4-Quinazolinones: Synthesis and reduction of prostaglandin E2 production

Article abstract of DOI:10.1016/S0014-827X(99)00102-0

We synthesized and evaluated the anti-inflammatory activity of a series of 4-quinazolinone derivatives. Two approaches were used to yield the title compounds. A first group of quinazolinone derivatives was obtained by the appropriate substituted anthranilates. A second group of quinazolinone compounds was prepared through the benzoxazin-4-ones intermediate. The pharmacological results reveal that the synthesized derivatives exhibit a significant anti-inflammatory effect in an experimental ocular inflammation model. In fact, all the tested compounds lowered the prostaglandin E₂ (PGE₂) production with respect to the control group (P < 0.05). The 3- cyclohexyl-6-chloro-quinazolin-4(3H)-one and 3-cyclohexyl-quinazolin-4(3H)- one derivatives were the most active compounds. These compounds significantly reduced PGE₂ levels even more than the reference drug tolmetin and significantly lower protein concentration and polymorphonuclear leukocytes number compared to the control group (P < 0.05). Therefore, these compounds may be useful to prevent ocular inflammatory reactions.

Full text of DOI:10.1016/S0014-827X(99)00102-0

www.elsevier.nl/locate/farmac
Il Farmaco 54 (1999) 780–784
4-Quinazolinones: synthesis and reduction of prostaglandin E2
production
Natale Alfredo Santagati *, Ennio Bousquet, Angelo Spadaro, Giuseppe Ronsisvalle
Dipartimento di Scienze Farmaceutiche, Uni6ersita` degli Studi di Catania, Viale Andrea Doria 6, 95125 Catania, Italy
Received 19 July 1999; accepted 28 September 1999
Abstract
We synthesized and evaluated the anti-inflammatory activity of a series of 4-quinazolinone derivatives. Two approaches were
used to yield the title compounds. A first group of quinazolinone derivatives was obtained by the appropriate substituted
anthranilates. A second group of quinazolinone compounds was prepared through the benzoxazin-4-ones intermediate. The
pharmacological results reveal that the synthesized derivatives exhibit a significant anti-inflammatory effect in an experimental
ocular inflammation model. In fact, all the tested compounds lowered the prostaglandin E2 (PGE2) production with respect to the
control group (PB0.05). The 3-cyclohexyl-6-chloro-quinazolin-4(3H)-one and 3-cyclohexyl-quinazolin-4(3H)-one derivatives were
the most active compounds. These compounds significantly reduced PGE2 levels even more than the reference drug tolmetin and
significantly lower protein concentration and polymorphonuclear leukocytes number compared to the control group (PB0.05).
Therefore, these compounds may be useful to prevent ocular inflammatory reactions. © 1999 Elsevier Science S.A. All rights
reserved.
Keywords: Quinazolinones; Synthesis; Antiinflammatory; Prostaglandins; Ocular model
Interaction of AA with cycloxygenase produces ini-
tially the cyclic endoperoxide prostaglandin G2 (PGG2)
and thence, through its peroxidase activity, to
prostaglandin H2 (PGH2). The action of prostaglandin
endoperoxide isomerase on PGH2 produces PGE2, an
important mediator on the inflammatory process [18].
1. Introduction
A large number of compounds with a 4-quinazoli-
nonic structure have been synthesized for biological
screening, and a variety of interesting pharmacological
properties were observed [1]. The most important activ-
ities regard their anticonvulsant [2–5] and their anti-
inflammatory actions [6–10]. Moreover, several
4-quinazolinone compounds have shown analgesic [11]
and antihypertensive [12,13] activities. Recently, a cen-
trally 5-HT2A antagonist activity [14] and a good
affinity for cholecystokinin CCK-B receptors [15,16]
have been shown from different derivatives with quina-
zolinonic structure.
2. Results and discussion
2.1. Chemistry
The synthetic route to the quinazolin-4(3H)-one
derivatives is summarized in Scheme 1.
