Synthesis and antimicrobial activity of some 2-[p-substituted-phenyl]benzoxazol-5-yl-arylcarboxyamides

Article abstract of DOI:10.1002/1521-4184(200208)335:6<283::AID-ARDP283>3.0.CO;2-M

New 2-[p-substituted-phenyl]benzoxazol-5-yl-arylcarboxyamides derivatives have been synthesized by reacting 5-amino-2-[p-substituted-phenyl]benzoxazoles with substituted-arylcarboxylic acid chlorides. The structures of the synthesized compounds were confirmed by IR and ¹H NMR spectral data. Antimicrobial activities of the compounds were investigated using the two-fold serial dilution technique against different Gram-positive and Gram-negative bacteria and the yeast C. albicans in comparison with standard drugs. Microbiological results indicated that the synthesized compounds possess a broad spectrum of activity, having an MIC value of 25-200 μg/mL at molar concentration values of 3.45 × 10^-5 and 5.74 × 10^-4 against the tested microorganisms.

Full text of DOI:10.1002/1521-4184(200208)335:6<283::AID-ARDP283>3.0.CO;2-M

Arch. Pharm. Pharm. Med. Chem. 2002, 6, 283–288
Synthesis and Antimicrobial Activity 283
Özlem Temiz-Arpacia),
Synthesis and Antimicrobial Activity of Some
2-[ p-Substituted-phenyl]benzoxazol-5-yl-
arylcarboxyamides
Esin Aki-S¸enera),
.
Ismail Yalçina),
Nurten Altanlarb)
a)
Ankara University, Faculty
of Pharmacy,
Department of
Pharmaceutical Chemistry,
Tandogan, Ankara, Turkey
New 2-[ p-substituted-phenyl]benzoxazol-5-yl-arylcarboxyamides derivatives have
been synthesized by reacting 5-amino-2-[ p-substituted-phenyl]benzoxazoles with
substituted-arylcarboxylic acid chlorides. The structures of the synthesized com-
pounds were confirmed by IR and 1H NMR spectral data. Antimicrobial activities of
the compounds were investigated using the two-fold serial dilution technique
against different Gram-positive and Gram-negative bacteria and the yeast C. albi-
cans in comparison with standard drugs. Microbiological results indicated that the
synthesized compounds possess a broad spectrum of activity, having an MIC value
of 25–200 µg/mL at molar concentration values of 3.45 × 10–5 and 5.74 × 10–4
against the tested microorganisms.
b)
Ankara University, Faculty
of Pharmacy Department of
Microbiology, Tandogan,
Ankara, Turkey
Keywords: Benzoxazole-5-yl-arylcarboxyamides; Antibacterial and antifungal ac-
tivity
Received: December 3, 2001 [FP 652]
series of 5-formyl-, 5-(aminocarbonyl)-, and 5- or 6-nitro
derivatives of 2-(4-methoxyphenyl)benzoxazoles (For-
mula II) was synthesized and tested as topoisomerase I
inhibitors [11].
Introduction
Benzoxazole derivatives have been at the focus of many
researchers’ interest for many years because they con-
stitute an important class of heterocyclic compounds
[1–22] with antibacterial and antifungal [1–4], HIV-1 re-
verse transcriptase inhibitor [5–10], topoisomerase Iin-
hibitors [11] and antitumor activities [12–17].
R = 5-formyl, 5-(aminocarbonyl), 5-nitro, 6-nitro
Formula II
An antibiotic, calcymycin (A 23187) which is isolated
from a strain of Streptomyces chartreusis and includes a
benzoxazole ring in its molecular structure, was found to
be very active, especially against some Gram-positive
bacteria by acting as a good ionophore [2].
L-697, 661
Formula I
Moreover, structure-activity relationships of benzoxa-
zole derivatives have revealed that the substitution of the
2nd position is decisive for the biological activity and po-
sition 5 is important for the intensity of the activity
[23–25].
A benzoxazole derivative, 3-(4,7-dichlorobenzoxazol-2-
ylmethylamino)-5-ethyl-6-methylpyridin-2(1H)-one (L-
697, 661) (Formula I), prevents the spread of human im-
munodeficiency virus type-1 (HIV-1) infection in cell cul-
ture by inhibiting HIV-1 reverse transcriptase [9, 10]. A
Therefore, in this study, a series of novel 2-[ p-substitut-
ed-phenyl]benzoxazole-5-yl-arylcarboxyamides (5–17)
(Formula III) has been synthesized as the target com-
pounds in order to examine their microbiological activitiy
against various Gram-positive and Gram-negative bac-
teria and against the yeast C. albicans in comparison
Correspondence: Esin Aki S¸ ener, Ankara University, Faculty
of Pharmacy, Department of Pharmaceutical Chem-
istry, TR-06100 Tandogan, Ankara, Turkey. Phone:
+ 90 312 223 69 40, Fax: + 90 312 223 69 40, e-mail:
sener@pharmacy.ankara.edu.tr
© WILEY-VCH Verlag GmbH, 69451 Weinheim, 2002
0365-6233/06/0283 $ 17.50+.50/0

