Design, synthesis, and anti-inflammatory activity of novel quinazolines

Article abstract of DOI:10.13005/ojc/330217

Several new fluorinated quinazolinone derivatives were prepared and evaluated for in vitro anti-inflammatory activity. The molecular modelling study was performed for compounds 4, 8, 9, 10 and 13. The tested compounds showed strong interactions at the COX

Full text of DOI:10.13005/ojc/330217

ISSN: 0970-020 X
CODEN: OJCHEG
2017, Vol. 33, No. (2):
Pg. 707-716
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Design, Synthesis, and Anti-inflammatory
Activity of Novel Quinazolines
SAID A. EL-FEKY, MOHD. IMRAN and NAIRA NAYEEM
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University,
Rafha 91911, P.O. Box 840, Kingdom of Saudi Arabia.
*Corresponding author E-mail: drsaid.elfeky@yahoo.com
http://dx.doi.org/10.13005/ojc/330217
(Received: March 10, 2017; Accepted: March 30, 2017)
ABSTRACT
Several new fluorinated quinazolinone derivatives were prepared and evaluated for in vitro
anti-inflammatory activity. The molecular modelling study was performed for compounds 4, 8, 9, 10
and 13.The tested compounds showed strong interactions at the COX-2 binding sites. Compounds
8, 13, 9, and 10 containing triazole, thiadiazole, and oxadiazole rings showed the highest in vitro
anti-inflammatory activity and the best binding into the COX-2 binding site.
Keywords: Design, Fluorinated quinazolinones, Molecular modelling study,
in vitro anti-inflammatory activity.
INTRODUCTION
is a selective COX-2 inhibitory anti-inflammatory drug
and has been reported to possess some side effects.
Therefore many efforts were performed to develop
leadcompoundspossessinggreaterefficacyandless
side effects than celecoxib3. Fluorine atom plays an
important role in medicinal chemistry4,5.The presence
of fluorine atom enhances the pharmacokinetic, the
physicochemical properties and the binding to the
targeted protein.6. Previously, we have synthesized
a number of quinoline derivatives bearing a fluorine
atom such as compound V (Fig. 1) which exhibited
high anti-inflammatory activity in comparison to the
celecoxib7. On the basis of bioisosterism concept, it
was a dream of interest to synthesize compounds
Heterocyclic compounds form the basis
of many pharmaceuticals, agrochemicals, and
veterinary products. Among a wide variety of
nitrogen heterocyclic moieties, quinazolinone
possess a diverse biological activity profile. The
pharmacodynamics versatility of quinazolin-4-
one moiety has been documented not only in its
synthetic derivatives, but also in several naturally
occurring alkaloids isolated from animals, plants,
and microorganisms, for example, tryptahthin and
rutaecarpine. Also proquazone and fluproquazone
are non-acidic anti-inflammatory drugs1,2.Celecoxib

708
EL-FEKY et al., Orient. J. Chem., Vol. 33(2), 707-716 (2017)
1-17 in the hope that one of them may become a 2-Mercapto-3-(4-fluorophenyl)-3H-quinazolin-4-
lead compound having potent anti-inflammatory one (1)
activity8, 9
.
Anthranilic acid (1 mmol) and
4-fluorophenylisothiocyanate (1.5 mmol) in 50 ml
ethanol was refluxed for 4 hours.The reaction mixture
was cooled at room temperature and the obtained
MATERIAL AND METHODS
Chemistry
solid was dried and recrystallized from ethanol to give
o
Melting points were obtained by open compound 1 in 95% yield. m.p. > 300 C; IR: 1695
1
capillarymethodusingBarnstead9100electrothermal (C=O), 2650 (-SH); H-NMR (DMSO-D6, d ppm):
melting apparatus. IR spectra (KBr) were generated 6.95-8.20 (m, 4H, Ar-H of 4-Fluorophenyl), 8.50-8.55
1
using Perkin-Elmer spectrometer (í cm-1). The H- (m, 4H, Ar-H of quinazoline), 12.96 (s, 1H); Mass
NMR spectra were obtained from Varian Gemini- (m/z): 272 [M+]; Elemental Analysis (C14H9FN2OS):
300 spectrophotometer.The 13C-NMR spectra were Calcd. C, 61.75; H, 3.33; N, 10.29; Found: C, 61.52;
generated on Brucker 500 MHz spectrophotometer. H, 3.47; N, 10.41.
