Synthesis and antimicrobial activity of some 5-[2-(morpholin-4-yl) acetamido] and/or 5-[2-(4-substituted piperazin-1-yl)acetamido]-2-(p-substituted phenyl)benzoxazoles

Article abstract of DOI:10.1002/ardp.200400923

In this study, a series of twelve novel 5-[2-(morpholin-4-yl)acetamido] and/or 5-[2-(4-substituted piperazine-1-yl)acetamido]-2-(p-substituted phenyl)benzoxazole derivatives have been synthesized and their structures were confirmed by IR, ¹H NM

Full text of DOI:10.1002/ardp.200400923

Arch. Pharm. Chem. Life Sci. 2005, 338, 105−111
DOI 10.1002/ardp.200400923
105
Synthesis and Antimicrobial Activity of Some
5-[2-(Morpholin-4-yl)acetamido] and/or
5-[2-(4-Substituted piperazin-1-yl)acetamido]-
2-(p-substituted phenyl)benzoxazoles
a
a
a
a
a
˙
˙
Özlem Temiz-Arpacı , Aliye Özdemir , Ismail Yalc¸ın , Ilkay Yıldız , Esin Akı-Sener ,
¸
Nurten Altanlarb
a Ankara University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Turkey
b Ankara University, Faculty of Pharmacy, Department of Microbiology, Ankara, Turkey
In this study, a series of twelve novel 5-[2-(morpholin-4-yl)acetamido] and/or 5-[2-(4-substituted pip-
erazine-1-yl)acetamido]-2-(p-substituted phenyl]benzoxazole derivatives have been synthesized and their
structures were confirmed by IR, 1H NMR, and mass spectral data. These compounds were prepared
by reacting 5-(2-chloroacetamido)-2-(4-p-substituted-phenyl)benzoxazoles, which were obtained by
using 5-amino-2-[p-substituted-phenyl]benzoxazoles with chloroacetyl chloride, in the presence of
morpholine or 1-substituted piperazines. All synthesized compounds 3Ϫ14 were tested by using the
method of twofold serial dilution technique for in vitro activities against certain strains of Gram-
positive, Gram-negative bacteria as well as the yeasts Candida albicans, Candida krusei, and Candida
glabrata in comparison with standard drugs. Microbiological results showed that the newly synthesized
compounds possessed a broad spectrum of activity, showing MIC values of 3.12Ϫ50 μg/mL against
the Candida species.
Keywords: Benzoxazoles; Antibacterial activity; Antifungal activity; Morpholine aceteamide; Piperazine
acetamide
Received: July 13, 2004; Accepted: February 6, 2005 [FP923]
Introduction
The rapidly increasing incidence of multiple drug-resistant
Gram-positive bacteria requires an urgent discovery of
novel active agents against these pathogenes [1, 2]. The
benzoxazoles have various biological activities such as anti-
bacterial, antifungal [3Ϫ12], antimycobacterial [13], anti-
tumoral [14Ϫ19], HIV-1 reverse transcriptase [20-26], and
topoisomerase I inhibitory activities [27].
Figure 1. A benzoxazole derivative.
A benzoxazole derivative (Figure 1) is significantly more
potent as inhibitors of topoisomerase I than camptothecin
[28]. UK-1 (Figure 2) is a unique natural bisbenzoxazole
product, isolated from a strain of Streptomyces, is a mag-
nesium ion-dependent DNA binding agent and inhibitor of
human topoisomerase II. It displays a wide spectrum of
potent anticancer activities in leukemia, lymphoma, and
certain solid tumor-derived cell lines with IC50 values as low
as 20 nM [16, 17, 29]. Routiennocin (Figure 3), which is a
spiroketal ionophore antibiotic, isolated from a strain of
Figure 2. UK-1.
