Synthesis, antihistaminic action and theoretical studies of (4-methoxybenzyl)(1,4,5,6-tetrahydropirimidin-2-yl)amine hydroiodide

Article abstract of DOI:10.1007/s11164-012-0813-5

In this study, (4-methoxybenzyl)(1,4,5,6-tetrahydropyrimidin-2-yl)amine hydroiodide (2) was synthesized by reaction of 2-methylmercapto-1,4,5,6- tetrahydropyrimidine hydroiodide (1) and 4-methoxybenzylamine. The synthesized compound was tested for its in vitro H1-antihistaminic activity on guinea pig trachea. A promising bronchorelaxant effect of 2 was observed in histamine-contracted guinea pig tracheal chain via H1 receptor antagonism. In addition, the molecular geometry and gauge including atomic orbital (GIAO) ¹H chemical shift values of the title compound in the ground state were calculated using the density functional method (DFT/UB3LYP) and Hartree-Fock (HF) approach using 6-311G+(d), 6-311G+(d,p), LANL2DZ, DGDZVP, and DGDZVP2 basis sets and compared with the experimental data. According to the experimental and theoretical results, HF/6-311G+(d) showed a better fit to experimental values in evaluating ¹H-nuclear magnetic resonance (NMR) chemical shift values. Theoretical studies supported our findings, revealing the N₁₂ atom as the most nucleophilic. In addition, other structures of the compound such as the aromatic ring and OCH₃ group increased this property.

Full text of DOI:10.1007/s11164-012-0813-5

Res Chem Intermed
DOI 10.1007/s11164-012-0813-5
Synthesis, antihistaminic action and theoretical studies
of (4-methoxybenzyl)(1,4,5,6-tetrahydropirimidin-2-yl)
amine hydroiodide
•
•
•
Murat Genc Engin Yılmaz Selcuk Ilhan
Zuhal Karagoz
Received: 5 June 2012 / Accepted: 28 July 2012
Ó Springer Science+Business Media B.V. 2012
Abstract In this study, (4-methoxybenzyl)(1,4,5,6-tetrahydropyrimidin-2-yl)
amine hydroiodide (2) was synthesized by reaction of 2-methylmercapto-1,4,5,
6-tetrahydropyrimidine hydroiodide (1) and 4-methoxybenzylamine. The synthe-
sized compound was tested for its in vitro H1-antihistaminic activity on guinea pig
trachea. A promising bronchorelaxant effect of 2 was observed in histamine-con-
tracted guinea pig tracheal chain via H1 receptor antagonism. In addition, the
1
molecular geometry and gauge including atomic orbital (GIAO) H chemical shift
values of the title compound in the ground state were calculated using the density
functional method (DFT/UB3LYP) and Hartree–Fock (HF) approach using
6–311G?(d), 6–311G?(d,p), LANL2DZ, DGDZVP, and DGDZVP2 basis sets and
compared with the experimental data. According to the experimental and theoretical
results, HF/6–311G?(d) showed a better fit to experimental values in evaluating
1H-nuclear magnetic resonance (NMR) chemical shift values. Theoretical studies
supported our findings, revealing the N12 atom as the most nucleophilic. In addition,
other structures of the compound such as the aromatic ring and OCH3 group
increased this property.
M. Genc (&)
Department of Chemistry, Faculty of Science and Arts, Adiyaman University,
02040 Adiyaman, Turkey
e-mail: mgenc23@gmail.com
E. Yılmaz
Department of Chemistry, Faculty of Science and Art, University of Bitlis Eren,
13800 Bitlis, Turkey
S. Ilhan
Department of Pharmacology, Faculty of Medicine, University of Firat, 23119 Elazig, Turkey
Z. Karagoz
Department of Chemistry, Faculty of Science, University of Firat, 23119 Elazig, Turkey
123

