Synthesis and antihyperlipidemic activity of novel condensed 2-fluoromethylpyrimidines

Article abstract of DOI:10.1007/s00044-012-0263-z

A series of novel condensed 2-fluoromethylpyrimidines has been synthesized and evaluated for antihyperlipidemic activity in high fat diet fed hyperlipidemic Sprague-Dawley rats. The aim of this study was to investigate the effect of the fluorine atom at the 2-methyl position of these compounds. Most of the synthesized compounds significantly affected the lipid profile of the test animals. Compound IIIb exhibited remarkably best effects in lowering the serum cholesterol and triglyceride levels and elevating the serum HDL levels, of the test animals. Graphical abstract: A series of novel condensed 2-fluoromethylpyrimidines was synthesized and evaluated for antihyperlipidemic activity in hyperlipidemic Spargue-Dawley rats. All compounds, especially IIIb, significantly affected the lipid profile of test animals.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s00044-012-0263-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:4286–4292
DOI 10.1007/s00044-012-0263-z
ORIGINAL RESEARCH
Synthesis and antihyperlipidemic activity of novel condensed
2-fluoromethylpyrimidines
•
Muthu K. Kathiravan Kapil D. More Vikas K. Raskar
•
•
•
Kishor S. Jain Mukta Maheshwar Sandeep Gadhwe
•
•
•
Dilpesh P. Jain Madhuri A. Nagras Manisha S. Phoujdar
•
Received: 10 April 2012 / Accepted: 27 September 2012 / Published online: 6 January 2013
ꢀ Springer Science+Business Media New York 2013
Abstract A series of novel condensed 2-fluoromethyl-
pyrimidines has been synthesized and evaluated for anti-
hyperlipidemic activity in high fat diet fed hyperlipidemic
Sprague–Dawley rats. The aim of this study was to
investigate the effect of the fluorine atom at the 2-methyl
position of these compounds. Most of the synthesized
compounds significantly affected the lipid profile of the test
animals. Compound IIIb exhibited remarkably best effects
in lowering the serum cholesterol and triglyceride levels
and elevating the serum HDL levels, of the test animals.
countries (Jain et al., 2007). By 2030, almost 23.6 million
people may die from CVDs and stroke (http://www.who.int/
mediacentre/factsheets/fs317/en). Elevated lipid levels can
be reduced by either the inhibition of the endogenous cho-
lesterol biosynthesis or promoting hepatic cholesterol
clearance from the plasma or by inhibiting the absorption of
dietary and biliary cholesterol from the intestine (Clader
et al., 1996).
Earlier, we have reported the synthesis and antihyperlipidemic
activity in series of condensed 2-substitutedmethylpyrimidin-
4(3H)-ones (Kathiravan et al., 2007a) (Fig. 1). Compound 1 has
already exhibited significant lipid lowering property in various
laboratory animals and has been a subject of pharmacokinetic and
bioavailability studies (Shishoo et al., 1996). The QSAR studies
(Shishoo et al., 1997; Kathiravan et al., 2011; Jain et al., 2011) on
thieno[3,2-d]-pyrimidin-4(3H)-ones 2, 3 and thieno[3,2-d]pyrim-
idines 4 have indicated the direct positive influence of the electron
withdrawing groups at the methyl substituent on their antihyper-
lipidemic activity.
Keywords Antihyperlipidemic Á Lipid profile Á
Condensed 2-fluoromethylpyrimidines
Introduction
Hyperlipidemia is a collective term used to describe elevated
human plasma levels of one or more classes of lipids, namely
cholesterol, triglycerides, phospholipids, and fatty acids
(Jain et al., 2007). Hyperlipidemia and atherosclerosis, are
two risk factors for stroke and cardiovascular diseases
(CVDs); the leading causes of death in many industrialized
Introducing a spacer (an ethyl group) at position 2- resulted
indecreaseinactivitywhile, introductionofa chlorineatomat
position 4- resulted in better activity (Fig. 2). The ‘‘condensed
2-chloromethylpyrimidine’’ nucleus, is therefore concluded
to be a potential pharmacophore for antihyperlipidemic
activity.
It was logically thought to introduce a group of higher
electronegativity such as fluorine atom on the 2-methyl
position of the basic pharmacophore and see its effect on
the lipid profiles of test animals. The variations for sub-
stitution introduced at positions 5- and 6- at the rings fused
to the pyrimidine were aliphatic, aromatic, alicyclic, as
well as, electron donating and withdrawing groups.
