Synthesis and antimicrobial activity of some new 4-hydroxy-2H-1,4-benzoxazin-3(4H)-ones

Article abstract of DOI:10.1016/S0014-827X(00)00098-7

Some 4-hydroxy-2H-1,4-benzoxazin-3(4H)-ones were synthesized and evaluated for their antimicrobial activities against Staphylococcus aureus, Escherichia coli and Candida albicans. Compounds 9, and 10 exhibited the best activity against Candida albicans. C

Full text of DOI:10.1016/S0014-827X(00)00098-7

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 715–718
Synthesis and antimicrobial activity of some new
4
-hydroxy-2H-1,4-benzoxazin-3(4H)-ones
a
a
a,
b
Se c¸ kin Ozden , Aydin Murat Ozt u¨ rk , Hakan G o¨ ker *, Nurten Altanlar
8 8
a
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara Uni6ersity, 06100 Tandogan, Ankara, Turkey
b
Department of Microbiology, Faculty of Pharmacy, Ankara Uni6ersity, 06100 Tandogan, Ankara, Turkey
Received 20 August 2000; accepted 12 September 2000
Abstract
Some 4-hydroxy-2H-1,4-benzoxazin-3(4H)-ones were synthesized and evaluated for their antimicrobial activities against
Staphylococcus aureus, Escherichia coli and Candida albicans. Compounds 9, and 10 exhibited the best activity against Candida
albicans. © 2000 Published by Elsevier Science S.A. All rights reserved.
Keywords: 4-Hydroxy-2H-1,4-benzoxazin-3(4H)-one; Antibacterial and antifungal activity
plants [5]. It is also possible to obtain the aglycones by
1
. Introduction
the aqueous extracts made at room temperature [1].
They exhibit antifungal and insecticide properties.
In view of this, it was considered of interest to
synthesize some new 4-hydroxy-2H-1,4-benzoxazin-
Cyclic hydroxamic acids derived from 1,4-benzox-
azin-3-ones (Hx) have been isolated from extracts of
cereals such as wheat, maize and rye [1]. It has been
suggested that these molecules play an important role
in the protection of plants against insects (aphids),
bacteria and fungi [2,3]. It was reported that, these
hydroxamic acids inhibit population growth or devel-
opment of several plant pathogens [4]. These molecules
are present naturally in the plants as glucosides from
which the aglycones are released rapidly by enzymatic
hydrolysis after physical and biological injury of the
3
(4H)-ones with a view to evaluating their antibacterial
and antifungal activity in vitro.
2
. Chemistry
The targeted compounds have been synthesized by
the two steps. (1) Potassium phenolate of the o-nitro-
phenol derivatives reacted with the ethyl ester of a-bro-
moalkanoic acids (15–28). (2) Reduction and
cyclization of these ether compounds using Zn–NH Cl
4
gave the 4-hydroxy-2H-1,4-benzoxazin-3(4H)-ones (1–
1
4) (Scheme 1).
3
. Experimental
M.p. were determined with a B u¨ chi SMP-20 melting
point apparatus and are uncorrected. The instrumental
analysis was performed by TUBITAK (Instrumental
analyse Lab., Ankara) by the Bruker AC 400 NMR
spectrophotometer, VG Platform II mass spectrometer
and Leco CHNS 932 elemental analyser. For the chro-
Scheme 1.
*
Corresponding author. Tel.: +90-312-222 0471; fax: +90-312-
2
0
13 1081.
E-mail address: goker@pharmacy.ankara.edu.tr (H. G o¨ ker).
014-827X/00/$ - see front matter © 2000 Published by Elsevier Science S.A. All rights reserved.
PII: S0014-827X(00)00098-7