The anthranilic acids (1) were coupled with the ap-
propriate acid chloride generating the corresponding
substituted anthranilates (2a), which underwent cycliza-
tion by treatment with boiling acetic anhydride to form
the intermediate benzoxazin-4-ones (3–6). The substi-
tuted benzoxazinones by treatment with ammonia or
methylamine solutions yielded the quinazolinone
derivatives 7–12. To prepare the compounds 13–16 we
followed a different synthesis method. The two interme-
diate anthranilates (2b), obtained by refluxing the acids
As part of an ongoing research project regarding the
development of substances with anti-inflammatory ac-
tivity [17] we have synthesized a series of 4-quinazoli-
none derivatives with different substituents at the 2, 3
and 6 positions in order to evaluate the decrease of
PGE2 levels after treatment with arachidonic acid (AA).
* Corresponding author. Tel.: +39-095-738 4004; fax: +39-095-
222 239.
E-mail address: santagat@mbox.unict.it (N. Alfredo Santagati)
0014-827X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00102-0

N.A. Santagati et al. / Il Farmaco 54 (1999) 780–784
781
Scheme 1. Synthetic routes to benzoxazinones (3–6) and quinazolin-4(3H)-ones (7–16).
(1) in benzene with 98% formic acid, were treated with
methylamine or cyclohexylamine and subsequently with
phosphorus tricloride, to yield the final derivatives 13–
16. The structures of the synthesized compounds were
confirmed by elemental analysis, IR and 1H NMR.
Structures, yields, melting points and recrystallization
solvents of the benzoxazinones and the quinazolinones
are presented in Tables 1 and 2, respectively.
benzoxazin-4-ones in aqueous environment undergo a
rapid hydrolytic reaction of the lactonic ring, as demon-
strated by high performance liquid chromatographic
analysis (data not shown). The 3-cyclohexyl-6-chloro-
quinazolin-4(3H)-one (16) and 3-cyclohexylquinazolin-
4(3H)-one (14) derivatives were the most active
compounds. In fact, these compounds significantly re-
duced PGE2 levels even more than the reference drug
with 5.5- and 3.8-fold decrease, respectively. In addition
these compounds showed a significant reduction in
protein concentration, and PMNS number compared to
the control group (PB0.05). The compounds 10 and 12
also reduced the PGE2 production even more than the
reference drug with a 3.3- and 2.5-fold decrease, respec-
tively. However, these compounds showed a non-signifi-
cant reduction in protein concentration, and PMNS
number with respect to the control group (P\0.05).
Regarding the compounds 7, 8, 9, 11, 13, 14 and 15 we
observed a decrease of PGE2 production following
arachidonate administration with respect to the control
2.2. Pharmacology
The anti-inflammatory activity of the synthesized 4-
quinazoline derivatives was evaluated in an ocular in-
flammation model previously described [19]. An in-
spection of pharmacological data, reported in Table 3,
reveals that all the compounds tested lowered the PGE2
production with respect to the control group (PB0.05).
We also evaluated the activity of benzoxazin-4-ones
intermediate compounds but we did not record any
activity. This result may be explained by the fact that
Table 1
Structures, yields and melting points of the prepared benzoxazinone derivatives a
Compound
R1
R2
Yield (%)
M.p. (°C)
Formula
3
4
5
6
H
H
Cl
Cl
Me
cHex
Me
88
78
92
85
86–87
67–69
124–125
104–06
C9H7NO2
C14H15NO2
C9H6NO2Cl
C14H14NO2Cl
cHex
a All compounds were recrystallized from petroleum ether (b.p. 80–100°C).