284 Temiz-Arpaci et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 6, 283–288
with several control drugs because of the need for new
and different antibacterial agents that are resistant to in-
activation by bacterial enzymes. Their structure-activity
relationships (SAR) were studied as well.
Results and discussion
The synthesized compounds showed some antibacteri-
al activity against the Gram-positive bacteria S. aureus
and S. faecalis, possessing MIC values between 25 and
100 µg/mL (6.64 × 10–5 and 1.64 × 10–4 molar) as given
in Table 2.
Furthermore, the antibacterial activity of compounds
5–17 against E. coli as a Gram-negative bacteria re-
vealed lower potencies than the comparison control
drugs. However, compound 15 indicated significant ac-
tivity with a molar concentration (C) 6.9 × 10–5 possess-
ing MIC value of 25 µg/mL against the Gram-negative
enterobacter P. aeruginosa, which is effective in noso-
comial infections and often resistant to antibiotic therapy.
R = H, C2H5, F, N(CH3)2
Ar = 2-furyl, 2-thienyl, substitutedphenyl
Formula III
Compounds 5–17 were also tested against C. albicans
for their antimycotic activity and most of the compounds
indicated significant antimycotic activity, giving MIC val-
ues between 12.5 and 50 µg/mL at molar concentration
values of 1.56 × 10–4 and 3.45 × 10–5. Compounds 11
and 15 were more active than the other tested com-
pounds, having a MIC value of 12.5 µg/mL at a molar
concentration value of 3.45 × 10–5. However, antimy-
cotic potencies of the comparison control drugs clotrim-
azole and haloprogin were higher than those of our cor-
responding compounds, showing MIC values of 6.2 µg/
mL and 3.1 µg/mL at molar concentrations values of
1.79 × 10–5 and 8.57 × 10–6.
Chemistry
5-Amino-2-phenyl- or 5-amino-2-(p-substituted-phe-
nyl)benzoxazoles (1–4) were obtained by heating substi-
tuted benzoic acids with 2,4-diaminophenol in PPA
(polyphosphoric acid) [26].
Compounds (5–17) were prepared from 5-amino-2-phe-
nyl- or 5-amino-2-(substituted-phenyl)benzoxazoles
with substituted benzoic acids or furan-2-carboxylic acid
or thiophene-2-carboxylic acid chlorides obtained by
treating carboxylic acids with thionyl chloride [27, 28].
Compounds 5–17 are new and their structures were
supported by spectral data.The IR and 1H NMR spectra
are in agreement with the proposed structures (Table 1).
In conclusion, compound 15 is the most active one in this
series against C. albicans and P. aeruginosa. Structure-
1–4
5–17
Scheme 1. Ar = substituted phenyl, 2-furyl, 2-thienyl; R = -H, –C2H5, F, N(CH3)2