The mass spectra were obtained with the help of a
Perkin-Elmer, Clarus 600 TGC / MS, spectrometer. Ethyl-2-[3-(4-fluorophenyl)-3,4-dihydro-4-
oxoquinazolin-2-yl)thio]acetate (2)
Compound 1 (1 mmol) and ethyl
2-bromoacetate (1.5 mmol) in 15 ml of acetone
O
containing K2CO3 (1.5 mmol) was stirred for 10
hours at room temperature. The precipitated solid
CH3
O
was filtered, and crystallized from ethanol to give
NH
N
N
o
F
compound 2 in 80% yield. m.p. 130-132 C; IR:
O
N
1
1692 and 1735 (C=O); H-NMR: 1.56 (t, 3H),
4.02 (s, 2H), 4.30-4.70 (q, 2H), 6.95-8.2 (m, 4H,
Ar-H of 4-fluorophenyl), 8.5-8.55 (m, 4H, Ar-H of
quinazoline);13C-NMR:14.11, 30.81, 60.62, 115.77,
115.69, 119.41, 120.91, 126.66, 126.77, 127.33,
128.33, 130.11, 133.41, 146.99, 159.35, 160.61,
162.91, 169.41; Mass (m/z): 358 (M+); Elemental
N
N
S
R
F
2 - 17
V
FIg. 1: Bioisosteric concept
O
F
F
Br
O
N
F
O
CH3
O
O
Br
F
F
N
O
N
N
S
O
CH3
N
SH
N
S
O
1
6
O
2
NH
H2
N
NH2
R
Cl
O
C2H5OH
F
F
O
N
O
N
N
N
NH
NH
S
R
S
NH2
O
O
3
5a) R = H, 5b) R = -Ph, 5c) R = 4-F-Ph
H
O
F
F
O
N
N
NH
S
N
O
F
4
Scheme 1

709
EL-FEKY et al., Orient. J. Chem., Vol. 33(2), 707-716 (2017)
Analysis (C18H15FN2O3S): Calcd. C, 60.33; H, 4.22;
N, 7.82; Found: C, 60.21; H, 4.11; N, 7.86.
55.81; H, 3.81; N, 16.27; Found: C, 55.66; H, 3.86;
N, 16.31.
2 - [ 3 - ( 4 - f l u o ro p h e ny ) - 3 , 4 - d i hy d ro - 4 -
oxoquinazolin-2-yl)thio]acetohydrazide (3)
Hydrazine hydrate (2 mmol) was added
( E ) - N - ( 4 - f l u o ro b e n z y l i d e n e ) - 2 - [ 3 - ( 4 -
fluorophenyl)-3,4-dihydro-4-oxoquinazolin-2-yl)
thio] acetohydrazide (4)
to compound 2 (1 mmol) in 10 ml absolute ethanol
and the reaction mixture was stirred for 12 hours.
The solid obtained was filtered and recrystallized
from ethanol to give compound 3 in 85% yield. m.p.
170-172 oC; IR: 1688 and 1660 (C=O), 3311, 3290,
C o m p o u n d 3 ( 1 . 5 m m o l ) a n d
p-fluorobenzaldehyde (1.5 mmol) in 15 ml of
absolute ethanol was stirred for 1 hour.The obtained
solid was filtered and crystallized from ethanol to give
compound 4 in 81% yield.m.p.182-184 oC;IR:1687
and 1655 (C=O), 3315 (-NH-), 1H-NMR:4.18 (s, 2H),
6.96-8.10 (m, 4H, Ar-H of 4-fluorophenyl), 8.50-8.55
(m, 4H, Ar-H of quinazoline), 10.95 (s, 0.5H), 11.05
(s, 0.5H); 13C-NMR: 30.77, 115.61, 115.61, 116.71
(2C), 120.81, 126.63, 126.71, 127.33, 128.33,
129.38, 130.16, 130.16, 130.81, 138.11, 138.82,
144.11, 146.11, 148.11, 160.61, 162.93, 165.22,
171.11; Mass (m/z): 450 (M+); Elemental Analysis
(C23H16F2N4O2S): Calcd. C, 61.33; H, 3.58; N, 12.44;
Found: C, 61.21; H, 3.55; N, 12.51.
1
3245 (N-H); H-NMR: 4.22 (s, 2H), 4.31 (s, 2H),
6.95-8.1 (m, 4H, Ar-H of 4-fluorophenyl), 8.50-8.56
(m, 4H, Ar-H of quinazoline), 9.18 (s, 1H); 13C-NMR:
30.44, 115.71, 115.72, 120.81, 126.61, 126.73,
127.32, 128.31, 130.11, 133.42, 146.22, 146.91,
159.33, 160.61, 162.96, 170.31; Mass (m/z): 344
(M+);;Elemental Analysis (C16H13FN4O2S):Calcd.C,
F
O
N
NH
Synthesis of compounds 5a-c
N
S
NH2
O
To compound 1 (2 mmol) in 15 ml acetone,
the respective 2-chloro-N-(substitutedphenyl) anilide
(2.1 mmol) and anhydrous K2CO3 (3 mmol) was
added and refluxed with stirring for 1 hour. The
precipitated solid was filtered, washed with water,
and recrystallized from ethanol.
