Antihypertensive activity of newer 1,4-dihydro-5-pyrimidine carboxamides: Synthesis and pharmacological evaluation

Article abstract of DOI:10.1016/j.ejmech.2010.08.022

A number of 5-(4-substituted phenyl)-2-(substituted benzylsulfanyl)-4- (substituted phenyl)-6-methyl-1,4-dihydro-5-pyrimidine carboxamides (1-30) were designed and synthesized keeping in view the structural requirements as suggested in the pharmacophore model for antihypertensive activity. All the synthesized compounds were tested for antihypertensive activity by non-invasive blood pressure (NIBP) measurements (tail-cuff method) in rats. Almost all the tested compounds displayed considerable decrease in the blood pressure as compared to control. Thirteen compounds showed significant antihypertensive activity comparable to the standard drug nifedipine.

Full text of DOI:10.1016/j.ejmech.2010.08.022

European Journal of Medicinal Chemistry 45 (2010) 5113e5119
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Antihypertensive activity of newer 1,4-dihydro-5-pyrimidine carboxamides:
Synthesis and pharmacological evaluation
*
Ozair Alam , Suroor A. Khan, Nadeem Siddiqui, Waquar Ahsan, Suraj P. Verma, Sadaf J. Gilani
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, Hamdard Nagar, New Delhi 110062, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of 5-(4-substituted phenyl)-2-(substituted benzylsulfanyl)-4-(substituted phenyl)-6-methyl-
1,4-dihydro-5-pyrimidine carboxamides (1e30) were designed and synthesized keeping in view the
structural requirements as suggested in the pharmacophore model for antihypertensive activity. All the
synthesized compounds were tested for antihypertensive activity by non-invasive blood pressure (NIBP)
measurements (tail-cuff method) in rats. Almost all the tested compounds displayed considerable
decrease in the blood pressure as compared to control. Thirteen compounds showed significant anti-
hypertensive activity comparable to the standard drug nifedipine.
Received 5 February 2010
Received in revised form
6 August 2010
Accepted 10 August 2010
Available online 14 August 2010
Keywords:
Ó 2010 Elsevier Masson SAS. All rights reserved.
Dihydropyrimidine
Dihydropyridine
DOCA-salt
Antihypertensive activity
1. Introduction
In light of these facts, we designed our compounds keeping in
view the suggested pharmacophore model for better antihyper-
Hypertension remains a major health problem in most countries
because of its impact on the mortality and morbidity of patients.
Indeed, hypertension accounts for more than 5.8% of total deaths,
1.9% of years of life lost and 1.4% disability adjusted life years all
over the world [1]. Therefore, hypertension prevention and control
in the community is currently a pivotal challenge.
tensive agents as suggested by Rovnyak et al. [7]. The present work
describes the synthesis of newer 1,4-dihydropyrimidine (DHPM)
derivatives that are substituted by different benzyl groups on the 2-
thioxo position and an aryl ring linked via an amide bond to the C-5
carboxy functionality.
The present popularity of dihydropyrimidine (DHPM) is mainly
due to their close structural relationship to the clinically important
dihydropyridine (DHP) calcium channel blockers such as nifedipine,
which are most studied class of medicinal compound since their
introduction and have become immensely important for the treat-
ment of hypertension [2]. DHPMs have been identified as a lead and
found to be more potent as well as long lasting derivatives in
spontaneously hypertensive rats. The traditional SAR is a useful tool
in search for new drugs and therefore SAR analogy has played a vital
rolein designing compoundswith higher potency [2e4]. One of such
structural analogy has been noticed between DHP and DHPM.
In the past decades, a broad range of biological effects, including
antiviral, anticancer, antibacterial and antihypertensive activity has
been ascribed to the DHPM derivatives and few of them have even
emerged as orally active antihypertensive agents [5,6].
2. Chemistry
The synthesis of titled compounds (1e30) was carried out
according to Scheme 1. Ethylacetoacetate was refluxed with
substituted anilines using toluene as solvent in basic conditions to
yield oxobutyramides that were used as 1,3-diketone adducts for
multicomponent Biginelli reaction. These were condensed with
thiourea and substituted benzaldehydes in presence of concen-
trated hydrochloric acid to get pyrimidine carboxamides. The
reaction time was found to vary from 7 to 9 h depending upon the
substitution on aryl aldehydes. In the final step, pyrimidine car-
boxamides were treated with substituted benzyl chlorides in
presence of potassium carbonate to afford the titled compounds
(1e30). The physicochemical properties of compounds are pre-
sented in Table 1.
3. Pharmacology
* Corresponding author. Tel.: þ91 11 26059688x5612.
All the synthesized compounds were tested for their antihy-
pertensive activity by non-invasive tail-cuff method. The animals
E-mail
addresses:
oalam@jamiahamdard.ac.in,
dr.ozairalam@gmail.com
(O. Alam).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.08.022

5114
O. Alam et al. / European Journal of Medicinal Chemistry 45 (2010) 5113e5119
Table 1
O
O
Physicochemical parameters of synthesized compounds (1e30).
R
H3C
NH2
+
O
CH3
Comp. R
R1
R2 Mol. formula (M.W.)a
Rfb
value
M.P.
(ꢁC)
%
Yield
(a)
1
2
3
4
5
4-F
3,4-
OCH3
3,4-
OCH3
3,4-
OCH3
3,4-
OCH3
3,4-
OCH3
4-NO2
4-NO2
H
C27H26FN3O3S (491.57) 0.61
212
218
176
207
204
61
71
59
54
66
NH
CH3
4-F
4-F
4-F
4-F
2- C27H25ClFN3O3S (526.02) 0.68
Cl
3- C27H25ClFN3O3S (526.02) 0.52
Cl
4- C27H25ClFN3O3S (526.02) 0.68
Cl
4-F C27H25F2N3O3S (509.56) 0.60
O
O
R
(I)
(b)
R1
6
7
4-F
4-F
H
C25H21FN4O3S (476.52) 0.74
215
167
69
52
R
2- C25H20ClFN4O3S (510.96) 0.78
O
Cl
8
9
4-F
4-F
4-F
4-NO2
4-NO2
4-NO2
3- C25H20ClFN4O3S (510.96) 0.75
Cl
4- C25H20ClFN4O3S (510.96) 0.62
Cl
225
222
62
48
NH
H3C
NH
N
S
H
10
11
4-F C25H20F2N4O3S (494.51) 0.71
234
149
71
73
(II)
(c)
4-Br 2,4-Cl
4-Br 2,4-Cl
4-Br 2,4-Cl
4-Br 2,4-Cl
4-Br 2,4-Cl
4-Br 4-OCH3
4-Br 4-OCH3 2- C26H23BrClN3O2S
Cl (556.90)
4-Br 4-OCH3 3- C26H23BrClN3O2S
Cl (556.90)
4-Br 4-OCH3 4- C26H23BrClN3O2S
Cl (556.90)
4-Br 4-OCH3 4-F C26H23BrFN3O2S (540.44) 0.64
4-
NO2
4-
NO2
4-
NO2
4-
NO2
4-
NO2
4-
NO2
4-
NO2
4-
H
C25H20BrCl2N3OS
(561.32)
0.52
0.67
0.69
0.77
0.65
12
13
14
15
2-
C
25H19BrCl3N3OS
188
151
162
187
63
68
57
51
Cl (595.76)
3- 25H19BrCl3N3OS
Cl (595.76)
4- 25H19BrCl3N3OS
Cl (595.76)
C
R1
R
C
O
4-F
C
25H19BrCl2FN3OS
(579.31)
C26H24BrN3O2S (522.45) 0.48
NH
N
16
17
H
222
146
45
57
0.52
0.56
0.67
H3C
N
S
R2
H
18
19
193
141
49
61
(1-30)
R = F, Br, NO2
R1 = 2,4-Cl, 4-Br, 3-NO2, 4-NO2, 3,4-OCH3, 4-OCH3
R2 = H, 2-Cl, 3-Cl, 4-Cl, 4-F
20
21
199
209
51
63
4-Br
H
C25H21BrN4O3S (537.42) 0.50
22
23
24
25
26
27
28
29
30
4-Br
2- C25H20BrClN4O3S
Cl (571.87)
3- C25H20BrClN4O3S
Cl (571.87)
4- C25H20BrClN4O3S
Cl (571.87)
0.64
0.69
0.78
211
186
201
223
216
169
220
188
192
61
58
54
64
69
51
62
53
62
Scheme 1. Reagents and conditions: (a) NaOH, EtOH, reflux, 5 h; (b) Thiourea,
substituted benzaldehydes, ethanol, conc. HCl, reflux, 7e9 h; (c) Substituted benzyl
chloride, DMF, K2CO3, reflux, 8e10 h.
