Design, Synthesis, and Biological Evaluation of Novel Quinazoline Clubbed Thiazoline Derivatives

Article abstract of DOI:10.1002/ardp.201600298

A novel series of quinazoline clubbed thiazoline derivatives was rationally designed and synthesized. The newly synthesized compounds were evaluated for in vitro dipeptidyl peptidase IV (DPP-4) inhibitory activity. Compounds that showed good to moderate a

Full text of DOI:10.1002/ardp.201600298

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Arch. Pharm. Chem. Life Sci. 2017, 349, e1600298
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Full Paper
Design, Synthesis, and Biological Evaluation of Novel Quinazoline
Clubbed Thiazoline Derivatives
Zulphikar Ali, Md J. Akhtar, Anees A. Siddiqui, Ahsan A. Khan, Md R. Haider, and Mohammad S. Yar
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Jamia Hamdard (Hamdard University),
Hamdard Nagar, New Delhi, India
A novel series of quinazoline clubbed thiazoline derivatives was rationally designed and synthesized.
The newly synthesized compounds were evaluated for in vitro dipeptidyl peptidase IV (DPP-4)
inhibitory activity. Compounds that showed good to moderate activity were compared using
linagliptin as standard. Compound 4x (IC50 ¼ 1.12 nM) exhibited the most promising results. The
special chemical feature of compound 4x also imparts good inhibition selectivity for DPP-4 over
DPP-8/9. Moreover, docking of compound 4x into the active site of DPP-4 illustrates its possible
binding interactions.
Keywords: Antidiabetic / DPP-4 inhibitors / Molecular docking / Quinazoline / Thiazoline
Received: October 14, 2016; Revised: December 8, 2016; Accepted: December 16, 2016
DOI 10.1002/ardp.201600298
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
Introduction
others [4]. Omarigliptin (MK-3102) (approved in Japan in
015) can be used as once-weekly treatment and is generally
2
Dipeptidyl peptidase IV (DPP-4) is
inactivates incretin hormones, glucagon-like peptide 1
a
protease which
well-tolerated throughout the base and extension studies.
Thus, the discovery of novel selective DPP-4 inhibitors
possessing antidiabetic activity is of great interest [5, 6].
Linagliptin (Fig. 1), a selective DPP-4 inhibitor, while used
for treatment of type 2 diabetes, may cause severe joint
pain [7, 8]. Many synthetic analogs of alogliptin by replacing
the cyanobenzyl group with the butynyl group have been
synthesized and tested as selective DPP-4 inhibitors [9].
Additionally, quinazolines [10], pyridopyrimidinedione [11],
pyrazolopyrimidinones [12], and pyrimidine [13] as DPP-IV
inhibitors are of particular interest in this field. Further-
more, various quinazoline, thiazoline, and quinazoline
clubbed thiazoline analogues proved to be effective
antidiabetic agents (Fig. 2) [14–17]. Based on the above
mentioned studies, the present work aims to design a
variety of ligands using various substituted quinazolines
which can better fit into active site of DPP-4. Toward this
goal, we describe herein the rational design, synthesis, and
characterizations of a novel class of substituted quinazoline
based hybrid of thiazoline (Fig. 3). The prepared compounds
were evaluated for DPP-4 inhibition activity. Additionally,
molecular docking studies were also carried out to identify
their possible binding mode within the catalytic domain of
DPP-4.
(
(
GLP-1) and glucose dependent insulin tropic polypeptide
GIP). Inhibiting DPP-4 prolongs the action of GLP-1 and GIP,
thus DPP-4 inhibitors play important roles in maintaining
glucose homeostasis. DPP-4 enzyme is an attractive drug
target owing to its significant therapeutic potential [1].
Although the in vivo functions of other members of DPP
family, that is, DPP-2, DPP-8, DPP-9 etc., are largely
unknown, the physiological effects of their inhibition have
been documented in the literature [2, 3]. Clinical trials on
diabetic patients confirmed DPP-4 inhibitors as an add-on
drug to oral hypoglycemic agents in type 2 diabetes.
Sitagliptin (Fig. 1) was the first DPP-4 inhibitor granted
FDA approval for treating patients with type 2 diabetes
followed by vildagliptin, saxagliptin, linagliptin, and
Correspondence: Dr. Mohammad Shahar Yar, Faculty of Pharmacy,
DepartmentofPharmaceuticalChemistry, Jamia Hamdard(Hamdard
University), Hamdard Nagar, New Delhi 110062, India.
E-mail: yarmsy@rediffmail.com
Fax: þ91-11-26059666
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Figure 1. Marketed DPP-IV inhibitors.
Results and discussion
Chemistry
mass spectra were used for the structural characterization
of the prepared compounds.
(
2
Un)Substituted anthranilic acid yielded corresponding
-chloromethyl-4H-benzoxazin-4-one (1a–c) when treated
with chloroacetyl chloride in the presence of dichloromethane
CH Cl ) by N-acylation via dehydrative cyclization mecha-
nism [18]. Condensation of 2-chloromethyl-4H-benzoxazine-
-one derivatives with 2-amino-4-(un)substitutedthiazole
Pharmacology
DPP-4 inhibition and selectivity against DPP-8/9
The synthesized compounds 4a–x were screened for their in
vitro DPP-4 inhibition. Screening of the compounds at 10 mM
and 100 nM concentrations are listed in Table
compounds with good inhibitory activity at 100 nM were
further selected to determine their IC50 values. These results
(Table 1) revealed that a proper combination of R
substituents is crucial for inhibitory activity (e.g., 4d vs. 4h; 4l
vs. 4p; 4t vs. 4x). For same R (OH) substitution, compound 4h
(having electron releasing group at R ) shows higher DPP-4
inhibitory activity as compared to compound 4d (having no
electron releasing/withdrawing group at R ) but lower DPP-4
(
2
2
1 and
4
afforded the subsequent 2-(thiazol-2-ylaminomethyl)-4H-
benzoxazin-4-one (2a–f) [19]. Compounds 2a–f on heating at
reflux with hydrazine monohydrate in alcoholic medium
afforded the corresponding 3-amino-3H-quinazolin-4-ones
1 2
and R
3
(
(
3a–f) in a good yield. Further, a series of different Schiff bases
4a–x) were synthesized by condensation of different substi-
2
tuted3-amino-3H-quinazolin-4-oneswithdifferentsubstituted
aromatic aldehydes [20] (Scheme 1). IR, H NMR, C NMR, and
2
1
13
inhibitory activity as compared to compound 4x (having
Figure 2. Quinazoline (structure I and II),
thiazoline (structure III) and quinazoline
clubbed thiazoline (structure IV) analogues
as antidiabetic agents.