782
N.A. Santagati et al. / Il Farmaco 54 (1999) 780–784
Table 2
Structures, yields and melting points of the prepared quinazolinones derivatives
Compound
R1
R2
R3
Yield (%)
M.p. (°C)
Formula
7 a
8 a
H
H
Cl
Cl
Me
cHex
Me
H
H
H
H
91
85
90
87
238–239
225–226
282–283
262
C9H8N2O
C14H16N2O
C9H7N2OCl
C14H15N2OCl
9 a
10 a
cHex
11 a
12 a
H
Cl
cHex
cHex
Me
Me
88
80
111–112
155–156
C15H18N2O
C15H17N2OCl
13 b
14 a
15 b
16 a
H
H
Cl
Cl
H
H
H
H
Me
cHex
Me
56
48
52
41
106
114
148
158
C9H8N2O
C14H16N2O
C9H7N2OCl
C14H15N2OCl
cHex
a Recrystallized from ethanol 95°C.
b Recrystallized from cyclohexane.
chlorine atom in position 6 caused a remarkable in-
crement of the activity with respect to the non-substi-
tuted analogues. The decrease of PGE2 levels after
drug treatment is particularly interesting because this
mediator plays an important role in the ocular infl-
ammation process. The results of this study suggest
that the compounds 3-cyclohexyl-6-chloro-quinazolin-
4(3H)-one (16) and 3-cyclohexyl-quinazolin-4(3H)-one
(14) may be employed topically to prevent ocular in-
flammatory reactions.
group. These compounds were less active than the
reference drug tolmetin. In addition these derivatives
were not able to reduce the protein concentration and
PMNS number compared to the control group.
It has been well demonstrated [19] that topical ad-
ministration of arachidonic acid causes a production
of PGE2 and leukotriene B4 (LTB4) in rabbit aqueous
humor as well as a breakdown of the blood–aqueous
barrier. LTB4 is a potent chemiotactic agent for
PMNs. The treatment with some of the synthesized
compounds decreased the number of PMNs in the
aqueous humor but not in significant measure, except
for compounds 14 and 16. This could be due to the
presence of LTB4 whose biosynthesis could be inhib-
ited in a different way from the drugs tested. Further-
more, the presence of proteins in the aqueous humor
indicates a breakdown of the blood–aqueous barrier
which was significantly contrasted by compounds 16
and 14.
The pharmacological results showed that the pres-
ence of the cyclohexylic group was important for the
anti-inflammatory activity with respect to the methyl
group. In particular, the activity is greater when cy-
cloaliphatic substituent was found in position 3 rather
than in position 2. The improvement in the activity
of the 3-cyclohexyl-derivatives was not due to the
blocking of the tautomerism of the –NH–CO–
group as demonstrated by the lower activity of the
corresponding 3-methyl-derivatives 12, 11, 5 and 13.
In all synthesized derivatives the introduction of a
Table 3
Prostaglandin E2 levels, protein concentration and number of poly-
morphonuclear leukocytes in the aqueous humor of albino rabbit 2 h
after arachidonate instillation in the eye pre- and post-treated with
quinazolin-4(3H)-ones (7–16) or reference drug tolmetin
a
Compound
PGE2
(ng/g)
PMNs a
Protein a
(mg/ml)
(PMNs/mm3)
7
8
9
10
11
12
13
14
15
16
Tolmetin
Control
7.6091.50 *
4.0090.96 *
6.5091.34 *
0.7590.02 *
4.1590.95 *
1.0090.15 *
6.0091.35 *
0.6590.15 *
5.5090.91 *
0.4590.11 *
2.5090.58 *
22.294.31
14809220
14209300
14509195
13509200
13809420
13909320
14009250
12009250 *
13809400
11009200 *
7009150
24.595.1
24.692.9
24.893.1
23.292.7
24.194.1
23.692.8
24.293.1
20.393.1 *
24.596.1
19.592.8 *
10.194.1
24.793.7
15009200
a n=8 eyes.
* PB0.05 with respect to control group.

N.A. Santagati et al. / Il Farmaco 54 (1999) 780–784
783
3. Experimental
3.1.2.4. 6-Chloro-2-cyclohexyl-4(3H)-quinazolinone (10).
