Design, synthesis and in vivo screening of some novel quinazoline analogs as anti-hyperlipidemic and hypoglycemic agents

Article abstract of DOI:10.1016/j.bmcl.2015.12.037

A novel series of substituted quinazoline derivatives were designed, synthesized and evaluated for their hypolipidemic activity in cholesterol induced hyperlipidemic rats. In vivo screening concluded that compounds A-4, C-5 and C-6 have shown potent antihyperlipidemic activity by decreasing the plasma level of triglycerides (TG), very low density lipoprotein (VLDL), low density lipoprotein (LDL), followed by increase in level of high density lipoprotein (HDL).

Full text of DOI:10.1016/j.bmcl.2015.12.037

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Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and in vivo screening of some novel quinazoline
analogs as anti-hyperlipidemic and hypoglycemic agents
a
a
a
b
Santosh N. Mokale a, , Akash D. Palkar , Pritam N. Dube , Nikhil S. Sakle , Pankaj B. Miniyar
⇑
a Dr. Rafiq Zakaria Campus, Y. B. Chavan College of Pharmacy, Aurangabad 431001, Maharashtra, India
b Department of Pharmaceutical Chemistry, Sinhgad Institute of Pharmacy, Narhe, Pune, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of substituted quinazoline derivatives were designed, synthesized and evaluated for their
hypolipidemic activity in cholesterol induced hyperlipidemic rats. In vivo screening concluded that com-
pounds A-4, C-5 and C-6 have shown potent antihyperlipidemic activity by decreasing the plasma level of
triglycerides (TG), very low density lipoprotein (VLDL), low density lipoprotein (LDL), followed by
increase in level of high density lipoprotein (HDL).
Received 25 October 2015
Revised 26 November 2015
Accepted 11 December 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Quinazoline
Antihyperlipidemic
Hypoglycemic
In industrialized world the rate of morbidity and mortality is
increased due to coronary heart diseases. Triglycerides and choles-
terol are major component of lipids circulating in the blood
stream.1,2 In human digestive system the hydrolyzed form of
triglycerides are produced, that is, free fatty acid and monoglyc-
erides which reabsorbed by intestine leading to different type of
cardiovascular and obesity diseases.3,4
The Scheme 1 consist of synthesis of 2-methyl-2-(4-(2-methyl-
4-oxoquinazolin-3(4H)-yl)phenoxy)propanoic acid (A-4) and 2-(4-
(2-methyl-4-oxoquinazolin-3(4H)-yl)phenoxy)acetic acid (A-5).
The first step consist of cyclization of 2-methyl-4H-benzo[d]
[1,3]oxazin-4-one (A-2) by addition of acetic anhydride to
the 2-amino benzoic acid. Then resultant compound was
refluxed with 4-amino phenol to give 3-(4-hydroxyphenyl)-2-
methylquinazolin-4(3H)-one (A-3).10 Finally compounds A-4 and
A-5 were synthesized by etherification of compound A-3 by
2-bromo-2-methyl propanoic acid and 2-chloro acetic acid
respectively.
The currently prescribed fibrates, such as clofibrate and fenofi-
brate have been effective ligands of PPARa receptor; specifically
involved in the regulation and expression of target genes responsi-
ble for lipid and lipoprotein metabolism.1The hypolipidemic effects
of fibrates are obtained through activation of PPRA
a
receptor, by
Similarly, compounds B-6, B-7, C-5, C-6, D-4 and D-5 were syn-
thesized as per stated in Schemes 2–4 and their structures have
been verified by IR, 1H NMR, 13C NMR and LC–MS spectroscopy.
The purity of these compounds was ascertained by TLC and spec-
tral analysis. The spectral data are provided in Experimental
section.
The hypoglycemic and hypolipidemic activity of the synthe-
sized compounds was studied in the high fat diet induced hyper-
lipidemic Sprague–Dawley rats for 30 days by oral administration
of the drug and compounds.3,6 The in vivo profile of the synthe-
sized compounds was compared with reference drug fenofibrate
at 250 mg/kg dose.
The body weight as well as hypoglycemic activity of synthe-
sized compounds was summarized Table 1. The compounds C5
(83.0 mg/dl) and C6 (85.3 mg/dl) showed most potent hypo-
glycemic effect as compare to standard (86.41 mg/dl) whereas
compounds A4 and A5 showed moderate activity.
lowering the level of TG, LDL and increasing the level of HDL by
increasing the transcription of apolipoprotein.5,6
The general structure of fibrate analogs comprised of lipophilic
tail, acidic pharmacophore and spacer in between.7 The phenoxy
acetic/propanoic acid pharmacophore is frequently coupled with
heterocycles for hyperlipidemic activity (Fig. 1). Instigated with
all the above facts and in continuation with our efforts towards
to form a rational design the heterocycle quinazoline is coupled
with phenoxy acetic acid and 2-methyl propanoic acid to form
active ligands of fibrates.8,9
In the present investigation, designed quinazoline derivatives
(Fig. 1) were prepared by the methods that have been outlined in
Schemes 1–4. The synthesized derivatives were evaluated for their
anti-hyperlipidemic and hypoglycemic activity.
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.bmcl.2015.12.037
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mokale, S. N.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.12.037

