Synthesis, molecular docking, and cardioprotective activity of 2-methylthio-1,4-dihydropyrimidines

Article abstract of DOI:10.1007/s00044-011-9700-7

A series of 2-methylthio-1,4-dihydropyrimidine derivatives (IIa-IIl) were synthesized in good yields by alkylation of 1,2,3,4-tetrahydropyrimidines (Ia-Il) with methyl iodide in the presence of pyridine. Their structures were confirmed by elemental analys

Full text of DOI:10.1007/s00044-011-9700-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1825–1832
DOI 10.1007/s00044-011-9700-7
ORIGINAL RESEARCH
Synthesis, molecular docking, and cardioprotective
activity of 2-methylthio-1,4-dihydropyrimidines
•
Ramesh L. Sawant Varsha I. Sarode
•
•
Ganesh D. Jadhav Jyoti B. Wadekar
Received: 25 January 2011 / Accepted: 9 June 2011 / Published online: 25 June 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of 2-methylthio-1,4-dihydropyrimidine
derivatives (IIa–IIl) were synthesized in good yields by
alkylation of 1,2,3,4-tetrahydropyrimidines (Ia–Il) with
methyl iodide in the presence of pyridine. Their structures
were confirmed by elemental analysis, IR, and 1H NMR
spectra. Molecular docking of title compounds was done
using VLife MDS 3.5 on voltage-dependent calcium
channel b subunit functional core and its complex with the
a1 interaction domain i.e. AID-b complex (PDB code
1T3L) to identify potential candidates with minimum dock
score for cardioprotective activity. Biological screening of
the potential candidates (IIf and IIi) was done for cardio-
protective activity. Adult Sprague–dawley rats were pre-
treated with test compounds IIf and IIi. After the treatment
period, adrenaline was subcutaneously injected to rats at an
interval of 24 h for 2 days to induce myocardial injury.
After 48 h, rats were anaesthetized and electrocardio-
graphic (ECG) observations were performed. Potential
compounds IIf and IIi showed significant cardioprotective
activity against adrenaline-induced myocardial infarction in
rats. Adrenaline-induced ECG alterations such as reduced
R–R interval, increased heart rate, reduced P duration, and
ST-segment elevation were brought to the near normal
values by pretreatment of compounds IIf and IIi.
Introduction
The term cardioprotection refers to the techniques used to
prevent or delay the development of myocardial injury,
particularly during ischemia. Ischemia and reperfusion pro-
duce profound effects on the function of molecules involved
in the control of calcium homeostasis, leading to increased
free cystolic Ca2? concentration. Calcium overload is one of
the most crucial alterations responsible for ischemia and
reperfusion injury. Calcium overload can trigger several
injurious mechanisms. Many ATP-consuming enzymes
require Ca2? for activity, so that calcium overload increases
ATP consumption and exacerbates the unbalance between
energy supply and energy demand, which is the metabolic
hallmark of ischemia (Zucchi et al., 2001).
From a quantitative point of view, under physiological
conditions, free calcium concentration is on the order of
100 nm during diastole, and it increases up to 0.5–1.5 lm
during systole. After a few minutes of ischemia, time-
averaged calcium concentrations in the range of 1–10 lm
have been reported. With the onset of reperfusion, calcium
concentration may show either further massive increase,
which is invariably associated with cell death (Zucchi
et al., 2001). Literature survey showed that calcium
channel blockers are cardioprotective, for e.g., nicorandil,
amlodipine, labedipinedilol A, and diltiazem (Sathish
et al., 2003; Liang et al., 2006; Malhotra et al., 1997).
The computational process of searching for a ligand that
is able to fit both geometrically and energetically into the
binding site of a protein is called molecular docking.
Molecular docking is an efficient tool for investigating
receptor-ligand interactions and for virtual screening,
which plays a key role in rational drug design, especially
when the crystal structure of a receptor or enzyme is
available (Teodoro et al., 2001).