M. Genc et al.
Keywords 2-Amino-1,4,5,6-tetrahydropyrimidines Á Antihistaminic effect Á
Hartree-Fock
Introduction
Pyrimidine and its derivatives belong to the family of nucleic acids. Pyrimidine-
containing compounds have been of considerable interest in the field of medicinal
chemistry, e.g., as inhibitors of human nitric oxide synthase isoforms, calcium
channel blockers, antihypertensives, anti-inflammatory agents, analgesics, and avb3
antagonists, and in the treatment of intestinal disorders, as well as demonstrating
antibacterial, antifungal, and anti-human immunodeficiency virus (HIV) activities
[1–8]. Specifically, drugs containing a pyrimidine with an oxygen in the 5-position
have found a wide range of applications in several therapeutic areas. Hirabayashi
et al. [9] found that imidazo[1,2-c]pyrimidine derivatives potently inhibit the Syk
family of kinases. Also, pyridopyrimidines are bioactive nitrogen heterocyclic
compounds, and several of their substituted derivatives have been associated with
diverse immunopharmacological activities such as analgesic, anti-inflammatory,
antiallergic, antiplatelet aggregatory, and antihistaminic actions [10–20].
The prevalence of asthma and other allergic diseases is increasing, providing a
rapidly expanding market for antiallergic drugs. First-generation antihistamines
penetrate the blood–brain barrier, and also possess anticholinergic properties, which
led to the development of a second generation of H1-antagonists, such as
terfenadine, cetirizine, and astemizole [21]. A common feature of first-generation
compounds is two aryl or heteroaryl rings linked to an aliphatic tertiary amine via
the side chain (e.g., diphenhydramine and pheniramine) [22], and second-generation
compounds (terfenadine and cetirizine) also contain many of the structural features
of first-generation compounds. The real breakthrough in nonsedative antihistamines
came in the early 1980s when modern antihistamines were discovered, being found
to exhibit potent antihistaminic activity without sleep-inducing effect [23]. This new
generation of H1-antihistamines containing condensed heterocycles (e.g., lorata-
dine, azelastine, and flazelastine) and lacking the above-mentioned pharmacophore
led to the discovery of many novel antihistamines such as temelastine and
mangostin [24, 25].
Prediction of the molecular and spectroscopic properties of molecules is an
important part in the design process. One of the most widely used methods to
calculate ground-state geometries in computational chemistry is density functional
theory (DFT). It is known that the absorption spectrum is related to the molecular
structure, and a relationship between the absorption maximum and the structure is
much desired. To achieve this, the experimental spectrum can be compared with the
calculated one. The extension of DFT to excited states is known as time-dependent
density functional theory (TD-DFT) and has been used to describe the optical and
spectroscopic properties of medium-sized and large molecules [26–30].
The localized Hartree–Fock (LHF) method, which is applied for the calculation
of NMR shielding constants in this study, represents an efficient and effective, exact
exchange method that is self-interaction free by construction, therefore leading to
123

Synthesis, antihistaminic action and theoretical studies
improved orbital energy spectra [31, 32]. Moreover, unlike the parent Hartree–
Fock method and hybrid functionals, it provides a local potential and thus allows
for efficient calculation of NMR shielding constants without the need to solve
the coupled Kohn–Sham equations if, as usual, current dependencies are neglected
[33].
The antihistaminic action and theoretical calculations of 2-amino-1,4,5,6-
tetrahydropyrimidine compounds have not been described in the literature to date.
The aim of this study is to synthesize (4-methoxybenzyl)(1,4,5,6-tetrahydropyr-
imidin-2-yl)amine hydroiodide and investigate its quantum parameters and antihis-
taminic properties.
Experimental
Instrumentation and chemicals
All reagents and solvents were obtained from commercial suppliers and were used
without further purification. Histamine was purchased from Sigma Aldrich Inc. (St.
Louis, MO, USA). Infrared (IR) spectrum was determined on a PerkinElmer
Spectrum One Fourier-transform infrared (FT-IR) spectrometer. NMR spectra were
recorded on a Bruker 300-MHz spectrometer. Melting point (uncorrected) was
determined with the the Stuart SMP 30 apparatus.
In this study, five guinea pigs were used. Guinea pigs (300–400 g) were procured
from Firat University Experimental Research Institute. Animals were maintained
under regulated environmental conditions (temperature 24 2 °C, humidity
50–80 %, 12 h light/dark cycle) and provided with pelleted rodent feed and water
ad libitum. The Institution of Firat university experimental research Animal Ethics
Committee approved the animal experiments.
Preparation of 2-methylmercapto-1,4,5,6-tetrahydropyrimidine hydroiodide
1,4,5,6-Tetrahydropyrimidine-2-thione (0.01 mol) and methyl iodide (0.01 mol) in
50 mL methanol were left at ambient temperature in a closed flask for 48 h. Then
the mixture was heated under reflux for 6 h. The solvent was removed by
evaporation; oily residue was cooled and triturated with diethyl ether. The crude
product was collected, and washed with cold ethanol [34, 35].
Synthesis of (4-methoxybenzyl)(1,4,5,6-tetrahydropyrimidin-2-yl)amine
hydroiodide
A solution of 4-methoxybenzylamine (2 mmol) and 2-methylmercapto-1,4,5,6-
tetrahydropyrimidine hydroiodide (1 mmol) in methanol (15 ml) were stirred at
room temperature. The mixture was refluxed for 8 h. The mixture was then poured
into diethyl ether, and the precipitate obtained was filtered, dried, and recrystallized
from ethanol.
123

