Synthesis and antioxidant activity of new analogs of Quin-C1

Article abstract of DOI:10.1007/s10593-013-1215-3

New derivatives of 4-oxo-1,2,3,4-tetrahydroquinazoline, analogs of Quin-C1, have been synthesized by the condensation of aroyl- and heteroaroylhydrazides of anthranilic acid with cinnamic, crotonic, and 4-hydroxy-3-methoxybenzoic aldehydes. The antioxidan

Full text of DOI:10.1007/s10593-013-1215-3

Chemistry of Heterocyclic Compounds, Vol. 48, No. 12, March, 2013 (Russian Original Vol. 48, No. 12, December, 2012)
SYNTHESIS AND ANTIOXIDANT ACTIVITY
OF NEW ANALOGS OF QUIN-C1
I. Mieriņa1, Z. Tetere1, D. Zicāne1, I. Rāviņa1, M. Turks1, and M. Jure1*
New derivatives of 4-oxo-1,2,3,4-tetrahydroquinazoline, analogs of Quin-C1, have been synthesized by
the condensation of aroyl- and heteroaroylhydrazides of anthranilic acid with cinnamic, crotonic, and
4-hydroxy-3-methoxybenzoic aldehydes. The antioxidant activity of the obtained compounds has been
determined.
Keywords: cinnamic aldehyde, crotonic aldehyde, (hetero)aroylhydrazides of anthranilic acid, 4-hydr-
oxy-3-methoxybenzoic aldehyde, quinazolines, antioxidant activity.
From the seventies of the past century 2-substituted and 2,3-disubstituted derivatives of 2,3-dihydro-
quinazolin-4(1H)-one I (4-oxo-1,2,3,4-tetrahydroquinazolines or 1,2-dihydroquinazolin-4(3H)-ones) have been
studied fairly widely. In particular, 2-aryl-2,3-dihydroquinazolin-4(1H)-ones are known as compounds
possessing anticancer activity [1-6]. Nevertheless, there is little information in the literature on the synthesis and
biological activity of 3-acylaminoquinazolinones II [7-10], especially N-(quinazolin-3-yl)amides of heteroaryl-
[11] and arylcarboxylic acids [7, 12-17]. The best known representative of this series is 4-butoxy-N-[2-(4-
methoxyphenyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-yl]benzamide (Quin-C1), which is a nonpeptide antagonist
of the FPRL1 receptor that participates in inflammatory processes [12, 18, 19].
R3
O
R3
O
H
N
R4
R5
R2
R1
R4
R5
R2
N
N
O
N
H
N
H
R1
R6
R6
I
II
Intensive investigations on the application of antioxidants in the treatment of cancer [20], ischemia
[21, 22] and other illnesses caused by oxidative stress [23], stimulate the constant search for new compounds
possessing these properties. The antioxidant activity of 3-acyl- and 3-(hetero)aroylamino-2,3-dihydro-
quinazolin-4(1H)-ones II has not been studied up to the present time, but there are data on the presence of such
activity in their non-hydrogenated analogs [24, 25].
_______
*To whom correspondence should be addressed, e-mail: mara@ktf.rtu.lv.
1Riga Technical University, 1 Kaļķu St., Riga 1658, Latvia.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1948-1955, December, 2012.
Original article submitted May 25, 2012.
1824
0009-3122/13/4812-1824©2013 Springer Science+Business Media New York