Streptomyces chartreusis possessing a benzoxazole ring in its
Correspondence: Esin Akı-Sener, Ankara University, Faculty of
¸
molecular structure, was found to be very active especially
against some Gram-positive bacteria by acting as a good
ionophore [4, 30]. Moreover, 5- and/or 6-amidinobenzox-
Pharmacy, Department of Pharmaceutical Chemistry, TR-06100
Tandogan, Ankara, Turkey. Phone: ؉ 90 312 223-6940, Fax: ϩ 90
312 223-6940, e-mail: sener@pharmacy.ankara.edu.tr
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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Temiz-Arpacı et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 105−111
Figure 3. Routiennocin.
Figure 4. Compounds 3Ϫ14.
azoles as well as benzimidazoles were found as inhibitors of
the bacterial KinA/Spo0F. Many of these inhibitors exhib-
ited good in vitro antibacterial activity against a variety of
susceptible and resistant Gram-positive organisms [25].
phenyl]benzoxazole derivatives 3Ϫ14 (Figure 4) has been
synthesized as the target compounds in order to examine
their microbiological activitiy against various Gram-positive
and Gram-negative bacteria and the different yeasts in com-
parison with several control drugs because in the need of
new and different antibacterial agents that are resistant to
inactivation by bacterial enzymes. Their structure-activity
relationships (SAR) were also studied by using either newly
or previously synthesized compounds [31] and the structures
of the newly synthesized compounds are supported by spec-
tral data (Table 2).
In our previous report, we described the preparation and in
vitro antimicrobial activity of 2-[p-substituted phenyl]-5-[2-
(substituted phenyl)acetamido]benzoxazole derivatives [31]
as seen in Table 1. This time, the substitution, which is at-
tached as acetamido moiety on the C-5 position of benz-
oxazole ring, has been changed to heterocyclic groups in-
stead of phenyl for the antimicrobial effect. Therefore, a
series of novel 5-[2-(morpholin-4-yl)acetamido] and/or 5-[2-
(4-substituted
piperazin-1-yl)acetamido]-2-[p-substituted
Table 1. The in vitro antimicrobial activity of newly and previously synthesized compounds with the control drugs (MIC in mg/mL).
Comp.
R
-C2H5
-C2H5
-C2H5
-H
A
S. a.
50
B. s.
50
E. c.
50
50
50
50
50
50
50
50
50
C. g.
25
C. a.
25
C. k.
12.5
12.5
6.25
25
3
4
50
25
12.5
25
25
5
25
25
50
6
25
50
25
50
7
-H
25
25
25
50
25
8
-H
100
25
100
25
25
50
25
9
-F
25
50
25
10
11
-F
50
50
25
25
50
-F
50
50
25
25
25
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 105−111
Table 1. (continued)
Synthesis and Activity of some new 5-Acetamido-benzoxazoles
107
Comp.
12
R
A
S. a.
50
B. s.
50
E. c.
50
C. g.
25
C. a.
50
C. k.
6.25
3.12
12.5
-C(CH3)3
-C(CH3)3
-C(CH3)3
13
50
50
50
12.5
12.5
50
14
25
25
50
25
15[33]
16[33]
17[33]
H
H
H
100
50
50
50
50
100
50
Ϫ
Ϫ
Ϫ
50
25
50
Ϫ
Ϫ
Ϫ
100
100
18[33]
19[33]
20[33]
H
H
50
50
50
200
200
50
50
25
50
Ϫ
Ϫ
Ϫ
25
25
50
Ϫ
Ϫ
Ϫ
C2H5
21[33]
22[33]
C2H5
C2H5
50
50
50
50
50
50
Ϫ
Ϫ
50
50
Ϫ
Ϫ
23[33]
H
50
100
25
Ϫ
25
Ϫ
Oxiconazole
Haloprogin
Micanazol
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
6.25
3.125
3.125
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
3.125
Ϫ
1.56
Ϫ
Ciprofloxazin
Gentamicin
3.125
3.125
1.56
1.56
3.125
12.5
Ϫ
Ϫ
Ϫ
S. a.: Staphylococcus aureus; B. s.: Bacillus subtilis; E. c.: Escherichia coli; C. g.: Candida glabrata; C. a.: Candida albicans; C. k.: Candida krusei
Results
5-[2-(Morpholin-4-yl)acetamido] and/or 5-[2-(4-substituted
piperazin-1-yl)acetamido]-2-(p-substituted phenyl)benz-
oxazoles (3Ϫ14) were prepared from amide compounds by
reacting with piperazine or morpholine derivatives. All of
the derivatives were supported by spectral data. Physical
and spectral data of the compounds are reported in Table 2.