4-Br
4-Br
4-Br
4-F C25H20BrFN4O3S (555.41) 0.75
were previously treated with Deoxycorticosterone Acetate salt
(DOCA-salt) that induces hypertension and the systolic blood
pressure was measured. The change in blood pressure due to the
synthesized compounds were noted and compared with that of
standard drug nifedipine.
3-NO2
3-NO2
3-NO2
3-NO2
3-NO2
H
C25H21N5O5S (503.52) 0.49
2- C25H20ClN5O5S (537.97) 0.51
Cl
3- C25H20ClN5O5S (537.97) 0.55
Cl
4- C25H20ClN5O5S (537.97) 0.69
Cl
4-F C25H20FN5O5S (521.52) 0.62
NO2
4-
NO2
4-
4. Results and discussion
NO2
4.1. Chemistry
a
Solvent of crystallization e ethanol.
Solvent system e toluene:ethyl acetate:formic acid (5:4:1).
b
All the synthesized compounds were obtained in good to high
yields that were purified and characterized by different spectroscopic
techniques. The IR spectra of compounds (1e30) showed character-
istic absorption bands at 3331e3307 cmꢀ1, 1678e1637 cmꢀ1, and
652e614 cmꢀ1 corresponding to the NeHstr, C]Ostr and CeSstr
functions in the structures. The formation of compounds was further
supported by disappearance of the IR band at 1210 cmꢀ1 due to the
C]S group and appearance of a new band at 652e614 cmꢀ1 due to
CeS bond.
The slightly upfield shift of methine (CH) protons present at C-4
position of 1,4-dihydropyrimidine ring was observed as a singlet at
5.07e5.18 ppm and is the most important diagnostic tool for titled
d
compounds (1e30).
The two multiplet regions were obtained at
d 6.52e6.89 and
d
7.01e7.94 ppm for aromatic protons. Further, two broad singlets
corresponding to NH (N-1 ring) and NH (carboxamides) were
obtained at 8.61e9.16 ppm and 9.64e10.10 respectively that
were D2O exchangeable.
d
d
The 1H NMR spectra of compounds (1e30) showed singlet at
d
2.21e2.32 ppm for CH3 proton. Methoxy protons were observed
as a singlet at 3.51e3.77 ppm. The singlet at 4.05e4.31 ppm was
assigned to the benzyl SCH2 proton.
The structures of compounds (1e30) were further supported by
their mass spectral data which showed presence of molecular ion
peak Mþ, M þ 1 and M þ 2 peaks at different m/z corresponding to
d
d

O. Alam et al. / European Journal of Medicinal Chemistry 45 (2010) 5113e5119
5115
Table 2
Antihypertensive activity data shown by compounds (1e30) at 10 mg/kg dose.
Compound
Average systolic blood pressure (mmHg) at time (min)
0
15
30
60
120
180
240
300
360
600
720
900
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
195 ꢂ 2
194 ꢂ 1
194 ꢂ 2
193 ꢂ 2
193 ꢂ 1
194 ꢂ 3
195 ꢂ 1
195 ꢂ 3
194 ꢂ 2
193 ꢂ 3
195 ꢂ 2
194 ꢂ 1
196 ꢂ 2
195 ꢂ 2
194 ꢂ 1
196 ꢂ 3
193 ꢂ 1
194 ꢂ 2
195 ꢂ 2
193 ꢂ 3
196 ꢂ 1
195 ꢂ 3
194 ꢂ 2
194 ꢂ 1
195 ꢂ 3
194 ꢂ 2
193 ꢂ 3
194 ꢂ 2
195 ꢂ 1
194 ꢂ 1
195 ꢂ 2
195 ꢂ 3
192 ꢂ 1
190 ꢂ 2
191 ꢂ 3
189 ꢂ 2
188 ꢂ 1
189 ꢂ 2
192 ꢂ 2
191 ꢂ 2
188 ꢂ 1
189 ꢂ 2
192 ꢂ 1
189 ꢂ 1
192 ꢂ 1
187 ꢂ 3
188 ꢂ 1
193 ꢂ 3
189 ꢂ 2
189 ꢂ 1
189 ꢂ 2
188 ꢂ 1
191 ꢂ 2
192 ꢂ 1
191 ꢂ 2
189 ꢂ 2
190 ꢂ 2
190 ꢂ 1
191 ꢂ 1
190 ꢂ 1
191 ꢂ 2
190 ꢂ 3
195 ꢂ 3
192 ꢂ 1
187 ꢂ 2
182 ꢂ 1
184 ꢂ 2
183 ꢂ 1
181 ꢂ 2
180 ꢂ 2
188 ꢂ 2
186 ꢂ 1
181 ꢂ 3
183 ꢂ 1
187 ꢂ 1
183 ꢂ 2
188 ꢂ 1
181 ꢂ 1
179 ꢂ 2
189 ꢂ 2
185 ꢂ 1
179 ꢂ 2
180 ꢂ 1
182 ꢂ 2
187 ꢂ 3
187 ꢂ 2
189 ꢂ 1
182 ꢂ 1
184 ꢂ 3
186 ꢂ 2
187 ꢂ 3
186 ꢂ 2
188 ꢂ 3
186 ꢂ 2
194 ꢂ 1
188 ꢂ 2
183 ꢂ 2
172 ꢂ 2
179 ꢂ 3
175 ꢂ 2
172 ꢂ 1
171 ꢂ 3
183 ꢂ 1
181 ꢂ 3
172 ꢂ 1
174 ꢂ 2
182 ꢂ 3
172 ꢂ 1
183 ꢂ 2
172 ꢂ 2
162 ꢂ 1
184 ꢂ 2
182 ꢂ 2
165 ꢂ 2
171 ꢂ 3
178 ꢂ 1
179 ꢂ 2
182 ꢂ 1
187 ꢂ 2
174 ꢂ 2
176 ꢂ 2
180 ꢂ 1
182 ꢂ 2
179 ꢂ 1
182 ꢂ 3
181 ꢂ 3
195 ꢂ 2
180 ꢂ 1
177 ꢂ 3
161 ꢂ 1
173 ꢂ 2
164 ꢂ 3
164 ꢂ 2
159 ꢂ 4
177 ꢂ 3
175 ꢂ 2
163 ꢂ 1
161 ꢂ 2
174 ꢂ 2
163 ꢂ 3
177 ꢂ 2
160 ꢂ 2
150 ꢂ 4
178 ꢂ 1
178 ꢂ 3
153 ꢂ 3
162 ꢂ 2
169 ꢂ 2
168 ꢂ 1
179 ꢂ 2
181 ꢂ 2
167 ꢂ 1
169 ꢂ 2
174 ꢂ 2
179 ꢂ 1
170 ꢂ 2
170 ꢂ 1
168 ꢂ 1
194 ꢂ 3
172 ꢂ 1
169 ꢂ 2
145 ꢂ 3
168 ꢂ 1
155 ꢂ 2
151 ꢂ 3
148 ꢂ 2
170 ꢂ 1
171 ꢂ 1
149 ꢂ 2
155 ꢂ 1
168 ꢂ 1
151 ꢂ 2
171 ꢂ 1
149 ꢂ 2
139 ꢂ 1
174 ꢂ 2
172 ꢂ 2
141 ꢂ 2
150 ꢂ 4
161 ꢂ 3
156 ꢂ 2
172 ꢂ 3
176 ꢂ 3
157 ꢂ 2
160 ꢂ 2
162 ꢂ 1
176 ꢂ 2
165 ꢂ 2
165 ꢂ 2
160 ꢂ 2
194 ꢂ 2
160 ꢂ 2
172 ꢂ 3
136 ꢂ 2
166 ꢂ 2
148 ꢂ 2
139 ꢂ 2
132 ꢂ 1
164 ꢂ 3
164 ꢂ 3
130 ꢂ 1
145 ꢂ 2
161 ꢂ 3
139 ꢂ 1
164 ꢂ 3
132 ꢂ 4
124 ꢂ 2
169 ꢂ 4
165 ꢂ 1
129 ꢂ 3
138 ꢂ 1
152 ꢂ 3
141 ꢂ 2
165 ꢂ 2
172 ꢂ 1
137 ꢂ 3
142 ꢂ 3
154 ꢂ 2
170 ꢂ 2
160 ꢂ 1
156 ꢂ 2
151 ꢂ 2
195 ꢂ 4
145 ꢂ 1
181 ꢂ 1
125 ꢂ 3
163 ꢂ 2
134 ꢂ 1
121 ꢂ 2
120 ꢂ 2
159 ꢂ 3
159 ꢂ 4
121 ꢂ 3
136 ꢂ 1
152 ꢂ 4
124 ꢂ 2
159 ꢂ 2
120 ꢂ 2
120 ꢂ 1
163 ꢂ 1
160 ꢂ 2
119 ꢂ 2
121 ꢂ 2
144 ꢂ 2
137 ꢂ 3
162 ꢂ 3
177 ꢂ 2
121 ꢂ 3
128 ꢂ 2