3
SNC
F
F
O
N
F
F
O
N
O
N
H
N
N
N
KOH
N
S
DCCD
N
N
N
S
NH
S
N
F
S
NH
NH
S
NH
O
O
10
7
8
F
2-[3-(4-fluorophenyl)-3, 4-dihydro-4-
oxoquinazolin-2-yl)thio]acetamide (5a)
Yield 85%; m.p. 177-179 oC; IR: 1682 and
F
Conc. H2SO
, RT
4
F
O
N
N
1
N
N
1651 (C=O), 3180 (N-H); H-NMR: 4.19 (s, 2H),
S
NH
S
6.91-8.10 (m, 4H, Ar-H of 4-fluorophenyl), 8.50-8.55
(m, 4H, Ar-H of quinazoline), 8.54 (s, 1H); 13C-NMR:
30.92, 115.71, 115.72, 120.81, 126.62, 126.63,
126.71, 127.33, 128.33, 130.11, 133.41, 146.91,
159.31, 160.63, 162.92, 170.81; Mass (m/z): 329
(M+); Elemental Analysis (C16H12FN3O2S): Calcd. C,
58.35; H, 3.67; N, 12.76; Found: C, 58.22; H, 3.55;
N, 12.55.
9
F
Scheme
2
Scheme 2
Table 1:Values for in vitro COX-1 / COX-2
enzyme inhibition by the designed compounds
2-[3-(4-fluorophenyl)-3, 4-dihydro-4-
oxoquinazolin-2-yl)thio]-N-phenylacetamide
(5b)
Compound No. COX-1
COX-2
SI
4
> 100
> 100
> 100
> 100
> 100
0.33
0.83
0.42
0.73
0.31
> 303.0
> 125.0
> 250
> 142.9
> 333.3
Yield 95%; m.p. 162-164 oC; IR: 1683 and
8
9
1
1655 (C=O), 3183 (N-H); H-NMR: 4.22 (s, 2H),
6.92-8.30 (m, 8H, Ar-H), 8.50-8.55 (m, 4H, Ar-H of
quinazoline), 8.57 (s, 1H); 13C-NMR: 28.33, 115.71,
10
13

710
EL-FEKY et al., Orient. J. Chem., Vol. 33(2), 707-716 (2017)
115.72, 121.61, 121.62, 126.61, 126.72, 127.31, (C22H15F2N3O2S): Calcd. C, 62.40; H, 3.57; N, 9.92;
128.11, 128.81, 128.33, 128.91, 130.32 (2C), 132.44, Found: C, 62.33; H, 3.81; N, 9.88.
133.41, 139.51, 146.92, 159.31, 160.61, 162.91,
168.22; Mass (m/z): 405 (M+); Elemental Analysis 2-(4-fluorophenacyl)thio]-3-(4-fluorophenyl)-3,4-
(C22H16FN3O2S): Calcd. C, 65.17; H, 3.98; N, 10.36; dihydro-4-oxoquinazolin (6)
Found: C, 65.22; H, 3.65; N, 10.22.
Compound 1 (1 mmol) in 20 ml acetone,
4-fluorophenacyl bromide (1.1 mmol) and K2CO3 (2
2 - [ 3 - ( 4 - f l u o ro p h e ny l ) - 3 , 4 - d i hy d ro - 4 - mmol) was heated under reflux for 5 hours. Ice cold
oxoquinazolin-2-yl)thio]-N-(4-fluorophenyl) water was added to the reaction mixture and the solid
acetamide (5c)
obtained was filtered and recrystallized from ethanol
Yield 85%; m.p. 152-154 oC; IR: 1682 and to give compound 6 in 71% yield. m.p. 157-159 oC;
1
1
1654 (C=O), 3182 (N-H); H-NMR: 4.22 (s, 2H), IR: 1682 and 1654 (C=O); H-NMR: 3.25 (s, 1H),
6.93-8.33 (m, 8H, Ar-H), 8.50-8.56 (m, 4H, Ar-H of 4.22 (s, 2H), 6.96-8.3 (m, 8H, Ar-H), 8.50-8.55 (m,
quinazoline), 8.58 (s, 1H); 13C-NMR: 29.22, 81.21, 4H, Ar-H of quinazoline); 13C-NMR: 35.81, 115.41,
110, 11, 115.71, 115.72, 120.81, 125.71, 126.61, 115.42, 115.71, 115.72, 120.81, 126.61, 126.71,
126.71, 127.31, 128.33, 130.11 (2C), 131.33, 133.41, 127.31, 128.31, 130.11 (2C), 131.0, 131.11 (2C),
137.51, 137.51, 146.91, 159.31, 160.61, 162.91, 133.41, 146.91, 159.31, 160.61, 162.91, 167.33,
167.33; Mass (m/z): 423 (M+); Elemental Analysis 194.11; Mass (m/z): 408 (M+); Elemental Analysis
(C22H14F2N2O5S): Calcd. C, 64.70; H, 3.46; N, 6.86;
Found: C, 64.66; H, 3.55; N, 7.11.