The fluorine atom, being very electronegative is known
to change the charge distribution (polarity) in compounds
into which it is placed, thereby altering their biological
Muthu K. Kathiravan and Kapil D. More contributed equally to this
study.
M. K. Kathiravan Á K. D. More Á V. K. Raskar Á
K. S. Jain Á M. Maheshwar Á S. Gadhwe Á
D. P. Jain Á M. A. Nagras Á M. S. Phoujdar (&)
Department of Pharmaceutical Chemistry, P. G. Research
Centre, Sinhgad College of Pharmacy, S. No. 44/1,
Vadgaon (Bk.), Off Sinhgad Road, Pune 411041,
Maharastra, India
e-mail: mphoujdar@hotmail.com
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4287
Fig. 1 Structure of lead
compounds 1–4
X
N
O
N
R1
N
O
CH2Cl
NH
N
O
CH2Cl
NH
N
NH
CH2Cl
R2
N
Cl
n
S
S
S
S
X = OH, Cl, n = 1, 2
1
2
3
4
Fig. 2 Basic pharmacophore
requirement for optimum
antihyperlipidemic activity
effects, chemical and metabolic stability, as well as bio-
availability (Kirk, 2006; O’Hagan, 2010).
to the title compounds by interfering in cholesterol reab-
sorption and to be effective by oral route (Shishoo et al.,
1997). These points led to the selection of ezetimibe as the
standard drug during the biological evaluation of the title
compounds.
Results and discussion
One week after the treatment all the animal groups were
fasted for 14 h and blood was withdrawn from retro orbital
plexus of the test animals for the evaluation of serum level
of total cholesterol, triglyceride, and HDL (Heek et al.,
2003; Santosh et al., 2006; Mali and Bodhankar, 2008).
The obtained results revealed that feeding rats with high
fat diet for 7 days significantly elevated the serum levels of
total cholesterol and triglycerides, as compared to the nor-
mal control rats. Moreover, induction of hyperlipidemia
significantly decreased serum HDL levels of these animals
as compared to the normal control ones. It was found that the
test compounds showed significant changes in lipid profile,
i.e., decrease in serum level of total cholesterol and tri-
glycerides and increase in HDL at a dose of 50 mg/kg body
weight p.o. as compared with the normal control group.
A perusal of Table 2 reveals that at 50 mg/kg body
weight p.o. dose levels, compounds IIIb caused significant
reduction in serum total cholesterol levels, comparable to
that caused by ezetimibe at a dose level of 1 mg/kg body
weight p.o. compounds, while compounds IIIa, IIIc, IIId,
IIIe, and IIIg remained moderately effective. The test
compounds IIIb, IIIf, and IIIa caused significant reduction
in serum triglycerides levels Table 2, comparable to that
caused by ezetimibe at a dose level of 1 mg/kg body
weight p.o. compounds, while compounds IIIc, IIId, IIIe,
IIIg, and IIIh remained moderately effective. The com-
pounds IIIf and IIIb also exhibited good HDL levels
enhancing activity in the test animals (Table 2), while
other compounds IIIa, IIIc, IIId, IIIe, IIIg, and IIIh
remained moderately effective in this activity.
Chemistry
Various ortho-amino substrates Ia–h were synthesized as per
earlier reported methods (Kathiravan et al., 2007b; Car-
penter et al., 1979). The intermediate compounds, condensed
2-chloromethylpyrimidin-4(3H)-ones IIa–h were synthe-
sized through the facile one pot HCl catalyzed cyclization of
appropriate 2-amino-3-carbethoxy/carbmethoxy substrates
with slight molar excess of chloroacetonitrile under MWI, by
the reported procedure from this laboratory (Jain et al., 2009)
(Table 1; Scheme 1).
The title compounds condensed 2-fluoromethylpyrimi-
din-4(3H)-ones (IIIa–h, Table 1) were synthesized through
the nucleophilic halogen exchange reaction of IIa–h with
NaF in the presence of TEBA-Cl in a dipolar aprotic sol-
vent, dimethyl sulfoxide (DMSO) at 135–140 ꢁC (Atkinson
and Lebedev, 2003; Robert, 1981) (Table 1; Scheme 1).
