Computer-aided design, synthesis, and biological evaluation of 5-substituted aminomethylenepyrimidine-2,4,6-triones as H1 antihistaminic agents(Part2)

Article abstract of DOI:10.2174/15734064113099990032

As a part of a research project pertaining to the synthesis of novel candidates as nonsedating, nonclassic H1 histaminergic (H1) blockers with low toxicity profiles, some new 5-substituted aminomethylenepyrimidine-2,4,6-triones were designed based on the H1 histaminic receptor pharmacophore model. The interactions between the designed compounds and the H1 receptor were studied using molecular docking on the homology model of H1 receptor. The designed compounds were synthesized and biologically evaluated for H1-blocking activity; using isolated segments of guinea pig ileum. Compounds 15,18,19 and 21 exhibited comparable activities to acrivastine (22) as reference nonsedating drug. The C log P of designed compounds revealed lower values in reference to acrivastine (22) which might indicate decreased tendency for crossing the blood brain barrier.

Full text of DOI:10.2174/15734064113099990032

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66
Medicinal Chemistry, 2014, 10, 66-73
Computer-aided Design, Synthesis, and Biological Evaluation of 5-
Substituted Aminomethylenepyrimidine-2,4,6-Triones as H1 Antihistaminic
Agents (Part2) ꢀ
Rasha Y. Elbayaa*
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
Abstract: As a part of a research project pertaining to the synthesis of novel candidates as nonsedating, nonclassic H1
histaminergic (H1) blockers with low toxicity profiles, some new 5-substituted aminomethylenepyrimidine-2,4,6-triones
were designed based on the H1 histaminic receptor pharmacophore model. The interactions between the designed
compounds and the H1 receptor were studied using molecular docking on the homology model of H1 receptor. The
designed compounds were synthesized and biologically evaluated for H1-blocking activity; using isolated segments of
guinea pig ileum. Compounds 15,18,19 and 21 exhibited comparable activities to acrivastine (22) as reference nonse-
dating drug. The C log P of designed compounds revealed lower values in reference to acrivastine (22) which might indi-
cate decreased tendency for crossing the blood brain barrier.
Keywords: Synthesis, aminomethylenepyrimidine-2,4,6-triones, antihistaminic, pharmacophore modeling, docking.
1. INTRODUCTION
profiles, our previously published work described the syn-
thesis of some substituted aminomethylenepyrimidine-2, 4,
6-triones with different aliphatic substituents at the side
chain of the pyrimidinyl moiety [9]. According to this inves-
tigation these derivatives exhibited pronounced antihista-
minic activities.
Histamine is namely one of the most frequently studied
local hormones, which plays an important role in several
physiological processes, specifically, in the central nervous,
gastrointestinal, respiratory and immune systems [1-4]. The
effects of histamine are mediated by a family of G protein
coupled receptors, H1, H2, H3 and H4 receptors [5]. The H1
receptor is mainly responsible for the inflammatory effect of
histamine, e.g. smooth muscle contraction, increasing blood
vessel permeability, releasing other local hormones [6]. It
has been considered an attractive target for drug discovery
for several years and H1 receptor antagonists have proved to
be effective therapeutic agents for respiratory distress, thus
contributing to an important class of drugs today.
The present work designed and generated a pharma-
cophore model using five of the previously synthesized
compounds which were then validated using other six of the
previously synthesized compounds.
According to this pharmacophore model new ami-
nomethylenepyrimidines (Fig. 1) linked to different aromatic
amines were designed and evaluated for H1-blocking activity
using isolated segments from guinea pig ileum. The newly
designed agents together with the previously prepared com-
pounds were all docked inside the binding site of the H1-
receptor homology model and the new ones showed better
docking scores comparable to the old members and the refer-
ence drug acrivastine (22).
The most recent antihistaminic compounds were almost
exclusively based on modifying the structure of some old H1
antagonists. Cloning of the human histamine H1 receptor
(hHR1) however, will be capable of opening new ways to
examine the binding of histamine and its antagonists, and to
find the important receptor-ligand interactions. It is also pos-
sible to compare the binding affinity of the newly synthe-
sized analogs to predict their expected pharmacological ac-
tion [7, 8].
In order to verify the nonsedating capacity of the newly
synthesized candidates, the partition coefficient Clog p was
calculated using a routine computer-assessed program
described by Leo [10].
