CH), 2916 (aliphatic CH), 1650 (CO).
Analysis calculated for C25H24BrClN4OS (543.92): C, 55.21; H, 4.45; N, 10.30.
Found: C, 55.05; H, 4.60; N, 10.20.
1.2.7. 3-(4-Bromophenyl)-7-methyl-6-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-
1-yl}ethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (11g):
1
Yield 32%; mp. 158-160o (ethanol-water). H-NMR (200 MHz, DMSO-d6) δ
2.46 (s, 3H, -CH3), 2.53 (t, 2H, J= 8 Hz, CH2CH2N-), 2.68 (br s, 4H, (CH2)2N1
piperazinyl), 2.74 (t, 2H, J= 8 Hz, -CH2CH2N-), 3.17 (br s, 4H, (CH2)2N4 piperazinyl),
6.69-7.70 (m, 9H, aromatic H). MS m/z (%): M+ 577.40 (0.25), 243 (100). Analysis
calculated for C26H24BrF3N4OS (577.47): C, 54.08; H, 4.19; N, 9.70. Found: C,
54.04; H, 4.39; N, 9.57.
1.2.8. 3-(4-Bromophenyl)-7-methyl-6-[2-(4-phenylpiperazin-1-yl)ethyl]-5H-
thiazolo[3,2-a]pyrimidin-5-one (11h):
1
Yield 46%; mp. 167-170o (isopropanol). H-NMR (200 MHz, CDCl3) δ 2.45 (s,
3H, -CH3), 2.53 (t, 2H, J= 8 Hz, CH2CH2N-), 2.74 (br s, 4H, (CH2)2N1 piperazinyl),
2.83 (t, 2H, J= 8 Hz, CH2CH2N-), 3.23 (br s, 4H, (CH2)2N4 piperazinyl), 6.66-7.66
(m, 10H, aromatic H). IR, Cm-1: 3060 (aromatic CH), 2920 (aliphatic CH), 1651
(CO). Analysis calculated for C25H25BrN4OS (509.47): C, 58.94; H, 4.95; N, 11.00.
Found: C, 59.26; H, 5.19; N, 10.77.

Synthesis, Pharmacophore Modeling, and Biological Evaluation of Novel …
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1.2.9. 3-(4-Methoxyphenyl)-6-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-7-
methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (11i):
1
Yield 54%; mp.180-182o (methanol). H-NMR (200 MHz, DMSO-d6) δ 2.37 (s,
3H, -CH3), 2.52 (t, 2H, J= 6.6 Hz, CH2CH2N), 2.60 (br s, 4H, (CH2)2N1 piperazinyl),
2.96 (t, 2H, J= 6.6 Hz, CH2CH2N-), 3.36 (br s, 4H, (CH2)2N4 piperazinyl), 3.78 ( s,
6H, 2 -OCH3 groups), 6.83-7.76 (m, 9H, aromatic H). IR, Cm-1: 3055 (aromatic CH),
2920 (aliphatic CH), 1663 (CO). Analysis calculated for C27H30N4O3S (490.63): C,
66.10; H, 6.16; N, 11.42. Found: C, 66.36; H, 6.63; N, 11.60.
1.2.10. 6-{2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl}-3-(4-methoxyphenyl)-7-
methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (11j):
Yield 57%; mp. 147-150o (methanol). 1H-NMR (200 MHz, DMSO-d6) δ 2.35 (s,
3H, -CH3), 2.51 (t, 2H, J= 6 Hz, CH2CH2N), 2.58 (br s, 4H, (CH2)2N1 piperazinyl),
2.94 (t, 2H, J= 6 Hz, CH2CH2N-), 3.10 (br s, 4H, (CH2)2N4 piperazinyl), 3.78 (s, 3H, -
OCH3), 6.81-7.73 (m, 9H, aromatic H). Analysis calculated for C26H27ClN4O2S
(495.05): C, 63.08; H, 5.50; N, 11.32. Found: C, 63.40; H, 4.88; N, 11.26.
1.2.11. 3-(4-Methoxyphenyl)-7-methyl-6-(2-{4-[3-(trifluoromethyl)phenyl]-
piperazin-1-yl}ethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (11k):
1
Yield 42%; mp. 171-174o (ethanol-water). H-NMR (200 MHz, CDCl3) δ 2.45
(s, 3H, CH3), 2.57 (t, 2H, J= 7.4 Hz, CH2CH2N), 2.77 (br s, 4H, (CH2)2N1
piperazinyl), 2.88 (t, 2H, J= 7.4 Hz, CH2CH2N-), 3.35 (br s, 4H, (CH2)2N4
piperazinyl), 3.81 (s, 3H, -OCH3), 6.56-7.71 (m, 9H, aromatic H). MS m/z (%): M+
528.2 (0.62), 243 (100). IR, Cm-1: 3057 (aromatic CH), 2922 (aliphatic CH), 1652
(CO). Analysis calculated for C27H27F3N4O2S (528.60): C, 61.36; H, 5.15; N, 10.60.
Found: C, 61.44; H, 5.19; N, 10.35.
1.2.12. 3-(4-Methoxyphenyl)-7-methyl-6-[2-(4-phenylpiperazin-1-yl)ethyl]-5H-
thiazolo[3,2-a]pyrimidin-5-one (11l):
Yield 49%; mp. 168-170o (ethanol). 1H-NMR (300 MHz, CDCl3) δ 2.42 (s, 3H, -
CH3), 2.52 (t, 2H, J= 7 Hz, CH2CH2N), 2.67 (br s, 4H, (CH2)2N1 piperazinyl), 2.75 (t,