145 ꢂ 1
164 ꢂ 1
154 ꢂ 2
148 ꢂ 1
142 ꢂ 3
195 ꢂ 1
132 ꢂ 3
187 ꢂ 3
118 ꢂ 2
155 ꢂ 1
122 ꢂ 2
122 ꢂ 3
119 ꢂ 4
152 ꢂ 4
153 ꢂ 2
117 ꢂ 2
130 ꢂ 2
147 ꢂ 1
120 ꢂ 3
154 ꢂ 1
117 ꢂ 3
115 ꢂ 2
158 ꢂ 3
154 ꢂ 1
117 ꢂ 1
118 ꢂ 2
129 ꢂ 3
121 ꢂ 2
167 ꢂ 1
180 ꢂ 1
118 ꢂ 2
119 ꢂ 1
131 ꢂ 2
160 ꢂ 1
152 ꢂ 1
130 ꢂ 3
124 ꢂ 1
194 ꢂ 2
120 ꢂ 2
189 ꢂ 1
136 ꢂ 2
161 ꢂ 2
143 ꢂ 3
154 ꢂ 2
132 ꢂ 2
161 ꢂ 4
163 ꢂ 2
140 ꢂ 4
145 ꢂ 1
161 ꢂ 2
147 ꢂ 2
165 ꢂ 3
136 ꢂ 4
130 ꢂ 3
173 ꢂ 1
169 ꢂ 2
131 ꢂ 4
136 ꢂ 2
148 ꢂ 2
142 ꢂ 1
176 ꢂ 2
185 ꢂ 1
128 ꢂ 2
132 ꢂ 2
142 ꢂ 1
169 ꢂ 2
158 ꢂ 3
144 ꢂ 1
136 ꢂ 2
195 ꢂ 3
148 ꢂ 1
191 ꢂ 2
149 ꢂ 3
164 ꢂ 3
151 ꢂ 2
161 ꢂ 3
141 ꢂ 1
167 ꢂ 3
169 ꢂ 1
151 ꢂ 2
156 ꢂ 3
172 ꢂ 3
154 ꢂ 4
172 ꢂ 3
144 ꢂ 2
141 ꢂ 2
180 ꢂ 1
173 ꢂ 3
142 ꢂ 2
148 ꢂ 1
157 ꢂ 1
153 ꢂ 2
181 ꢂ 3
189 ꢂ 1
137 ꢂ 2
141 ꢂ 3
160 ꢂ 2
172 ꢂ 2
169 ꢂ 2
164 ꢂ 2
155 ꢂ 1
194 ꢂ 3
158 ꢂ 2
193 ꢂ 3
154 ꢂ 2
169 ꢂ 2
156 ꢂ 2
165 ꢂ 1
154 ꢂ 2
173 ꢂ 2
174 ꢂ 2
162 ꢂ 2
168 ꢂ 4
179 ꢂ 3
163 ꢂ 2
181 ꢂ 2
152 ꢂ 1
150 ꢂ 3
184 ꢂ 1
181 ꢂ 4
151 ꢂ 1
156 ꢂ 4
165 ꢂ 2
157 ꢂ 3
187 ꢂ 2
190 ꢂ 2
158 ꢂ 1
151 ꢂ 2
166 ꢂ 3
181 ꢂ 3
174 ꢂ 2
171 ꢂ 2
165 ꢂ 2
195 ꢂ 2
162 ꢂ 1
Control
Nifedipine
Table 3
Comparative study of inhibition (%) for antihypertensive activity shown by compounds (1e30) and standard as compared to control.
Compound
Inhibition (%)
0
15
30
60
6.2
11.8
8.2
10.3
11.8
12.3
6.2
120
180
240
300
360
600
720
900
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
0.0
0.5
0.5
1.0
1.0
0.5
0.0
0.0
0.5
1.0
0.0
0.5
ꢀ0.5
0.0
0.5
0.5
1.0
0.5
0.0
1.0
0.0
0.0
0.5
0.5
0.0
0.5
1.0
0.5
0.0
0.5
e
1.5
2.6
2.1
3.1
3.6
3.1
1.5
2.1
3.6
3.1
1.5
3.1
1.5
4.1
3.6
1.0
3.1
3.1
3.1
3.6
2.1
1.5
2.1
3.1
2.6
2.6
2.1
2.6
2.1
2.6
e
3.6
6.2
5.2
5.7
6.7
7.2
3.1
4.1
6.7
5.7
3.6
5.7
3.1
6.7
7.7
2.6
4.6
7.7
7.2
6.2
3.6
3.6
2.6
6.2
5.2
4.1
3.6
4.1
3.1
4.1
e
8.8
17.0
10.8
15.5
15.5
18.0
8.8
12.9
25.3
13.4
20.1
22.2
23.7
12.4
11.9
23.2
20.1
13.4
22.2
11.9
23.2
28.4
10.3
11.3
27.3
22.7
17.0
19.6
11.3
9.3
11.8
30.3
14.9
24.1
28.7
32.3
15.9
15.9
33.3
25.6
17.4
28.7
15.9
32.3
36.4
13.3
15.4
33.8
29.2
22.1
27.7
15.4
11.8
29.7
27.2
21.0
12.8
17.9
20.0
22.6
e
7.2
35.9
16.4
31.3
37.9
38.5
18.5
18.5
37.9
30.3
22.1
36.4
18.5
38.5
38.5
16.4
17.9
39.0
37.9
26.2
29.7
16.9
9.2
3.6
39.2
20.1
37.1
37.1
38.7
21.6
21.1
39.7
33.0
24.2
38.1
20.6
39.7
40.7
18.6
20.6
39.7
39.2
33.5
37.6
13.9
7.2
3.1
30.3
17.4
26.7
21.0
32.3
17.4
16.4
28.2
25.6
17.4
24.6
15.4
30.3
33.3
11.3
13.3
32.8
30.3
24.1
27.2
9.7
1.5
23.2
15.5
22.2
17.0
27.3
13.9
12.9
22.2
19.6
11.3
20.6
11.3
25.8
27.3
7.2
1.0
21.0
13.3
20.0
15.4
21.0
11.3
10.8
16.9
13.8
8.2
16.4
7.2
22.1
23.1
5.6
7.2
9.8
11.8
10.8
6.7
11.8
6.2
11.8
16.9
5.6
16.0
17.0
10.3
16.0
8.8
17.5
22.7
8.2
6.7
8.2
10.8
26.8
23.7
19.1
21.1
6.7
7.2
15.4
12.3
8.7
8.2
6.7
4.1
10.8
9.7
7.7
6.7
21.1
16.5
12.9
13.4
7.7
22.6
20.0
15.4
19.5
4.1
6.7
5.1
2.6
2.6
13.9
12.9
10.3
7.7
12.4
12.4
13.4
e
19.1
17.5
16.5
9.3
14.9
14.9
17.5
e
37.9
34.4
25.6
15.9
21.0
24.1
27.2
e
39.2
38.7
32.5
17.5
21.6
33.0
36.1
e
34.4
32.3
27.2
13.3
19.0
26.2
30.3
e
29.4
27.3
17.5
11.3
12.9
15.5
20.1
e
19.0
22.6
14.9
7.2
10.8
12.3
15.4
e
8.2
6.7
7.2
e
Control
Nifedipine
0.0
1.5
3.1
7.7
11.3
17.5
25.6
32.3
38.1
24.1
18.6
16.9

5116
O. Alam et al. / European Journal of Medicinal Chemistry 45 (2010) 5113e5119
1
6. Experimental
2
3
4
45.0
5
6.1. Chemistry
6
7
8
9
40.0
35.0
30.0
25.0
20.0
15.0
10.0
5.0
The melting points were determined in open capillary tubes in
10
11
a Hicon melting point apparatus and are uncorrected. The homogen
elemental analyses (C, H, N) of all compounds were performed on
the CHNS Elimentar (Analysen systime, GmbH) Germany Vario EL
III. All the Fourier transform infra red (FTIR) spectra were recorded
in KBr pellets on a Jasco FT/IR 410 spectrometer. The 1H NMR
spectra were taken on a Bruker 400 Ultra shieldÔ (400 MHz) NMR
12
13
14
15
16
17
18
19
20
21
22
23
24
spectrometer. Chemical shifts (d) are expressed in ppm relative to
0.0
25
26
0
15
30
60
120 180 240 300 360 600 720 900
Time (min)
tetramethylsilane (TMS) as an internal standard. The homogeneity
of the compounds was checked by thin layer chromatography (TLC)
on silica gel G (Merck) coated plates by using toluene:ethyl aceta-
te:formic acid (5:4:1) as solvent system. Iodine chamber and UV
lamp were used for the visualization of TLC spots.
27
28
29
30
Control
Nifedipine
Fig. 1. Graph showing % decrease in the systolic blood pressure (SBP) exhibited by
compounds (1e30) and standard as compared to control.