Keywords 2-Methylthio-1 Á 4-Dihydropyrimidine Á
Biginelli reaction Á Synthesis Á Molecular docking Á
Cardioprotective activity
R. L. Sawant (&) Á V. I. Sarode Á G. D. Jadhav Á J. B. Wadekar
Department of Pharmaceutical Chemistry and PG Studies,
PDVVPF’S College of Pharmacy, Post MIDC, Vilad Ghat,
Ahmednagar 414111, MS, India
e-mail: sawantrl@yahoo.com
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In recent years, acid-catalyzed cyclocondensation of
chromatography. After cooling, precipitate was formed
which was filtered and washed with cold methanol (I).
Compound I (0.01 mol), methyl iodide (0.011 mol) in
methanol (20 mL) was placed in round bottom flask and
refluxed for 2 h. Pyridine (0.037 mol) was then added and
refluxed again for 10 min. After cooling, the reaction
mixture was poured onto crushed ice (approx. 200 g) and
stirred for 5 min. Compound II obtained was filtered.
acetoacetate with aldehydes and (thio)ureas, known as the
Biginelli reaction, has attracted significant attention (Mo-
hammad and Zahra, 2009; Ezzat and Hadi, 2006; Kothar-
kar et al., 2006; Ahmad and Abbas, 2005; Shinde et al.,
2008; Arfan et al., 2007; Chen-Jiang and Ji-De, 2009;
Yang et al., 2007; Fang et al., 2007). The resulting dihy-
dropyrimidines (DHPMs) have been reported to have
antibacterial (Chitra et al., 2010), antiviral (Kappe, 2000),
anti-inflammatory (Mohammad et al., 2008), analgesic
(Chikhale et al., 2009), antihypertensive as well as calcium
channel blocker (Inci et al., 2006; Rovnyak et al., 1992),
and antioxidant (Ismaili et al., 2008) activities. Recently,
structurally simple DHPM derivative monastrol has
emerged as a mitotic kinesin Eg5 motor protein inhibitor
for the development of anticancer drugs (Bose et al., 2005).
Furthermore, the biological activity of several recently
isolated marine alkaloids has also been attributed to the
dihydropyrimidinone moiety in the structure. Among them
the batzelladine alkaloids A and B which inhibit the
binding of HIV envelope protein gp-120 to human CD4
cells are potential compounds in AIDS therapy (Snider and
Chen, 1998).
Ethyl 6-methyl-2-(methylthio)-4-phenyl-1,4-
dihydropyrimidine-5-carboxylate (IIa)
Yield: 82.10%. mp 160–162°C. IR (KBr), m, cm-1: 3328.53
(NH), 2974 (Ar C–H), 1665.23 (C=O), 1576.52 (C=N). 1H
NMR (300 MHz, DMSO, TMS):d 9.18 (s, 1H, NH),
7.75–7.20 (m, 5H, C6H5), 5.988 (S, 1H, CH), 3.98 (q, 2H,
OCH2CH3), 2.35 (s, 1H, S-CH3), 2.193 (s, 3H, CH3), 1.11
(t, 3H, OCH2CH3).
Methyl 6-methyl-2-(methylthio)-4-phenyl-1,4-
dihydropyrimidine-5-carboxylate (IIb)
Yield: 67.51%. mp 100–102°C. IR (KBr), m, cm-1: 3328.53
(NH), 2948.63 (Ar C–H), 1712.48 (C=O), 1641.13 (C=N).
1H NMR (300 MHz, DMSO, TMS): d 9.876 (s, 1H, NH),
7.751–7.201 (m, 5H, C6H5), 5.988 (s, 1H, CH), 3.71 (s, 3H,
OCH3), 2.351 (s, 1H, S-CH3), 2.193 (s, 3H, CH3).
In the present work, we propose to synthesize a series of
2-methylthio-1,4-dihydropyrimidines by alkylation of
1,2,3,4-tetrahydropyrimidines, confirm their structures by
spectral analysis, molecular docking studies of the title
compounds to ascertain their calcium channel blocking
activity and will try to correlate the same with cardiopro-
tective activity.
