ACS Medicinal Chemistry Letters
Letter
a
Table 2. Second Series of Quinazoline Derivatives
Table 4. IC50 Values for COX-1 and COX-2 Enzymes
IC50 COX-1
IC50 COX-2
selectivity index (COX-2/
COX-1)
compound
(μM)
(μM)
3
3
3
3
6
6
7
8
8
9
9
b
c
1.57 ± 0.54
1.89 ± 0.63
1.90 ± 0.69
3.14 ± 0.99
0.376 ± 0.189
0.142 ± 0.014
1.39 ± 0.72
0.78 ± 0.64
1.58 ± 0.89
0.141 ± 0.045
0.064 ± 0.044
2.19 ± 0.78
0.006 ± 0.003
43.0 ± 10.3
37.3 ± 9.36
10.1 ± 1.38
>50
27.4
19.7
5.32
k
v
c
e
o
a
b
a
b
COX-1-selective
COX-1-selective
COX-1-selective
COX-1-selective
COX-1-selective
COX-1-selective
COX-1-selective
COX-1-selective
1.51
product (yield
%)
>50
>50
>50
>50
>50
>50
>50
entry reactant
R3 (intermediate)
R4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
4-methoxyphenyl (6a) morpholin-1-yl
4-methoxyphenyl (6a) pyrrolidin-1-yl
4-methoxyphenyl (6a) piperazin-1-yl
4-methoxyphenyl (6a) diethylamino
4-fluorophenyl (6b)
4-fluorophenyl (6b)
4-fluorophenyl (6b)
4-fluorophenyl (6b)
thiophen-2-yl (6c)
thiophen-2-yl (6c)
7a (89.8)
7b (80.2)
7c (79.6)
7d (40.7)
7e (94.9)
7f (96.6)
7g (90.8)
7h (34.7)
7i (82.6)
7j (87.6)
7k (90.1)
7l (91.8)
7m (84.9)
7n (54.4)
7o (90.5)
morpholin-1-yl
pyrrolidin-1-yl
piperazin-1-yl
diethylamino
morpholin-1-yl
pyrrolidin-1-yl
ibuprofen
SC-560
3.30 ± 0.96
1.03 ± 0.40
179.5
0
1
2
3
4
5
phosphoryl chloride (POCl ) afforded (E)-4-chloro-2-styryl-
3
4-methoxyphenyl (6d) morpholin-1-yl
4-methoxyphenyl (6d) pyrrolidin-1-yl
4-methoxyphenyl (6d) piperazin-1-yl
4-methoxyphenyl (6d) diethylamino
quinazoline (2a) (Scheme 1). Final compounds (3a−v) were
prepared via amination of quinazoline 2a with variously
substituted anilines or amines (Table 1).
The synthesis of the second series began with the
preparation of 7-bromo-2,4-dichloroquinazoline (4) from the
commercially available 2-amino-4-bromobenzoic acid (1b), by
thiophen-2-yl (6e)
morpholin-1-yl
a
Reagents and conditions: (a) corresponding boronic acid or ester,
K CO , PdCl (PPh ) , toluene/dioxane/water (10:5:8, v/v/v), 90 °C,
the reaction with urea followed by a treatment with POCl ,
2
3
2
3
2
3
29
overnight; (b) corresponding secondary amine, KI, K CO , N,N-
according to published procedure (Scheme 2). The step-by-
step modification of three functional groups in quinazoline 4
afforded the desired final quinazolines. Shortly, the 4-chloro
position was aminated using two different benzylamines to give
the intermediates 5a,b (Scheme 2), which underwent a Suzuki
2
3
diisopropylethylamine, dimethylformamide, 110 °C, overnight.
The derivatization of the quinazoline core in positions 2, 4, and
was chosen in order to resemble the shape of a letter “V”,
which is typical for numerous diarylheterocyclic COX-1
inhibitors. Although several of the selective COX-2 inhibitors
coxibs) also possess the diarylheterocyclic moiety, they always
7
3
0
cross-coupling reaction of the 7-bromo position with three
aromatic boronic acids to afford intermediates 6a−e. Finally,
the 2-chloro position was aminated using four different
secondary amines to give the final quinazoline derivatives
7a−o (Table 2).
(
contain either a sulfonamide or methylsulfamoyl group.
Instead, we decided to bet on the substitution with a styryl
group to partly resemble the structure of stilbenes, a class of
selective COX-1 inhibitors. Other substituents were chosen
with the aim to offer distinct electronic and steric properties of
the final compounds as well as potential variability in H-
bonding with the amino acids within the COX-1 binding site.
The synthesized compounds were evaluated in vitro for their
ability to inhibit COX-1 and COX-2 isoenzymes. The results
were also supported by in silico modeling.
The synthesis of the first series started with the preparation
of (E)-4-chloro-2-styrylquinazoline (2a) from the commer-
cially available anthranilic acid (1a), following a literature
procedure. Shortly, the treatment of 1a with acetic
anhydride, followed by the reaction with benzaldehyde in
acetic acid gave an intermediate, which upon exposure to
Out of the synthesized compounds, seven exerted potent
activity toward COX-1. For these, IC values were determined
27
5
0
on both COX isoforms, while compounds exhibiting less than
3c, 3k) exerted single-digit micromolar inhibitory activity
toward COX-1, which was comparable with the inhibitory
activity of the reference inhibitor ibuprofen, while their
inhibitory activity toward COX-2 was rather moderate
(Table 4). Their selectivity index was between 5 and 27. On
the other hand, one compound from the first series (3v) and
three compounds from the second series (6c, 6e, and 7o) were
totally COX-1-selective, as they did not inhibit COX-2 even at
2
8
a
Table 3. Third Series of Quinazoline Derivatives
entry
reagent 1: RNH2
product (yield %)
reagent 2: R B(OH)2
product (yield %)
2
1
2
4-methylaniline
3,4-difluorobenzylamine
8a (53.4)
8b (93.2)
thiophene-2-boronic acid pinacol ester
9a (77.0)
9b (85.3)
a
Reagents and conditions: (a) Corresponding aniline or benzylamine, DMAP, Et N, toluene, reflux, 3 h; (b) thiophene-2-boronic acid pinacol
3
ester, K CO , PdCl (PPh ) , toluene/dioxane/water (10:5:8, v/v/v), 90 °C, overnight.
2
3
2
3 2
6
12
ACS Med. Chem. Lett. 2021, 12, 610−616