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F. M. Awadallah:
2H, J= 7 Hz, CH2 CH2N-), 3.19 (br s, 4H, (CH2)2N4 piperazinyl), 3.82 (s, 3H, -
13
OCH3), 6.56-7.71 (m, 10H, aromatic H). C-NMR (75.45 MHz, CDCl3) δ 21.80
(CH3), 23.50 (CH2CH2N), 49.05 ((CH2)2N4 piperazinyl), 53.07 (CH2CH2N), 55.26
((CH2)2N1 piperazinyl), 56.62 (OCH3), 100.94, 108.38, 112.96, 113.91, 115.92,
119.50, 124.27, 127.23, 129.02, 130.46 (aromatic C), 138.59 (aromatic C-1 of
phenylpiperazine), 151.06 (C-7 of thiazolopyrimidine ring), 159.04 (aromatic C-4 of
methoxyphenyl ring), 160.25 (C=O), 167.12 (-S-C(N)=N- of thiazolopyrimidine ring).
MS m/z (%): M+ 460.25 (1.82), 175 (100). Analysis calculated for C26H28N4O2S
(460.60): C, 67.80; H, 6.13; N, 12.16. Found: C, 67.46; H, 6.10; N, 12.8.
1.2.13. 6-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}-7-methyl-3-(4-
methylphenyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (11m):
1
Yield 42%; mp. 165-166o (isopropanol). H-NMR (200 MHz, DMSO-d6) δ 2.32
(s, 3H, -CH3 tolyl), 2.34 (s, 3H, -CH3), 2.56 (t, 2H, J= 6.6 Hz, CH2CH2N), 2.76 (br s,
4H, (CH2)2N1 piperazinyl), 2.92 (t, 2H, J= 6.6 Hz, CH2CH2N-), 3.35 (br s, 4H,
(CH2)2N4 piperazinyl), 3.79 (s, 3H, -OCH3), 6.88-7.81 (m, 9H, aromatic H). MS m/z
(%): M+ 474.15 (1.08), 205 (100). Analysis calculated for C27H30N4O2S (474.63): C,
68.33; H, 6.37; N, 11.80. Found: C, 68.51; H, 5.96; N, 11.21.
1.2.14. 6-{2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl}-7-methyl-3-(4-
methylphenyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (11n):
Yield 46%; mp. 130-133o (methanol). 1H-NMR (200 MHz, DMSO-d6) δ 2.31 (s,
3H, -CH3 tolyl), 2.36 (s, 3H, -CH3), 2.52 (t, 2H, J= 6.6 Hz, CH2CH2N), 2.78 (br s, 4H,
(CH2)2N1 piperazinyl), 2.91 (t, 2H, J= 6.6 Hz, CH2CH2N-), 3.35 (br s, 4H, (CH2)2N4
piperazinyl), 6.93-7.71 (m, 9H, aromatic H). Analysis calculated for C26H27ClN4OS
(479.05): C, 65.19; H, 5.68; N, 11.70. Found: C, 65.30; H, 5.30; N, 11.46.
1.2.15. 7-Methyl-3-(4-methylphenyl)-6-(2-{4-[3-(trifluoromethyl)phenyl]-
piperazin-1-yl}ethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (11o):
1
Yield 35%; mp. 123-126o (ethanol-water). H-NMR (200 MHz, DMSO-d6) δ
2.32 (s, 3H, -CH3 tolyl), 2.34 (s, 3H, -CH3), 2.53 (t, 2H, J= 7 Hz, CH2CH2N), 2.81 (br