O
As a result of our interest to establish potential nonsedat-
ing, nonclassic histaminergic (H1) blockers with low toxicity
R
HN
N
H
*Address correspondence to this author at the Department of Pharmaceuti-
cal Chemistry, Faculty of Pharmacy, University of Alexandria, 1 Elkhar-
toum Square, Azarita, Alexandria, Egypt; Tel: 002-03-4871317; Fax: 002-
03-4873-273; E-mails: rashabayaa72@gmail.com and
O
N
H
O
rasha_bayaa@yahoo.com
Fig. (1). Molecular structure of newly synthesized substituted ami-
nomethylenepyrimidine-2, 4, 6-triones.
ꢀA part of the work was presented at 4th EuCheMS Chemistry Congress,
Prague, Czech Republic 26-30/8/2012.
1875-6638/14 $58.00+.00
© 2014 Bentham Science Publishers

Design and Evaluation of Aminomethylenepyrimidines
Medicinal Chemistry, 2014, Vol. 10, No. 1 67
O
O
O
Cl
HN
N
H
HN
N
HN
N
O
N
O
N
H
1
O
O
N
H
3
O
O
N
H
2
O
O
O
O
OH
HN
N
H
HN
N
H
O
N
H
4
O
O
N
H
5
O
Fig. (2). H1-antagonists used for building the pharmacophore model.
having the lowest root mean square distance (RMSD) was
selected. This procedure was also used for mapping the new
designed compounds 15-21 (Fig. 5) on the pharmacophore
model.
2.1.2. Molecular Docking Study
A docking study was performed using Molegro Virtual
Docker (MVD) [12] version 2010.4.0.2. All docking calcula-
tions were carried out using the grid-based MolDock score
(GRID) function available in MVD with a grid resolution of
0.30 ꢁ. The binding site on the receptor was defined as a
sphere with a radius of 15 Å extending from the center of the
largest cavity which was identified using the Detect Cavities
function present in MVD. The MolDock SE search algo-
rithm with a maximum of ten runs was used through the cal-
culations, with all other parameters kept as defaults. One
pose per run was retained and all poses were examined
manually and the best pose was used. Ligand interactions
were generated using the Ligand Interactions module in
MOE.
2.2. Chemistry
Melting points were determined in open glass capillaries
on a Gallenkamp melting point apparatus and were uncor-
rected. The infrared (IR) spectra were recorded on Perkin-
Elmer 1430 infrared spectrophotometer using the KBr plate
technique. 1H-NMR spectra were determined on Jeol spec-
trometer (500 MHz) at the Microanalytical unit, Faculty of
Science, Alexandria University and on a Varian spectrometer
(300 MHz), Faculty of Science, Cairo University using
tetramethylsilane (TMS) as the internal standard and DMSO-
d6 as the solvent (Chemical shifts in ꢂ, ppm). Splitting pat-
terns were designated as follows: bs: broad singlet; s: singlet;
d: doublet; m: multiplet; t: triplet. Microanalyses were per-
formed at the Microanalytical Unit, Faculty of Science,
Cairo University, Egypt. The found values were within
0.4% of the theoretical values. Follow up of the reactions
and checking the homogeneity of the compounds were made
by TLC on silica gel-protected glass plates and the spots
were detected by exposure to UV-lamp at ꢃ 254.
Fig. (3). Pharmacophore model which derived from H1-antagonists
and used in the selection of the proposed compounds (numbers
indicate distances in Å).
2. MATERIALS AND METHODS
2.1. Molecular Modeling
2.1.1. Generation of the Pharmacophore Model
All compounds were built using the Builder module of
the Molecular Operating Environment (MOE) version
2008.10 [11] program and subjected to energy minimization
using MMFF94X force field.
The training set compounds 1-5 (Fig. 2) were used for
pharmacophore model generation (Fig. 3) using the Unified
scheme present in the Pharmacophore Elucidation module.
The generated pharmacophore model (query) was saved as
.ph4 file.