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Figure 3. Structure of antidiabetic agents
(
alogliptin, linagliptin, and teneligliptin) and
rationally designed template for targeted
compounds.
electron releasing group at R
1
and R
2
). Compounds with
revealed the presence of one important hydrogen bond
between nitrogen of the quinazoline ring and Tyr 631 of
compound 4x which is believed for interaction between test
compound (4x) and Tyr 631, hence very important for DPP-4
binding affinity. A salt bridge between Glu 206 and Glu 205
with the hydroxyl group of compound 4x was observed which
was similar to the interaction with the amine group attached
to the pyrimidine ring of the linagliptin. Further, compound
4x showed hydrogen bond interaction with Arg 125, Hie 740
(tautomer of His 740), Ser 630, and Try 629 whereas standard
drug linagliptin showed p–p interaction with these amino
acids. This could be reason that compound 4x showed
wonderful inhibition to DPP-4 receptors. Figures 5 and 6 give
details of the docking analysis of the compound 4x.
6
-iodo substitution were found to have less inhibitory activity
as compared to compounds without 6-iodo substitution.
Compound with 4-OH substituted phenyl ring was found to
be more effective compound of the series with highest DPP-4
inhibitory activity, with an IC50 value of 1.12 nM followed by
4
f, 4r, 4h, 4e, 4d, 4g, 4v, and 4t with IC50 value of 1.25, 1.32,
1
.45, 1.49, 1.52, 1.54, 1.65, and 1.68 nM, respectively.
Quinazoline has 10000 times selectivity for DPP-4 over DPP-
and DPP-9 due to H-bond interaction with Tyr 631 [2, 21, 22].
Since compound 4x also showed H-bond interaction with Tyr
31, Arg 125, and Glu 205/206, this suggests its selectivity for
8
6
DPP-4 over DPP-8 and DPP-9.
Antidiabetic activity
To further confirm the anti-diabetic behavior of most potent
compounds, blood glucose lowering test was performed on
streptozotocin induced diabetic rats. The in vivo results of
these compounds were complementary to the results
obtained from in vitro DPP-IV inhibition assay. Compound
Conclusion
Novel quinazoline based hybrids were designed, synthesized,
and characterized by different spectroscopic techniques. The
prepared compounds retain good-to-moderate DPP-4 inhibi-
tory activity. The OH group substituted compound 4x was the
most potent inhibitor of DPP-4 in this series with an IC50 of
1.12 nM. Compound 4x also exerted most significant in vivo
hypoglycemic activity followed by compound 4f, 4r, and 4h,
respectively. Molecular docking suggested that binding of 4x
with DPP-4 active site is responsible for its high inhibitory
activity.
4
x displayed most significant decrease in blood glucose level
followed by compounds 4f, 4r, and 4h (Fig. 4).
Molecular docking
In order to correlate the in vivo and in vitro results and to get
better understanding of the structure–activity relationship,
the docking studies were carried out by positioning com-
pound 4x into the linagliptin binding site. Compound 4x
exhibited better binding and subsequent inhibitory capacity
when compared with the docking score of the standard ligand
(
i.e., linagliptin). Docking score of the standard ligand was
Experimental
found to be much lower (ꢀ5.959) as compared to test
compound 4x (ꢀ7.370). The test compound 4x exhibited
better ligand binding efficiency with minimum state penalty.
This fact may explain the reason for better in vivo activity of
compound as compared to other test compounds. The results
Chemistry
General
Melting points were determined by the open tube capillary
method and were uncorrected. IR spectra were recorded on a
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Scheme 1. Synthesis of the quinazolin-4(3H)-
one based hybrids of thiazoline.
Shimadzu infrared spectrometer (FTIR-8400S) using KBr pellets
in anhydrous pyridine was added dropwise with constant
stirring at 2–8°C for 1 h. The resulting reaction mixture was
stirred for another 2 h mechanically at room temperature; the
solid mass thus obtained was filtered, washed successively
with cold water followed by 5% diethyl ether (Et O) in
2
hexane. Drying and recrystallization from ethanol gave the
desired compound in its pure form.
1
at Jamia Hamdard. H NMR was recorded in DMSO-d
6
or CDCl3
on Bruker 300MHz instrument using TMS as internal standard.
Mass spectra were recorded on LCMS/MS (PerkinElmer and
LABINDIA, Applied Biosystems) model no. API 3000, presented
as m/z. The purity of the compounds was checked by thin-layer
chromatography(TLC)plates(silicagelG)whichwerevisualized
by exposing to iodine vapors and UV light.
TheNMRspectraaswellastheInChIcodesoftheinvestigated
compounds together with some biological activity data are
provided as Supporting Information.
Synthesis of 2-(thiazol-2-ylaminmethyl)-4H-benzoxazin-4-
one (2a–f)
A mixture of compound 1a (0.01 mol), thiazol-2-amine
(
0.01 mol) in 30 mL of pyridine was taken in a round-bottomed
Synthesis of 2-chloromethyl-4H-benzoxazin-4-one (1a–c)
To a solution of (un)substituted anthranilic acid (0.1 mol) in
flask and heated under reflux for 4 h. After the completion of
the reaction, the contents of the flask was poured onto
crushed ice, the solid separated was filtered and dried. The
product 2a was obtained after recrystallization from ethanol.
Similarly compounds 2b–f were also synthesized.
6
2 2
0 mL of dichloromethane (CH Cl ) and anhydrous triethyl-
amine (TEA, 0.2 M) cooled under ice in an inert atmosphere of
nitrogen, a solution of chloroacetyl chloride (0.2 mol, 15 mL)
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Table 1. DPP-4 inhibitory activity and IC50 values for compounds 4a–x.