Ethyl 4-(4-methoxyphenyl)-6-methyl-2-(methylthio)-
1,4-dihydropyrimidine-5-carboxylate (IIc)
Yield: 78.94%. mp 116–117°C. IR (KBr), m, cm-1: 3304.43
(NH), 2961.16 (Ar C–H), 1652.7 (C=0), 1267.97 (C–O–C).
1H NMR (300 MHz, DMSO, TMS): d 9.876 (s, 1H, NH),
7.68–7.069 (m, 4H, C6H4), 5.988 (s, 1H, CH), 3.98 (q, 2H,
OCH2CH3), 3.605 (s, 3H, OCH3), 2.351 (s, 3H, S-CH3),
2.193 (s, 3H, CH3), 1.11 (t, 3H, OCH2CH3).
Experimental section
Melting points were determined in open capillaries and are
uncorrected. All compounds were characterized by ele-
mental analysis, IR, and 1H NMR spectra. The IR spectra
were recorded on a JASCO FT-IR 4100 spectrometer,
using KBr discs. The 1H NMR spectra were obtained on a
Varian-NMR-mercury 300 spectrometer in DMSO-d6 as
solvent and TMS as internal standard, chemical shifts are
given in ppm.
Methyl 4-(4-methoxyphenyl)-6-methyl-2-(methylthio)-
1,4-dihydropyrimidine-5-carboxylate (IId)
Yield: 73.68%. mp 146–147°C. IR (KBr), m, cm-1: 3316.
96 (NH), 2940.91 (Ar C–H), 1665.23 (C=O), 1244.83 (C–
1
O–C). H NMR (300 MHz, DMSO, TMS): d 9.87 (s, 1H,
General procedure for the synthesis
of compounds (IIa–IIl)
NH), 7.68–7.069 (m, 4H, C6H4), 5.988 (s, 1H, CH), 3.708
(s, 3H, OCH3), 3.605 (s, 3H, OCH3), 2.351 (s, 3H, S-CH3),
2.193 (s, 3H, CH3).
A mixture of appropriate aldehyde (0.02 mol), acetoacetate
(0.02 mol), thiourea (0.03 mol), catalyst aluminum chlo-
ride (0.01 mol) in methanol (10 ml), and concentrated
hydrochloric acid (2 drops) was placed in round bottom
flask. The mixture was stirred well and then refluxed. The
completion of reaction was monitored by thin layer
Ethyl 4-(4-chlorophenyl)-6-methyl-2-(methylthio)-
1,4-dihydropyrimidine-5-carboxylate (IIe)
Yield: 92.98%. mp 138–139°C. IR (KBr), m, cm-1: 3326.61
(NH), 2982.37 (Ar C–H), 1671.02 (C=O), 1569.77 (C=N),
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1
748.245 (C–Cl). 1H NMR (300 MHz, DMSO, TMS): d
9.876 (s, 1H, NH), 7.778–7.396 (m, 4H, C6H4), 5.988 (s,
1H, CH), 3.98 (q, 2H, OCH2CH3), 2.351 (s, 3H, S-CH3),
2.193 (s, 3H, CH3), 1.11 (t, 3H, OCH2CH3).
(C=N),1185.04, 1132.01 (C–O–C). H NMR (300 MHz,
DMSO, TMS): d 9.87 (s, 1H, NH), 5.874 (s, 1H, CH), 3.98
(q, 2H, OCH2CH3), 3.83 (s, 9H, OCH3), 2.351 (s, 3H,
S-CH3), 2.193 (s, 3H, CH3), 1.11 (t, 3H, OCH2CH3).