1H NMR (DMSO-d6): l 1.17–1.93 (m, 10H, CH2–
cHex), 2.51–2.56 (m, 1H, CH–cHex), 7.59–8.01 (m, 3H,
ArH), 12.24 (s, 1H, NH).
3.1. Chemistry
2-Amino-benzoic acid and 2-amino-5-chloro-benzoic
acid are commercially available from Fluka Chimica
(Milan). All other chemicals or solvents were of reagent
grade.
3.1.2.5. 2 - Cyclohexyl - 3 - methyl - 4(3H) - quinazolinone
(11). H NMR (CDCl3): l 1.59–2.13 (m, 10H, CH2–
cHex), 2.54–2.75 (m, 1H, CH–cHex), 3.52 (s, 3H,
CH3), 7.11–8.01 (m, 4H, ArH).
1
IR spectra were recorded on a Perkin–Elmer 1720
spectrophotometer as KBr disks. Melting points were
determined with a Bu¨chi 510 apparatus and are not
corrected. NMR spectra were performed on a Varian
Inova 200 MHz spectrometer. Elemental analyses for
C, H and N were obtained on a Carlo Erba 1106
analyser and were within 90.4% of theoretical values.
Thin-layer chromatography (TLC) was carried out on
Merck Silica Gel 60 F254 (0.25 mm thickness). Column
chromatography was performed by the flash procedure.
3.1.2.6. 6-Chloro-2-cyclohexyl-3-methyl-4(3H)-quina-
1
zolinone (12). H NMR (CDCl3): l 1.34–1.98 (m, 10H,
CH2–cHex), 2.49–2.70 (m, 1H, CH–cHex), 3.56 (s,
3H, CH3), 7.41–8.09 (m, 3H, ArH).
3.1.3. General procedure for the synthesis of
quinazolin-4(3H)-ones (13–16)
A solution of compound type 2b (0.1 mol) in pyridine
(50 ml) was treated with an excess of methylamine 40%
solution (20 ml) or cyclohexylamine (0.1 mol) and PCl3
(0.12 mol). The mixture was kept in a water bath at
40°C for 90 min. The pyridine excess was then elimi-
nated at reduced pressure, the residue was dissolved by
hot HCl (10%). After filtration and cooling at r.t., the
filtrate was neutralized by NaOH (20%) and then left to
precipitate the final compounds, which were dried and
crystallized by opportune solvents. IR (cm−1): 1670–
1700 (CꢀO), 1600–1610 (CꢀN) (see Table 2).
3.1.1. General procedure for the synthesis of
benzoxazinones (3–6)
The intermediate benzoxazin-4-ones 3–6 were pre-
pared according to the literature method [20]. A mix-
ture of the opportune anthranilate derivative of general
structure 2a (50 mmol) and acetic anhydride (45 ml)
was refluxed for 3 h. The solution was concentrated
under reduced pressure until an oily residue was ob-
tained, which, after cooling at room temperature (r.t.),
solidified. IR (cm−1): 1735–1760 (CꢀO), 1590–1600
(CꢀN) (see Table 1).
3.1.3.1. 3-Methyl-4(3H)-quinazolinone (13). 1H NMR
(CDCl3): l 3.59 (s, 3H, CH3), 7.25–8.10 (m, 4H, ArH),
7.39 (s, 1H, CH).
3.1.2. General procedure for the synthesis of
quinazolin-4(3H)-ones (7–12)
3.1.3.2. 3-Cyclohexyl-4(3H)-quinazolinone (14). 1H
NMR (CDCl3): l 1.20–2.03 (m, 10H, CH2–cHex),
4.74–4.87 (m, 1H, CH–cHex), 7.44–8.33 (m, 4H,
ArH), 8.12 (s, 1H, CH).