A series of twelve 5-[2-(morpholin-4-yl)acetamido] and/or
5-[2-(4-substituted
piperazin-1-yl)acetamido]-2-(p-substi-
tuted phenyl)benzoxazole derivatives has been synthesized
by using a two step procedure as seen in Scheme 1. 5-
Amino-2-(p-substituted phenyl)benzoxazoles (1) were ob-
tained by heating p-substituted benzoic acids with 2,4-diam-
inophenol in PPA (polyphosphoric acid) [31]. Amide com-
pounds (2) were obtained from 5-amino-2-(p-substituted
phenyl)benzoxazoles with chloroacetyl chloride [32Ϫ34].
To investigate the antimicrobial activity of the synthesized
compounds (3Ϫ14) against two Gram-positive and one
Gram-negative bacteria and three Candida species were
screened using the twofold serial dilution technique. All the
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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Temiz-Arpacı et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 105−111
biological results of the compounds are given in Table 1.
The combined data reported that the newly synthesized
compounds showing MIC values between 3.12Ϫ100 μg/mL
were able to inhibit the in vitro growth of the microorgan-
isms screened.
against Gram-positive and Gram-negative bacteria and the
antifungal activity against C. albicans, C. glabrate, and
C. krusei of the benzoxazoles, we put a heterocyclic ring
system instead of phenyl to the acetamido moiety on the
C-5 position of benzoxazole.
All the newly synthesized compounds 3-14 showed some
antibacterial activity against the Gram-positive bacteria
such as S. aureus and B. subtilis possessing MIC values be-
tween 25 and 100 μg/mL as given in Table 1. Comparing
the newly prepared compounds to previously synthesized
compounds it was found that if the heterocyclic ring was
attached to the acetamido moiety at the C-5 position of
Discussion
Previously, we evaluated the antimicrobial activity of very
similar structures which had 2-(p-substituted phenyl)-5-[2-
(substituted phenyl)acetamido]benzoxazole derivatives, in
continuing our efforts to enhance the antibacterial activity
Table 2. Physicochemical properties and spectral data of the compounds 3Ϫ14.
Comp.
3
R
X
Formula
Mp. Yield
IR [cm؊1
]
1H-NMR [δ ppm]
Mass [m/e]
[°C] [%]
-C2H5
O
C21H23N3O3 153
27 3300Ϫ2819, 1672,
1612, 1580Ϫ1527,
1484, 1271Ϫ1016
1.35 (t, 3H), 2.81Ϫ2.90 (6H), 3.32
(s, 2H), 3.84 (s, 4H), 7.57Ϫ7.72
(m, 4H), 8.12 (s, 1H), 8.20Ϫ8.31
(d, 2H), 9.35(1H)
365 (Mϩ),
98 (%100)
4
-C2H5
NCH3 C22H26N4O2 138
68 3282Ϫ2805, 1682,
1610, 1580Ϫ1500,
1481, 1299Ϫ1016