6.1.1. General procedure for the synthesis of titled compounds
(1e30)
N-(substituted phenyl)-3-oxo-butyramide (I). A mixture of ethyl
acetatoacetate (0.01 mol) and substituted aniline (0.01 mol) in
20 mL of ethanol containing 0.3 g sodium hydroxide was refluxed
for 5 h. Reaction mixture was concentrated and the solid product
was filtered off and recrystallized with ethyl acetate. Yield: 76%;
M.p. 136 ꢁC, IR (KBr, cmꢀ1): 3315 (NH), 3070 (Ar-CHstr), 1672 (C]O),
their molecular weights. In most compounds, prominent peaks
resulted from the elimination of CO group.
4.2. Antihypertensive activity
All the synthesized compounds have been screened for their
antihypertensive activity by using tail-cuff method that measures
the systolic blood pressure. Change from control was observed and
the activity was compared to the standard drug nifedipine. Data are
summarized in Table 2. The percent decrease in the systolic blood
pressure both by the synthesized compounds and by the standard
drug has been calculated and the results are shown in Table 3.
Almost all the tested compounds were found to be active against
the hypertension induced by DOCA-salt. Thirteen compounds have
shown significant antihypertensive activity as they markedly
decrease the systolic blood pressure comparable to the standard
drug nifedipine. They were found to decrease the blood pressure to
normal after 6 h and a moderate rise afterwards, which may be due
to the excretion of compound from body after 6 h as shown in
graph in Fig. 1. Nifedipine was also found to express the similar
profile when tested at the same dose at similar time intervals. Other
compounds that have shown considerable antihypertensive
activity were found to be 10, 12, 20, 26 and 29. These compounds
decreased the blood pressure considerably but were not able to
bring the blood pressure up to normal at any time interval. Rest all
the compounds have shown moderate decrease in hypertension.
Structure activity relationship studies revealed that the substi-
tutions at the phenyl ring attached to the pyrimidine moiety played
1629 (C]O); 1H NMR (DMSO-d6):
CH2), 7.12e7.83 (m, 4H, ArH), 8.52 (bs, 1H, NH, D2O exchangeable);
13C NMR (CDCl3):
34.67 (CH3), 55.43 (CH2), 121.32 (Ar-CH), 128.46
d 2.15 (s, 3H, CH3), 3.78 (s, 2H,
d
(Ar-CH), 134. 45 (Ar-CH), 148.12 (Ar-C-), 174.24 (C]O), 215.34 (CH3-
C]O).
6-Methyl-4-(substituted phenyl)-2-thioxo-1,2,3,4-tetrahydro-pyrim-
idine-5-carboxylic acid (4-substituted phenyl)-amides (II). A mixture of
N-(4-substituted phenyl)-3-oxo-butyramide (I, 0.01 mol), substituted
aryl aldehydes (0.011 mol) and thiourea (0.015 mol) in 20 mL of
ethanol was refluxed for 7e9 h in presence of catalytic amount of
concentrated hydrochloric acid. The reaction mixture was kept
overnight and the precipitate obtained was filtered and recrystallized
with ethanol. Yield: 63%; M.p. 179 ꢁC, IR (KBr, cmꢀ1): 3416 (NH), 3358
(NH), 3340 (NH), 3019 (Ar-CHstr), 1658 (C]O), 1304 (C]S); 1H NMR
(DMSO-d6):
d 2.21 (s, 3H, CH3), 5.11 (s, 1H, CH), 7.09e7.73 (m, 8H,
ArH), 9.20 (bs, 1H, NH, D2O exchangeable), 9.65 (bs, 1H, NH, D2O
exchangeable), 9.86 (bs, 1H, NH, D2O exchangeable); 13C NMR
(CDCl3): d 17.41 (Ar-CH3), 64.39 (Ar-CH),118.45 (Ar-C-),120.14 (Ar-CH),
123. 23 (Ar-CH), 125.14 (Ar-CH-), 127.23 (Ar-CH-), 129.31 (Ar-CH-),
132.45 (Ar-CH-), 144.32 (Ar-C-), 147.37 (Ar-C-), 170.13 (C]O), 181.54
(C]S).
5-(4-Substituted
phenyl)-2-(substituted
benzylsulfanyl)-4-
(substituted phenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide
(1e30). A mixture of substituted pyrimidine-5-carboxylic acid
amides (II, 0.01 mol) and substituted benzyl chloride (0.01 mol) in
20 mL of anhydrous DMF was refluxed for 8e10 h in presence of
0.3 g anhydrous K2CO3. Reaction mixture was concentrated and
poured into ice cold water and the solid product was filtered off and
recrystallized from mixture of hexane and ethyl acetate to give
desired compound.
a
significant role in governing the antihypertensive activity.
Substitutions by the electron releasing groups such as 4-OCH3 and
3,4-OCH3 tend to increase the activity. Substitutions at other phenyl
rings were also seemingly important as the para substituted benzyl
derivatives were more active in the series. The chloro substituted
derivatives were found to be more active than the other halogen.
The phenyl ring attached to the amide linkage does not seem to
have any marked effect on antihypertensive activity.