Antihyperlipidemic activity
The test compounds IIIa–h were evaluated for antihyper-
lipidemic activity in high fat diet fed Sprague–Dawley rats
for 1 week. The test animals were divided broadly into 11
groups. Compounds were administered at dose 50 mg/kg,
p.o., whereas, ezetimibe (Kathiravan et al., 2009) a well-
known cholesterol absorption inhibitor was administered as
the standard drug at dose 1 mg/kg p.o. The standard drug,
ezetimibe, also has fluoro substituents. Further, the pro-
posed mechanism of action for compounds closely related
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Med Chem Res (2013) 22:4286–4292
Table 1 Physical data for the condensed 2-fluoromethylpyrimidin-4(3H)-ones (IIIa–h)
Comp no.
M.P (ꢁC)
(Solv. of recryst.)
Rf
Yield (%)
IIIa
IIIb
258–260 (D–M)
189–190 (D–M)
0.56
0.52
76
78
IIIc
237–239 (D–M)
0.55
75
IIId
IIIe
258–260 (D–M)
226–227 (D–M)
0.51
0.52
75
73
IIIf
262–264 (D–M)
0.58
74
IIIg
IIIh
190–192 (D–M)
210–212 (D–M)
0.56
0.53
71
67
D dichloromethane, M methanol
Scheme 1 Scheme for the
synthesis of target compounds
O
O
O
NaF, TEBA.Cl
N
MWI, 20 W
NH
NH
OR
Cl
F
Cl
DMSO
Conc. HCl
25-35 mins
N
N
NH2
Ia-h
R= CH3, C2H5
130-140 oC,
6 hrs
IIa-h
IIIa-h
The compounds IIIb, IIIf, and IIIa exhibit good VLDL
and LDL reducing activity, comparable to that caused by
ezetimibe at a dose level of 1 mg/kg body weight p.o.
(Table 2) while compounds IIIc, IIId, IIIe, IIIg, and IIIh
remained moderately effective. All compounds exhibit
good atherogenic index (Normal value of AI = \3.5).
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Total two test compounds IIIb and IIIf of the series
significantly affect the lipid profile (decreasing total cho-
lesterol and triglycerides and increasing the HDL levels) of
the test animals and can be looked upon as potential leads
for further development and investigations.
Experimental
Chemistry
All reagents and chemicals used were of LR grade and
standard quality. Melting points were determined on sci-
entific melting point apparatus in open capillaries and were
uncorrected. The 1H NMR spectra were recorded in
DMSO-d6 using NMR Varian Mercury YH-300 MHz
spectrometer and chemical shifts are given in units as parts
per million, downfield from TMS (tetramethylsilane) as an
internal standard. Mass spectra were obtained on a Shi-
madzu GCMS-QP2010 spectrometer. Elemental analyses
were obtained using a Flash EA 1112 Thermofinnigan
instrument. The IR spectra of the synthesized compounds
were recorded on Perkin Elmer (USA) Spectrum BX2 FT–IR
spectrophotometer in potassium bromide disks.
General synthesis procedure of condensed
2-chloromethylpyrimidin-4(3H)-ones (IIa–h)
A mixture of an appropriate o-aminoester substrate
(0.01 mol), chloroacetonitrile (1.51 g, 0.02 mol), and cat-
alytic amount of HCl were irradiated under microwave for
25–35 min at 20 W. The progress of reaction was moni-
tored (TLC; Toluene: methanol: 4.5: 0.5) at 5 min inter-
vals. After completion of the reaction (25–35 min), the
reaction mixture was allowed to cool to room temperature
and poured onto ice-water mixture (100 ml). The resultant
product was filtered, washed with chilled water, and dried.
The crude product on recrystallization from dioxane yiel-
ded fine crystals of intermediate compounds. (IIa–h).
General synthesis procedure of condensed
2-fluoromethylpyrimidin-4(3H)-ones (IIIa–h)
A mixture of appropriate 2-chloromethylpyrimidin-4(3H)-
one (0.01 mol), sodium fluoride (0.025 mol), and TEBA
Chloride (0.002 mol) in DMSO (30 ml) were heated at
130–140 ꢁC for 6–8 h. The progress of reaction was
monitored by TLC. Upon completion, the reaction mixture
was thereafter cooled to room temperature and poured onto
ice-water mixture (100–150 ml). The solid separated was
filtered, washed with water, and dried. The crude product
on recrystallization from mixture of methanol and
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methylene chloride (5 %) yielded crystals of target com-
274 (M?), Anal. Calcd. for C14H11FN2OS; C, 61.30; H, 4.04;
N, 10.21; Found: C, 61.25; H, 4.18; N, 10.30.
pounds, IIIa–h.