2.2.1. Synthesis of 5- Ethoxymethylenepyrimidine-2,4,6-
trione (14)
The pharmacophore model was then validated by map-
ping compounds 6-11 (Fig. 4) on the pharmacophore model
using the Pharmacophore Search module and the conformer
A mixture of pyrimidine-2,4,6-trione (12) (1.28 g, 0.01
mol) and triethyl orthoformate (13) (7.4 g, 0.05 mol) was
heated under reflux for 30 min. After cooling, ether was

68 Medicinal Chemistry, 2014, Vol. 10, No. 1
Rasha Y. Elbayaa
O
OH
OH
O
O
HN
N
H
OH
HN
HN
N
H
HN
HN
N
H
O
N
H
O
O
O
N
H
O
O
O
O
N
H
8
O
O
6
7
O
O
O
N
N
HN
N
H
O
N
H
N
H
O
N
H
O
9
10
11
Fig. (4). H1-antagonists used for validating the pharmacophore model.
Br
Cl
O
O
O
HN
N
HN
N
H
HN
N
H
H
O
O
N
H
16
O
O
O
N
H
17
O
O
N
H
15
O
OCH3
O
O
O
HN
O
N
H
HN
N
H
HN
N
H
OCH3
N
H
20
O
O
N
H
18
O
N
H
19
N
O
O
N
HN
N
H
OH
O
N
H
21
O
22
Fig. (5). Chemical structure of the newly designed H1-antagonists and Acrivastine (22).
added to the reaction mixture, the separated product was
filtered, dried and utilized, directly in the next step, without
further purification [9].
(d, J=6.3 Hz, 1H, -C=CH); 10.34 (bs, 3H, NH, D2O ex-
changeable). Anal. Calcd for C12H11N3O3 (245.23): C, 58.77;
H, 4.52; N, 17.13. Found: C, 58.41; H, 4.71; N, 17.31.
2.2.2.2. 5-[(4-Bromophenylamino)methylene]pyrimidine-
2,4,6-trione(16)
2.2.2. General Procedure for the Synthesis of 5- (Substi-
tuted Aminomethylene)pyrimidine-2,4,6-triones(15-21)
Yield: 73%, mp: > 300oC .IR (cm-1): 3427 (NH); 3095
(=C-H); 1702 (C=O); 1599(C=N); 1506 (C=C); 1H-NMR (ꢀ
ppm): 7.27 (d, J= 6.1 Hz, 2H, Ar-H); 7.48 (d, J= 6.2 Hz, 2H,
Ar-H); 8.54 (d, J= 6.1 Hz, 1H, -C=CH); 10.92 (bs, 3H, NH,
D2O exchangeable). Anal. Calcd for C11H8BrN3O3 (310.10):
C, 42.60; H, 2.60; N, 13.55. Found: C, 42.87; H, 2.29; N,
13.36.
A mixture of the appropriate amine (0.003 mol) and the
ethoxymethylene derivative 14 (0.184 g, 0.001mol) con-
tained in a round bottomed flask, was gently heated until
fusion. The fused reaction mixture was maintained at 150 °C
for 1 h. The mixture was then allowed to cool to RT, tritu-
rated with water, filtered, dried and recrystallized from etha-
nol/water.
2.2.2.3. 5-[(4-Chlorophenylamino)methylene]pyrimidine-
2,4,6-trione(17)
2.2.2.1. 5-[(Benzylamino)methylene]pyrimidine-2,4,6-tri-
one(15)
Yield: 76%, mp: > 300oC .IR (cm-1): 3399 (NH); 3058
(=C-H); 1699 (C=O); 1597(C=N); 1496 (C=C); 1H-NMR (ꢀ
ppm): 7.25 (d, J=6.1 Hz, 2H, Ar-H); 7.43 (d, J=6.2 Hz, 2H,
Ar-H); 8.53 (d, J=6.1Hz, 1H, -C=CH); 10.89 (bs, 3H, NH,
Yield: 81%, mp: > 300oC .IR (cm-1): 3421(NH); 3078
(=C-H); 1695 (C=O); 1510 (C=C); 1H-NMR (ꢀ ppm): 4.69
(d, J= 6.3Hz, 2H, CH2); 7.28 (d, J= 6.3 Hz, 2H, Ar-H); 7.31
(t, J= 6.3 Hz ,2H, Ar-H); 7.36 (t, J=6.3Hz, 1H, Ar-H); 8.24

Design and Evaluation of Aminomethylenepyrimidines
Medicinal Chemistry, 2014, Vol. 10, No. 1 69
D2O exchangeable). Anal. Calcd for C11H8ClN3O3 (265.65):
C, 49.73; H, 3.04; N, 15.82. Found: C, 49.49; H, 3.25; N,
15.60.