5-(4-Fluorophenyl)-2-benzylsulfanyl-4-(3,4-dimethoxyphenyl)-6-
methyl-1,4-dihydro-5-pyrimidinecarboxamide (1). IR (KBr, cmꢀ1):
3354 (NeHstr), 3313 (NeHstr), 2975 (Ar-CHstr), 1653 (C]O), 635
5. Conclusions
(CeS); 1H NMR (DMSO-d6):
d ppm 2.31 (s, 3H, CH3), 3.55 (s, 3H,
A newer series of ring substituted pyrimidine carboxamides has
been identified as antihypertensive agents. The promising activity
of these agents further gave emphasis to the pharmacophore model
suggested and need to be explored further to get better agents.
These derivatives pose strong future commitments.
OCH3), 3.59 (s, 3H, OCH3), 4.07 (s, 2H, SeCH2), 5.11 (s, 1H, CH-pyr.),
6.59e6.78 (m, 3H, ArH), 7.01e7.76 (m, 9H, ArH), 8.83 (bs, 1H, NH,
D2O exchangeable), 9.78 (bs, 1H, NH-Amide, D2O exchangeable);
13C NMR (CDCl3):
d
19.23 (Ar-CH3), 38.21 (CH2), 55.18 (Ar-CH), 59.45
(OCH3), 61.23 (OCH3), 115.24 (Ar-CH), 116.24 (Ar-CH), 117.13 (Ar-CH),

O. Alam et al. / European Journal of Medicinal Chemistry 45 (2010) 5113e5119
5117
118.33 (Ar-C-), 119.45 (Ar-CH), 120.56 (Ar-CH), 122.71 (Ar-CH),
123.34 (Ar-CH), 125.14 (Ar-CH-), 126.22 (Ar-CH-), 128.67 (Ar-CH-),
131.34 (Ar-CH-), 150.17 (Ar-C-), 158.23 (Ar-C-), 171.87 (C]O); %Anal.
Cal. (found) ¼ C 65.97 (65.94), H 5.33 (5.38), N 8.55 (8.51); Mass
(EI): m/z 490.28 (Mþ).
5-(4-Fluorophenyl)-2-(4-chlorobenzylsulfanyl)-4-(4-nitrophenyl)-
6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (9) IR (KBr, cmꢀ1):
3416 (NeHstr), 3325 (NeHstr), 1649 (C]O), 645 (CeS); 1H NMR
(DMSO-d6): d ppm 2.23 (s, 3H, CH3), 4.21 (s, 2H, SeCH2), 5.18 (s, 1H,
CH-pyr.), 7.15e7.72 (m, 12H, ArH), 9.12 (bs, 1H, NH, D2O
exchangeable), 10.05 (bs, 1H, NH-Amide, D2O exchangeable), %Anal.
Cal. (found) ¼ C 58.76 (58.71), H 3.95 (3.92), N 10.96 (10.91); Mass
(EI): m/z 511.89 (M þ 1).
5-(4-Fluorophenyl)-2-(2-chlorobenzylsulfanyl)-4-(3,4-dimethox-
yphenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (2). IR
(KBr, cmꢀ1): 3368 (NeHstr), 3331(NeHstr), 1665 (C]O), 642 (CeS);
1H NMR (DMSO-d6):
d
2.28 (s, 3H, CH3), 3.52 (s, 3H, OCH3), 3.57 (s,
5-(4-Fluorophenyl)-2-(4-fluorobenzylsulfanyl)-4-(4-nitrophenyl)-
6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (10) IR (KBr, cmꢀ1):
3391 (NeHstr), 3308 (NeHstr), 1678 (C]O), 625 (CeS); 1H NMR
3H, OCH3), 4.11 (s, 2H, SeCH2), 5.07 (s, 1H, CH-pyr.), 6.52e6.81 (m,
3H, ArH), 7.15e7.63 (m, 8H, ArH), 8.78 (bs, 1H, NH, D2O exchange-
able), 9.80 (bs, 1H, NH-Amide, D2O exchangeable); %Anal. Cal.
(found) ¼ C 61.65 (61.68), H 4.79 (4.74), N 7.99 (7.93); Mass (EI): m/z
527.36 (M þ 1).
(DMSO-d6): d ppm 2.26 (s, 3H, CH3), 4.25 (s, 2H, SeCH2), 5.11 (s, 1H,
CH-pyr.), 7.25e7.89 (m, 12H, ArH), 9.08 (bs, 1H, NH, D2O
exchangeable), 10.10 (bs, 1H, NH-Amide, D2O exchangeable); %Anal.
Cal (found) ¼ C 60.72 (60.75), H 4.08 (4.06), N 11.33 (11.36); Mass
(EI): m/z 493.28 (Mþ).
5-(4-Bromophenyl)-2-benzylsulfanyl-4-(2,4-dichlorophenyl)-6-
methyl-1,4-dihydro-5-pyrimidinecarboxamide (11) IR (KBr, cmꢀ1):
3368 (NeHstr), 3321 (NeHstr), 1668 (C]O), 650 (CeS); 1H NMR
5-(4-Fluorophenyl)-2-(3-chlorobenzylsulfanyl)-4-(3,4-dimethox-
yphenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (3) IR
(KBr, cmꢀ1): 3412 (NeHstr), 3318 (NeHstr),1638 (C]O), 619 (CeS);
1H NMR (DMSO-d6):
d ppm 2.25 (s, 3H, CH3), 3.51 (s, 3H, OCH3), 3.65
(s, 3H, OCH3), 4.14 (s, 2H, SeCH2), 5.11 (s, 1H, CH-pyr.), 6.61e6.89
(m, 3H, ArH), 7.21e7.70 (m, 8H, ArH), 8.86 (bs, 1H, NH, D2O
exchangeable), 9.83 (bs, 1H, NH-Amide, D2O exchangeable); %Anal.
Cal. (found) ¼ C 61.65 (61.61), H 4.79 (4.76), N 7.99 (8.05); Mass (EI):
m/z 526.98 (M þ 1).
(DMSO-d6): d ppm 2.31 (s, 3H, CH3), 4.05 (s, 2H, SeCH2), 5.15 (s, 1H,
CH-pyr.), 7.02e7.69 (m, 12H, ArH), 8.98 (bs, 1H, NH, D2O
exchangeable), 9.77 (bs, 1H, NH-Amide, D2O exchangeable); %Anal.
Cal (found) ¼ C 53.49 (53.45), H 3.59 (3.58), N 7.49 (7.46); Mass (EI):
m/z 563.29 (M þ 2).
5-(4-Fluorophenyl)-2-(4-chlorobenzylsulfanyl)-4-(3,4-dimethox-
yphenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (4) IR
(KBr, cmꢀ1): 3456 (NeHstr), 3312 (NeHstr), 1645 (C]O), 636 (CeS);
5-(4-Bromophenyl)-2-(2-chlorobenzylsulfanyl)-4-(2,4-dichlor-
ophenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (12) IR
(KBr, cmꢀ1): 3426 (NeHstr), 3314 (NeHstr), 1661 (C]O), 652 (CeS);
1H NMR (DMSO-d6):
d ppm 2.30 (s, 3H, CH3), 3.55 (s, 3H, OCH3),
3.68 (s, 3H, OCH3), 4.21 (s, 2H, SeCH2), 5.11 (s, 1H, CH-pyr.),
6.58e6.72 (m, 3H, ArH), 7.18e7.82 (m, 8H, ArH), 8.69 (bs, 1H, NH,
D2O exchangeable), 9.90 (bs, 1H, NH-Amide, D2O exchangeable); %
Anal. Cal. (found) ¼ C 61.65 (61.62), H 4.79 (4.84), N 7.99 (7.94);
Mass (EI): m/z 527.10 (M þ 1).
1H NMR (DMSO-d6):
d ppm 2.28 (s, 3H, CH3), 4.15 (s, 2H, SeCH2),
5.18 (s, 1H, CH-pyr.), 7.19e7.71 (m, 11H, ArH), 9.10 (bs, 1H, NH, D2O
exchangeable), 9.82 (bs, 1H, NH-Amide, D2O exchangeable); %Anal.