0.99Ϫ1.04 (t, 3H), 1.40Ϫ1.48 (m,
2H), 2.61 (s, 3H), 2.86Ϫ2.96 (8H),
3.37 (s, 2H), 7.49Ϫ7.51 (m, 4H),
8.13 (s, 1H), 8.29Ϫ8.31(d, 2H),
9.18 (s, 1H)
378 (Mϩ),
113 (%100)
5
6
-C2H5
-H
NH C21H24N4O2 140
35 3290Ϫ2800, 1681,
1620, 1540, 1480,
1285Ϫ1020
1.2Ϫ1.3 (s, 3H), 2.4Ϫ2.5 (6H),
2.7Ϫ2.8 (5H), 3.1 (s, 2H), 7.5Ϫ7.7
(m, 4H), 8.1Ϫ8.2 (m, 3H), 9.85
(s, 1H)
364 (Mϩ),
99 (%100)
O
C19H18N3O3 196
40 3300Ϫ2818, 1672,
1555, 1526, 1483,
1270Ϫ1052
2,86 (s, 4H), 3.39 (s, 2H), 3.98
(s, 4H), 7.66Ϫ7.71 (m, 5H), 8.2
(s, 1H), 8.38Ϫ8.40 (m, 2H), 9.80
(1H)
337 (Mϩ),
99 (%100)
7
-H
NCH3 C20H21N4O2 135
NH C19H19N4O2 156
25 3272Ϫ2800, 1681,
1556, 1585Ϫ1525,
1482, 1297Ϫ1015
2.57 (s, 3H), 2.79Ϫ2.91 (8H), 3.36
(s, 2H), 7.66Ϫ7.73 (m, 5H), 8.16
(d, 1H), 8.38Ϫ8.40 (m, 2H), 9.37
(s, 1H)
350 (Mϩ),
113 (%100)
8
-H
30 3299Ϫ2819, 1672,
1555, 1526, 1482,
1273Ϫ1024
2.96 (s, 1H), 3.32Ϫ3.40 (8H), 3.55
(s, 2H), 7.41Ϫ7.69 (m, 5H), 8.19
(d, 1H), 8.38Ϫ8.41 (m, 2H), 9.23
(s, 1H)
335 (Mϩ),
99 (%100)
9
-F
O
C19H17N3O3F 179
67 3432Ϫ2852, 1683,
1605, 1530, 1484,
1275Ϫ1011, 852
2.68Ϫ2.70 (t, 4H), 3.22 (s, 2H),
3.82Ϫ3.84 (t, 4H), 7.21Ϫ7.55
(m, 4H), 8.05 (s, 1H), 8.25Ϫ8.28
(m, 2H), 9.,23 (s, 1H)
355 (Mϩ),
99 (%100)
10
-F
NCH3 C20H20N4O2F 149
25 3343Ϫ2800, 1662,
1624, 1582, 1499,
1116Ϫ1011, 814
2.48 (s, 3H), 2.73Ϫ2.82 (8H), 3.25
(s, 2H), 7.21Ϫ7.59 (m, 4H), 8.02
(d, 1H), 8.25Ϫ8.28 (m, 2H), 9.20
(s, 1H)
368 (Mϩ),
113 (%100)
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 105−111
Table 2. (continued).
Synthesis and Activity of some new 5-Acetamido-benzoxazoles
109
Comp.
11
R
X
Formula
Mp. Yield
IR [cm؊1
]
1H-NMR [δ ppm]
Mass [m/e]
[°C] [%]
-F
NH C19H18N4O2F 176
30 3320-2828, 1676,
1605, 1562, 1486,
1290-1014, 855
3.05 (s, 1H), 3.35- 3.55 (8H), 3.91
(s, 2H), 7.34-7.69 (m, 4H), 8.16 (d,
1H), 8.37-8.41 (m, 2H), 9.11 (s, 1H)
354 (Mϩ),
99 (%100)
12
13
14
-C(CH3)3
O
C23H27N3O3 227
40 3290-2800, 1681,
1620, 1540, 1480,
1285-1020
1.25 (s, 9H), 2.5-2.6 (4H), 3.2
(s, 2H), 3.3- 3.40 (4H), 3.6 (s, 1H),
7.6-7.8 (m, 4H), 8.1- 8.2 (m, 3H), 9.9
(s, 1H)
393 (Mϩ),
100 (%100)
-C(CH3)3 NCH3 C24H30N4O2 178
30 3200-2830, 1676,
1550, 1530, 1480,
1280-1042
1.35 (s, 9H), 2.1Ϫ2.2 (s, 3H), 2.5
(8H), 3.15 (s, 2H), 7.55Ϫ7.75
(m, 4H), 8.1Ϫ8.2 (m, 3H), 9.9
(s, 1H)
406 (Mϩ),
113 (%100)
-C(CH3)3
NH C23H28N4O2 212
37 3386-2840, 1680,
1596, 1560, 1492,
1250-1100
1.25 (s, 9H), 2.4Ϫ2.6 (7H),
2.84Ϫ 2.90 (4H), 7.52Ϫ7.72
(m, 4H), 8.06Ϫ8.16 (m, 3H), 9.9
(s, 1H)
392 (Mϩ),
99 (%100)
Scheme 1. Synthetic pathway to get 5-(substituted-acetamido)benzoxazole derivatives 3Ϫ14.