Inhibition (%)
Compound
R
1
R
2
R
3
IC50 (nM)
10 mM
100 nM
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
H
H
H
H
H
2-CN
3-NO
4-OH
H
NT
NT
54.3
87.4
66.9
93.3
56.7
79.3
73.9
92.2
94.5
64.8
50.6
76.4
70.5
64.9
90.8
94.5
85.1
55.6
79.2
94.1
74.3
81.5
96.3
82.0
93.8
45.2
ꢀ0.84
58.3
82.6
55.4
77.3
70.6
79.2
48.3
39.5
NT
H
H
H
H
H
H
H
I
I
I
I
I
2
15.8
1.52
1.49
1.25
1.54
1.45
NT
NT
NT
19.4
NT
NT
H
CH
CH
CH
CH
H
H
H
3
3
3
3
2-CN
3-NO
4-OH
H
2
2-CN
3-NO
4-OH
H
2
H
73.7
NT
NT
CH
CH
CH
CH
H
H
H
3
3
3
3
I
I
I
2-CN
3-NO
4-OH
H
2
NT
86.4
85.9
50.9
54.2
NT
79.1
48.2
75.3
91.4
80.3
96.1
16.3
30.2
1.32
NT
1.68
NT
1.65
17.3
1.12
0.76
CH
CH
CH
CH
CH
CH
CH
CH
–
3
3
3
3
3
3
3
3
2-CN
s
t
u
v
w
x
3-NO
4-OH
H
2
H
CH
CH
CH
CH
–
3
3
3
3
2-CN
3-NO
4-OH
–
2
Linagliptin
Synthesis of 3-amino 2-(thiazol-2-ylaminomethyl)-4H-
quinazolin-4-one (3a–f)
To an ethanolic solution (30 mL) of 10 mmol of 2-(thiazol-2-
benzaldehydes was refluxed in presence of few drops of
glacial acetic acid. Reaction on completion was cooled. The
precipitated solid was collected, washed with distilled water,
dried, and recrystallized from ethanol to get the desired final
compounds.
ylaminmethyl)-4H-benzoxazin-4-one intermediates 2a–f,
2
0 mmol of hydrazinemonohydrate was added and the
mixture was heated under reflux for 4 h. The reaction mixture
was concentrated and allowed to cool. The solid product thus
obtained was filtered off, washed with distilled water and
dried. Recrystallization from ethanol afforded the desired
solid compounds.
(E)-3-(Benzylideneamino)-2-{(thiazol-2-ylamino)-methyl}-
quinazolin-4(3H)-one 4a
Yield: 75%; m.p. 212–214°C; IR (KBr, in cm ): 3315 (N–H str.),
ꢀ
1
1664 (C–O str.), 1640 (C–N str.), 1512 (ring C–C str.), 1450 (Ar
1
C–N str.), 630 (C–S str.); H NMR (300 MHz, DMSO-d
6
, d in ppm):
General procedure for the synthesis of the title compounds
9.71 (t, 1H, NH), 8.96 (s, 1H, H–C–N), 7.76–8.14 (m, 4H, ArH),
4
a–x
7.40–7.62 (m, 5H, ArH), 6.82–7.36 (s, H, thiazole), 3.52 (s, 2H,
1
3
An equimolar ethanolic mixture of 3-amino-2-(thiazol-2-
CH
2
); C NMR (75 MHz, CDCl3, d in ppm): 164.27, 161.23,
ylaminomethyl)-4H-quinazolin-4-one (3a–f) and substituted
155.12, 145.18, 137.0, 135.17, 133.21, 131.24, 130.34, 129.12,
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Figure 4. In vivo blood glucose lowering effect.
þ
1
27.43, 122.13, 115.22, 52.81; ESI MS (m/z): 362.11 (M ); Anal.
calcd. for C19 OS: C 63.14, H 4.18, N 19.38, S 8.87%.
Found: C 63.13, H 4.19, N 19.35, S 8.84.
C
19
H
14
N
6
O
3
S: C 56.15, H 3.47, N 20.68, S 7.89%. Found: C
H N
15 5
56.11, H 3.42, N 20.63, S 7.86%.
(
E)-3-(4-Hydroxybenzylideneamino)-2-{(thiazol-2-
(
E)-2-[4-Oxo-2-{(thiazol-2-ylamino)-methyl}-quinazolin-3(4H)-
ylimino]-methylbenzonitrile 4b
Yield: 74%; m.p. 240–242°C; IR (KBr, in cm ): 3292 (N–H str.),
ylamino)-methyl}-quinazolin-4(3H)-one 4d
Yield: 76%; m.p. 266–268°C; IR (KBr, in cm ): 3322 (N–H str.),
3214 (O–H str. for –OH), 1668 (C –– O str.), 1647 (C –– N str.), 1556
ꢀ
1
ꢀ
1
1
ꢀꢀ
–
–
1
–
2
232 (C ꢀꢀ N str.), 1668 (C–O str.), 1645 (C–N str.), 1510 (ring
(ring C–C str.), 1370 (Ar C–N str.), 640 (C–S str.); H NMR
ꢀꢀ
C –– C str.), 1446 (Ar C–N str.), 642 (C–S str.); H NMR (300 MHz,
DMSO-d
, d in ppm): 9.69 (t, 1H, NH), 8.68 (s, 1H, H–C –– N),
.78–8.16 (m, 4H, ArH), 7.52–7.74 (m, 4H, ArH), 6.57–734 (s,
(300 MHz, DMSO-d
H–C –– N), 7.82–8.05 (m, 3H, ArH), 7.18–7.62 (m, 5H, ArH),
6.73–7.20 (s, 1H, thiazole), 5.52 (s, 1H, OH), 3.64 (s, 2H, CH );
, d in ppm): 9.66 (t, 1H, NH), 9.07 (s, 1H,
6
6
7
1
2
13
13
H, thiazole), 3.56 (s, 2H, CH
2
); C NMR (75 MHz, CDCl3, d in
C NMR (75 MHz, CDCl3, d in ppm): 164.38, 158.29, 154.24,
ppm): 163.33, 158.32, 153.18, 146.18, 142.08, 138.17, 136.21,
147.36, 143.43, 138.17, 136.55, 134.58, 133.62, 131.80,
1
34.24, 133.44, 131.22, 128.41, 124.42, 116.18, 112.24, 54.76;
130.33, 127.22, 120.14, 116.41, 58.62; ESI MS (m/z): 378.11
þ
þ
ESI MS (m/z): 387.12 (M ); Anal. calcd. for C20
H
14
N
6
OS: C
(M ); Anal. calcd. for C19
H
15
N
5
O
2
S: C 60.46, H 4.01, N 18.56, S
6
2
2.16, H 3.65, N 21.75, S 8.30%. Found: C 62.19, H 3.67, N
1.78, S 8.33%.