O
F
F
O
H3
C
O
O
CH3
N
Br
N
2-[2-[3-(4-fluorophenyl)-3, 4-dihydro-
4-oxoquinazolin-2-yl]thio]acetyl-N-(4-
fluorophenylhydrazine)-1-carbothioamide (7)
Compound 3 (2 mmol) in 20 ml absolute
N
S
N
SH
O
CH3
1
H3
C
O
11
ethanolwasrefluxedwith4-fluorophenylisothiocyanate
(2.1 mmol) for 1 hour.The obtained solid was filtered
and recrystallized from ethanol to give compound
7 in 83% yield. m.p. 171-173 oC; IR: 3384, 3187 (2
N-H), 1676, 1650 (C=O) and 1350 (C=S); 1H-NMR:
4.01 (s, 2H), 6.94-8.20 (m, 8H, Ar-H), 8.51-8.56
(m, 4H, Ar-H of quinazoline), 10.33 (s, 1H), 9.24 (s,
1H), 8.61 (s, 1H); 13C-NMR: 31.11, 115.71, 115.72,
115.81, 115.82, 120.81, 126.61, 126.71, 127.32,
128.31, 128.32, 130.11, 131.11 (2C), 131.22, 133.41,
146.91, 159.33, 160.62, 162.91, 163.33, 170.33,
181.11; Mass (m/z): 497 (M+); Elemental Analysis
(C23H17F2N5O2S2):Calcd.C, 55.52;H, 3.44;N, 14.08;
Found: C, 55.66; H, 3.35; N, 14.11.
Semicarbazide
F
F
O
O
N
N
N
S
O
N
S
N
N
NH
H3
C
NH
NH2
H3
C
OH
N
H
O
13
12
Scheme 3
O
F
F
O
N
H3
C
O
O
CH3
N
C
Br
N
S
N
SH
O
CH3
1
H3
O
11
2-([(4-fluorophenyl-5-mercapto-4H-1,2,4-triazol-3-
yl)methyl]thio)-3-(4-fluorophenyl)-3,4-dihydro-4-
oxoquinazolin (8)
Semicarbazide
F
F
O
O
Compound 7 (2 mmol) was refluxed with
N
N
C
aqueous KOH (3 mmol) for 2 hours.The clear solution
was neutralized with 10% HCl and the obtained solid
was filtered, washed with water and recrystallized
from ethanol to give compound 8 in 81% yield. m.p.
221-223 oC; IR: 1687 (C=O); 1H-NMR: 4.47 (s, 2H),
6.93-8.31 (m, 8H, Ar-H), 8.51-8.53 (m, 4H, Ar-H of
N
S
O
N
S
N
N
NH
H3
C
NH
NH2
H3
OH
N
H
O
13
12
Scheme 3 : Synthesis and cycli zation of 4(3H)-
quinazoline bearing 1, 2, 4- triazole ring

711
EL-FEKY et al., Orient. J. Chem., Vol. 33(2), 707-716 (2017)
Table 2: Molecular modeling data for compounds 4, 8, 9, 10, 13 and Celecoxib during
docking in COX-2 (PDB ID: 1CX2) active site
Compound
COX-2
Functional Interaction
group
Affinity
Kcal/mol
Distance (in Ao)
from
2d caption
main residue
4
8
0.9
3.01
3.13
3.88
4.03
3.40
3.31
2.94
3.60
Glu524
Glu524
Arg120
Val349
-S-
-S-
-Ph-ring
-S-
-S-
=N-
=S
=S
H-donor
H-donor
pi-cation
H-donor
H-donor
H-acceptor
Fig. 2
Fig. 3
-5.3
-1.0
-0.6
-0.1
-1.1
-2.2
-1.3
Leu352
Ser353
Arg513
Arg513
Lys83
Arg513
Glu524
Lys83
Arg513
Arg120
Arg120
Arg513
Arg120
H-acceptor
H-acceptor
H-acceptor
pi-cation
H-donor
H-acceptor
pi-cation
H-acceptor
H-acceptor
H-acceptor
H-acceptor
9
-1.4
-0.6
-5.1
-11.3
-0.7
-1.2
-1.8
-6.5
3.70
4.36
2.82
3.06
4.08
3.13
3.14
2.91
2.51
-S-
Fig. 4
Fig. 5
-Ph-ring
-NH-
=N-
-Ph-ring
=N-
=N-
-SO2
-SO2
10
13
Fig. 6
Fig. 7
Celecoxib
F
O
N
F
O
N
F
O
N
N
H
N
N
N
CN
N
N
N
N
O
S
S
N
N
S
N
F
S
CH2=CH-CN
N
F
CH 2O
S
S
N
F
H
N
8
16
14
O
CH 3I / K2CO 3, RT
F
O
N
N
N
N
S
S
N
F
CH3
15
CH 3I / DMF
F
O
CH3
N
N
N
N
S
S
N
F
17
Scheme 4

712
EL-FEKY et al., Orient. J. Chem., Vol. 33(2), 707-716 (2017)
o
1
quinazoline), 13.89 (s, 1H); 13C-NMR: 29.11, 115.71 271-273 C; IR: 3182 (N-H) and 1686 (C=O); H-
(2C), 115.81 (2C), 120.81, 126.61, 127.33, 128.31, NMR: 4.62 (s, 2H), 4.68 (s, 1H), 6.91-8.28 (m, 8H,