Synthesis, Pharmacophore Modeling, and Biological Evaluation of Novel …
431
s, 4H, (CH2)2N1 piperazinyl), 2.89 (t, 2H, J= 7 Hz, CH2CH2N-), 3.38 (br s, 4H,
(CH2)2N4 piperazinyl), 6.99-7.83 (m, 9H, aromatic H). MS m/z (%): M+ 512.15
(2.84), 243 (100). IR, Cm-1: 3060 (aromatic CH), 2919 (aliphatic CH), 1661 (CO).
Analysis calculated for C27H27F3N4OS (512.60): C, 63.27; H, 5.31; N, 10.93. Found:
C, 63.30; H, 5.40; N, 10.66.
1.2.16. 7-Methyl-3-(4-methylphenyl)-6-[2-(4-phenylpiperazin-1-yl)ethyl]-5H-
thiazolo[3,2-a]pyrimidin-5-one (11p):
1
Yield 41%; mp. 155-157o (isopropanol). H-NMR (200 MHz, CDCl3) δ 2.39 (s,
3H, -CH3 tolyl), 2.44 (s, 3H, -CH3), 2.50 (t, 2H, J= 7 Hz, CH2CH2N), 2.76 (br s, 4H,
(CH2)2N1 piperazinyl), 2.89 (t, 2H, J= 7 Hz, CH2CH2N-), 3.23 (br s, 4H, (br s, 4H,
(CH2)2N4 piperazinyl), 6.65-7.71(m, 10 H, aromatic H). MS m/z (%): M+ 444.15
(3.17), 175 (100). IR, Cm-1: 3059 (aromatic CH), 2918 (aliphatic CH), 1657 (CO).
Analysis calculated for C26H28N4OS (444.60): C, 70.24; H, 6.35; N, 12.60. Found: C,
70.52; H, 6.38; N, 12.85.
2. Pharmacological screening
Inhibition of 5-HTP induced head twitches in mice.
The antagonism of 5-HT2A receptors was determined in vivo by inhibition of
5-HTP induced head twitches in mice [18]. The animals were divided into
seventeen groups each of six male mice (18–22g) to test compounds 11a–p and
risperidone as the standard drug (Tab. 1). The animals received 75mg/kg pargyline
HCl as a solution in water intraperitoneally (ip). Thirty minutes later, they were
treated with the test drug ip in a dose of 24.4 mmol/kg as a suspension in saline
and Tween 80. Thirty minutes after the test drug, the animals were injected ip with
10mg/kg DL-5-HTP as a suspension in saline and Tween 80. An additional group of
six mice was used as a control group which was injected with water-Tween 80 as a
vehicle. An animal was considered to give positive response if it does not show
head twitches 20 min. after 5-HTP injection. According to the observed response%,
the experiment was repeated similarly using a lower and a higher dose of the drug

432
F. M. Awadallah:
(12.2 and 48.8 mmol/kg). Inhibition of head twitches after treatment with the drug
was observed relative to a control group of six mice treated with pargyline and
5-HTP only.
Using the inhibition of 5-HTP induced head twitches in mice, the effects of the
treatment with the new compounds on the dose-response% were graphically
illustrated in comparison with that of risperidone (Fig. 7).
The potencies (ED50) of the tested compounds (Tab. 2), and statistical t-test
for comparison between the potencies of the tested compounds and risperidone
were performed by Prism 3 software.
3. Pharmacophore modeling study
All molecular modeling calculations were performed using "Molecular
Operating Environment (MOE) version 2007.09", Chemical Computing Group Inc.,
running on "Windows XP" operating system installed on an Intel Pentium IV PC with
a 2.8 MHz processor and 512 RAM.
General methodology:
1-Alignment of the training set compounds:
The training set compounds, consisting of ten known 5-HT2A antagonists of
diverse chemical structure, were built using the builder interface of the MOE
software. The compounds were aligned using the flexible alignment tool of the
program adjusting the energy cut off to 10 kcal/mol and root mean square deviation
(RMSD) tolerance to 0.5. The stochastic conformation search option was used as
the method of alignment (Fig. 1).