8.50%. Found: C 6.47, H 4.03, N 18.52, S 8.53%.
(
E)-3-(Benzylideneamino)-2-{(4-methylthiazol-2-ylamino)-
(
E)-3-(3-Nitrobenzylideneamino)-2-{(thiazol-2-ylamino)-
methyl}-quinazolin-4(3H)-one 4c
Yield: 72%; m.p. 244–246°C; IR (KBr, in cm ): 3340 (N–H str.),
methyl}-quinazolin-4(3H)-one 4e
Yield: 75%; m.p. 210–212°C IR (KBr, in cm ): 3318 (N–H str.),
ꢀ1
ꢀ
1
1665(C –– Ostr.),1648(C –– Nstr.),1517(ringC –– Cstr.),1452(ArC–N
1
1
676 (C –– O str.), 1644 (C –– N str.), 1506 (ring C –– C str.), 1460 (Ar
str.), 632 (C–S str.); H NMR (300 MHz, DMSO-d
6
, d in ppm): 9.58
1
C–N str.), 1342 (N –– O str. for ArNO
300 MHz, DMSO-d
H–C –– N), 7.91–8.40 (m, 4H, ArH), 7.51–7.66 (m, 4H, ArH),
); 638 (C–S str.); H NMR
(t, 1H, NH), 9.25 (s, 1H, H–C –– N), 77.72–8.10 (m, 4H, ArH),
0.36–7.58 (m, 5H, ArH), 6.02 (s, 1H, thiazole), 3.78 (s, 2H, CH ),
); C NMR (75MHz, CDCl3, d in ppm): 163.41,
2
(
6
, d in ppm): 9.77 (t, 1H, NH), 9.03 (s, 1H,
2
1
3
2.54 (s, 3H, CH
3
1
3
6
.63–7.10 (s, 1H, thiazole), 3.50 (s, 2H, CH
2
);
C NMR
160.46, 156.41, 146.65, 142.48, 138.33, 135.93, 134.63, 133.75,
(
1
1
75 MHz, CDCl3, d in ppm): 164.30, 161.28, 157.25, 145.14,
131.67, 130.83, 128.12,121.44,118.52,57.23, 18.66;ESIMS(m/z)
þ
37.08, 135.12, 133.14, 132.26, 130.48, 128.32, 122.16,
17 5
: 376.13 (M ); Anal. calcd. for C20H N OS: C 63.98, H 4.56, N
þ
14.21, 53.42; ESI MS (m/z): 407.10 (M ); Anal. calcd. for
18.65, S 8.54%. Found: C 63.94, H 4.58, N 18.67, S 8.51%.
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Figure 5. 2D representation of the binding mode
of compound 4x in complex with the DPP-4
receptors (PDB ID: 2RGU).
(
E)-2-[2-{(4-Methylthiazol-2-ylamino)-methyl}-4-
(E)-3-(4-Hydroxybenzylideneamino)-2-{(4-methylthiazol-
oxoquinazolin-3(4H)-ylimino]-methylbenzonitrile 4f
Yield: 71%; m.p. 206–208°C; IR (KBr, in cm ): 3295 (N–H str.),
2-ylamino)-methyl}-quinazolin-4(3H)-one 4h
Yield: 74%; m.p. 238–240°C; IR (KBr, in cm ): 3318 (N–H str.),
ꢀ
1
ꢀ1
1
680 (C–O str.), 1652 (C–N str.), 1517 (ring C–C str.), 1458 (Ar
3226 (O–H str. for –OH), 1674 (C–O str.), 1656 (C–N str.), 1558
1
1
ꢀꢀ
–
C–N str.), 2235 (C ꢀꢀ N str.), 647 (C–S str.); H NMR (300 MHz,
(ring C–C str.), 1373 (Ar C–N str.), 646 (C–S str.); H NMR
ꢀ
ꢀ
DMSO-d
6
, d in ppm): 7.57–7.70 (m, 4H, ArH), 7.81–8.07 (m, 4H,
), 9.73 (t, 1H, NH),
(300 MHz, DMSO-d
H–C–N), 7.88–8.17 (m, 3H, ArH), 7.30–7.64 (m, 5H, ArH), 6.53
(S, 1H, thiazole), 5.82 (s, 1H, OH), 3.88 (s, 2H, CH ), 2.92 (s, 3H,
); C NMR (75 MHz, CDCl3, d in ppm): 158.32, 154.51,
6
, d in ppm): 9.83 (t, 1H, NH), 9.47 (s, 1H,
ArH), 8.93 (s, 1H, H–C–N), 3.75 (s, 2H, CH
.37 (s, 1H, thiazole), 2.71 (s, 3H, CH
2
1
3
6
3
); C NMR (75 MHz,
2
1
3
CDCl3, d in ppm): 162.43, 159.26, 153.52, 145.13, 142.76,
CH
3
1
1
38.62, 136.48, 135.39, 132.88, 130.26, 127.38, 125.72, 116.85,
14.17, 51.62, 17.34; ESI MS (m/z): 401.12 (M ); Anal. calcd. for
147.61, 142.48, 138.34, 136.75, 134.69, 133.62, 132.80, 129.37,
125.78, 123.17, 118.38, 56.59, 21.54; ESI MS (m/z): 392.11 (M );
þ
þ
C
H N
21 16 6
OS: C 62.98, H 4.03, N 20.99, S 8.01%. Found: C 62.93,
17 5 2
Anal. calcd. for C20H N O S: C 61.37, H 4.38, N 17.89, 8.17, S
H 4.07, N 20.96, S 8.04%.
8.19%. Found: C 61.41, H 4.33, N 17.84, 8.16, S 8.22%.