Table 1
Some physico-chemical properties and spectral findings of compounds 1–14
No. M.p. (°C)
Formula
C, H, N)
Yield
(%)
NMR (l ppm)
MS (70 eV, EI)
(
1
2
3
167–169 [6] (169) C H NO
8 7
3
148–149 [8] (152) C H NO
9
9
3
+
128–130
C10H11NO3
41
35
40
30
24
1.06 (t, 3H, J=7.2), 1.92 (m, 2H), 4.63 (s, 1H), 6.96 (m, 1H), 7.05 193 (M , 28), 148 (100), 136 (25), 120 (56), 106 (18), 93 (23), 80
(
m, 2H), 7.33 (1H), 9.0 (br.s, 1H)
(59)
+
4
5
6
7
87–89
C11H13NO3
0.94 (t, 3H, J=7.4), 1.54 (m, 2H), 1.86 (m, 2H), 4.72 (dd, 1H),
6.94 (m, 1H), 7.04 (m, 2H), 7.35 (m, 1H)
207 (M , 73), 191 (11), 162 (100), 148 (15), 136 (39), 120 (98),
·
0.25 HOH
106 (19), 93 (13), 80 (55), 78 (34)
+
213–215
136–138
110–112
C H ClNO
4.63 (s, 2H), 6.96 (t, 1H, J=8.1), 7.04 (dd, 1H, J =8.1 J =1.4), 199 (M , 36), 201 (12), 154 (100), 156 (33), 127 (24), 99 (45), 101
8
6
3
3
o m
7
.27 (dd, 1H, J =8.1 J =1.4)
(15)
o
m
+
C H ClNO
1.62 (d, 3H, J=6.8), 4.91 (q, 1H, J=6.8), 6.99 (t, 1H, J =8.1),
213 (M , 30), 215 (10), 168 (100), 170 (33), 127 (24), 99 (43)
9
8
o
·
HOH
7.1 (dd, 1H), 7.27 (dd, 1H)
1.1 (t, 3H, J=7.4), 1.91 (m, 2H), 4.74 (dd, 1H, J=6.5), 6.98 (t,
+
C10H10ClNO3
C11H12ClNO3
C12H14ClNO3·
227 (M , 51), 229 (17), 182 (100), 184 (33), 170 (47), 172 (16),
1
H, J=8.1), 7.10 (dd, 1H, J =8.2 J =1.4), 7.28 (dd, 1H,
154 (78), 156 (26), 127 (30), 99 (47)
/
o
m
J =8.2 J =1.4)
o
m
+
8
9
0
134–136
132–3
43
35
16
0.96 (t, 3H, J=7.4), 1.58 (m, 2H), 1.85 (m, 2H), 4.81 (dd, 1H,
J=6.5), 6.98 (t, 1H, J=8.1), 7.10 (dd, 1H, J =8.2 J =1.4),
241 (M , 12), 225 (16), 196 (75), 198 (25), 183 (73), 185 (24), 154
(14), 99 (21), 41 (100)
o
m
7
.27 (dd, 1H, J =8.2 J =1.4)
o m
+
0.9 (t, 3H, J=7.3), 1.4 and 1.6 (m, 4H), 1.9 (m, 2H), 4.84 (dd,
1H, J=4.7), 7.03 (t, 1H, J=8.1), 7.13 (dd, 1H, J =8 J =1.2),
255 (M , 33), 257 (9.5), 239 (7), 210 (28), 212 (9), 198 (9), 183
(
2
0
0
0
)
0
.4 HOH
(14), 170 (18), 154 (26), 55 (24), 32 (100).
o
m
7
.31 (dd, 1H, J =8 J =1.2)
o m
+
1
120–1
C13H16ClNO3·
.8 HOH
0.9 (t, 3H, J=7.3), 1.3, 1.55 and 1.63 (m, 6H), 1.9 (m, 2H), 4.85
269 (M , 42), 271 (13), 253 (44), 255 (12), 224 (33), 226 (9), 183
715
0
(dd, 1H, J=4.7), 7.02 (t, 1H, J=8.06) 7.13 (dd, 1H, J =8.2
(61), 170 (24), 154 (52), 55 (87), 32 (100).
o
718
J =1.4), 7.28 (dd, 1H, J =8.2 J =1.4)
m
o
m
1
1
1
2
147–149 [9] (147) C H NO
9 9 4
+
116–118
C10H11NO4
C11H13NO4
C12H15NO4
17
9.5
19
1.54 (d, 3H, J=6.8), 3.8 (s, 3H), 4.73 (q, 1H, J=6.8), 6.56 (dd,
H, J =8.8 J =2.5), 6.86 (d, 1H, J =8.8), 6.96 (d, 1H,
Jm=2.5)
209 (M , 96), 193 (11), 164 (100), 136 (24), 123 (33), 108 (25), 95
(32)
1
o
m
o
+
1
3
4
92–94
1.05 (t, 3H,J=7.4), 1.90 (m, 2H), 3.79 (s, 3H), 4.57 (dd, 1H), 6.55 223 (M , 67), 178 (100), 150 (44), 136 (23), 123 (26), 108 (28), 95
(
dd, 1H, J =8.8 J =2.5), 6.86 (d, 1H, J =8.8), 6.93 (d, 1H,
(24)
o
m
o
Jm=2.5)
+
1
85–87
0.92 (t, 3H, J=7.4), 1.50 (m, 2H), 1.80 (m, 2H), 3.73 (s, 3H), 4.59 237 (M , 10), 221 (42), 192 (18), 178 (12), 150 (59), 136 (11), 123
(
dd, 1H), 6.51 (dd, 1H, J =8.8 J =2.5), 6.79 (d, 1H, J =8.8),
(17), 108 (18), 107 (13), 95 (23), 55 (100)
o
m
o
6
.97 (d, 1H, J =2.5)
m