Derivatives II are mostly synthesized by the interaction of acylhydrazides (R2 = alkyl) of anthranilic
acid with aldehydes at room temperature or by heating in ethanol [7] or DMF [8]. The reaction may also be
carried out in one step by the condensation of anthranilic hydrazide with acid anhydrides, without isolating the
intermediately formed acyl hydrazides, with subsequent heating with aldehydes in acetonitrile [9].
Benzhydrazides II (R2 = aryl) were synthesized analogously by the interaction of aroyl hydrazides of anthranilic
acid with aldehydes [7, 12, 13]. A description has been published recently of the synthesis of N-(2-aryl-4-oxo-
1,2-dihydroquinazolin-3(4H)-yl)benzamides II by triturating the starting materials with citric acid at room
temperature without solvent, the yield of products was 85-99% [14]. Dimeric 3,3'-bis-1,2,3,4-tetrahydro-
quinazolin-4-ones have been obtained by the reaction of N,N'-di(2-aminobenzoyl)hydrazines with aldehydes
[15].
Furthermore, derivatives II may be obtained by acylation of the amino group of 2-alkyl-3-amino-1,2-di-
hydroquinazolin-4(3H)-one I [16], and also by nucleophilic addition of lithium alkyls to the C=N bond of 3-acyl-
amino-4(3H)quinazolinone [10]. By reduction of the C=N bond of the corresponding quinazolin-4(3H)-one with
sodium cyanoborohydride, the only known heteroaryl analog of compound II was obtained, viz. the N-(4-oxo-
1,4-dihydro-2H-quinazolin-3-yl)amide of 5-chloro-2-indolecarboxylic acid [11].
In view of the data presented above we have synthesized a series of new 3-aroyl- and 3-heteroaroyl-
amino-2-substituted 4-oxo-1,2,3,4-tetrahydroquinazolines and have also determined their antioxidant activity.
O
O
H
O
N
O
N
O
+
H
R
NH
R
NH2
N
H
O
NH2
2a–g
1
3a–g
O
R1
O
H
N
O
H
N
4–6
R
N
H
R1
7–9 a–g
2, 3, 7–9 a R = Ph, b R = 4-BrC6H4, c R = 3-BrC6H4, d R = 4-ClC6H4, e R = 2-HOC6H4,
f R = 3-pyridyl, g R = 4-pyridyl; 4, 7a–g R1 = (trans)-HC=CHPh;
5, 8a–g R1 = (trans)-HC=CHMe; 6, 9a–g R1 = 3-MeO-4-HOC6H3
Anthranilic acid (hetero)aroylhydrazides 3a-g were used as starting materials, and were synthesized
from isatoic anhydride 1 and hydrazides of benzoic, 4-bromobenzoic, 3-bromobenzoic, 4-chlorobenzoic,
salicylic, nicotinic, and isonicotinic acids 2a-g by known procedures [26, 27]. Reactions of hydrazides 3a-g
with cinnamic, crotonic, and 4-hydroxy-3-methoxybenzoic aldehydes 4-6 were carried out by refluxing in
ethanol in the presence of an excess of aldehyde. The greatest reactivity was possessed by cinnamic aldehyde,
reaction with crotonic and 4-hydroxy-3-methoxybenzoic aldehydes were slower.
The obtained 2,3-disubstituted 4-oxo-1,2,3,4-tetrahydroquinazolines 7-9 a-g were crystalline
substances, the structures of which were confirmed by the results of elemental analysis (Table 1) and by data of
1H NMR spectra (Table 2), in which the proton signals of all the fragments of the molecules had the expected
shifts.
1825