Cal (found) ¼ C 50.40 (50.36), H 3.21 (3.24), N 7.05 (7.03); Mass (EI):
m/z 597.68 (M þ 2).
5-(4-Fluorophenyl)-2-(4-fluorobenzylsulfanyl)-4-(3,4-dimethox-
yphenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (5) IR
(KBr, cmꢀ1): 3378 (NeHstr), 3324 (NeHstr), 1651 (C]O), 621 (CeS);
5-(4-Bromophenyl)-2-(3-chlorobenzylsulfanyl)-4-(2,4-dichlor-
ophenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (13) IR
(KBr, cmꢀ1): 3387 (NeHstr), 3311 (NeHstr), 1644 (C]O), 633 (CeS);
1H NMR (DMSO-d6):
d
ppm 2.26 (s, 3H, CH3), 3.61 (s, 3H, OCH3), 3.67
1H NMR (DMSO-d6):
d ppm 2.26 (s, 3H, CH3), 4.12 (s, 2H, SeCH2),
(s, 3H, OCH3), 4.19 (s, 2H, SeCH2), 5.08 (s, 1H, CH-pyr.), 6.62e6.88
(m, 3H, ArH), 7.32e7.85 (m, 8H, ArH), 8.88 (bs, 1H, NH, D2O
exchangeable),10.01 (bs,1H, NH-Amide, D2O exchangeable); %Anal.
Cal. (found) ¼ C 63.64 (63.62), H 4.95 (4.98), N 8.25 (8.19); Mass
(EI): m/z 508.18 (Mþ).
5-(4-Fluorophenyl)-2-benzylsulfanyl-4-(4-nitrophenyl)-6-methyl-
1,4-dihydro-5-pyrimidinecarboxamide (6) IR (KBr, cmꢀ1): 3412
(NeHstr), 3314 (NeHstr), 1661 (C]O), 652 (CeS); 1H NMR (DMSO-
5.13 (s, 1H, CH-pyr.), 7.17e7.78 (m, 11H, ArH), 8.78 (bs, 1H, NH, D2O
exchangeable), 9.80 (bs, 1H, NH-Amide, D2O exchangeable); %Anal.
Cal (found) ¼ C 50.40 (50.42), H 3.21 (3.27), N 7.05 (7.09); Mass (EI):
m/z 597.47 (M þ 2).
5-(4-Bromophenyl)-2-(4-chlorobenzylsulfanyl)-4-(2,4-dichlor-
ophenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (14) IR
(KBr, cmꢀ1): 3416 (NeHstr), 3328 (NeHstr), 1672 (C]O), 615 (CeS);
1H NMR (DMSO-d6):
d ppm 2.22 (s, 3H, CH3), 4.25 (s, 2H, SeCH2),
d6):
d
ppm 2.29 (s, 3H, CH3), 4.09 (s, 2H, SeCH2), 5.08 (s, 1H, CH-
5.14 (s, 1H, CH-pyr.), 7.31e7.82 (m, 11H, ArH), 9.02 (bs, 1H, NH, D2O
exchangeable), 9.81 (bs, 1H, NH-Amide, D2O exchangeable); %Anal.
Cal (found) ¼ C 50.40 (50.36), H 3.21 (3.18), N 7.05 (7.07); Mass (EI):
m/z 597.29 (M þ 2).
pyr.), 6.99e7.68 (m, 13H, ArH), 9.10 (bs, 1H, NH, D2O exchangeable),
9.82 (bs, 1H, NH-Amide, D2O exchangeable), %Anal. Cal. (found) ¼ C
63.01 (63.05%), H 4.81 (4.84), N 11.76 (11.71); Mass (EI): m/z 475.23
(Mþ).
5-(4-Fluorophenyl)-2-(2-chlorobenzylsulfanyl)-4-(4-nitrophenyl)-
6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (7) IR (KBr, cmꢀ1):
3379 (NeHstr), 3311 (NeHstr), 1644 (C]O), 633 (CeS); 1H NMR
5-(4-Bromophenyl)-2-(4-fluorobenzylsulfanyl)-4-(2,4-dichlor-
ophenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (15) IR
(KBr, cmꢀ1): 3379 (NeHstr), 3325 (NeHstr), 1649 (C]O), 645 (CeS);
1H NMR (DMSO-d6):
d ppm 2.32 (s, 3H, CH3), 4.30 (s, 2H, SeCH2),
(DMSO-d6):
d
ppm 2.30 (s, 3H, CH3), 4.11 (s, 2H, SeCH2), 5.16 (s, 1H,
5.10 (s, 1H, CH-pyr.), 7.36e7.89 (m, 11H, ArH), 9.11 (bs, 1H, NH, D2O
exchangeable), 9.84 (bs, 1H, NH-Amide, D2O exchangeable), %Anal.
Cal (found) ¼ C 51.83 (51.86), H 3.31 (3.35), N 7.25 (7.22); Mass (EI):
m/z 581.06 (M þ 2).
CH-pyr.), 7.23e7.76 (m, 12H, ArH), 8.99 (bs, 1H, NH, D2O
exchangeable), 9.92 (bs, 1H, NH-Amide, D2O exchangeable), %Anal.
Cal. (found) ¼ C 58.76 (58.73), H 3.95 (4.02), N 10.96 (10.92); Mass
(EI): m/z 511.17 (M þ 1).
5-(4-Bromophenyl)-2-benzylsulfanyl-4-(4-methoxyphenyl)-6-
methyl-1,4-dihydro-5-pyrimidinecarboxamide (16) IR (KBr, cmꢀ1):
3381 (NeHstr), 3308 (NeHstr), 1678 (C]O), 625 (CeS); 1H NMR
5-(4-Fluorophenyl)-2-(3-chlorobenzylsulfanyl)-4-(4-nitrophenyl)-
6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (8) IR (KBr, cmꢀ1):
3367 (NeHstr), 3328 (NeHstr), 1672 (C]O), 615 (CeS); 1H NMR
(DMSO-d6): d ppm 2.27 (s, 3H, CH3), 3.68 (s, 3H, OCH3), 4.10 (s, 2H,
(DMSO-d6):
d
ppm 2.25 (s, 3H, CH3), 4.18 (s, 2H, SeCH2), 5.14 (s, 1H,
SeCH2), 5.09 (s, 1H, CH-pyr.), 6.55e6.72 (m, 4H, ArH), 7.15e7.55
(m, 9H, ArH), 8.73 (bs, 1H, NH, D2O exchangeable), 9.69 (bs, 1H,
NH-Amide, D2O exchangeable); %Anal. Cal. (found) ¼ C 59.77
(59.73), H 4.63 (4.68), N 8.04 (8.08); Mass (EI): m/z 524.87
(M þ 2).
CH-pyr.), 7.18e7.80 (m, 12H, ArH), 9.05 (bs, 1H, NH, D2O
exchangeable), 9.91 (bs, 1H, NH-Amide, D2O exchangeable), %Anal.
Cal. (found) ¼ C 58.76 (58.78), H 3.95 (4.04), N 10.96 (10.98); Mass
(EI): m/z 511.68 (M þ 1).

5118
O. Alam et al. / European Journal of Medicinal Chemistry 45 (2010) 5113e5119
5-(4-Bromophenyl)-2-(2-chlorobenzylsulfanyl)-4-(4-methox-
(KBr, cmꢀ1): 3424 (NeHstr), 3323 (NeHstr), 1650 (C]O), 620 (CeS),
1H NMR (DMSO-d6):
ppm 2.21(s, 3H, CH3), 4.31 (s, 2H, SeCH2),
yphenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (17) IR
d
(KBr, cmꢀ1): 3402 (NeHstr), 3311 (NeHstr),1643 (C]O), 621 (CeS);
5.16 (s, 1H, CH-pyr.), 7.26e7.94 (m, 12H, ArH), 9.11 (bs, 1H, NH, D2O
exchangeable), 9.88 (bs, 1H, NH-Amide, D2O exchangeable), %Anal.