Arch. Pharm. Pharm. Med. Chem. 2002, 6, 283–288
Synthesis and Antimicrobial Activity 285
Table 1. Data of the compounds 5–17.
Com.
No.
Ar
R
Mp Yield
(°C) (%)
Empirical
formula
IR (cm–1)
1H NMR
δ ppm (J = Hz)
5
6
7
8
9
F
H
212 47 C18H11FN2 O2S 3320, 3100, 1660, 1620,
7.00–7.40 (4H, m), 7.50–8.00
(4 H, m), 8.1–8.3 (2 H, m)
1566, 1478, 1290, 1250,
960–404
179 43 C18H12N2O2S 3340, 3120, 1600, 1580,
1480, 1230, 1020,
7.10–7.20 (1 H, t, J = 7.30),
7.50–7.90 (7 H, m), 8.02 (1 H,
s), 8.24–8.30 (2 H, m)
6.45–6.60 (1 H, s), 6.85–7.70
(5 H, m), 7.9–8.30 (4 H, m)
970–690
F
202 39 C18H11FN2O3
172 46 C18H12N2O3
3342, 3095, 1670, 1623,
1565, 1484, 1290, 1059,
927–418
3410, 3100, 1670, 1545,
1480, 1040, 1230,
970–730
H
6.55–6.60 (1 H, d, J = 2.37),
7.50–7.90 (7 H, m), 8.10 (1 H,
s), 8.22–8.32 (2 H, m)
1.00–1.400 (3 H, t, J = 7.20),
2.10–2.30 (2 H, q, J = 7.30),
7.00–7.70 (6 H, m), 7.80–8.30
(4 H, m)
C2H5
186 64 C20H16N2O2S 3270, 3080, 2960, 1621,
1557, 1480, 1294, 1060,
926–618
10
C2H5
162 43 C20H16N2O3S 3274, 3120, 2965, 1656,
1623, 1541, 1481, 1289,
1.00–1.30 (3 H, t, J = 7.20),
2.50–2.90 (2 H, q, J = 7.30),
6.50–6.60 (1 H, s), 7.20–7.70
(5 H, m), 8.00–8.30 (4 H, m)
3.20 (6 H, s), 7.70–8.00 (5 H,
m), 8.00–8.20 (5 H, m), 10.5
(1 H, s)
3.00 (6 H, s), 6.50–6.90 (4 H,
m), 7.20–7.70 (2 H, m), 7.90–
8.30 (4 H, m)
1060, 939–518
11
12
13
14
N(CH3)2 241 32 C20H17N3O2S 3422, 3083, 1650, 1612,
1562, 1473, 1296, 1064,
943–410
3322, 3095, 1654, 1608,
1552, 1424, 1296, 1059,
943–435
N(CH3)2 235 21 C20H17N2O3
F
224 55 C20H12ClFN2O2 3359, 3100, 1652, 1610,
7.10–7.70 (5 H, m), 7.80–8.00
(4 H, m), 8.10–8.30 (2 H, m)
1566, 1488, 1244, 1056,
926–411
233 36 C22H17ClN2O2 3337, 3095, 2967, 1645,
1486, 1288, 1088,
C2H5
1.00–1.40 (3 H, t, J = 7.10),
2.60–3.00 (2 H, q, J = 7.30),
7.20–7.60 (5 H, m), 7.70–8.20
(6 H, m)
924–473
15
C2H5
182 45 C23H20NO3
3276, 3100, 2990, 1632,
1557, 1480, 1253, 1031,
867–455
1.00–1.40 (3 H, t, J = 7.20),
2.60–2.90 (2 H, q, J = 7.30), 3.9
(3 H, s), 6.80–7.00 (2 H,d), 7.2–
7.7 (4 H, m), 7.8–8.3 (4 H, m)
6.65–7.00 (4 H, m), 7.40–7.70
(2 H, m), 7.80–8.20 (5 H, m),
10.60 (1 H,s)
1.00–1.30 (3 H, t, J = 7.20),
2.60–2.90 (2 H, q, J = 7.20),
7.00–7.60 (6 H, m), 7.80–8.30
(5 H,m)
16
17
F
227 20 C20H12F2N2O2 3291, 3100, 1644, 1607,
1549, 1503, 1287, 1056,
926–414
C2H5
220 48 C22H17FN2O2
3274, 3074, 2968, 1635,
1557, 1479, 1270, 1058,
967–547