129.51, 130.11 (2C), 133.41, 135.11, 135.12, Ar-H), 8.52-8.56 (m, 4H, Ar-H of quinazoline), 9.88
146.91, 157.11, 159.33, 160.63, 162.92, 163.31, (s, 1H); 13C-NMR: 24.41, 115.71, 115.72, 116.32,
166.71; Mass (m/z): 479 (M+); Elemental Analysis 116.33, 116.34, 120.61, 120.62, 120.64, 120.82,
(C23H15F2N5OS2): Calcd. C, 57.61; H, 3.15; N, 14.61; 126.71, 127.33, 128.34, 130.11, 130.13, 134.51,
Found: C, 57.55; H, 3.16; N, 14.21.
146.92, 157.33, 159.32, 160.61, 162.92, 163.24,
169.33; Mass (m/z): 463 (M+); Elemental Analysis
2-([(5-(4-fluorophenyl)amino)1,3,4-thiadiazole-2- (C23H15F2N5O2S): Calcd. C, 69.61; H, 3.26; N, 15.11;
yl)methyl]thio)-3-(4-fluorophenyl)-3,4-dihydro-4- Found: C, 69.55; H, 3.11; N, 15.22.
oxoquinazolin (9)
Compound 7 (2 mmol) and concentrated Ethyl 2-(3-(4-fluorophenyl)-4-oxo-3,4-
H2SO4 (5ml) was stirred at room temperature for 12 dihydroquinazolin-2-yl) thio) propanoate (11)
hours. The reaction mixture was neutralized with
Compound 1 (1 mmol) was dissolved in 15
KHCO3 and the obtained solid was crystallized to ml of absolute ethanol and KOH (1.5 mmol). Ethyl
o
give compound 9 74% yield. m.p. 228-230 C; IR: ethyl-2-bromopropanoate (1.5 mmol) was added
3182 (N-H) and 1683 (C=O); 1H-NMR: 4.67 (s, 2H), dropwise to the reaction mixture and refluxed for 6
6.92-8.23 (m, 8H, Ar-H), 8.52-8.56 (m, 4H, Ar-H hours. The reaction mixture was poured on ice cold
of quinazoline), 9.82 (s, 1H, NH); 13C-NMR: 24.41, water and the precipitated solid was filtered, and
115.71, 115.72, 116.31, 116.33, 120.62, 120.82, recrystallized from ethanol to give compound 11 in
126.62, 126.72, 127.34, 128.33, 128.36, 130.11, 75% yield. m.p. 190-192 oC; IR: 1733 (C=O, ester),
1
133.41, 138.11, 146.91, 152.72, 157.31, 159.32, 1687 (C=O, quinazolinone); H-NMR: 0.82 (t, 3H),
159.33, 160.61, 162.92, 168.01; Mass (m/z): 479 1.19 (d, 3H), 2.73 (q, 1H), 3.32 (q, 2H), 7.20-8.20
(M+); Elemental Analysis (C23H15F2N5OS2): Calcd. C, (m, 8H, Ar-H); 13C-NMR: 14.11, 18.52, 37.11, 60.92,
57.61; H, 3.15; N, 14.61; Found: C, 57.55; H, 3.33; 115.72, 120.81, 126.61, 126.72, 128.72, 128.33,
N, 14.75.
130.11, 130.12, 133.41, 146.92, 155.74, 159.32,
160.62, 162.92, 170.82; Mass (m/z): 372 (M+);
2-([(5-(4-fluorophenyl)amino)-1,3,4-oxadiazol-2- Elemental Analysis (C19H17FN2O3S):Calcd.C, 61.28;
yl)methyl]thio-3-(4-fluorophenyl)-3,4-dihydro-4- H, 4.60; N, 7.52; Found: C, 61.33; H, 4.77; N, 8.11.
oxoquinazolin (10)
To compound 7 (1 mmol) in toluene (20 2 - ( 3 - ( 4 - f l u o r o p h e n y l ) - 4 - o x o - 3 , 4 -
ml), DCCD (1.5 mmol) was added and the reaction dihydroquinazolin-2-yl)thio)propanoyl
mixture was refluxed for 6 hours. On cooling the semicarbazide (12)
obtained solid was filtered and recrystallized from
Compound 30.11, 130.16, 133.44, 146.91,
ethanol to give compound 10 in 63% yield. m.p. 157.41, 159.33, 160.62, 162.93, 174.82;Mass (m/z):
Fig. 2
Fig. 3

713
EL-FEKY et al., Orient. J. Chem., Vol. 33(2), 707-716 (2017)
401 (M+);Elemental Analysis (C18H16FN5O3S):Calcd.