Methyl 4-(4-chlorophenyl)-6-methyl-2-(methylthio)-
Ethyl 6-methyl-2-(methylthio)-1,4-dihydropyrimidine-
1,4-dihydropyrimidine-5-carboxylate (IIf)
5-carboxylate (IIk)
Yield: 57.89%. mp 130–132°C. IR (KBr), m, cm-1: 3310.21
(NH), 2945.73 (Ar C–H), 1665.23 (C=O), 1475.28 (C=N),
777.172 (C–Cl). 1H NMR (300 MHz, DMSO, TMS): d 9.876
(s, 1H, NH), 7.778–7.396 (m, 4H, C6H4), 5.988 (s, 1H, CH),
3.708 (s, 3H, OCH3), 2.351 (s, 3H, S-CH3), 2.193 (s, 3H, CH3).
Yield: 65.47%. mp 210–211°C. IR (KBr), m, cm-1: 3204.15
(NH), 2992.45 (Ar C–H), 1659.45 (C=O), 1505.17 (C=N).
1H NMR (300 MHz, DMSO, TMS):d 9.179 (s, 1H, NH),
4.723 (S, 2H, CH2), 4.089 (q, 2H, OCH2CH3), 2.402 (s, 3H,
S-CH3), 2.173 (s, 3H, CH3), 1.222 (t, 3H, OCH2CH3).
Ethyl 4-[4-(dimethylamino)phenyl]-6-methyl-2-
(methylthio)-1,4-dihydropyrimidine-5-carboxylate
(IIg)
Methyl 6-methyl-2-(methylthio)-1,4-
dihydropyrimidine-5-carboxylate (IIl)
Yield: 54.05%. mp 198–200°C. IR (KBr), m, cm-1: 3314.07
(NH), 3008.41 (Ar C–H), 1665.23 (C=O),1587.13 (C=N).
1H NMR (300 MHz, DMSO, TMS):d 9.17 (s, 1H, NH),
4.723 (S, 2H, CH2), 3.705 (s, 3H, OCH3), 2.402 (s, 3H,
S-CH3), 2.173 (s, 3H, CH3).
Yield: 62.93%. mp 124–126°C. IR (KBr), m, cm-1: 3319.86
(NH), 2975.62 (Ar C–H), 1653.66 (C=O), 1515.78 (C=N).
1H NMR (300 MHz, DMSO, TMS): d 9.876 (s, 1H, NH),
7.532–6.577 (m, 4H, C6H4), 5.988 (s, 1H, CH), 3.98 (q, 2H,
OCH2CH3), 2.831 (s, 6H, N(CH3)2), 2.351 (s, 3H, S-CH3),
2.193 (s, 3H, CH3), 1.11 (t, 3H, OCH2CH3).
Docking studies
Methyl 4-[4-(dimethylamino)phenyl]-6-methyl-2-
(methylthio)-1,4-dihydropyrimidine-5-carboxylate
(IIh)
Docking studies of the title compounds was done on VLife
MDS 3.5 using grid-based docking method to ascertain
calcium channel blocking activity. The involvement of
b-subunit in trafficking of a1 subunit to plasma membrane
suggests that an inhibitor of this complex could have sig-
nificant therapeutic potential. Therefore, AID-b complex of
L-type calcium channel is selected as a biological target for
carrying out the docking study of title compounds. The
crystal structure of AID-b complex was obtained from
protein data bank, opened in MDS sheet, saved by removing
water molecule and used further for docking purpose.
The 2D structures of the compounds were built and then
converted into the 3D with the help of VLife MDS 3.5
software. The 3D structures were then energetically mini-
mized up to the rms gradient of 0.01 using Merck Molec-
ular Force Field (MMFF).
Yield: 75.75%. mp 214–216°C. IR (KBr), m, cm-1: 3319.86
(NH), 2809.78 (Ar C–H), 1671.02 (C=O), 1557.24 (C=N).
1H NMR (300 MHz, DMSO, TMS): d 9.876 (s, 1H, NH),
7.532–6.577 (m, 4H, C6H4), 5.988 (s, 1H, CH), 3.708 (s,
3H, OCH3), 2.831 (s, 6H, N(CH3)2), 2.351 (s, 3H, S-CH3),
2.193 (s, 3H, CH3).