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S. N. Mokale et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
Figure 1. Designed pharmacophore for quinazoline fibrates.
OH
N
O
CH3
K.acetate
N
O
CH3
Glacial acetic
O
2hrs
N
acid
p-amino phenol
16hrs
O
Acetic anhydride
NH2
OH
2-aminobenzoic acid
2-methyl-4H-benzo[d]
3-(4-hydroxyphenyl)-2-
methylquinazolin -4(3H)-one
[1,3]oxazin-4-one
A-1
A-3
A-2
Br
O
O
Cl
2-bromo-2-methyl
propanoic acid
OH
OH
4 hrs
DMF
4 hrs
DMF
Chloro
Acetic acid
N
CH3
N
CH3
N
N
O
OH
O
O
OH
O
O
2-methyl-2-(4-(2-methyl-4-oxoquinazolin-
2-(4-(2-methyl-4-oxoquinazolin- O
3(4H)-yl)phenoxy)acetic acid
3(4H)-yl)phenoxy)propanoic acid
A-4
A-5
Scheme 1. Synthesis of designed compounds A4 and A5.
The hypolipidemic activity of compounds were tabulated in
activity. The compounds containing 1-phenyl 2-methyl quinazoli-
none and 2-phenyl quinazolinone nucleus was shown lesser hypo-
glycemic and hypolipidemic activity. Compound B6 demonstrated
more emphasis on hypocholesterolemic rather than hypotriglyc-
eridemic activity in assessing the hypolipidemic activity of test
compounds.
Table 2. The total lipid profile, that is, cholesterol, TG, VLDL, LDL,
HDL, CHO/HDL were shown that all the compounds possess good
to moderate hypolipidemic activity. Experimental values of blood
lipids reduction of compounds A5, C5 and C6 were more potent
as compare to fenofibrate.
The structure activity relationship showed that the compounds
containing 7-hydroxy 2-methyl quinazolinone moiety (compounds
C5 and C6) were shown better activity than other synthesized
compounds whereas 2-methyl quinazolinone derivatives (com-
pounds A4 and A5) showed moderate to potent hypolipidemic
In this study we synthesized the novel quinazoline derivatives
containing acetic acid and 2-methyl propanoic acid as
pharmacophore for their hypoglycemic and hypolipidemic activity.
Hence the present series could be developed as a novel class of
hypolipidemic and hypoglycemic agents.
Please cite this article in press as: Mokale, S. N.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.12.037