(
E)-2-{(4-Methylthiazol-2-ylamino)-methyl}-3-(3-
(E)-3-(Benzylideneamino)-6-iodo-2-{(thiazol-2-ylamino)-
nitrobenzylideneamino)-quinazolin-4(3H)-one 4g
Yield: 68%; m.p. 228–230°C; IR (KBr, in cm ): 3342 (N–H str.),
methyl}-quinazolin-4(3H)-one 4i
Yield: 77%; m.p. 232–234°C; IR (KBr, in cm ): 3312 (N–H
ꢀ
1
ꢀ1
1
673 (C–O str.), 1642 (C–N str.), 1508 (ring C–C str.), 1461 (Ar
str.), 1662 (C –– O str.), 1642 (C –– N str.), 1514 (ring C –– C str.),
1452 (Ar C–N str.); 632 (C–S str.); H NMR (300 MHz, DMSO, d
in ppm): 9.76 (t, 1H, NH), 9.41 (s, 1H, H–C –– N), 7.92–8.43 (m,
1
1
C–N str.), 1343 (N–O str. for ArNO
300 MHz, DMSO-d
H–C–N), 7.89–8.36 (m, 4H, ArH), 7.54–7.70 (m, 4H, ArH), 6.43
), 636 (C–S str.); H NMR
2
(
6
, d in ppm): 9.63 (t, 1H, NH), 9.32 (s, 1H,
4H, ArH), 7.35–7.80 (m, 4H, ArH), 6.10–7.03 (s, 1H, thiazole),
13
13
(
s, 1H, thiazole), 3.81 (s, 2H, CH
2
), 2.59 (s, 3H, CH
3
); C NMR
2
3.88 (s, 2H, CH ); C NMR (75 MHz, CDCl3, d in ppm): 164.38,
(
75 MHz, CDCl3, d in ppm): 164.58, 162.31, 156.53, 144.41,
161.34, 155.27, 145.29, 137.11, 135.27, 133.31, 131.34,
1
5
36.54, 135.28, 134.17, 132.00, 131.65, 129.40, 123.54, 115.53,
4.43, 18.13, ESI MS (m/z): 421.12 (M ); Anal. calcd. for
130.44, 129.23, 127.54, 122.24, 115.33, 93.75, 52.92; ESI MS
þ
þ
(m/z): 488.02 (M ); Anal. calcd. for C19
H
14IN
5
OS: C 46.83, H
C
20
H
16
N
6
O
3
S: C 57.13, H 3.84, N 19.99, S 7.63%. Found: C 57.15,
2.90, N 14.37, S 6.58%. Found: C 46.81, H 2.93, N 14.34, S
6.54%.
H 3.87, N 19.95, S 7.61%.
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Z. Ali et al.
ARC HH PHARM
Archiv der Pharmazie
Figure 6. 3D representation of the docking
mode of compound 4x showing the interac-
tion with the amino acids of the DPP4
receptor (PDB ID: 2RGU).
(
E)-2-[6-Iodo-4-oxo-2-{(thiazol-2-ylamino)-methyl}-
154.41, 148.49, 143.31, 140.34, 137.68, 135.35, 133.75,
quinazolin-3(4H)-ylimino]-methylbenzonitrile 4j
Yield: 70%; m.p. 2016–218°C; IR (KBr, in cm ): 3297 (N–H
131.93, 130.46, 128.35, 120.27, 115.54, 95.83, 56.75; ESI
ꢀ1
þ
MS (m/z): 503.97 (M ); Anal. calcd. for C19
H
14IN
5
O
2
S: C
ꢀ
ꢀ
–
–
str.), 2236 (C ꢀꢀ N str.), 1671 (C–O str.), 1654 (C–N str.), 1517
45.34, H 2.80, N 13.91, S 6.37%. Found: C 45.32, H 2.83, N
13.88, S 6.39%.
ꢀ
ꢀ
1
(
(
ring C –– C str.), 1448 (Ar C–N str.), 646 (C–S str.); H NMR
300 MHz, DMSO-d , d in ppm): 9.74 (t, 1H, NH), 8.81 (s, 1H,
6
H–C –– N), 7.91–8.29 (m, 3H, ArH), 7.39–7.61 (m, 4H, ArH),
(E)-3-(Benzylideneamino)-6-iodo-2-{(4-methylthiazol-2-
1
3
6
.70–7.47 (s, 1H, thiazole), 3.69 (s, 2H, CH
2
);
C NMR
ylamino)-methyl}-quinazolin-4(3H)-one 4m
ꢀ
1
(
75 MHz, CDCl3, d in ppm): 162.39, 158.48, 155.19, 145.53,
Yield: 72%; m.p. 226–228°C; IR (KBr, in cm ): 3319 (N–H str.),
1
1
40.36, 138.32, 136.42, 134.54, 133.11, 131.76, 129.29,
1660 (C–O str.), 1644 (C–N str.), 1516 (ring C–C str.), 1454 (Ar
1
24.60, 118.23, 112.46, 94.16, 54.85, ESI MS (m/z): 512.98
C–N str.), 634 (C–S str.); H NMR (300 MHz, DMSO-d
6
d in ppm):
þ
(
M ); Anal. calcd. for C20
H
13IN
6
OS: C 46.89, H 2.56, 24.77, N
9.54 (t, 1H, NH), 9.53 (s, 1H, H–C–N), 7.97–8.21 (m, 4H, ArH),
7.39–7.65 (m, 4H, ArH), 6.29 (s, 1H, thiazole), 3.77 (s, 2H, CH ),
); C NMR (75 MHz, CDCl3, d in ppm): 162.53,
59.35, 157.52, 146.54, 142.59, 138.39, 136.04, 134.74, 133.66,
1
6
6.40, S 6.26%. Found: C 46.86, H 2.54, 24.75, N 16.41, S
.30%.
2
1
3
3.02 (s, 3H, CH
3
1
(
E)-6-Iodo-3-(3-nitrobenzylideneamino)-2-{(thiazol-2-
131.67, 130.72, 128.23, 122.55, 118.63, 94.81, 57.34, 18.77; ESI
þ
ylamino)-methyl}-quinazolin-4(3H)-one 4k
MS (m/z): 502.02 (M ); Anal. calcd. for C20
H16IN
5
OS: C 47.91, H
ꢀ
1
Yield: 66%; m.p. 244–246°C; IR (KBr, in cm ): 3351 (N–H str.),
687 (C –– O str.), 1655 (C –– N str.), 1517 (ring C –– C str.), 1471
Ar C–N str.), 1353 (N –– O str. for ArNO
), 649 (C–S str.);
, d in ppm): 9.66 (t, 1H, NH), 9.20
s, 1H, H–C –– N), 8.08–8.57 (m, 4H, ArH), 7.68–7.83 (m, 3H,
3.22, N 13.97, S 6.40%. Found: C 47.93, H 3.26, N 13.94,
S 6.42%.