Ethyl 6-methyl-2-(methylthio)-4-(4-nitrophenyl)-1,4-
dihydropyrimidine-5-carboxylate (IIi)
Yield: 83.68%. mp 180–182°C. IR (KBr), m, cm-1: 3227.29
(NH), 2980.45 (Ar C–H), 1694.16 (C=O), 1522.52 (Asy
Ar-NO2), 1345.11 (Sym Ar-NO2), 847.561 (C–N). 1H
NMR (300 MHz, DMSO, TMS): d 9.876 (s, 1H, NH),
7.89–8.10 (m, 4H, C6H4), 5.988 (s, 1H, CH), 3.98 (q, 2H,
OCH2CH3), 2.351 (s, 3H, S-CH3), 2.193 (s, 3H, CH3), 1.11
(t, 3H, OCH2CH3).
By using cavity determination option of software, cavi-
ties of enzyme were determined. The cavities in the receptor
were mapped to assign an appropriate active site, the basic
feature used to map the cavities was the surface mapping of
the receptor and identifying the geometric voids as well as
scaling the void for its hydrophobic characteristics. Hence,
all the cavities that are present in receptor are identified and
ranked based on their size and hydrophobic surface area.
Cavity no. 1 is selected for docking. The active site for
Ethyl 6-methyl-2-(methylthio)-4-(3,4,5-
trimethoxyphenyl)-1,4-dihydropyrimidine-5-
carboxylate (IIj)
Yield: 75.14%. mp 206–208°C. IR (KBr), m, cm-1: 3298.64
(NH), 2980.45 (Ar C–H), 1659.45 (C=O), 1576.52
docking was defined as all atoms within 5 A radius. Using
˚
biopredicta tool of software, open docking and then batch
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Table 1 Chemical structures and physicochemical characteristic of title compounds (IIa–IIl)
Compound
R1
R2
Molecular
formula
Molecular
weight
Melting
point (°C)
Yield
(%)
Rf value
IIa
IIb
OC2H5
OCH3
C15H18N2O2S
C14H16N2O2S
290.38
276.35
160–162
82.1
0.56
0.64
100–102
67.51
CH3
IIc
IId
OC2H5
OCH3
C16H20N2O3S
C15H18N2O3S
320.4
320.4
116–117
146–147
78.94
73.68
0.56
0.51
O
CH3
O
Cl
Cl
IIe
IIf
OC2H5
OCH3
C15H17ClN2O2S
C14H15ClN2O2S
324.82
310.79
138–139
130–132
92.98
57.89
0.72
0.69
H3
C
CH3
IIg
IIh
IIi
OC2H5
OCH3
C17H23N3O2S
C16H21N3O2S
C15H17N3O4S
C18H24N2O5S
333.44
319.42
335.37
380.45
124–126
214–216
180–182
206–208
62.93
75.75
83.68
75.14
0.56
0.48
0.46
0.33
N
H3
C
CH3
N
NO2
OC2H5
OC2H5
CH3
IIj
CH3
O
O
O
CH3
IIk
IIl
H
H
OC2H5
OCH3
C9H14N2O2S
C8H12N2O2S
214.28
200.25
210–211
198–200
65.47
54.05
0.3
0.72
grid docking. Batch docking shows browsing of receptor,
ligand (molecule), and the result generated was saved in
output file. Molecules saved in output file as a docked ligand
format with proper conformation and further used to check
binding interactions. Result generated was saved as log file
in output folder.
Cardioprotective activity
Chemical and reagents
Adrenaline (Sigma-Aldrich) was purchased from market
and 2-methylthio-1,4-diydropyrimidines synthesized on lab
scale (IIf and IIi).
For checking binding interaction, first receptor structure
was opened in MDS followed by compound which was
saved as ligand dock file. From tool option clicked on
merge molecule so that compound and receptor is merged
together. From biopredicta tool edited this complex and
selected ligand and receptor structure to check their
interactions.