Cairo, Egypt. All test agents were directly solubilized in dis-
tilled water.
Male Hartley guinea pigs (6 weeks of age, 250 50g
body weight) were of local breed and obtained from the ani-
mal house located at the Medical Research Institute, Univer-
sity of Alexandria, Egypt.
2.2.2.4. 5-[(2-Methoxyphenylamino)methylene]pyrimidine-
2,4,6-trione (18)
Yield: 43%, mp: > 300oC. IR (cm-1): 3420 (NH); 3070
(=C-H); 1701 (C=O); 1596(C=N); 1521(C=C); 1H-NMR (ꢀ
ppm): 3.64 (s, 3H, OCH3); 7.26 (d, J=14.1Hz, 1H, Ar-H);
7.31 (t, J=6.2 Hz, 2H, Ar-H); 7.38 (d, J= 6.1Hz, 1H, Ar-H);
8.51 (d, J= 6.1Hz, 1H, -C=CH); 10.76 (s, 1H, -NH D2O
exchangeable), 10.87 (s, 1H, -NH D2O exchangeable);
11.83(d, 1H, -NH D2O exchangeable J=14.1),. Anal. Calcd
for C12H11N3O4 (261.23): C, 55.17; H, 4.24; N, 16.09.
Found: C, 54.88; H, 4.37; N, 15.78.
Male guinea pigs were sacrificed by a blow to the base of
the skull and cervical dislocation. Clean ileal segments of 2–
3 cm long were prepared from the guinea pigs. One end was
fixed to a glass aerating tube and the other to isotonic trans-
ducer (Bioscience, England). The whole preparation was set
up in 10-mL organ bath containing aerated Tyrode solution
(NaCl: 1.0; CaCl2:0.2; KCl: 0.2; MgCl2.6H2O: 0.2;
NaH2PO4: 0.05; NaHCO3: 1, and glucose: 2.0 g/dL). The
Tyrode solution was maintained at 37 oC.
2.2.2.5. 5-[(4-Methoxyphenylamino)methylene]pyrimidine-
2,4,6-trione (19)
The submaximal dose of histamine was estimated to be
2.63 x 10-3 M and taken as control (100% agonist effect).
Yield: 56%, mp: > 300oC. IR (cm-1): 3418 (NH); 3067
(=C-H); 1705 (C=O); 1581(C=N); 1513 (C=C); 1H-NMR (ꢀ
ppm): 3.71 (s, 3H, OCH3); 7.22 (d, J=6.1,2H, Ar-H); 7.48 (d,
J=6.2Hz, 1H, Ar-H); 8.51 (d, J=6.1Hz, 1H, -C=CH); 10.82
(s, 1H, -NH D2O exchangeable), 10.96 (s, 1H, -NH D2O
exchangeable); 11.88 (d, 1H, -NH D2O exchangeable
J=14.1),. Anal. Calcd for C12H11N3O4 (261.23): C, 55.17; H,
4.24; N, 16.09. Found: C, 55.50; H, 3.95; N, 16.21.
The maximum % inhibition of histamine induced con-
tractions (Imax), for acrivastine and the test new compounds
were measured at the submaximal dose level of 10- 3 M.
The % inhibition, for each agent was calculated from the
difference in heights induced by histamine in absence and
presence of the test agent. Each assigned submaximal dose
was added into the organ bath two min prior to histamine
challenge.
2.2.2.6. 5-[(Phenylamino)methylene]pyrimidine-2,4,6-
trione (20)
The partition coefficient [C log P] for the newly synthe-
sized compounds compared with the anti-histaminic acri-
vastine 22 was calculated by applying the procedure de-
scribed by Leo [10] in 1993, where log P values of the com-
pounds could be computed using a routine method "calcu-
lated log P" included in pc-soft ware package (Mac log P
2.0. Bio Byte Corp. CA, USA). A representation of the mo-
lecular structure, where hydrogens would be omitted or sup-
pressed (SMILES notation) could be introduced into the pro-
gram, which would compute the log P based on the fragment
method.