TABLE 1. Physicochemical Characteristics of the Synthesized
Compounds 7-9 a-g
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp*, °С
Yield, %
С
Н
N
C23H19N3O2
C23H18BrN3O2
C23H18BrN3O2
C23H18ClN3O2
C23H19N3O3
C22H18N4O2
C22H18N4O2
C18H17N3O2
C18H16BrN3O2
C18H16BrN3O2
C18H16ClN3O2
C18H17N3O3
C17H16N4O2
C17H16N4O2
C22H19N3O4
C22H18BrN3O4
C22H18BrN3O4
C22H18ClN3O4
C22H19N3O5
C21H18N4O4
C21H18N4O4
74.87
74.78
61.90
61.62
61.52
61.62
68.40
68.40
71.44
71.67
71.00
71.34
71.54
71.34
70.25
70.34
56.01
55.97
55.81
55.97
63.25
63.25
66.61
66.86
66.29
66.22
66.31
66.22
67.79
67.86
56.32
56.43
5.26
5.18
4.17
4.05
4.00
4.05
4.50
4.49
4.88
4.97
4.88
4.90
5.01
4.90
5.65
5.58
4.08
4.18
4.23
4.18
4.70
4.72
5.27
5.30
5.28
5.23
5.30
5.23
4.85
4.92
3.75
3.87
11.43
11.37
9.36
9.37
9.34
9.37
10.30
10.40
10.89
10.90
15.04
15.13
15.31
15.13
13.70
13.67
10.96
10.88
10.99
10.88
12.23
12.29
12.88
12.99
18.20
18.17
18.21
18.17
10.68
10.79
8.87
8.97
200-201
256-257
210-211
247-248
239-240
236-237
224-225
199-200
220-221
186-187
176-177
203-204
125-126
175-176
228-229
223-224
218-220
222-223
243-245
178-180
166-167
68
91
79
83
86
70
80
86
88
76
83
75
86
89
94
74
88
64
95
63
83
7a
7b
7c
7d
7e
7f
7g
8a
8b
8с
8d
8e
8f
8g
9a
9b
9c
9d
9e
9f
56.32
56.43
62.28
62.34
65.36
65.18
64.49
64.61
3.79
3.87
4.20
4.28
4.75
4.72
4.73
4.65
8.89
8.97
9.86
9.91
10.11
10.37
14.44
14.35
64.50
64.61
4.58
4.65
14.27
14.35
9g
________
*Solvents for recrystallization: EtOH–water, 10:1 (compounds 8b-e), EtOH (remaining
compounds).
We tested the antioxidant activity of the synthesized 3-aroyl- and 3-heteroaroylamino-4-oxo-1,2,3,4-tetra-
hydroquinazolines 7-9. Among the multitude of methods of determining antioxidant activity [28], the test using
2,2-diphenyl-1-picrylhydrazyl (DPPH) as oxidizing agent was selected for characterizing compounds 7-9.
The antioxidant activity of compounds was determined at a 1:1 molar ratio with DPPH and was
expressed as percent inhibition of the DPPH free radical. The tested compounds displayed weak activity (Table
3). Compounds 9a-g showed the greatest effect (15-25% inhibition of DPPH), which is evidently linked with
the presence in their structure of a 4-hydroxy-3-methoxybenzoic fragment. The activity of these derivatives
reached 62% of the action of the widely used antioxidant butylhydroxytoluene (37.79 ± 2.56%).
1826