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

110
Temiz-Arpacı et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 105−111
tained with a Bruker DPX-400 High Performance Digital FT-NMR
spectrometer (Bruker, Rheinstetten, Germany) in d-chloroform;
tetramethylsilan (TMS) was used as an internal standard. MASS
spectra were recorded by Micromass UK Platform II LC-MS (Mi-
cromass, Manchester, UK). Elemental analyses were carried out
with a LECO CHN 932 analyzer (Leco, St. Joseph, MI, USA). The
results (C, H, N) were within 0.4% of the calculated values.
benzoxazole, the antibacterial activity pretty much in-
creased against S. aureus and B. subtilis. Interestingly, the
activity decreased when nonsubstituted-piperazine was at-
tached to the acetamido of position 5 of 2-phenylbenz-
oxazole.
Furthermore, the antibacterial activity of compounds 3Ϫ14
against E. coli as Gram-negative bacteria indicated a MIC
value of 50 μg/mL. However, all the new compounds
showed lower antibacterial activity than the standard drugs
against the screened Gram-positive or Gram-negative bac-
teria. It should be considered that 4-propyloxyphenyl
(comp. 19) or 2-chlorophenyl (comp. 23) groups attached to
acetamido on the C-5 position of benzoxazole could en-
hance the activity against E. coli as demonstrated in Table 1.
General procedure for the synthesis of 5-amino-2-(p-substituted
phenyl) benzoxazoles (1)
5-Amino-2-phenylbenzoxazole, 5-amino-2-(p-ethylphenyl)benzoxa-
zole, 5-amino-2-(p-tert-butylphenyl)benzoxazole and 5-amino-2-(p-
fluorophenyl) benzoxazole were synthesized by heating 0.01 mol
2,4-diaminophenol.2 HCl with 0.01 mol benzoic acid, p-ethylben-
zoic acid, p-tert-butylbenzoic acid and p-fluorobenzoic acid in 24 g
polyphosphoric acid with stirring for 2.5 h. At the end of the reac-
tion period, the residue was poured into ice-water mixture and neu-
tralized with an excess of 10% NaOH solution, extracted with ben-
zene, the benzene solution was dried over anhydrous sodium sul-
phate, and evaporated under diminished pressure. The residue was
boiled with 200 mg charcoal in ethanol and filtered. After the evap-
oration of the solvent in vacuo, the crude product was obtained and
recrystallized [31].
On the other side, all compounds 3Ϫ23 showed notable ac-
tivity against C. albicans, C. krusei, and C. glabrata with
MIC values of 3.12-50 μg/mL. There were no significant
results when the role of the substitution on acetamido group
on C-5 of benzoxazole for C. albicans was considered. Fur-
thermore, compounds 4, 13, and 14 were found to be more
active against C. glabrata than the others with a MIC value
of 12.5 μg/mL. Moreover, compound 13 was also the most
active among the compounds having a MIC value of 3.12
μg/mL against C. krusei. Noteworthy, compound 13 was
found to be one dilution less active than the compared drug,
mycanazol. The compounds 5 and 12 were also very active
ones in these series against C. krusei with a MIC value of
6.25 μg/mL. The SAR of the synthesized compounds re-
vealed that those possessing a p-tert-butyl substituent of
phenyl ring at the C-2 position of benzoxazole came up with
the enhanching antifungal activity against C. krusei and
C. glabrata. Consequently, for developing new antifungal
agents against C. krusei, compound 13 could be the lead for
further studies.