C, 53.86;H, 4.02;N, 17.45;Found:C, 53.77;H, 4.11;
N, 17.66.
1.16 (t, 2H), 3.98 (t, 2H), 4.20 (s, 2H), 6.92-8.23 (m,
8H, Ar-H), 8.52-8.56 (m, 4H, Ar-H of quinazoline);
13C-NMR: 29.91, 115.71, 115.81, 120.81, 125.62,
125.71, 126.61, 126.71, 127.33, 127.34, 127.38,
128.55, 128.56, 130.11, 130.13, 130.14, 133.42,
135.01, 135.03, 146.91, 157.81, 159.22, 160.61,
162.9, 167.61, 190.33; Mass (m/z): 532 (M+);
Elemental Analysis (C26H18F2N6OS2): Calcd. C,
58.64; H, 3.41; N, 15.78; Found: C, 58.55; H, 3.22;
N, 15.66.
3 - [ 1 - ( 3 - ( 4 - f l u o r o p h e n y l ) - 4 - ox o - 3 , 4 -
dihydroquinazolin-2-yl-thio)ethyl]-4H-1,2,4-
triazol-5-ol (13)
Compound 12 (1 mmol) and 20% aqueous
KOH (25 ml) was refluxed for 12 hours.The mixture
was cooled, poured into ice cold water, stirred and
neutralized by gradual addition of (1:1) hydrochloric
acid. The precipitate was filtered, washed with H2O
and recrystallized from ethanol to give compound
2-(4-(4-fluorophenyl)-5-methylthio-s-triazol-
3-ylmethyl)-3-(4-fluorophenyl)-3,4-dihydro-4-
oxoquinazoline (15)
o
13 in 90% yield. m.p. > 300 C; IR: 3444 (O-H),
1
3377 (N-H), 1685 (C=O), 1639 (C=N); H-NMR:
To a mixture of 8 (1 mmol) and fused sodium
1.58 (d, 3H), 2.83 (q, 1H), 5.1 (s, 1H), 7.41-8.32
(m, 8H, Ar-H), 9.81 (s, 1H); 13C-NMR: 17.91, 33.81,
115.72, 115.75, 120.81, 126.61, 127.32, 128.33,
128.73, 131.11, 131.12, 133.44, 148.92, 152.11,
159.33, 159.34, 160.61, 162.93; Mass (m/z): 383
(M+); Elemental Analysis (C18H14FN5O2S): Calcd. C,
56.39; H, 3.68; N, 18.27; Found: C, 56.29; H, 3.55;
N, 18.11.
acetate (2 mmol), methyl iodide (1 mmol) was added.
The mixture was heated for 2 hours, cooled to RT
and poured on crushed ice, then scratched with a
glass rod and kept overnight in a refrigerator. The
white solid was filtered and recrystallized from
ethanol to give compound 15 in 65% yield. m.p.
185-187 oC; IR: 1683 (C=O); 1H-NMR: 2.43 (s, 3H),
4.28 (s, 2H), 6.92-8.23 (m, 8H, Ar-H), 8.52-8.56 (m,
4H, Ar-H of quinazoline); 13C-NMR: 14.81, 21.42,
113.42, 115.51, 115.52, 115.72, 115.73, 120.82,
125.52, 126.26, 126.71, 127.33, 128.35, 128.41,
130.11, 130.14, 140.11, 141.42, 146.91, 147.33,
153.01, 159.32, 162.91, 162.94; Mass (m/z): 493
(M+);Elemental Analysis (C24H17F2N5OS2):Calcd.C,
58.41; H, 3.47; N, 14.19; Found: C, 58.22; H, 3.55;
N, 14.20.
2-(1-b-cyanoethyl-4-(4-fluorophenyl)-5-thioxo-∆
s-triazolin-3-ylmethyl)-3-(4-fluorophenyl) -3,4-
dihydro-4-oxo-quinazolin (14)
The solution of compound 8 (1 mmol) in
water (5 ml) and pyridine (20 ml) was treated with
acrylonitrile (1 ml). The mixture was refluxed for 4
hours and the volume was reduced to half.The solid
was filtered, washed with water and recrystallized
from ethanol to give compound 14 in 50% yield.m.p.