M. Genc et al.
N
SH
N
H
M-OH
rt,48h
CH3I
N
N
M-OH
N
+
NH2
H3CO
H3CO
H
.
reflax, 8h
HI
SCH3
.
HI
HN
N
H
1
2
Scheme 1 Synthesis of (4-methoxybenzyl)(1,4,5,6-tetrahydropyrimidin-2-yl)amine hydroiodide
Caution
Noxious gas CH3SH is evolved during the synthesis and should be trapped with a
concentrated aqueous solution of NaOH and then destroyed with sodium
hypochlorite.
Colorless; mp.: 150–153 °C; IR (near, cm-1) mmax: 3150, 3004, 2998, 2909,
1
2986, 1638, 1610, 1254; H-NMR (300 MHz, CHCl3-d): 1.95 (m, 2H, pyrimidine
CH2), 3.36 (m, 4H, pyrimidine N–CH2), 3.82 (s, 3H, OCH3), 4.38 (s, 2H, benzylic
CH2), 6.75 (br, 1H, NH), 6.91 (d, J: 8.4 Hz, 2H, Ar–H), 7.33 (d, J: 8.7 Hz, 2H, Ar–
H), 7.49 (1H, ?NH). 8.00 (br, 1H, NH); 13C-NMR (75 MHz, CHCl3-d): 159.89,
130.95, 129.25, 126.24, 114.48, 55.73, 55.67, 42.28, 38.60; Anal. calcd. for
C12H18IN3O (347.20): C, 41.51; H, 5.23; N, 12.10;. Found: C, 41.59; H, 5.38; N,
12.17 (yield 57 %). (Scheme 1)
Determination of smooth muscle relaxant activity
Trachea (cleaned of adherent fat and connective tissue) was removed from guinea
pigs and put into a Petri dish containing Krebs–Henseleit solution prewarmed to
37 °C. The tracheal chain was then mounted under initial tension of 2 g in the organ
bath filled with Krebs–Henseleit solution maintained at 37 °C. The pH of the buffer
was maintained at 7.4 by continuous aeration of the organ bath with 95 % O2/5 %
CO2 mixture. The strip was allowed to equilibrate for 1 h and rinsed every 15 min
with buffer. After the equilibration period, contraction was elicited by addition of
histamine to the bath volume (submaximal effect). The maximum effect was
observed with 1.25 mM histamine (cumulative). Pyrimidine solutions were added
from 1 9 10-9 to 1 9 10-1 M. The mean values of relaxation were recorded.
Computational procedure
In the first step of the calculation, the potential energy surface (PES) of the molecule
was obtained by performing a relaxed scan of dihedral angles using the
semiempirical method at the PM3 level of theory. Geometrical parameters of this
123