1
(
2
1
H NMR (300 MHz, DMSO-d
6
(E)-2-[6-Iodo-2-{(4-methylthiazol-2-ylamino)-methyl}-4-
(
oxoquinazolin-3(4H)-ylimino]-methylbenzonitrile 4n
1
3
ꢀ1
ArH), 6.48–7.02 (s, 1H, thiazole), 3.67 (s, 2H, CH
2
); C NMR
Yield: 70%; m.p. 252–254°C; IR (KBr, in cm ): 3305 (N–H str.),
ꢀꢀ
2241 (C ꢀꢀ N str.), 1679 (C–O str.), 1657 (C–N str.), 1516 (ring
ꢀꢀ
1
–
–
(
1
1
75 MHz, CDCl3, d in ppm): 164.47, 161.45, 157.42, 145.31,
37.25, 135.29, 133.31, 132.43, 130.65, 128.49, 122.33,
C –– C str.), 1452 (Ar C–N str.), 653 (C–S str.); H NMR (300 MHz,
DMSO-d
d in ppm): 9.61 (t, 1H, NH), 9.57 (s, 1H, H–C –– N),
7.68–8.33 (m, 4H, ArH), 7.32–7.61 (m, 3H, ArH), 6.44 (s, 1H,
þ
14.38, 93.92, 53.59, ESI MS (m/z): 532.99 (M ); Anal. calcd.
6
for C19
4
6 3
H13IN O S: C 42.87, H 2.46, N 15.79, S 6.02%. Found: C
2.84, H 2.42, N 15.77, S 6.05%.
13
thiazole); 3.83 (s, 2H, CH
2 3
), 2.57 (s, 3H, CH ); C NMR
(
75 MHz, CDCl3, d in ppm): 162.38, 160.51, 154.81, 145.36,
(
E)-3-(4-Hydroxybenzylideneamino)-6-iodo-2-{(thiazol-2-
143.73, 138.76, 136.52, 135.41, 132.80, 130.33, 128.31,
ylamino)-methyl}-quinazolin-4(3H)-one 4l
Yield: 72%; m.p. 236–238°C; IR (KBr, in cm ): 3313 (N–H
str.), 3205 (O–H str. for –OH), 1659 (C –– O str.), 1656 (C –– N
125.61, 119.73, 116.21, 94.81, 52.73, 17.37; ESI MS (m/z):
ꢀ1
þ
527.02 (M ); Anal. calcd. for C21
H
15IN
6
OS: C 47.92, H 2.87, N
15.97, S 6.09 %. Found: C 47.88, H 2.83, N 15.96, S 6.11%.
str.), 1565 (ring C –– C str.), 1361 (Ar C–N str.), 631 (C–S str.);
1
H NMR (300 MHz, DMSO-d
6
, d in ppm): 9.88 (t, 1H, NH), 8.95
(E)-6-Iodo-2-{(4-methylthiazol-2-ylamino)-methyl}-3-(3-
(
s, 1H, H–C –– N), 7.91–8.39 (m, 4H, ArH), 6.96–7.40 (m, 3H,
nitrobenzylideneamino)-quinazolin-4(3H)-one 4o
ꢀ1
ArH), 6.77–6.92 (s, 1H, thiazole), 5.75 (s, 1H, OH), 3.87 (s, 2H,
CH ); C NMR (75 MHz, CDCl3, d in ppm): 164.51, 158.64,
2
Yield: 64%; m.p. 248–250°C; IR (KBr, in cm ): 3341 (N–H
str.), 1675 (C –– O str.), 1646 (C –– N str.), 1504 (ring C –– C str.),
1
3
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Novel Quinazoline Clubbed Thiazoline Derivatives
ARC HH PHARM
Archiv der Pharmazie
1
463 (Ar C–N str.), 1345 (N –– O str. for ArNO
H NMR (300 MHz, DMSO, d in ppm): 9.67 (t, 1H, NH), 9.27
s, 1H, H–C –– N), 7.93–8.41 (m, 4H, ArH), 7.50–7.73 (m, 3H,
2
), 637 (C–S str.);
(E)-6-Methyl-3-(3-nitrobenzylideneamino)-2-{(thiazol-2-
1
ylamino)-methyl}-quinazolin-4(3H)-one 4s
ꢀ
1
(
Yield: 63%; m.p. 246–248°C; IR (KBr, in cm ): 3335 (N–H str.),
ArH), 6.23 (s, 1H, thiazole), 3.66 (s, 2H, CH
2
), 2.91 (s, 3H,
1678 (C –– O str.), 1640 (C –– N str.), 1523 (ring C –– C str.), 1472 (Ar
1
3
1
CH
3
); C NMR (75 MHz, CDCl3, d in ppm): 164.59, 162.33,
C–N str.), 1337 (N –– O str. for ArNO
2
), 650 (C–S str.); H NMR
1
1
5
56.51, 144.42, 136.55, 135.29, 134.18, 132.10, 131.64,
(300 MHz, DMSO, d in ppm): 9.86 (t, 1H, NH), 8.98 (s, 1H,
H–C –– N), 8.02–8.36 (m, 4H, ArH), 7.44–7.76 (m, 3H, ArH),
29.39, 123.53, 115.54, 98.72, 54.44, 18.12; ESI MS (m/z):
þ
47.01 (M ); Anal. calcd. for C20
H
15IN
6
O
3
S: C 43.97, H 2.77,
6.27–7.12 (d, 2H, thiazole), 3.71 (s, 2H, CH
C NMR (75 MHz, CDCl3, d in ppm): 167.45, 164.43, 160.40,
2
), 2.43 (s, 3H, CH
3
);
1
3
N 15.38, 8.79, S 5.87%. Found: C 43.95, H 2.73, N 15.36,
.83, S 5.85%.
8
148.33, 140.28, 138.31, 136.29, 135.41, 133.62, 131.46,
þ
1
25.31, 117.36, 56.57, 24.28; ESI MS (m/z): 421.12 (M );
(
E)-3-(4-Hydroxybenzylideneamino)-6-iodo-2-{(4-
16 6 3
Anal. calcd. for C20H N O S: C 57.13, H 3.84, N 19.99, S
methylthiazol-2-ylamino)-methyl}-quinazolin-4(3H)-one
7.63%. Found: C 57.15, H 3.85, N 19.97, S 7.66%.