Yield: 63%, mp: 301-302 oC. IR (cm-1): 3428 (NH); 3054
(=C-H); 1687 (C=O); 1594(C=N); 1521 (C=C); 1H-NMR (ꢀ
ppm): 7.28 (d, J=6.3Hz, 2H, Ar-H); 7.31(t, J=6.3Hz, 1H,
Ar-H); 7.36 (t, J=6.3Hz, 2H,Ar-H); 8.24 (d, J=6.2Hz,1H,
-C=CH); 10.26 (bs, 3H, NH, D2O exchangeable). Anal.
Calcd for C11H9N3O3 (231.21): C, 57.14; H, 3.92; N, 18.17.
Found: C, 57.14; H, 3.92; N, 18.17.
2.2.2.7. 5-[(p-Tolylamino)methylene]pyrimidine-2,4,6-
trione(21)
Yield: 59%, mp: 305-307 oC .IR (cm-1): 3434 (NH); 3086
(=C-H); 1699(C=O); 1597(C=N); 1H-NMR (ꢀ ppm): 2.47 (s,
3H, CH3); 7.24 (d, J=6.1Hz, 2H, Ar-H); 7.26 (d, J=6.2 Hz,
1H,Ar-H); 8.51 (d, J=6.1Hz,1H, -C=CH); 10.90 (bs, 3H,
NH, D2O exchangeable). Anal. Calcd for C12H11N3O3
(245.23): C, 58.77; H, 4.52; N, 17.13. Found: C, 58.87; H,
4.38; N, 17.02.
3. RESULTS AND DISCUSSION
3.1. Molecular Modeling
3.1.1. Generation of the Pharmacophore Model
The pharmacophore model was generated derived from a
training set containing 5 H1-antagonists (Fig. 2) and then
validated using a validation set containing 6 H1-antagonists
(Fig. 3) [12]. This model was made up of an aromatic or ꢀ-
ring system (Aro|PiR), a hydrophobic group (Hyd), a H-bond
donor (Don2) and a H-bond acceptor (Acc2) (Fig. 4). In the
derived model, the aromatic or ꢀ-ring system is associated
with the pyrimidine core of the H1-antagonists, the H-bond
donor corresponding to the pyrimidine N1 Hydrogen, the H-
bond acceptor corresponding to the pyrimidine C4 Oxygen
and a hydrophobic moiety which is attached to the
pyrimidine C5.
2.3. Pharmacology
Investigation of the antihistaminic activity for representa-
tives of the newly synthesized compounds has been assessed
through the process of histamine-induced spasms in isolated
segments of guinea pig ileum. Acrivastine (22) has been util-
ized as reference drug (Fig. 5). The investigation conformed
to the guide for the Care and Use of Laboratory Animals
published by US National Institute of Health (NIH Publica-
tion No. 83-23, revised 1996). The Local Ethics Committee
approved this study.
Using this pharmacophore model, the designed com-
pounds (15-21) (Fig. 5) were mapped in order to confirm
that these compounds are capable of binding to the H1-
receptor with a similar set of interactions. Mapping of com-
All new compounds 15- 20 and 21 were tested for their
antihistaminic activity. Acrivastine (22) was donated by
Glaxo-Welcome pharmaceutical company, Elsalam City,

70 Medicinal Chemistry, 2014, Vol. 10, No. 1
Rasha Y. Elbayaa
Table 1. RMSD Values of Compounds 15-21
Compound
RMSD (Å)
15
16
17
18
19
20
21
0.6350
0.6302
0.6302
0.6306
0.6299
0.6310
0.6328
Table 2. MolDock Score and H-bond Score of the Docked
Compounds
Compound
MolDock Score
H-bond score
Acrivastine (22)
1
-83.23
-89.43
-108.67
-92.24
-94.61
-75.91
-86.82
-97.12
-88.24
-88.96
-87.42
-107.98
-101.81
-101.67
-102.15
-106.31
-95.78
-106.57
-150.21
-2.72
-1.15
-1.69
-5.79
-0.13
-11.75
-4.64
-4.51
-3.34
-2.69
-1.17
-3.15
-2.59
-2.92
-2.79
-2.90
-2.94
-3.77
-2.71
2
3
4
5
6
7
8
9
10
11
15
16
15
17
18
Fig. (6). Binding of Acrivastine (22) and compound 15 to the H1-
receptor homology model.