Synthesis, antihistaminic action and theoretical studies
structure were further optimized by using density functional theory and HF methods
on the basis of the lowest energy conformer: the potential energy curve (PES) of
molecule was obtained performing a relaxed scan of a, b, c dihedral angles at
semiempiric method PM3 level of theory, respectively. For each curve, the
stationary points were confirmed by frequency analysis as minima with all-real
frequencies and no imaginary frequency, implying no transition state. For the lowest
energy conformer, the geometric structure was reoptimized at the HF and DFT
levels.
c
b
HN
HN
a
N
O
CH3
The HF method seemed to be more appropriate than the DFT method for
1
calculation of H-NMR chemical shifts (data for DFT methods not presented in
text). Calculations of nuclear shielding of carbons were performed using the
GAUSSIAN 09 program with the DFT functional and different basis sets:
6–311G?(d), 6–311G?(d,p) LANL2DZ, DGDZVP, and DGDZVP2. 1H-NMR
chemical shifts were calculated within the GIAO approach by applying the same
methods and basis set as used for geometry optimization.
Results and discussion
Comparing the calculations and the experimental data, the energy values of exo-NH
and endo-NH salts were examined to find the most appropriate structure of the
molecule. The lowest energy value was observed for the endo-NH salt (exo-NH,
-668.005; endo NH, -668.152 hartrees). The experimental data are shown and the
occurrence of NH salt because pyrimidines N-CH2 protons have same chemical shift
1
in H-NMR. We studied relationship between the calculation and the experimental
data and obtained the following linear formulae: y = 0.831x ? 0.336 (r2 = 0.603)
for 6–311G?(d), y = 0.812x ? 0.228 (r2 = 0.596) for 6–311G?(d,p), y =
0.928x - 1.346 (r2 = 0.601) for LANL2DZ, y = 0.812x - 0.203 (r2 = 0.553) for
DGDZVP, and y = 0.868x - 0.024 (r2 = 0.599) for DGDZVP2. According to these
1
results, the HF/6311G?(d) method has shown better fit to experimental for H
chemical shifts.
1
Theoretical and experimental H-NMR values for (4-methoxybenzyl)(1,4,5,6-
tetrahydropyrimidin-2-yl)amine hydroiodide are presented in Table 1 and Fig. 1.
The calculated results show that the N12 atom has the largest negative charge along
with its suitable spatial configuration in HF/6–311G?(d), making it a potential site
for reaction with metallic cores. Possibility of protonation of the N12 atom is the
highest. Seeing in Fig. 1 has shown that 6–311G?(d) more suitable for real data for
1H-NMR.
123

M. Genc et al.
Experimental
Table 1 Theoretical and experimental 1H-NMR values
6–311(d)
6.311(d,p)
LANL2DZ
DGDZVP
DGDZVP2
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
7.27
7.69
7.87
8.02
2.74
2.41
6.97
7.49
7.63
7.82
2.58
2.30
6.27
7.19
6.97
7.19
1.30
1.17
6.70
7.18
7.29
7.53
2.05
1.85
7.29
7.74
7.82
8.18
2.52
2.24
6.91
6.91
7.33
7.33
4.34
4.34
8.00
7.49
3.82
3.82
3.82
6.75
3.36
3.36
1.95
1.95
3.36
3.36
3.85
3.85
4.25
3.85
3.35
3.35
3.27
1.97
1.97
3.27
3.35
3.57
3.57
4.01
3.57
3.16
3.16
3.16
1.88
1.88
3.07
3.16
2.80
2.58
3.08
2.58
1.73
1.84
1.84
0.55
0.55
1.95
1.95
2.97
3.20
3.57
3.20
2.33
2.83
2.83
1.36
1.36
2.69
2.74
3.49
3.49
3.81
3.49
3.22
3.04
3.04
1.89
1.89
3.04
3.04
Figure 2 shows the atom numbering scheme adopted in this study for (4-
methoxybenzyl)(1,4,5,6-tetrahydropyrimidin-2-yl)amine hydroiodide.
The Mulliken charges of (4-methoxybenzyl)(1,4,5,6-tetrahydropyrimidin-2-
yl)amine hydroiodide are shown in Fig. 3, while Fig. 4 shows the total electron
contours of the compound.
Figure 5 shows the highest occupied molecular orbital (HOMO)-1, HOMO,
lowest unoccupied molecular orbital (LUMO), and LUMO?1 orbitals of 2, calculated
at the HF/6–311G?(d) level. The occupied orbitals (HOMO-1 and HOMO) of 2 have
a large contribution from the NH group, OCH3 group, and aromatic ring. In addition,
the HOMO and LUMO values of the compound are -0.18476 and -0.28414 hartrees,
respectively.
In our study, the (4-methoxybenzyl)(1,4,5,6-tetrahydropyrimidin-2-yl)amine
hydroiodide compound was synthesized and evaluated for its antihistaminic effect
on guinea pig trachea. The isolated guinea-pig trachea pre-contracted with histamine
was used to study the relaxation of the test material. The isolated constituent, (4-
methoxybenzyl)(1,4,5,6-tetrahydropyrimidin-2-yl)amine (2) caused 80 % relaxa-
tion of maximal contraction produced by histamine at a concentration of 1,25 mg/
ml (cumulative). Relaxant effect of compound (2) on contractions of guinea
pig tracheal chains induced by histamine with an EC50 of 3.01 9 x10-5
M
(Fig. 6).
123