2-Fluoromethyl-5,6,7,8-tetrahydrobenzo(b)thieno-[2,
3-d]pyrimidin-4(3H)-one (IIIa)
2-Fluoromethyl-5-(4-chlorophenyl)thieno[2,3-d]pyrimidin-
4(3H)-one (IIIf)
IR (KBr) : 3366.81 (cNH), 2854.42 (cC–H), 1654.14(cC=O),
1070.28 (cC–F). 1H NMR (300 MHz, DMSO):1.72 (4H, s,
CH2 at 6 & 7), 2.71 (2H, s, CH2 at 8), 2.85 (2H, s, CH2 at 5),
4.35 (2H, s, CH2 at 2), 11.97 (1H, s, NH at 3). MS
(m/e): 238(M?), 237, 217, 196, 182 and 163. Anal. Calcd.
for C11H11FN2OS: C, 55.45; H, 4.65; N, 11.76; Found:
C, 55.61; H, 4.85; N, 11.85.
IR (KBr) : 3091.64 [cArH]; 1670.11 [cCONH]; 1037.15
(cC–F). H NMR (300 MHz, DMSO):4.48 (2H, s, CH2,),
7.41–7.56 (4H, m, Ar–H and 1H at 6 position), 11.69 (1H,
s, br, NH). MS (m/e): 294 (M?). Anal. Calcd. for:
C13H8ClFN2OS: C, 52.98; H, 2.74; Cl, 12.03; N, 9.50;
Found: C, 53.09; H, 2.65; N, 9.69.
1
2-Fluoromethylquinazolin-4(3H)-one (IIIg)
Ethyl 2-fluoromethyl-5-methylthieno[2,3-d]pyrimidine-6-
carboxylate (IIIb)
IR (KBr) : 3064.10[cArH]; 2847.86(cC–H), 1676.17(cCONH),
1130.02 (cC–F). H NMR (300 MHz, DMSO): 4.35 (2H, s,
1
IR (KBr) : 3247.43(cNH), 2917.69(cC–H), 1718.02(cC=O),
1684.32(cCONH), 1032.64 (cC–F). 1H NMR (300 MHz,
DMSO): 1.41 (3H, t, J = 7.0, CH3), 2.95 (3H, s, CH3).
4.38 (2H, quartlet, J = 7.0, CH2), 4.57 (2H, s, CH2), 10.62
(1H, s, NH). MS (m/e): 270 (M?), Anal. Calcd. for
C11H11FN2O3S: C, 48.88; H, 4.10; N, 10.36; Found: C,
48.97; H, 4.23; N, 10.13.
CH2), 7.2–7.5 (4H, m, ArH), 10.36 (1H, s, NH). MS (m/e):
178 (M?). Anal. Calcd. for: C9H7FN2O: C, 60.67; H, 3.96;
N, 15.72; Found: C, 60.75; H, 4.12; N, 15.81.
2-Fluoromethyl-6,7-dimethoxyquinazolin-4(3H)-one (IIIh)
IR (KBr) : 2927.25(cC–H), 1669.99[cCONH]; 1097.53 (cC–F).
1H NMR (300 MHz, DMSO):2.5–2.8 (6H, s, CH3); 4.3
(2H, s, CH2 at 6); 7.2–7.5 (2H, m, ArH). MS (m/e): 238
(M?). Anal. Calcd. for C11H11FN2O3: C, 55.46; H, 4.65;
N, 11.76; Found: C, 55.54; H, 4.78; N, 11.87.
2-Fluoromethyl-5,6-dimethylthieno[2,3-d]pyrimidin-
4(3H)-one (IIIc)
IR (KBr) : 3394.19(cNH), 2851.08(cC–H), 1654.82(cC=O),
1037.99 (cC–F). 1H NMR (300 MHz, DMSO): 2.33 (3H, s,
CH3), 2.36 (3H, s, CH3), 4.35 (2H, s, CH2), 11.95(1H, s, br,
NH). MS m/e: 212 (M?), 210, 192, 181, 166, 153, 138.
Anal. Calcd. for C9H9FN2OS: C, 50.93; H, 4.27; N, 13.20;
Found: C, 51.03; H, 4.38; N, 13.36.