19
20
21
studies using Molegro Virtual Docker (MVD) version
2010.4.0.2 [12].
The H1-receptor homology model was built by submit-
ting the amino acids sequence of H1-receptor obtained from
GenBank [13, 14] (protein code: EAW64092.1) was submit-
ted to SWISS-MODEL server [15, 16].
Acrivastine (22)
pounds 15-21 on the pharmacophore model showed good
fitting with low RMSD between the model feature and their
matching ligand target points (Table 1). Afterwards, the in-
teractions between compounds 1-11, 15-21 and H1-receptor
were studied using molecular docking.
Compounds 1-11, 15-21 and Acrivastine (22) were then
docked inside the binding site of the H1-receptor homology
model. The MolDock score and H-bond scores of the docked
compounds are presented in (Table 2). The results showed
that compounds 15-21 had good docking scores with H-bond
scores comparable to or higher than Acrivastine. The binding
of Acrivastine (22) and compounds 15 to the H1-receptor
homology model are shown in (Fig. 6).
3.1.2. Molecular Docking Study
In the present study, an attempt was made to investigate
the ligand-receptor interactions of compounds 1-11, 15-21
against H1-receptor homology model, by performing docking

Design and Evaluation of Aminomethylenepyrimidines
Medicinal Chemistry, 2014, Vol. 10, No. 1 71
Scheme 1.
Table 3. Establishment of the Submaximal Inhibitory Dose for Acrivastine (22) in Relevance to the Effects Obtained for the Test
Newly Synthesized Compounds a, b
M
Cpd
10-6
10-5
10-4
10-3
10-2
15
33.3 0.33
6.6 0.33
5.0 0.57
0.0 0.00
25.0 0.33
17.2 0.33
20.0 0.33
16.6 0.57
75.5 0.57
26.0 0.33
10.0 0.33
22.2 0.33
45.0 0.57
18.0 0.57
44.4 0.57
27.0 0.33
81.9 0.57
54.2 0.57
28.9 0.57
55.5 0.57
64.3 0.33
20.7 0.33
66.0 0.33
55.0 0.57
90.0 0.57
66.0 0.33
55.5 0
100.0 0.57
88.0 0.33
77.8 0
16
17
18
75.0 0.57
75.5 0.57
25.0 0.57
80.0 0.57
100.0 0
95.1 0.33
100.0 0.57
29.1 0.57
100. 0 0.57
100. 0 0
19
20
21
Acrivastine
a Data are presented as molar concentrations (M) and are average of five replicates standard error of the mean.
b Histamine effect was produced using the histamine submaximal dose-agonist response.
3.2. Chemistry
groups as well as for the D2O exchangeable proton of the NH
functions.
The general synthetic strategy employed to obtain the
target compounds is depicted in Scheme 1.
The structures for all new compounds have been substan-
1
tiated by elemental analyses, IR and by H-NMR spectra.
It describes the synthesis of 5-substituted aminomethyle-
nepyrimidine-2,4,6-triones (15-21) through amination of the
key intermediate 5-ethoxymethylene-2,4,6-trione (14), ob-
tained from the condensation of pyrimidine-2,4,6-trione
(barbituric acid) (12) with triethyl orthoformate (13) [9].
Both analytical and spectral data of all the compounds are in
full agreement with the proposed structures. Moreover, com-
parison of the spectroscopic data of the new compounds with
those of the previously reported analogs further confirmed
the above structures.
The IR spectra for all compounds 15-21 displayed
stretching absorption bands at the expected regions of NH,
and C=O groups.
3.3. Biological Screening
Investigation of the antihistaminic activity for representa-
tives of the newly synthesized compounds has been assessed
through the process of histamine-induced spasms in isolated
segments of guinea pig ileum [17-19]. Acrivastine (22) has
been utilized as reference drug.
1
The H-NMR spectra for compounds 15-21 lacked the
triplet and quartet of the ethyl group present in the parent
compound 14 [9], but exhibited signals corresponding to the
existing CH3, CH2, methylene CH and / or regular CH

72 Medicinal Chemistry, 2014, Vol. 10, No. 1
Rasha Y. Elbayaa
150
15
16
17
18
19
20
100
50
21
acrivastine(22)
0
-7
-6
-5
-4
-3
-2
-1
Concentration (LogM)
Fig. (7). The log dose-response curve of the tested newly synthesized pyrimidine -2,4,6-trions (15-21) in relevance to acrivastine (22).