S. O
8
zden et al. / Il Farmaco 55 (2000) 715–718
717
Table 2
The in vitro antibacterial and antifungal activity of 1–14
4
. Antimicrobial activity technique
a
Antimicrobial activity of the synthesised compounds
No*
Staphylococcus Escherichia coli Candida
was determined with the previously reported standard
method [10]. A paper disc (8 mm in diameter) was
soaked in a 2000 mg/ml solution of the test compound
in propylene glycol 1–14 and placed on an agar plate
containing fungi or bacteria cells, which was incubated
at a temperature of 37°C for 24 h. Propylene glycol as
a blank has no inhibition zone. The diameter of the
growth inhibition zone around the paper disc was
measured.
aureus
albicans
1
2
3
4
5
6
7
8
9
10
9
9
9
13
10
12
10
11
9
10
10
12
9
14
15
16
9
10
10
11
16
28
9
10
13
10
11
12
13
14
5. Results and discussion
Compounds 1–14 were evaluated for antimicrobial
activity against Staphylococcus aureus, Escherichia coli
and Candida albicans in vitro. Table 2 shows the results
of in vitro activity determination by a paper disc assay
Fluconazole
Ketoconazole
Ampicilline
29
22
a
Growth-inhibition zone diameter (mm).
(
measuring the diameter of the inhibition zone around
a paper disc soaked in a solution of test compounds).
All of the compounds have no important inhibitory
activity towards S. aureus and E. coli. However, on the
whole chlorosubstituted derivatives 5–10, exhibited bet-
ter activity than others. Among them, compounds hav-
ing long alkyl chain on the second position of the
benzoxazine ring 9 and 10 showed good antifungal
activity which was comparable to that of fluconazole.
The antifungal activity increases with the length of
alkyl chain on the C-2. While 1–4 have no inhibitory
activity against C. albicans, 11–14 were slightly active.
matographic analysis Merck Silica Gel 60 (230–400
mesh ASTM) was used.
3.1. General procedure for the synthesis of 15–28
A suspension of related powdered potassium 2-nitro-
phenolates (0.03 mol, prepared by the treatment of
metallic potassium and 2-nitrophenoles, precipitated
with ether, red coloured) in related ethyl a-alkylbro-
moacetate (0.045 mol) is heated under reflux until the
colour has turned from orange to yellow (30 min).
After cooling, the reaction mixture was diluted with
CH Cl . The potassium bromide that precipitated was
2
2
References
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2
2
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coloured oily residues and used for the further step
without purification. Compounds 15 [6], 16 [7] and 17
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3.2. General procedure for the synthesis of 1–14
After adding a solution of NH Cl (0.05mol) in water
4
(
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