4
p
ꢀ1
Yield: 66%; m.p. 244–246°C; IR (KBr, in cm ): 3325 (N–H
str.), 3217 (O–H str. for –OH), 1671 (C –– O str.), 1650 (C –– N
str.), 1560 (ring C –– C str.), 1376 (Ar C–N str.), 643 (C–S str.);
(E)-3-(4-Hydroxybenzylideneamino)-6-methyl-2-{(thiazol-
2-ylamino)-methyl}-quinazolin-4(3H)-one 4t
ꢀ1
Yield: 75%; m.p. 268–270°C; IR (KBr, in cm ): 3322 (N–H str.),
3217 (O–H str. for –OH), 1671 (C –– O str.), 1649 (C–N str.), 1558
(ring C –– C str.), 1377 (Ar C–N str.), 640 (C–S str.); 1H NMR
(300 MHz,DMSO,dinppm):9.55(t,1H, NH),8.84(s,1H, H–C –– N),
1
H NMR (300 MHz, DMSO, d in ppm): 9.84 (t, 1H, NH), 9.76 (s,
1
6
H, H–C –– N), 7.81–8.13 (m, 3H, ArH), 7.28–7.61 (m, 4H, ArH),
.55 (s, 1H, thiazole), 5.77 (s, 1H, OH), 3.59 (s, 2H, CH ), 3.17
); C NMR (75 MHz, CDCl3, d in ppm): 158.39,
2
1
3
(
s, 3H, CH
3
8.17–8.43 (m, 4H, ArH), 7.63–7.91 (m, 3H, ArH), 6.29–7.44 (s, 1H,
1
3
1
1
54.58, 147.68, 142.55, 138.41, 136.82, 134.76, 133.69,
2 3
thiazole), 3.49 (s, 2H, CH ), 2.49 (s, 3H, CH ); C NMR (75 MHz,
32.87, 129.44, 125.85, 123.24, 118.45, 94.77, 56.66, 21.61,
CDCl3, d in ppm):165.72, 159.85, 155.62, 149.70, 144.52, 141.55,
þ
ESI MS (m/z): 518.00 (M ); Anal. calcd. for C20
H
16IN
5
O
2
S: C
138.89, 136.56, 134.96, 132.98, 131.67, 129.56, 121.48, 116.75,
þ
4
1
6.43, H 3.12, N 13.54, S 6.20%. Found: C 46.41, H 3.15, N
3.57, S 6.23%.
57.96, 22.51; ESI MS (m/z): 392.11 (M ); Anal. calcd. for
20 17 5
C H N O
2
S: C 61.37, H 4.38, N 17.89, S 8.19%. Found: C
6
1.39, H 4.41, N 17.91, S 8.21%.
(
E)-3-(Benzylideneamino)-6-methyl-2-{(thiazol-2-
ylamino)-methyl}-quinazolin-4(3H)-one 4q
Yield: 72%; m.p. 258–260°C; IR (KBr, in cm ): 3314 (N–H str.),
(E)-3-(Benzylideneamino)-6-methyl-2-{(4-methylthiazol-2-
ꢀ
1
ylamino)-methyl}-quinazolin-4(3H)-one 4u
ꢀ
1
1
663 (C –– O str.), 1638 (C –– N str.), 1518 (ring C –– C str.), 1444 (Ar
C–N str.), 630 (C–S str.); H NMR (300 MHz, DMSO, d in ppm):
Yield: 58%; m.p. 264–266°C; IR (KBr, in cm ): 3326 (N–H str.),
1675 (C–O str.), 1653 (C–N str.), 1525 (ring C–C str.), 1461 (Ar
1
1
2
.38 (s, 3H, CH
3
), 9.67 (t, 1H, NH), 8.87 (s, 1H, H–C –– N), 8.22
), 7.23–7.47 (m, 5H, ArH),
.63–7.19 (s, 1H, thiazole); C NMR (75 MHz, CDCl3, d in
C–N Str), 641 (C–S str.); H NMR (300 MHz, DMSO, d in ppm):
(
m, 3H, ArH), 7.93–3.82 (s, 2H, CH
2
9.62 (t, 1H, NH), 9.35 (s, 1H, H–C–N), 7.88–8.34 (m, 4H, ArH),
1
3
6
7.43–7.71 (m, 4H, ArH), 6.33 (s, 1H, thiazole), 3.81 (s, 2H, CH
2
),
1
3
ppm): 163.51, 160.34, 158.56, 148.57, 142.61, 140.43, 136.27,
2.42–2.56 (s, 6H, CH ); C NMR (75 MHz, CDCl3, d in ppm):
3
1
5
C
34.53, 133.17, 131.63, 130.28, 129.24, 122.52, 117.61, 95.80,
7.35, 20.36; ESI MS (m/z): 376.11 (M ); Anal. calcd. for
163.60, 160.42, 158.59, 147.61, 143.66, 139.46, 136.11, 135.81,
þ
134.73, 132.74, 131.79, 128.30, 123.62, 119.70, 58.41, 22.37,
þ
20
H
17
N
5
OS: C 63.98, H 4.56, N 18.65, S 8.54%. Found: C
19.84; ESI MS (m/z): 390.12 (M ); Anal. calcd. for C21
H N
19 5
OS: C
6
3.96, H 4.59, N 18.61, S 8.56%.
64.76, H 4.92, N 17.98, S 8.23%. Found: C 64.73, H 4.91, N
7.95, S 8.27%.