286 Temiz-Arpaci et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 6, 283–288

Arch. Pharm. Pharm. Med. Chem. 2002, 6, 283–288
Synthesis and Antimicrobial Activity 287
bacterial strains are Staphylococcus aureus ATCC 6538,
Streptococcus faecalis ATCC 10541, and Bacillus subtilis
ATCC 6033 as Gram-positive and Escherichia coli ATCC
10536, andPseudomonas aeruginosa RSKK 355 as Gram-
negative bacteria. RSKK 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 Faculty of Phar-
macy of Ankara University.
activity relationships of the synthesized compounds,
which reveal that the presence of a 2-(thienyl)carbo-
nylamino group at position 5 of the fused heterocyclic
system with a dimethylamino group at the para position
of the 2-phenyl moiety increases the antimicrobial activi-
ty against S. aureus, S. feacalis, B. subtilis, and E. coli,
and the antimycotic activity against C. albicans. These
observations offer some predictions of value in the de-
sign of further antimicrobial active compounds prior to
their synthesis.
Ampicillin, amoxycillin, tetracycline, streptomycin, ketoconazo-
le, and fluconazole were used as control drugs.The data on the
antimicrobial activity of the compounds and the control drugs
as MIC, mg/mL, and molar concentration values are given in
Table 2.
Acknowledgment
Antibacterial andantifungal assay
The cultures were obtained from Mueller-Hinton broth (Difco)
for all the bacterial strains after 24 h of incubation at 37 1 °C.
Candida albicans was maintained in Sabouraud dextrose broth
(Difco) after 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 the two-fold serial dilution technique was
applied. The final inoculum size was 105 CFU/mL for the anti-
bacterial assay and 104 CFU/mL for the antifungal assay. A set
of tubes containing only inoculated broth was used as controls.
For the antibacterial assay after incubation for 24 h at 37 1 °C
and after incubation for 48 h at 25 1 °C for the antifungal as-
say, the last tube with no growth of microorganism and/or yeast
was recorded to represent the MIC expressed in µg/mL. Every
experiment in the antibacterial and antifungal assays was repli-
cated twice.
We thank the Research Fund of Ankara University
(Grant No. 98-30-00-06) for the financial support of this
research.
Experimental procedures
Chemistry
Silicagel HF254 chromatoplates (0.3 mm) were used for TLC.
The solvent systems was chloroform:methanol (15:0.5) for
compounds 5–17. Melting points were measured on a Büchi
SMP 20 capillary apparatus and are uncorrected. IR spectra
were recorded by FT/IR 420 on a Shimadzu IR-470 spectrome-
ter (Shimadzu, Japan) on KBr discs. 1H NMR spectra were ob-
tained with a Bruker 80 MHz spectrometer in chloroform;
tetramethylsilane (TMS) was used as an internal standard.Ele-
mental analyses were carried out with a Perkin Elmer model
240-C analyzer.The results (C, H, N) were within 0.4 % of the
calculated values.
General procedure for amide derivatives 5–17
Appropriate carboxylic acid (0.5 mmol) and thionyl chloride
(1.5 mL) were refluxed in benzene (5 mL) at 80 °C for 3 h. Ex-
cess thionyl chloride was removed in vacuo. The residue was
dissolved in ether (10 mL) and this solution added over 1 h to a
stirred, ice-cold mixture of 5-amino-2-( p-substituted-phenyl)-
benzoxazoles 4 (0.5 mmol), sodium bicarbonate (0.5 mmol), di-
ethyl ether (10 mL), and water (10 mL). The mixture was kept
stirred overnight at room temperature and filtered.The precipi-
tate was washed with water, 2 N HCl, and water, respectively,
and finally with ether to give 5–17.The products were recrystal-
lized from ethanol-water as needles which are dried in vacuo.
The chemical, physical and spectral data of the compounds
5–17 are reported in Table 1.
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