2-(4-(4-fluorophenyl)-1-morpholinomethyl)-
5-thioxo-∆-s-triazolin-3-ylmethyl)-4-(4-
o
172-174 C; IR: 1682 (C=O), 2230 (CN); 1H-NMR:
Fig. 4
Fig. 5

714
EL-FEKY et al., Orient. J. Chem., Vol. 33(2), 707-716 (2017)
fluorophenyl)-3,4-dihydro-4-oxoquinazolin (16)
In Vitro Anti-inflammatory Activity
An ethanolic solution of 8 was stirred with
It was carried out by the colorimetric COX
37% formaldehyde solution (1 ml) and ethanolic (ovine) inhibitor screening assay adopting the
solution of morpholine (9 mmol) for 2 hours at RT. reported procedure10-12
The mixture was kept in a refrigerator overnight
.
and the precipitated solid was filtered, washed with Docking Methodology
cold ethanol and recrystallized from ethanol to give
Molecular modelling was performed as
compound 16 in 90% yield.m.p.215-217 oC;IR:1683 provided in our previous report8.
1
(C=O); H-NMR: 2.76 (m, 4H), 3.76 (m, 4H), 4.21
(s, 2H), 6.92-8.23 (m, 8H, Ar-H), 8.52-8.56 (m, 4H,
Ar-H of quinazoline);13C-NMR:2.31, 2.32, 2.38, 2.39,
19.21, 24.42, 36.92, 59.21, 104.32, 105.81, 113.42, Chemistry
115.11, 115.72, 115.73, 126.33, 126.62, 127.33,
RESULTS AND DISCUSSIONS
Compound 1 was obtained via the reaction
128.32, 128.71, 130.11, 130.13, 133.41, 141.42, of anthranilic acid and 4-fluorophenyl isothiocyante
146.92, 151.01, 159.32, 160.41, 162.43;Mass (m/z): (Scheme 1). The IR spectra of compound 1
578 (M+); Elemental Analysis (C28H24F2N6O2S2): revealed a signal at 1690 cm-1 corresponding to
Calcd. C, 58.18; H, 4.18; N, 14.52; Found: C, 58.17; C=O of quinazolinone 1. Reaction of compound 1
H, 4.11; N, 14.57.
with ethyl bromoacetate gave the corresponding
ester 2 which on reaction with hydrazine hydrate in
2-(4-(4-Fluorophenyl)-3-methyl-5-thioxo-∆-s- ethanol produced the corresponding hydrazide 3.
triazolin-3-ylmethyl)-3-(4-fluorophenyl)-3,4- Reaction of compound 3 with 4-fluorobenzaldehyde
dihydro-4-oxoquinazoline (17)
produced the corresponding hydrazone derivative 4.
The solution of 15 (5 mmol) and methyl On the other hand, treatment of 1 with 2-chloro-N-
iodide (9 mmol) in DMF (20 ml) was heated for one (substitutedphenyl)anilides gave the corresponding
hour. The mixture was poured into ice cold water acetamide derivatives 5a-c. Moreover, reaction of
and the precipitate was recrystallized from ethanol 1 with 4-fluorophenacyl bromide gave compound 6
to give compound 17 in 60% yield. m.p. 196-198 oC; (Scheme 1).
1
IR: 1682 (C=O), 1140 and 1470 (C=S); H-NMR:
2.55 (s, 3H), 4.29 (s, 2H), 6.92-8.29 (m, 8H, Ar-H),
Scheme 2 was achieved by reaction of
8.51-8.57 (m, 4H, Ar-H of quinazoline); Elemental compound 3 with 4-fluorophenylisothiocyanate to
Analysis (C24H17F2N5OS2): Calcd. C, 58.41; H, 3.47; produce the carbothioamide derivative 7 which was
N, 14.19; Found: C, 58.41; H, 3.47; N, 14.11.
used as starting compound for the synthesis of the
Fig. 7: Docked pose of cyclooxygenase enzyme
with Celecoxib (2D).
Fig.6

715
EL-FEKY et al., Orient. J. Chem., Vol. 33(2), 707-716 (2017)
corresponding triazole, thiadiazole and oxadiazole
Molecular Modelling Studies
derivatives. Compound 7 was reacted with aqueous
KOH under refluxed to give the corresponding
triazole derivative 8. Similarly, when compound 7
was stirred with concentrated sulfuric acid, it gave
the corresponding 1,3,4-thiadiazole derivative 9.
Finally, the compound 7 was cyclodesulfurised by
hrating under reflux with DCCD in toluene to give
the oxadiazole derivative 10.
These were performed using MOE 2007.09
program14. The crystallographic enzyme ligand
complex with SC-558 was obtained from the RCSB
protein data bank (PDB entry ICX2)15, 16
.
CONCLUSION
In the present study, novel fluorinated
quinazolinones having triazole, thiadiazole, and
oxadiazole rings were synthesized and evaluated
for their in vitro anti-inflammatory activity. Molecular
modelling studies were performed to examine
the selectivity on cyclooxygenase 2 enzyme.