General procedure for amide derivatives (2)
Chloroacetyl chlorid (0.04 mol) was added over a period of 1 h to
a stirred, ice-cooled mixture of 5-amino-2-(p-substituted phenyl)-
benzoxazoles (0.04 mol), sodiumbicarbonate (0.04 mol), diethyl-
ether (80 mL), and water (40 mL). The mixture was continuously
stirred overnight at room temperature and filtered. The precipitate
was washed with water, 2N HCl, water, respectively and finally with
ether to give 2. The product was recrystallized from ethanol-water
mixture and needles were dried in vacuo [31].
General procedure for 5-[2-(morpholin-4-yl)acetamido]-2-(p-substi-
tuted phenyl)benzoxazoles (2)
The mixture of amide derivatives (3 mmol) and morpoline (3 mmol)
in DMF (0.2 mL) was stirred and heated at 60 °C for 4 h. The
reaction mixture was poured into ice-water, then, was made alkaline
with 4N NaOH and saturated with NaCl. It was extracted with
CHCl3, the organic layer was dried with Na2SO4 and evaporated.
The products were crystallized with ethanol and were dried in vacuo.
Acknowledgments
General procedure for 5-[2-(4-substituted piperazin-1-yl)acetamido]-
2-(p-substituted phenyl)benzoxazoles (3Ϫ14)
We thank the Research Fund of Ankara University (Grant
No. 2001-08-03-27) for the financial support of this re-
search.
2 mmol amide derivatives in 3 mL DMF were added to 3 mmol 1-
substituted piperazine and 6 mmol triethylamine solutions in 2 mL
DMF. The mixture was stirred at room temperature for 24 h. At
the end of the reaction time, the mixture was poured into ice-water
and the precipitate formed was filtered. Purification by flash chro-
matography: silica-gel column from appropriate solvents.
Experimental
Chemistry
Microbiological assays
Silicagel HF254 chromatoplates (0.3 mm; Merck, Darmstadt, Ger-
many) were used for TLC. The solvent systems were chloro-
form:methanol (10:1) for compounds 3, 6, 9, 12; chloroform:2-pro-
panol:ammonia (10:5:0.3) for compounds 7, 10, 13, 14; chloro-
form:2-propanol: ammonia (10:3:0.3) for compounds 4, 5, 8, 11.
Melting points were taken on a Büchi SMP 20 capillary apparatus
(Büchi Labortechnik, Flawil, Switzerland) and are uncorrected. IR
spectra were recorded by FT/IRϪ420 in KBr discs (Shimadzu IR-
470 spectrometer, Jasco, Tokyo, Japan). 1H NMR spectra were ob-
For the antibacterial and antimycotic assays, the compounds were
dissolved in absolute ethanol (0.8 mg/mL). Further dilutions of the
compounds and standard drugs in the test medium were prepared
at the required quantities of 400, 200, 100, 50, 25, 12.5, 6.25, 3.12,
1.56, 0.78 μg/mL concentrations with Mueller-Hinton broth and Sa-
bouraud dextrose broth. The minimum inhibitory concentrations
(MIC) were determined using the twofold serial dilution technique
[35, 36]. A control test was also performed containing inoculated
broth supplemented with ethanol only at the same dilutions used in
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 105−111
Synthesis and Activity of some new 5-Acetamido-benzoxazoles
111
our experiments and found inactive in the culture medium. All the
compounds were tested for their in vitro growth inhibitory activity
against different bacteria and the yeasts Candida albicans ATCC
10145, Candida krusei ATCC 6258, Candida glabrate (isolated). The
origins of bacterial strains are Staphylococcus aureus ATCC 24923,
Bacillus subtilis ATCC 6633 as Gram-positive and Escherichia coli
ATCC 23556 as Gram-negative bacteria. ATCC strains of the
microorganisms used in this study were obtained from the culture
collection of Refik Saydam Health Institution of Health Ministry,
Ankara, and maintained at the Microbiology Department of the
Faculty of Pharmacy of Ankara University.
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Antibacterial and antifungal assay
The cultures were obtained from Mueller-Hinton broth (Difco,
Detroit, MI, USA) for all the bacterial strains after 24 h of incu-
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incubation for 24 h at 25 1°C. Testing was carried out in Mueller-
Hinton broth and Sabouraud dextrose broth (Difco) at pH 7.4 and
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