The title compounds were prepared according to a
literature method [21]. A mixture of opportune benzox-
azinone derivative 3–6 (40 mmol) in absolute ethanol
(20 ml) was treated with an excess of NH3 33% solution
(40 ml) or methylamine 40% solution (40 ml) and left at
r.t. for 48 h. The solid, obtained as light-thin crystals,
was filtered, dried, and crystallized by opportune sol-
vent and purified by flash chromatography
(toluene:methanol, 95:5 v/v). IR (cm−1): 1665–1700
(CꢀO), 1590–1600 (CꢀN) (see Table 2).
3.1.3.3. 6-Chloro-3-methyl-4(3H)-quinazolinone (15). 1H
NMR (CDCl3): l 3.90 (s, 3H, CH3), 7.40 (9s, 1H, CH,
7.48–8.11 (m, 3H, ArH).
3.1.3.4. 6 - Chloro - 3 - cyclohexyl - 4(3H) - quinazolinone
1
(16). H NMR (CDCl3): l 1.01–1.87 (m, 10H, CH2–
cHex), 4.56–4.63 (m, 1H, CH–cHex), 7.61–8.03 (m,
3H, ArH), 8.10 (s, 1H, CH).
3.1.2.1. 2-Methyl-4(3H)-quinazolinone (7). 1H NMR
(DMSO-d6): l 2.36 (s, 3H, CH3), 7.41–8.10 (m, 4H,
ArH), 12.22 (s, 1H, NH).
3.2. Pharmacology
3.1.2.2. 2-Cyclohexyl-4(3H)-quinazolinone (8). 1H
NMR (CDCl3): l 1.40–2.09 (m, 10H, CH2–cHex),
2.69–2.80 (m, 1H, CH–cHex), 7.42–8.31 (m, 4H,
ArH), 11.78 (s, 1H, NH).
Arachidonic acid and Tolmetin (used as control
drug) were obtained from Sigma Chemical Company
(St. Louis, MO, USA). Ketamine HCl (Ketalar®) was
obtained from Parke-Davis (Milan, Italy). The
prostaglandin E2 (PGE2) enzyme immunoassay kit was
purchased from Amersham Life Science (Milan, Italy)
and Coomassie solution was obtained from Pierce
(Rockford, IL, USA).
1
3.1.2.3. 6-Chloro-2-methyl-4(3H)-quinazolinone (9). H
NMR (DMSO-d6): l 2.35 (s, 3H, CH3), 7.57–8.00 (m,
3H, ArH), 12.38 (s, 1H, NH).

784
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(carboxymethylcellulose 1%, NaCl, phosphate buffer).
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3.2.2. Animals
Female New Zealand albino rabbits (Charles River,
Calco, Italy), 1.8–2.2 kg, free of any signs of ocular
inflammation or gross abnormality, were used. Animal
procedures conformed to the ARVO (Association for
Research in Vision and Ophthalmology) resolution on
the use of animals in research.
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3.2.3. Ocular inflammation
Ocular inflammation was induced as described previ-
ously [19] by topical administration (50 ml) of 0.5%
sodium arachidonate dissolved in phosphate-buffered
saline (pH 7.4). Drug formulations (50 ml) were instilled
into the conjunctival sac 180, 120, 90 and 30 min before
induction of ocular inflammation by arachidonate (pre-
treatment) and then again 60 min thereafter (post-treat-
ment). Two hours after the arachidonate instillation the
rabbits were anesthetized by intravenous injection of 20
mg/kg of Ketamine HCl. Aqueous humor was with-
drawn by a tuberculin syringe and divided into three
aliquots in order to evaluate the content of PGE2 by
enzyme immunoassay, the protein concentration by
Coomassie solution and polymorphonuclear leukocyte
(PMNs) levels by an improved Neubauer chamber. The
experimental plan included a group of four animals for
each drug tested including the reference group (treated
with the reference drug tolmetin) and the control group
that received no treatment.
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3.2.4. Statistical analysis
Results are expressed as the mean9SD Student’s
t-test was used to evaluate the significance between the
groups of animals. The statistical significance was fixed
at PB0.05.
Acknowledgements
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The authors are grateful to the Ministero dell’Uni-
versita`
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(MURST) for financial assistance.
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