Antihyperlipidemic activity
The experiments were carried on Sprague–Dawley rats
(150–200 g) of either sex. The animals were housed at a
temperature of 20 2 ꢁC with relative humidity of
50 10 % with 12 h light and dark cycles. All the study
protocols were reviewed and approved (SCOP/IAEC/
Approval/2010-11/02) by the Institutional Animal ethical
committee. Acute toxicity studies were done according to
OECD guidelines GL-423. Ezetimibe (1 mg/kg) was used
as standard for the comparison antihyperlipidemic activity.
Normal diet was made available for 7 days to Group I
(normal control) and vehicle (2 % acacia solution. p.o.)
was administered for 7 days. Hyperlipidemia was induced
to Group II (cholesterol fed diet control) by orally
administering with a suspension of cholesterol (500 mg/kg)
and cholic acid (250 mg/kg) in groundnut oil (10 ml/kg)
daily for 7 days. Standard treatment groups (Group III)
were orally administered ezetimibe at dose 1 mg/kg p.o.,
respectively for 7 days daily in cholesterol fed animals.
Test groups (Groups IV–XI) were orally administered eight
synthesized compounds at dose 50 mg/kg, respectively for
7 days daily in high fat diet fed animals.
2-Fluoromethyl-5-phenylthieno[2,3-d]pyrimidin-4(3H)-
one (IIId)
IR (KBr) : 3101.24(cNH), 2849.80(cC–H), 1663.33(cCONH),
1
1051.09 (cC–F). H NMR (300 MHz, DMSO): 4.42 (2H, s,
CH2,), 7.36–7.54 (5H, m, Ar–H and 1H at 6 position),
12.11 (1H, s, br, NH). MS m/e: 260(M?), 258, 239. Anal.
Calcd. for C13H9FN2OS: C, 59.99; H, 3.49; N, 10.76;
Found: C, 60.12; H, 3.58; N, 10.85.
2-Fluoromethyl-6-methyl-5-phenylthieno [2,3-d]pyrimidin-
4(3H)-one (IIIe)
IR (KBr) : 3134.36[cArH]; 2921.68(cC–H), 1664.10[cCONH];
1
1055.33 (cC–F). H NMR (300 MHz, DMSO): 2.40 (3H, s,
CH3), 4.42 (2H, s, CH2), 7.38–7.44 (5H, m, Ar–H). MS (m/e):
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The blood was collected on 8th day; animals were kept
on fasting 14 h before the blood withdrawal. The blood
was withdrawn by retro orbital method under light ether
anesthesia and serum was separated by centrifugation at
3,000 rpm for 10 min and evaluated for serum total cho-
lesterol, triglyceride, and HDL level using commercial
diagnostic kits (Biolabs Pvt. Ltd., Mumbai, India) whereas
atherogenic index, coronary risk index, serum LDL, and
VLDL levels were calculated by the reported formulae
(Mali and Bodhankar, 2008; Friedewald et al., 1972; Stern
et al., 2000).
compounds IIIb and IIIf, showed the best activity in
reducing serum cholesterol and triglyceride levels. Com-
pound IIIf showed the most significant HDL enhancing
effects. Overall, the title compounds IIIb and IIIf can be
looked upon as potential leads for further development and
investigations.
Research highlights
•
•
•
Condensed 2-fluoromethylpyrimidines were synthesized.
Their antihyperlipidemic activity was evaluated.
The presence of fluorine atom at 2-methyl position is
important.
Statistical analysis
All the values were expressed as the mean SEM and
were subjected to one-way analysis of variance (ANOVA)
followed by Tukey’s test, where P \ 0.001 was considered
as statistical significant.
•
At 5- and 6- positions electron withdrawing groups are
favorable.
Acknowledgments The authors acknowledge the contributions of
Prof. M. N. Navale, President, and Dr. (Mrs.) S. M. Navale, Secretary,
Sinhgad Technical Education Society, Pune and University of Pune
for providing necessary facilities to carry out the research & spectral
analysis.
Structure activity relationship
•
The synthesized compounds have shown good antihy-
perlipidemic activity by significantly affecting the lipid
profile (decreasing total cholesterol and triglycerides
and increasing the HDL levels) of the test animals.
The 2-halo or 2-chloromethylpyrimidin-4-one is the
basic structural requirement for optimum antihyperlip-
idemic activity. The rings fused to the scaffold at its
5- and 6- position as junction also play a significant role
in the potency of the title compound.
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