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3
O
OH
Cl
O
OH
NH
O
N
O
O
Pyridine
6hrs
Acetic anhydride
2hrs
+
O
NH2
2-aminobenzoic acid
benzoyl chloride
2-benzamidobenzoic acid
B-1
2-phenyl-4H-benzo[d]
B-2
[1,3]oxazin-4-one
B-3
B-4
N
N
O
K.acetate
p-amino phenol
Glacial acetic
acid
Br
O
OH
16 hrs
O
2
-
b
r
o
n
O
p
m
r
o
o
-
c
OH
p
2
a
-
m
o
i
e
N
t
h
2-methyl-2-(4-(4-oxo-2-phenylquinazolin-3
a
c
i
y
l
d
(4H)-yl)phenoxy)propanoic acid
N
DMF
O
O
B-6
OH
4 hrs
3-(4-hydroxyphenyl)-2-
phenylquinazolin -4(3H)-one
OH
Cl
N
N
B-5
Chloro
Acetic acid
O
OH
O
O
2-(4-(4-oxo-2-phenylquinazolin-3(4H)-yl)phenoxy)acetic acid
B-7
Scheme 2. Synthesis of designed compounds B6 and B7.
N
HO
CH3
OH
Acetic
anhydride
HO
O
O
2hrs
O
NH2
7-hydroxy-2-methyl-4H
2-amino-5-hydroxybenzoic acid
-benzo[d][1,3]oxazin-4-one
C-2
C-1
OH
O
OH
Cl
OH
Br
O
+
H2N
+
H2N
OH
4-aminophenol
2-chloroacetic acid
2-bromo-2-methyl
propanoic acid
4-aminophenol
DMF
Reflux
2hrs.
K2CO3
DMF
Reflux
2hrs.
K2CO3
O
O
O
OH
O
OH
H2N
H2N
2-(4-aminophenoxy)acetic acid
2-(4-aminophenoxy)-2-methylpropanoic acid
C-4
C-3
+
+
N
HO
CH3
HO
N
CH3
O
O
O
O
7-hydroxy-2-methyl-4H
-benzo[d][1,3]oxazin-4-one
7-hydroxy-2-methyl-4H
-benzo[d][1,3]oxazin-4-one
C-2
C-2
Glacial acetic
acid
Pot acetate
8hrs
Glacial acetic
acid
Pot acetate
8hrs
HO
N
CH3
HO
N
O
CH3
N
O
N
O
OH
OH
O
O
O
2-(4-(7-hydroxy-2-methyl-4-oxoquinazolin
-3(4H)-yl)phenoxy)-2-methylpropanoic acid
2-(4-(7-hydroxy-2-methyl-4-oxoquinazolin-
3(4H)-yl)phenoxy)acetic acid
C-5
C-6
Scheme 3. Synthesis of designed compounds C5 and C6.
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O
K.acetate
OH
Glacial acetic acid
Acetic anhydride
2hrs
N
O
CH3
N
O
CH3
NH
p-amino phenol
16hrs
O
N
OH
2-(phenylamino)
benzoic acid
D-1
2-methyl-1-phenyl-1H-benzo
[d][1,3]oxazin-4(2H)-one
D-2
3-(4-hydroxyphenyl)-2-methyl-1-phenyl-
2,3-dihydroquinazolin-4(1H)-one
D-3
Br
O
O
l
y
h
t
Cl
DMF,
e
m
OH
-
d
i
2
OH
-
c
a
2 hrs
Chloro
o
m
c
i
o
o
Aceticacid
r
n
b
-
a
p
N
O
2
F,
CH3
o
r
p
D
M
2
h
N
rs
N
O
CH3
OH
O
N
O
OH
2-methyl-2-(4-(2-methyl-4-oxo-1-phenyl-1,2-dihydroquinazolin
O
-3(4H)-yl)phenoxy)propanoic acid
O
2-(4-(2-methyl-4-oxo-1-phenyl-1,2-dihydro
quinazolin-3(4H)-yl)phenoxy)acetic acid
D-4
D-5
Scheme 4. Synthesis of designed compounds D4 and D5.
Table 1
Data of body weight and blood glucose level
Body weight (g)
Blood glucose (mg/dl)
Control
PC
Std
207.67 1.20
294 1.5a
63.70 0.70
122.15 0.61a
86.41 0.55a
89.19 0.53a
91.80 0.51a
114.8 1.49a
112.8 0.87a
83.0 0.89a
85.3 0.43a
115 1.43a
269 1.06a
A-4
A-5
B-6
B-7
C-5
C-6
D-4
D-5
272.17 0.74a
273.85 0.74a
284.5 1.08a
281.2 0.65a
260.1 1.0a
261.7 0.55a
277.3 0.57a
274.7 0.97a
114.1 1.49a
Test compound = 250 mg/kg.
Reference standard, fenofibrate = 250 mg/kg.
The results are expressed as Mean SEM. The data is analyzed using One-way Analysis of Variance (ANOVA) followed by Tukey test, (n = 6).
a
P <0.001.
Table 2
Interpretation of pathological investigations (mg/dl) after 30 days
Groups
Parameter in mg/dl
CH
TG
74.3 0.48
VLDL
LDL
HDL
37.5 0.96
CH:HDL
Control
PC
Std
70.8 0.5
23.48 0.78
47.66 0.95a
37 0.57a
22.42 0.41
73.12 0.70a
54.66 0.45a
44.66 0.45a
47.66 063a
64.33 2.1d
57.22 1.9d
35.81 6.5a
47.05 2.5a
54.78 0.4a
70.91 3d
1.88 0.05
8.19 0.41a
2.49 0.08a
2.32 0.06a
1.99 0.03a
3.11 0.20a
3.26 0.10a
1.90 0.07a
1.88 0.06a
4.15 0.12a
2.67 0.05a
112 1.2a
85.4 0.8a
93 2.7a
161.3 0.76a
125.3 1.3a
154.1 0.74b
117.1 1.54a
158 0.73d
144.8 0.70a
114.8 0.70a
116.8 2a
13.8 0.67a
34.38 1.02a
40.0 0.57a
39.1 0.28a
31.6 1.37a
33.7 0.79a
40.8 1.04a
40.5 0.70a
25.5 0.74a
41.4 1.02a
A-4
A-5
B-6
B-7
C-5
C-6
D-4
D-5
37.05 0.17a
34.89 1.28a
24.30 1.26a
28.16 0.46a
35.38 1.34a
37.70 0.99a
22.05 2.14a
12.21 0.60a
78.5 1.1a
97.5 3b
110.8 3d
77.7 2.2a
77 2a
106.4 3.1d
108.9 2.1d
154.8 0.70c
158.8 2.08d
Test compound = 250 mg/kg.
Reference standard, fenofibrate = 250 mg/kg.
The results are expressed as Mean SEM. The data is analyzed using One-way Analysis of Variance (ANOVA) followed by Tukey’s test, (n = 6).
a
P <0.001.
P <0.01.
P <0.05.
Non significant.
b
c
d
Please cite this article in press as: Mokale, S. N.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.12.037