Cal. (found) ¼ C 54.06 (54.11), H 3.63 (3.67), N 10.09 (10.03); Mass
(EI): m/z 557.12 (M þ 2).
1H NMR (DMSO-d6):
d ppm 2.30 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 4.19
(s, 2H, SeCH2), 5.17 (s, 1H, CH-pyr.), 6.60e6.79 (m, 4H, ArH),
7.25e7.65 (m, 8H, ArH), 8.61 (bs, 1H, NH, D2O exchangeable), 9.75
(bs,1H, NH-Amide, D2O exchangeable); %Anal. Cal. (found) ¼ C 56.07
(56.12), H 4.16 (4.18), N 7.55 (7.50); Mass (EI): m/z 558.98 (M þ 2).
5-(4-Bromophenyl)-2-(3-chlorobenzylsulfanyl)-4-(4-methox-
5-(4-Nitrophenyl)-2-(benzylsulfanyl)-4-(3-nitrophenyl)-6-
methyl-1,4-dihydro-5-pyrimidinecarboxamide (26). IR (KBr, cmꢀ1):
3381 (NeHstr), 3315 (NeHstr), 1660 (C]O), 651 (CeS); 1H NMR
yphenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (18) IR
(DMSO-d6): d ppm 2.28 (s, 3H, CH3), 4.08 (s, 2H, SeCH2), 5.07 (s, 1H,
(KBr, cmꢀ1): 3369 (NeHstr), 3307 (NeHstr),1641 (C]O), 650 (CeS);
CH-pyr.), 6.98e7.67 (m, 13H, ArH), 9.09 (bs, 1H, NH, D2O
exchangeable), 9.81 (bs, 1H, NH-Amide, D2O exchangeable), %Anal.
Cal. (found) ¼ C 59.63 (59.61), H 4.20 (4.25), N 13.91 (13.93); Mass
(EI): m/z 502.74 (Mþ).
5-(4-Nitrophenyl)-2-(2-chlorobenzylsulfanyl)-4-(3-nitrophenyl)-
6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (27). IR (KBr, cmꢀ1):
3397 (NeHstr), 3310 (NeHstr), 1643 (C]O), 632 (CeS), 1H NMR
1H NMR (DMSO-d6):
d ppm 2.25 (s, 3H, CH3), 3.64 (s, 3H, OCH3), 4.25
(s, 2H, SeCH2), 5.11 (s, 1H, CH-pyr.), 6.62e6.71 (m, 4H, ArH),
7.21e7.69 (m, 9H, ArH), 8.63(bs,1H, NH, D2O exchangeable), 9.78(bs,
1H, NH-Amide, D2O exchangeable); %Anal. Cal. (found) ¼ C 56.07
(56.02), H 4.16 (4.14), N 7.55 (7.59); Mass (EI): m/z 558.94 (M þ 2).
5-(4-Bromophenyl)-2-(4-chlorobenzylsulfanyl)-4-(4-methox-
yphenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (19) IR
(DMSO-d6): d ppm 2.31 (s, 3H, CH3), 4.12 (s, 2H, SeCH2), 5.17 (s, 1H,
(KBr, cmꢀ1): 3387 (NeHstr), 3315 (NeHstr),1652 (C]O), 641 (CeS);
CH-pyr.), 7.24e7.77 (m, 12H, ArH), 9.00 (bs, 1H, NH, D2O
exchangeable), 9.93 (bs, 1H, NH-Amide, D2O exchangeable), %Anal.
Cal. (found) ¼ C 55.81 (55.83), H 3.75 (3.71), N 13.02 (13.03); Mass
(EI): m/z 538.79 (M þ 1).
1H NMR (DMSO-d6):
d ppm 2.27(s, 3H, CH3), 3.77 (s, 3H, OCH3), 4.28
(s, 2H, SeCH2), 5.16 (s, 1H, CH-pyr.), 6.52e6.78 (m, 4H, ArH),
7.20e7.72 (m, 8H, ArH), 8.75 (bs, 1H, NH, D2O exchangeable), 9.64
(bs,1H, NH-Amide, D2O exchangeable); %Anal. Cal. (found) ¼ C 56.07
(56.09), H 4.16 (4.11), N 7.55 (7.53); Mass (EI): m/z 559.08 (M þ 2).
5-(4-Bromophenyl)-2-(2-fluorobenzylsulfanyl)-4-(4-methox-
5-(4-Nitrophenyl)-2-(3-chlorobenzylsulfanyl)-4-(3-nitrophenyl)-
6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (28). IR (KBr, cmꢀ1):
3402 (NeHstr), 3327 (NeHstr), 1671 (C]O), 614 (CeS), 1H NMR
yphenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (20) IR
(DMSO-d6): d ppm 2.24 (s, 3H, CH3), 4.18 (s, 2H, SeCH2), 5.13 (s, 1H,
(KBr, cmꢀ1): 3391 (NeHstr), 3310 (NeHstr),1672 (C]O), 638 (CeS);
CH-pyr.), 7.17e7.81 (m, 12H, ArH), 9.04 (bs, 1H, NH, D2O
exchangeable), 9.91 (bs, 1H, NH-Amide, D2O exchangeable), %Anal.
Cal. (found) ¼ C 55.81 (55.78), H 3.75 (3.77), N 13.02 (12.98); Mass
(EI): m/z 539.06 (M þ 1).
1H NMR (DMSO-d6):
d ppm 2.32 (s, 3H, CH3), 3.71 (s, 3H, OCH3), 4.30
(s, 2H, SeCH2), 5.12 (s, 1H, CH-pyr.), 6.75e6.84 (m, 4H, ArH),
7.29e7.88 (m, 8H, ArH), 9.11 (bs,1H, NH, D2O exchangeable), 9.80 (bs,
1H, NH-Amide, D2O exchangeable); %Anal. Cal. (found) ¼ C 57.78
(57.79), H 4.29 (4.23), N 7.78 (7.83); Mass (EI): m/z 542.68 (M þ 2).
5-(4-Nitrophenyl)-2-(benzylsulfanyl)-4-(4-bromophenyl)-6-
5-(4-Nitrophenyl)-2-(4-chlorobenzylsulfanyl)-4-(3-nitrophenyl)-
6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (29). IR (KBr, cmꢀ1):
3416 (NeHstr), 3324 (NeHstr), 1648 (C]O), 644 (CeS), 1H NMR
methyl-1,4-dihydro-5-pyrimidinecarboxamide (21) IR (KBr, cmꢀ1):
(DMSO-d6): d ppm 2.22 (s, 3H, CH3), 4.20 (s, 2H, SeCH2), 5.17 (s, 1H,
3394 (NeHstr), 3313 (NeHstr),1652 (C]O), 634 (CeS); 1H NMR
CH-pyr.), 7.19e7.74 (m, 12H, ArH), 9.11 (bs, 1H, NH, D2O exchange-
able), 10.04 (bs, 1H, NH-Amide, D2O exchangeable), %Anal. Cal.
(found) ¼ C 55.81 (55.79), H 3.75 (3.72), N 13.02 (13.08); Mass (EI):
m/z 538.84 (M þ 1).
(DMSO-d6): d ppm 2.25 (s, 3H, CH3), 4.05 (s, 2H, SeCH2), 5.10 (s, 1H,
CH-pyr.), 6.95e7.78 (m, 13H, ArH), 9.12 (bs, 1H, NH, D2O
exchangeable), 9.84 (bs, 1H, NH-Amide, D2O exchangeable); %Anal.
Cal. (found) ¼ C 55.87 (55.89), H 3.94 (3.93), N 10.42 (10.43); Mass
(EI): m/z 539.71 (M þ 2).