1
(
E)-2-[6-Methyl-4-oxo-2-{(thiazol-2-ylamino)-methyl}-
quinazolin-3(4H)-ylimino]-methylbenzonitrile 4r
Yield: 71%; m.p. 252–254°C; IR (KBr, in cm ): 3290 (N–H
(E)-2-[6-Methyl-2-{(4-methylthiazol-2-ylamino)-methyl}-4-
ꢀ1
oxoquinazolin-3(4H)-ylimino]methylbenzonitrile 4v
ꢀ
1
ꢀ
–
–
str.), 2228 (CꢀN str.), 1648 (C–O str.), 1657 (C–N str.), 1513
Yield: 62%; m.p. 254–256°C; IR (KBr, in cm ): 3301 (N–H str.),
ꢀ
1
ring C –– C str.), 1447 (Ar C–N Str), 651 (C–S str.); H NMR
300 MHz, DMSO, d in ppm): 9.59 (t, 1H, NH), 8.89 (s, 1H,
ꢀꢀ
2245 (C ꢀꢀ N str.), 1680 (C–O str.), 1657 (C–N str.), 1521 (ring
ꢀꢀ
1
–
–
(
(
C –– C str.), 1458 (Ar C–N str.), 642 (C–S str.); H NMR (300 MHz,
DMSO, d in ppm): 9.83 (t, 1H, NH), 8.91 (s, 1H, H–C –– N), 8.35
H–C –– N), 7.97–8.33 (m, 3H, ArH), 7.32–7.73 (m, 4H, ArH),
6
CH
.27–7.44 (s, 1H, thiazole), 3.88 (s, 2H, CH
2
), 2.56 (s, 3H,
(m, 4H, ArH), 7.86–3.65 (s, 2H, CH
6.59 (s, 1H, thiazole), 2.57–2.81 (s, 6H, CH
2
), 7.51–7.73 (m, 3H, ArH),
1
3
13
3
); C NMR (75 MHz, CDCl3, d in ppm): 163.41, 158.52,
3
);
C NMR
1
1
54.67, 145.39, 144.31, 138.28, 137.40, 134.51, 133.58,
(75 MHz, CDCl3, d in ppm): 163.46, 161.32, 156.26, 143.41,
32.72, 130.32, 125.57, 120.22, 114.41, 55.83, 21.49; ESI MS
135.43, 134.72, 133.63, 131.18, 130.10, 128.40, 113.58, 52.39,
þ
þ
(
m/z): 401.10 (M ); Anal. calcd. for C21
H
16
N
6
OS: C 62.98, H
21.52, 17.12; ESI MS (m/z): 415.14 (M ); Anal. calcd. for
4
.03, N 20.99, S 8.01%. Found: C 62.94, H 4.05, N 20.96,
22 18 6
C H N OS: C 63.75, H 4.38, N 20.28, S 7.74%. Found: C
S 8.05%.
63.72, H 4.35, N 24.28, S 7.72%.
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(9 of 11) e1600298

Arch. Pharm. Chem. Life Sci. 2017, 349, e1600298
Z. Ali et al.
ARC HH PHARM
Archiv der Pharmazie
(
E)-6-Methyl-2-{(4-methylthiazol-2-ylamino)-methyl}-3-(3-
group. The blood glucose levels were monitored at 30, 60, 90,
120, 150, and 180min intervals [24].
nitrobenzylideneamino)-quinazolin-4(3H)-one 4w
Yield: 70%; m.p. 260–262°C; IR (KBr, in cm ): 3344 (N–H str.),
ꢀ1
1
680 (C –– O str.), 1648 (C –– N str.), 1510 (ring C –– C str.), 1464 (Ar
Molecular docking study
1
C–N str.), 1346 (N–O str. for ArNO
2
), 642 (C–S str.); H NMR
Molecular docking studies of four potent compounds based
on in vivo results were carried out using Maestro 10.5
program (Schrodinger 2016). Crystal structure of the target
enzyme DPP-4 was downloaded from RCSB Protein Data
Bank (PDB ID: 2RGU) [21] and processed using module
Protein Preparation Wizard of the program. The protein
preparation was done in three steps, that is, preprocess,
review and modify and refinement. In these steps, water
molecules were deleted and hydrogen atoms were added.
The Energy of the structure was minimized using OPLS 2005
force field. Similarly, the structures of ligands were drawn,
converted into mol files. The module LigPrep of the program
was used to process and generate all possible conformations
of the ligands and their energy was minimized using OPLS
2005 force field. Receptor grid generation program was run
by clicking any atom of the ligand and the default box
(
300 MHz,DMSO,dinppm):9.74(t,1H, NH),9.04(s,1H, H–C –– N),
7
.80–8.26 (m, 4H, ArH), 7.43–7.67 (m, 3H, ArH), 6.37 (s, 1H,
1
3
2 3
thiazole), 3.41 (s, 2H, CH ), 2.52–2.81 (s, 6H, CH ); C NMR
(
75 MHz, CDCl3, d in ppm): 163.64, 161.38, 155.56, 143.47,
1
5
35.60, 134.34, 133.23, 131.15, 130.69, 128.44, 122.58, 114.59,
3.49, 20.35, 17.15; ESI MS (m/z): 435.12 (M ); Anal. calcd. for
þ
21 18 6
C H N O
3
S: C 58.05, H 4.18, N 19.34, S 7.38%. Found: C 58.08,
H 4.15, N 19.31, S 7.40%.
(
E)-3-(4-Hydroxybenzylideneamino)-6-methyl-2-{(4-
methylthiazol-2-ylamino)-methyl}-quinazolin-4(3H)-one
4
x
ꢀ
1
Yield: 66%; m.p. 262–264°C; IR (KBr, in cm ): 3319 (N–H str.),
3
(
(
211 (O–H str. for –OH), 1665 (C –– O str.), 1643 (C –– N str.), 1553
ring C –– C str.), 1367 (Ar C–N Str), 637 (C–S str.); H NMR
300 MHz, DMSO, d in ppm): 9.68 (t, 1H, NH), 8.93 (s, 1H, H–C––
1
̊
3
2 ꢁ 2 ꢁ 2 A was prepared. The ligand was docked into the
grid generated from the protein using extra precision (XP).
The results were evaluated by glide score (docking score).
Images depicting ligand–receptor interactions were also
recorded for the study.
N), 7.76–8.09 (m, 3H, ArH), 7.31–7.58 (m, 4H, ArH), 6.47 (s, 1H,
thiazole), 5.63 (s, 1H, OH), 3.40 (s, 2H, CH ), 2.98–3.02 (s, 6H,
); C NMR (75 MHz, CDCl3, d in ppm): 162.31, 158.32,
2
1
3
CH
3
1
1
51.42, 146.11, 142.34, 140.36, 138.64, 137.61, 136.74,
34.57, 129.98, 127.37, 114.58, 60.79, 24.74, 19.93; ESI MS
þ
(
m/z): 406.12 (M ); Anal. calcd. for C21
H
19
N
5
O
2
S: C 62.21, H
Authors acknowledge University Grants Commission (UGC)
New Delhi (41-731/2012-SR) for providing financial assistance
and AICTE, New Delhi (8-99/RIFD/RPS/POLICY-3/2013-14) for
molecular docking of the present study.
4
7
.72, N 17.27, S 7.91%. Found: C 62.24, H 4.71, N 17.29, S
.94%.
Pharmacology
Assay for inhibition of DPP-4
The authors have declared no conflict of interest.
The synthesized compounds 4a–x were screened for their
in vitro DPP-4 inhibition using DPP-4 activity assay kit
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(10 of 11) e1600298

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