Synthesis, Pharmacophore Modeling, and Biological Evaluation of Novel …
433
Compound 11a
Compound 11b
150
100
50
150
Compound 11a
Compound 11b
Risperidone
Risperidone
100
50
0
0
0
10
20
30
40
50
60
0
10
20
30
40
50
60
Dose mmol/kg(Ip)
Dose mmol/kg (ip)
Compound 11c
Compound 11d
150
100
50
150
100
50
Compound 11d
Risperidone
Compound 11c
Risperidone
0
0
0
10
20
30
40
50
60
0
10
20
30
40
50
60
Dose mmol/kg (ip)
Dose mmol/kg (ip)
Compound 11f
Compound 11e
150
100
50
150
Compound 11f
Risperidone
Compound 11e
Risperidone
100
50
0
0
0
10
20
30
40
50
60
0
10
20
30
40
50
60
Dose mmol/kg (ip)
Dose mmol/kg (ip)
Compound 11h
Compound 11g
150
100
50
150
100
50
Compound 11h
Risperidone
Compound 11g
Risperidone
0
0
0
10
20
30
40
50
60
0
10
20
30
40
50
60
Dose mmol/kg (ip)
Dose mmol/kg (ip)
Fig. 7. Dose-response% curves showing pharmacological activity of the tested
compounds in inhibition of 5-HTP induced head twitches in relation to risperidone.

434
F. M. Awadallah:
Compound 11j
Compound 11i
150
100
50
150
100
50
Compound 11i
Compound 11j
Risperidone
Risperidone
0
0
0
10
20
30
40
50
60
0
10
20
30
40
50
60
Dose mmol/kg (ip)
Dose mmol/kg (ip)
Compound 11k
Compound 11l
150
100
50
150
100
50
Compound 11l
Risperidone
Compound 11k
Risperidone
0
0
0
10
20
30
40
50
60
0
10
20
30
40
50
60
Dose mmol/kg (ip)
Dose mmol/kg (ip)
Compound 11m
Compound 11n
150
150
100
50
Compound 11m
Risperidone
Compound 11n
Risperidone
100
50
0
0
0
10
20
30
40
50
60
0
10
20
30
40
50
60
Dose mmol/kg (ip)
Dose mmol/kg (ip)
Compound 11p
Compound 11o
150
100
50
150
100
50
Compound 11p
Risperidone
Compound 11o
Risperidone
0
0
0
10
20
30
40
50
60
0
10
20
30
40
50
60
Dose mmol/kg (ip)
Dose mmol/kg (ip)
Fig. 7. (Cont.).

Synthesis, Pharmacophore Modeling, and Biological Evaluation of Novel …
435
2-Target compounds optimization:
Conformational analyses of the built molecules were performed in a two-step
procedure. First, the target compounds were subjected to energy minimization tool
using the included MOPAC 7.0. The geometry of the compounds was optimized
with the semiemperical PM3 Hamiltonian using Restricted Hartree-Fock (RHF) and
RMS gradient of 0.05 Kcal/mol. Then, the produced model was subjected to the
‘Systematic Conformational Search’ of the MOE. All items were set as default with
RMS gradient of 0.01 Kcal/mol and RMS distance of 0.1 Ǻ. The obtained data were
then saved as MBD file to be used in the pharmacophore fitting calculations.
3-Pharmacophore Building:
A pharmacophore model was created using the ‘Pharmacophore Query
Editor’. The aligned training set compounds were used as the template for building
the model. The settings of the software parameters were adjusted to:
‘Unified’ as the scheme of annotation
‘Consensus method’ for model building
Tolerance was set to 1.2 Ǻ and the threshold was set to 50%.
The produced model was saved as *.ph file for testing compound-
pharmacophore fitting and further calculations (Fig. 2).
4-Fitting of the target compounds on the built model:
Using the generated pharmacophore model and the saved conformations of
each molecule; the fitting of the target compounds 11a–d into the model was tested
(Figs. 3-6). The root mean square deviation value for each conformer was
calculated and the one having the lowest RMSD value was taken for further visual
and energy inspection.
Acknowledgement
I am grateful to Dr. Rania Khalef AbdelKader, research assistant in the
Pharmacology laboratory, Theodore Bilharz Institute, Giza, Egypt, for her kind help

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F. M. Awadallah:
and advice in the pharmacological screening. Also, I acknowledge Dr. Mohammed
Kamal Abdel-Hamid, assistant lecturer in Pharmaceutical Chemistry Department,
Faculty of Pharmacy, Assiut University, Assiut, Egypt, for performing the modeling
study.
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Received April 19th, 2008
Accepted (after revision) August 5th, 2008
Available online at www.scipharm.at August 9th, 2008