5-(4-Nitrophenyl)-2-(4-fluorobenzylsulfanyl)-4-(3-nitrophenyl)-
6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (30). IR (KBr, cmꢀ1):
3429 (NeHstr), 3309 (NeHstr), 1677 (C]O), 624 (CeS); 1H NMR
5-(4-Nitrophenyl)-2-(2-chlorobenzylsulfanyl)-4-(4-bromo-
phenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (22) IR
(KBr, cmꢀ1): 3358 (NeHstr), 3331(NeHstr),1664 (C]O), 641 (CeS);
(DMSO-d6): d ppm 2.27 (s, 3H, CH3), 4.26 (s, 2H, SeCH2), 5.12 (s, 1H,
CH-pyr.), 7.26e7.90 (m, 12H, ArH), 9.09 (bs, 1H, NH, D2O
exchangeable), 10.10 (bs, 1H, NH-Amide, D2O exchangeable), %Anal.
Cal. (found) ¼ C 57.58 (57.59), H 3.87 (3.83), N 13.43 (13.48); Mass
(EI): m/z 520.66 (Mþ).
1H NMR (DMSO-d6):
d ppm 2.28 (s, 3H, CH3), 4.15(s, 2H, SeCH2),
5.21 (s, 1H, CH-pyr.), 7.27e7.82 (m, 12H, ArH), 9.08 (bs, 1H, NH, D2O
exchangeable), 9.99 (bs, 1H, NH-Amide, D2O exchangeable), %Anal.
Cal. (found) ¼ C 52.51 (52.56), H 3.53 (3.51), N 9.80 (9.83); Mass
(EI): m/z 573.84 (M þ 2).
6.2. Pharmacology
5-(4-Nitrophenyl)-2-(3-chlorobenzylsulfanyl)-4-(4-bromophenyl)-
6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (23). IR (KBr, cmꢀ1):
3429(NeHstr), 3317(NeHstr),1637(C]O), 618(CeS),1HNMR(DMSO-
The investigations were conducted on albino rats weighing
200e250 g of either sex. All rats were housed in a temperature and
humiditycontrolled room at an ambient temperature of 25 ꢂ 2 ꢁCwith
12 h light/dark cycle and allowed free access to food and water except
at the time they were brought out of the cage. All the experimental
protocols were carried out with the permission from Institutional
Animal Ethics committee (IAEC), form no. 443 and the guidelines
provided by the Committee for the Purpose of Control and Supervision
of Experiments in Animal (CPCSEA). Animals were obtained from
Central Animal House Facility, Hamdard University, New Delhi-62.
Registration no. and date of registration is 173/CPCSEA, 28 Jan., 2000.
d6): d ppm 2.21 (s, 3H, CH3), 4.26 (s, 2H, SeCH2), 5.11 (s, 1H, CH-pyr.),
7.22e7.86 (m,12H, ArH), 9.10 (bs,1H, NH, D2O exchangeable), 9.89(bs,
1H, NH-Amide, D2O exchangeable), %Anal. Cal. (found) ¼ C 52.51
(52.54), H 3.53 (3.55), N 9.80 (9.77); Mass (EI): m/z 573.84 (M þ 2).
5-(4-Nitrophenyl)-2-(4-chlorobenzylsulfanyl)-4-(4-bromo-
phenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (24). IR
(KBr, cmꢀ1): 3458 (NeHstr), 3311 (NeHstr), 1644 (C]O), 635 (CeS),
1H NMR (DMSO-d6):
d ppm 2.30 (s, 3H, CH3), 4.23 (s, 2H, SeCH2),
5.17 (s, 1H, CH-pyr.), 7.26e7.82 (m, 12H, ArH), 9.16 (bs, 1H, NH, D2O
exchangeable), 10.08 (bs, 1H, NH-Amide, D2O exchangeable), %Anal.
Cal. (found) ¼ C 52.51 (52.47), H 3.53 (3.56), N 9.80 (9.78); Mass
(EI): m/z 574.01 (M þ 2).
6.2.1. Antihypertensive activity
Antihypertensive activity of synthesized compounds was assessed
by Deoxycorticosterone Acetate salt (DOCA-salt) induced hyper-
tension in rats [8e11] and the non-invasive tail-cuff method was
5-(4-Nitrophenyl)-2-(4-fluorobenzylsulfanyl)-4-(4-bromo-
phenyl)-6-methyl-1,4-dihydro-5-pyrimidinecarboxamide (25). IR

O. Alam et al. / European Journal of Medicinal Chemistry 45 (2010) 5113e5119
5119
employed to determine systolic blood pressure (SBP) in rats. Nifedi-
pine was used as standard drug.
maximal inflated cuff pressures, maximal inflation was set at
200 mmHg. Blood pressure recording was considered to be
successful if the rat did not move and a clear initial pulse could be
seen. Ten tail-cuff measurements were made in a session. The BP for
the session was accepted as the average of four BP readings that
were within 5 mm Hg or the average of 10 readings that were
within 8 mmHg. BP measurements were done thrice per week for
two weeks. Twelve groups of six rats weighing between 200 and
250 g were made. Animals hypertension was induced as detailed
above. Rats were trained for the experiment. On the first day of
experiment the test compounds were administered by oral feeding
using an oral feeding needle. The test compounds (1e30) were
prepared in 0.5% carboxymethyl cellulose (CMC) and dose of 10 mg/
kg orally. One group of animal was treated with standard drug
Nifedipine. One of the six groups was treated with vehicle. Prior to
dosing the animals, initial graph reading was taken to record the BP.
After 1 h of dosing recordings were taken as mentioned above. Each
compound was evaluated three times in one week, and average of
the recordings was recorded accordingly. Average readings were
calculated by employing ANOVA method.
6.2.1.1. DOCA-salt hypertension. Hypertension in rats was induced
by injecting twice weekly with 20 mg/kg sac. deoxycortisone
acetate (DOCA) in olive oil for 4 weeks. Drinking water was
replaced by 1% w/v NaCl solution [12]. Injection of DOCA-salt was
not administered to the control group of rats that received vehicle
injections and tap water instead. Blood pressure started to rise after
one week and the systolic value reached between 160 and 180 mm
Hg after 4 weeks. Animals were divided into three groups. Group-I
served as control, group-II received newly synthesized compounds
(1e30) and group-III received standard drug nifedipine.
6.2.1.2. Non-invasive blood pressure (NIBP) measurements (tail-cuff
method). The blood pressure (BP) was determined with a BIOPAC
student, Inc, NIBP with computerized BP monitor. This system
measures blood pressure (BP) by recording the cuff pressure at
which the interrupted blood flow returns to the tail. Training the
rats for tail-cuff blood pressure measurements was necessary to
reduce the stress associated with the BP measurements and hence
reduces the variability of BP with successive measurements [13].
Training consisted of six sessions over 3 days. On day one, rats were
introduced into cylindrical restrainer for 5 min per session. The tail-
cuff was inflated five times in quick succession. By day three, the
training was extended to 10 min per session. The effect of training
was to reduce the standard deviation around mean BP. At the end of
session rats were ready for BP recording. They were restrained by
being placed into cylindrical restrainer. For better detection of tail
pulse, the tail artery was dilated by placement of restrained rats
into thermostatically controlled Lucite box, heated at it was placed
on a heated surgical surface maintained at 37 ꢁC for 2e5 min before
BP measurement was started. Tail pulse was detected by passage of
tail through a narrow tail-cuff sensor attached to the amplifier. BP
measurements were started by automatic inflation of tail-cuff to
greater than 200 mmHg and release of pressure. The results were
recorded in form of graph. The computer provides two tracings that
start and stop at the same time. The lower trace channel plots cuff
pressure, which is calibrated at 500 mmHg at full scale. The tracing
sharply rises when applied to the tail-cuff and falls off gradually
during the 15e20 s of the test. The upper trace channel monitors
pulse, with fluctuations about the centre line suddenly appearing at
the onset of pulsations. The first onset of pulse is taken as the
systolic blood pressure. Initiation of pulse pressure was determined
when the baseline amplitude increased in accordance to the set
Acknowledgments
Authors are thankful to the Department of Pharmaceutical
Chemistry, Faculty of Pharmacy, Hamdard University for providing
necessary facilities to carry out the research work.
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