Animals
Adult rats of Sprague–dawley strain were aged between 2
and 3 months of both sexes, weighing between 180 and
220 g. All the animals were obtained from animal house.
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1829
They were kept in medium-sized plastic cages. They were
allowed to live at room temperature, fed on standard pellets
of rat’s food and allowed to drink water ad libitum.
All the protocols of animal experiments were approved
by the Institutional Animal Ethics Committee in accor-
dance with the guidelines of Committee for the Purpose of
Control and Supervision of Experiments on Animals,
Ministry of Social Justice and Empowerment, Government
of India, New Delhi.
Experimental design
Adrenaline-induced cardiac hypertrophy
and cardiotoxicity
The experimental rats were divided into six groups (n = 6
in each group) and treated as follows:
Group 1: Normal control rats treated with distilled water.
Group 2: Rats treated with adrenaline (2 mg/kg for 2
consecutive days, s.c.).
Scheme 1
Group 3: Rats treated with test compounds (5 mg/kg
body weight/day orally for 15 days).
The purity of the synthesized compounds was monitored
by TLC using silica gel G and visualization was done using
iodine vapor. Their structures were confirmed by elemental
Group 4: Rats pretreated with test compounds (5 mg/kg
body weight/day orally for 15 days) and adrenaline
(2 mg/kg for 2 days, s.c. on 14th and 15th day).
Group 5: Rats treated with nifedipine (5 mg/kg body
weight/day orally for 15 days).
1
analysis, IR, and H NMR spectra. The amount of carbon,
hydrogen, and nitrogen found by elemental analysis is in
good agreement with calculated.
Group 6: Rats pretreated with nifedipine (5 mg/kg body
weight/day orally 15 days) and adrenaline (2 mg/kg for
2 days, s.c. on 14th and 15th day).
VLife MDS 3.5 was used for docking studies of the title
compounds to ascertain calcium channel blocking activity
and hence cardioprotection using AID-b complex of L-type
calcium channel as a target obtained from PDB with code
1T3L (Fig. 1). The docking of the title compounds yielded
fitness scores ranging from -3.952602 to -5.262574
(Table 2). The docking study revealed that the title com-
pounds have good interaction with AID-b complex, and
compounds IIf and IIi are potential candidates as a car-
dioprotective agent because of the highest negative dock
score (-4.978000 of compounds IIf and -5.262574 of
compounds IIi). Compound IIf bind with AID-b complex
Group 5 and Group 6 are positive control.
Measurement of ECG
At the end of experimental period (after 24 h of second
adrenaline injection), the rats were anesthetized with ure-
thane and ECGs were recorded using computerized data
acquisition system (Power Lab AD instrument).
Results and discussion
The 1,2,3,4-tetrahydropyrimidine-2-thione derivatives were
prepared by Biginelli three-component reaction of appro-
priate aldehydes, acetoacetate, and thiourea. Alkylation
reaction was used for the formation of C-2 modified DHPM
derivatives of type II. The title compounds, 2-methylthio-
1,4-dihydropyrimidine derivatives (Table 1) were synthe-
sized from the respective tetrahydropyrimidine-2-thiones
by reaction with methyl iodide in the presence of pyridine
(Scheme 1).
Fig. 1 AID-b complex of L-type calcium channel (PDB code 1T3L)
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Table 2 Docking score of title compounds (IIa–IIl)
Sl. no.
Compound
Dock score (kcal/mol)
1
IIa
-4.506683
-4.902032
-4.452957
-4.523580
-4.693726
-4.978000
-4.625088
-4.713718
-5.262574
-3.952602
-4.691329
-4.769786
-4.564425
2
IIb
IIc
3
4
IId
IIe
5
6
IIf
7
IIg
8
IIh
IIi
9
10
11
12
13
IIj
Fig. 3 Interaction of compound IIf with AID-b complex of L-type
Ca2? channel
IIk
IIl
Nifedipine
of L-type calcium channel by forming hydrogen bond
interaction with amino acid residue THR58, hydrophobic
interaction with amino acid residue THR58, LYS59,
PRO60, VAL61, LYS97, LEU314, SER415, and van der
Waals interaction with amino acid residue THR58, LYS59,
PRO60, VAL61, LYS97, GLN315, SER415 (Figs. 2, 3).