Compounds 4, 8, 9, 10, and 13 showed interesting
anti-inflammatory activity and a good binding with
the COX-2 enzyme. Therefore, these compounds
may represent lead compounds for developing
anti-inflammatory agents with high binding affinity
with the receptor and no side effects. Also, fluorine
will very likely continue to contribute in drug design
and discovery by playing multifaceted17, 18 roles in
enhancing future medical advances.
The compound 11 was prepared by
the reaction of the compound 1 with ethyl-2-
bromopropanoate (Scheme 3) to give the ester
11 which was converted to the corresponding
semicarbazide12 by the reaction with semicarbazide.
The corresponding hydroxyl triazole derivative
13 was obtained by cyclocondenzation of 12 with
aqueous NaOH.
The triazole derivative 8 was subjected
to cyanomethylation using acrylonitrile or
aminomethylation using Mannich reaction conditions
to afford the products 14 and 16, respectively.
Methylation of 8 in acetone in the presence of sodium
acetate resulted in the kinetically controlled reaction
product 15 as proved by the conversion of 15 to the
thermodynamically controlled reaction product 16
upon heating in dimethylformamide in the presence
of methyl iodide, as what have been reported by
Molina and Alajarin13. Structure elucidation of the
N-substitution was confirmed by elemental analysis
as well as spectral data.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the
approval and support of this research study by the
grant no. PHM-2016-1-6-F-5682 K.S.A. at Northern
Border University, Arar from the Deanship of
Scientific Research.
In vitro COX inhibition assay
The highly scored docked derivatives 4, 8,
9, 10, and 13 were evaluated using an in vitro COX-1
/ COX-2 inhibition assay (Table 1).
REFERENCES
1.
Lee E.S., Kim S.I, Lee S.H., JeongT.C., Moon
T.C., Chang H.W., Jahng Y.D., Bull. Korean
Chem. Soc.2005,26(12), 1975-1980.
JahngY., Arch.Pharm.Res.2013, 36(5), 517-
535.
Abdel-Aziz A.A., Abou-Zeid L.A., ElTahir K.E.,
Mohamed M.A., Abu El-Enin M.A., El-Azab
A.S. Bioorg. Med. Chem.2016, 24(16), 3818-
3828.
4.
5.
6.
7.
Mahin R., Ali D. J. Fluorine Chem.2017,193,
89-97.
Wei W., Yuan Z., Hao P., Hong-Wu H., Xing-
Tao L. J. Fluorine Chem.2017,193, 8-16.
Shah P., Westwell A.D.J.Enzyme Inhib.Med.
Chem.2007,22(5), 527-540.
2.
3.
Said A.E., Hamdy K.T., Mustafa T.U. J.

716
EL-FEKY et al., Orient. J. Chem., Vol. 33(2), 707-716 (2017)
Fluorine Chem.2014,161, 87-94. 415.
8.
Said A.H.E., Zakaria K.A.E., Nermine A.O.,
Jasmine L., Mohamed A.K., Hamdy K.T.
Bioorg. Chem.2015,58, 104-116.
Said A.E., Hamdy K.T., Mahmoud M.E.M.
Orient. J. Chem.2015, 31(2), 709-718.
El-Sayed M.A., Abdel-Aziz N.I., Abdel-Aziz
A.A., El-Azab A.S., Asiri Y.A., Eltahir K.E.
Bioorg. Med. Chem.2011, 19(11), 3416-
3424.
Alanazi A.M., El-Azab A.S., Al-Suwaidan
I.A., ElTahir K.E., Asiri Y.A., Abdel-Aziz N.I.,
Abdel-Aziz A.A. Eur. J. Med. Chem.2015,92,
115-123.
Uddin M.J., Rao P.N., KnausE.E..Bioorg.Med.
Chem.2004,12(22), 5929-5940.
14.
https://www.chemcomp.com/MOE-
Molecular_Operating_Environment.htm
Kurumbail R.G., Stevens A.M., Gierse J.K.,
McDonald J.J., Stegeman R.A., Pak J.Y.,
Gildehaus D., Miyashiro J.M., Penning T.D.,
Seibert K., Isakson P.C., Stallings W.C.
Nature.1996, 384(6610), 644-648.
Xu S., Hermanson D.J., Banerjee S.,
Ghebreselasie K., Clayton G.M., Garavito
R.M., Marnett L.J. J. Biol. Chem.2014,
289(10), 6799-6808.
15.
9.
10.
16.
11.
17.
18.
Iwao O. J. Org. Chem.2013, 78(13), 6358-
6383.
Fyaz M.D. J. Fluorine Chem.2002,118, 1-2,
27-33.
12.
13.
Molina P., Alajarin M. Synthesis1983, 5, 414-