1827

1828

TABLE 3. Antioxidant Activity of Compounds 7-9 a-g in Relation to DPPH
Com-
pound
Com-
pound
Com-
pound
Activity, %
Activity, %
Activity, %
9.47±3.14
–
1.29±1.50
3.05±0.52
0.92±0.35
2.73±0.77
2.95±1.67
0.95±1.72
0.02±2.54
21.21±4.87
16.79±4.32
20.75±3.65
19.38±3.91
12.55±2.55
23.43±5.44
17.90±3.89
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
9a
9b
9c
9d
9e
9f
0.59±1.05
–
0.02±0.56
2.04±0.50
0.64±1.38
7g
8g
9g
New 3-acylamino-2,3-dihydroquinazolin-4(1H)-ones have been synthesized from anthranilic acid
aroylhydrazides and cinnamic, crotonic, and 4-hydroxy-3-methoxybenzoic aldehydes, and their antioxidant
activity has been determined. It was established that the greatest activity was possessed by compounds
containing a 4-hydroxy-3-methoxyphenyl fragment.
EXPERIMENTAL
The 1H NMR spectra were recorded on a Bruker 300 spectrometer (300 MHz) in DMSO-d6 (compounds
7a-g; 8a-c,e,f; 9a-g) or CDCl3 (compounds 8d,g), internal standard was TMS. Elemental analysis was carried
out on an EA1108 analyzer (Carlo-Erba Instruments). Melting points were determined on a Fisher digital
melting point analyzer, Model 355. The progress of reactions and the purity of synthesized compounds was
controlled by TLC on Merck silica gel 60 F254 plates in the solvent system CHCl3–MeOH, 9:1.
Acylhydrazides 3a,e-g were synthesized by the procedure of [26], and compound 3c by the procedure of
[27].
Derivatives 3b,d were obtained as indicated in [26], from isatoic anhydride (10 mmol) and an equimolar
quantity of the hydrazides of 4-chloro- and 4-bromobenzoic acids 2b,d.
N'-[(2-Aminophenyl)carbonyl]-4-bromobenzoylhydrazide (3b). Yield 2.28 g (67%). Mp 224-225°C
1
(EtOH) (mp 216-218°C (EtOH–H2O) [7]). The H NMR spectral data agreed with literature values. Found, %:
C 50.14; H 3.70; N 12.72. C14H12BrN3O2. Calculated, %: C 50.32; H 3.62; N 12.57.
N'-[(2-Aminophenyl)carbonyl]-4-chlorobenzoylhydrazide (3d). Yield 2.23 g (69%). Mp 225-226°C
(EtOH) (mp 225°C [29]). 1H NMR spectrum, δ, ppm : 6.44 (2H, br. s, NH2); 6.56 (1H, t, J = 7.7, H-4'(5')); 6.74
(1H, d, J = 7.7, H-3'(6')); 7.20 (1H, t, J = 7.7, H-5'(4')); 7.58-7.63 (3H, m, H-6'(3'), H Ar); 7.93-7.98 (2H, m,
H Ar); 10.22 (1H, br. s, NH); 10.48 (1H, s, NH). Found, %: C 58.24; H 4.27; N 14.58. C14H12ClN3O2.
Calculated, %: C 58.04; H 4.17; N 14.50.
N-{4-Oxo-2-[(E)-2-phenylethenyl]-1,2,3,4-tetrahydroquinazolin-3-yl}amides 7a-g (General Method).
A suspension of acylhydrazide 3a-g (1.1 mmol) and cinnamic aldehyde 4 (0.15 ml, 1.3 mmol) in EtOH (5 ml)
was heated to reflux. After several minutes, acylhydrazides 3b,c,d dissolved and a solid precipitate of
quinazoline derivative 7b,c,d began to form, after which refluxing was discontinued, the mixture cooled, stirred
for 1 h, and filtered. In the case of acylhydrazides 3e,g, the mixture was refluxed for 2 h, and of acylhydrazides
3a,f for 4 h. After cooling, compounds 7a,e,g were separated on a filter. For the reaction solution containing
quinazoline 7f, an equal volume of water was added before filtering.
N-{4-Oxo-2[(1E)-prop-1-en-1-yl]-1,2,3,4-tetrahydroquinazolin-3-yl}amides 8a-g (General Method). A
suspension of acylhydrazide 3a-g (0.74 mmol) and crotonaldehyde (5) (0.8 ml, 1.00 mmol) in EtOH (5 ml) was
refluxed for ~6 h until disappearance of the starting acylhydrazide. Refluxing was discontinued, H2O (1 ml) was
added to the hot solution, which was left until the start of crystallization, then filtered 3 h later. To obtain
quinazoline 8f, the solvent was distilled off, and the residue was recrystallized.
1829

N-[2-(4-Hydroxy-3-methoxyphenyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-3-yl]amides 9a-g (General
Method). A suspension of acylhydrazide 3a-g (0.75 mmol) and 4-hydroxy-3-methoxybenzaldehyde (6) (0.12 g,
0.80 mmol) in EtOH (8 ml) was refluxed until disappearance of the starting acylhydrazide: 3a for 1 h, 3d and 3g
for 3 h, 3e and 3f for 4 h, 3c for 5 h, and 3b for 6 h. After refluxing, the reaction mixture was cooled, stirred for
3 h, filtered, and the solid was washed with EtOH.
Determination of the Antioxidant Activity of the Synthesized Compounds 7-9 a-g. A mixture of
ethanolic solutions of DPPH and the corresponding compound 7-9 a-g (2 ml, concentration 200 μM) was
maintained at room temperature for 30 min, after which the absorption of the solution at 515 nm was measured.
All the measurements were repeated three times. Antioxidant activity (AA) was measured as the ability to
inhibit DPPH according to the equation:
AA = ((IDPPH – Icomp) / IDPPH) · 100%,
where IDPPH is absorption of a sample of DPPH, containing none of the compound being investigated;
I
comp is absorption of a sample containing DPPH and the compound 7-9 a-g being investigated.
The work was carried out with the assistance of the European Social Fund within the framework of the
project "Support For Doctoral Development at the Riga Technical University (RTU)" and the Latvian Council
of Science (grant 09.1617).
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