Compound IIi binds with AID-b complex of L-type cal-
cium channel by forming hydrogen bond interaction with
amino acid residue THR313, hydrophobic interaction with
amino acid residue PRO60, VAL61, THR313, LEU314,
SER415, and van der Waals interaction with amino acid
residue LYS57, THR58, PRO60, VAL61, LYS97,
ARG312, THR313, HIS411, SER414 (Figs. 4, 5). Com-
pounds IIf and IIi showed significant cardioprotective
activity on adrenaline-induced myocardial infarction in rats
(Table 3). Electrocardiographic (ECG) abnormalities are
the main criteria generally used for the diagnosis of myo-
cardial infarction. Significant alterations in ECG patterns
were observed in adrenaline-administered rats as compared
to normal control rats. Adrenaline showed significant
Fig. 4 Compound IIi docked in cavity no 1 of AID-b complex of
L-type Ca2? channel
Fig. 5 Interaction of compound IIi with AID-b complex of L-type
Ca2? channel
elevation in ST interval, reduction in R–R interval, and P
duration. In addition, there was increase in heart rate and
prolongation of QT interval (Fig. 6). Pretreatment with test
compounds and adrenaline significantly prevented these
Fig. 2 Compound IIf docked in cavity no 1of AID-b complex of
L-type Ca2? channel
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Table 3 Cardioprotective activity of compounds IIf and IIi against adrenaline-induced myocardial infarction in rats
Compound
R–R interval (s)
Heart rate (BPM)
ST interval (s)
P-duration (s)
QT interval (s)
Control
0.1812 0.0189
0.135 0.0176##
0.1533 0.0367**
0.1852 0.0294**
0.2146 0.0294**
338.2 6.541
422.76 6.158##
382.03 8.760**
315.766 5.121**
278.5 7.143**
0.04677 0.0084
0.0829 0.0024##
0.0545 0.0062**
0.05879 0.0026**
0.0455 0.0013**
0.01657 0.0029
0.06466 0.0017
Adrenaline
0.01136 0.0044##
0.01358 0.0016**
0.01660 0.0048**
0.01815 0.0011**
0.08205 0.0023##
0.03879 0.0024**
0.06664 0.0054**
0.06101 0.0040**
IIf ? Adrenaline
IIi ? Adrenaline
Nifedipine
Values are expressed as Mean SEM. Statistical comparisons were performed by one-way ANOVA followed by Dunnett’s test
The ECG parameters are expressed in seconds (s) and the heart rate as Beats Per Minute (BPM)
##
P \ 0.01 was considered significant when compared with control
** P \ 0.01 was considered significant when compared with adrenaline
Fig. 6 ECG after administration of adrenaline
Fig. 9 ECG after administration of compound IIi ? adrenaline
Fig. 7 ECG of control
Fig. 10 ECG after administration of nifedipine ? adrenaline
alterations and restored ECG values to near control
(Figs. 7, 8, 9, 10).
Conclusion
The docking of 2-methylthio-1,4-dihydropyrimidines with
AID-b complex of L-type calcium channel and subsequent
evaluation of shortlisted compounds, methyl 4-(4-chloro-
phenyl)-6-methyl-2-(methylthio)-1,4-dihydropyrimidine-5-
carboxylate (IIf) and ethyl 6-methyl-2-(methylthio)-4-(4-
nitrophenyl)-1,4-dihydropyrimidine-5-carboxylate (IIi), for
Fig. 8 ECG after administration of compound IIf ? adrenaline
123

1832
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cardioprotective activity reveals that the observed cardio
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of L-type calcium channel and thus reducing calcium
influx.
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