Synthesis, antihistaminic action and theoretical studies
Chemical shift HF 6-311 (d,p) y= 0,812X+0,228 r2=0,596
Chemical shift HF 6-311 (d) y= 0,831X+0,336 r2=0,603
10
10
8
6
4
2
0
8
6
4
2
0
0
2
4
6
8
0
2
4
6
8
Experimental (ppm)
Experimental (ppm)
Chemical shift HF DGDZVP y= 0,812X-0,203 r2=0,553
Chemical shift HF LANL2DZ (d,p) y= 0,928X-1,346 r2=0,601
8
8
6
4
2
0
6
4
2
0
0
2
4
6
8
0
2
4
6
8
Experimental (ppm)
Experimental (ppm)
Chemical shift HF DGDZVP2 y= 0,868X-0,024 r2=0,599
10
8
6
4
2
0
0
2
4
6
8
Experimental (ppm)
Fig. 1 1H-NMR data theoretical and experimental values of compound 2
Histamine is an important mediator of airway smooth muscle contraction, and bronchial
obstruction occurs via H1-receptors. H1-receptor blockade results in bronchodilation
[36–38]. The presented data indicate a relaxant effect of (4-methoxybenzyl)(1,4,5,
6-tetrahydropyrimidin-2-yl)amine hydroiodide on histamine-contracted isolated guinea
pig tracheal smooth muscle, possibly via histamine H1-receptor antagonistic activity.
These results are comparable to those of promethazine, which is known as an H1-receptor
antagonist [39]. The present findings reveal that compound (2), via its H1 antihistaminic
nature, has potential activity to increase the threshold for bronchoconstriction, leading to
bronchodilation.
123

M. Genc et al.
Fig. 2 Atom numbering scheme for compound 2
Fig. 3 Mulliken charges of
compound 2
Theoretical studies showed that the NH group, OCH3 group, and aromatic ring
play critical roles in the antihistaminic activity. The endo-nitrogen atom, however,
significantly contributed to the HOMO of the compound, suggesting that it is an
additional nucleophilic site for activity.
123

Synthesis, antihistaminic action and theoretical studies
Fig. 4 Total electron contours map of compound 2
Fig. 5 Calculated orbital population from HOMO-1 to LUMO?1 of compound 2
These calculations also indicate that the nucleophilic property of 2-amino-
1,4,5,6-tetrahydropyrimidines is a critical feature for the antihistaminic activity of
these compounds.
It can be suggested that the relaxant effect of the title compound on histamine-
induced tracheal contraction may be via its antihistaminic effect.
123

M. Genc et al.
Fig. 6 The relaxant effect of test materials on contractions of guinea pig tracheal chain induced by
histamine (1.25 mM cumulative). EC50 = 3.01 X 10–5
M
Acknowledgments We are indebted to the Adiyaman University Research Foundation (FEFBAP2010/
004) for financial support of this work. The authors would like to thank Assist. Prof. Dr. Halil Berber from
Anadolu University, Faculty of Science, Department of Chemistry for providing Gaussian 09W software
(Gaussian 09, rev. B.01, version EM64T/Linux).
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