100
15
16
17
18
19
20
21
80
60
40
20
0
acrivastine
Tested compounds
Fig. (8). Histogram illustrating the blocking effects of acrivastine and the test newly synthesized compounds; upon using the histamine –
submaximal dose agonist - response.
Table 4. Comparison between the Maximum % Inhibition of
Compounds 15- 19, and 21 showed promising activity
Histamine Induced Contractions (Imax) for Acri-
among the newly synthesized compounds.
a, b, c
vastine
and the Test Newly Synthesized Com-
Different dose levels (10-6-10-2 M) of acrivastine and the
test new compounds were used for establishement of sub-
maximal inhibitory doses (Table 3) and for construction of
log dose-response curves (Fig. 7).
pounds; Together with Comparative Study for the
Data of C log Pd Computed Values
Cpd
Imax SEM
C log Pd
The maximum % inhibition of histamine induced con-
tractions (Imax), for acrivastine and the new compounds were
measured at the submaximal dose level of 10- 3 M (Table 4).
The C log P values, for each, are also listed in (Table 4); in
order to validate the new assumption within the present in-
vestigation concerning the ability for crossing the blood
brain barrier (BBB) [20]. The % change of histamine agonist
responses for acrivastine and the test new compounds at the
assigned submaximal dose levels are also represented as his-
togram (Fig. 8).
Acrivastine
100.0 0
90.0 0.57
66.0 0.33
55.5 0
4.34
0.86
2.10
1.95
1.04
1.04
0.94
1.44
15
16
17
18
19
20
21
75.0 0.57
75.5 0.57
25.0 0.57
80.0 0.57
All test new compounds displayed lower C log P values
when compared with the reference drug acrivastine.
The applied in vitro investigation revealed decrement
responses, for histaminergic (H1) activity, at submaximal
dose levels of 10-3 M, in the order of acrivastine 22(100%) >
15 (90.0%) > 21 (80.0%) > 19 (75.5%) > 18 (75.0%) > 16
(66.0%) >17 (55.5%) >20 (25.0%) (Table 4).
adoses used were the submaximal concentrations obtained from (Table 4).
bdata were presented as mean value of five replicates
standard error of the
mean(SEM).
cHistamine effect was produced using the histamine submaximal dose-agonist
response.
dcalculated log partition coefficient.

Design and Evaluation of Aminomethylenepyrimidines
Medicinal Chemistry, 2014, Vol. 10, No. 1 73
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CONCLUSION
The aim of the present study was to synthesize and inves-
tigate the H1-blocking activity of 5-substituted aminomethyl-
enepyrimidine-2,4,6-triones with the hope of discovery new
structural leads serving as anti-histaminics. MOE based mo-
lecular docking results showed that compounds 15-21 had
better docking scores with H-bond scores comparable to or
higher than acrivastine. Also, the obtained in-vitro testing
results revealed that compounds 15, 18, 19, and 21 exhibited
moderate to considerable antihistaminic activity when using
isolated segments from guinea pig ileum. In addition, their C
log P values were lower than the reference drug. These facts
would suggest that such compounds might be effective in
blocking H1 receptors with less liability to cross the BBB.
[6]
[7]
[8]
[9]
[10]
[11]
Consequently, 5-substituted aminomethylenepyrimidine-
2,4,6-triones would represent a promising template for the
design of new class of non-sedating H1 antihistaminic agents.
Computing
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Montreal,
Quebec,
Canada.
http://www.chemcomp.com
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CONFLICT OF INTEREST
Benson, D. A.; Karsch-Mizrachi, I.; Lipman, D. J.; Ostell, J.;
Wheeler, D. L. GenBank. Nucl. Acids Res., 2005, 33 (suppl 1),
D34-38.
The authors confirm that this article content has no
conflict of interest.
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National
Center
for
Biotechnology
Information.
http://www.ncbi.nlm.nih.gov/.
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ACKNOWLEDGEMENTS
Declared none.
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Received: January 07, 2012
Revised: July 15, 2013
Accepted: July 15, 2013