Synthesis, Characterization, and Antimicrobial Assessment of Some Computationally Bioactive 1,2-Oxazole Derivatives

Article abstract of DOI:10.1134/S1070363218090207

1,2-Oxazole derivatives 1–6 were designed and evaluated computationally to calculate the physicochemical properties and the bioactivity score by Mol-inspiration, and were determined to possess very good activity score. 1,2-Oxazoles were then synthesized,

Full text of DOI:10.1134/S1070363218090207

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 9, pp. 1886–1891. © Pleiades Publishing, Ltd., 2018.
Synthesis, Characterization, and Antimicrobial Assessment
of Some Computationally Bioactive 1,2-Oxazole Derivatives1
M. Arshada*
a Department of Basic Sciences, College of Medicine Al-Dawadmi, Shaqra University, Saudi Arabia
*e-mail: m.arshad@su.edu.sa; mohdarshad1985@gmail.com
Received June 21, 2018
Abstract—1,2-Oxazole derivatives 1–6 were designed and evaluated computationally to calculate the
physicochemical properties and the bioactivity score by Mol-inspiration, and were determined to possess very
1
good activity score. 1,2-Oxazoles were then synthesized, characterized by FT-IR, H NMR and mass
spectroscopy, and tested for antibacterial activity against the pathogens (Staphylococcus aureus, Staphylococcus
epidermidis, Escherichia coli, and Proteus mirabilis). The antibacterial therapeutic effect strongly supported
the prior computational results. Four synthesized compounds 2, 4–6 demonstrated antibacterial potential higher
than the standard drug Ciprofloxacin.
Keywords: 1,2-oxazole, computational properties, synthesis, characterization, antibacterial screening
DOI: 10.1134/S1070363218090207
INTRODUCTION
elemental analysis data. FT-IR spectra were recorded
on a Perkin-Elmer model 1600 FT-IR RX1. H NMR
1
The increasing demand of creating efficient anti-
microbial agents [1] is induced by development of
bacteria resistance against the presently available
antibiotics. Oxazole nucleus containing compounds
have been studied extensively due to their versatile
potential therapeutic effects [2], such as anti-tubercular
[3, 4], antifungal [5], anti-HCV [6], antimicrobial [7–
11], antiproliferative [12, 13], antitumor [14, 15], and
more [16–22]. Some of presently available antibiotics
like Cloxacillin, Dicloxacillin and Flucloxacillin
contain oxazole nucleus in their molecules [23]. The
biological properties of oxazoles in combination with
sulphonamide groups, initiated our synthesis of some
oxazole containing molecules that could be
biologically active according to computed data, and
their antimicrobial screening.
spectra were measured in CDCl3 on a Bruker Avance
300 MHz spectrometer. Mass spectra were measured
on a Micromass Quattro II triple quadrupole mass
spectrometer. Pre-coated silica gel aluminium sheets
were used for testing purity of the products and
monitoring the reaction and visualized under UV lamp.
Structures of the designed compounds were drawn
by Chem Draw Ultra 8.0 and the smile files were
prepared. The software can be reached at
www.molinspiration.com for calculating the physico-
chemical and bioactivity level score, the complete
procedure and the detail of properties calculated are
reported in the literature [24–27].
Synthesis of 4-[3-(substituted-phenyl)-1,2-oxazol-
3-yl]benzenesulfonamide (1–6) (general procedure).
A mixture of synthesized chalcones and hydroxyl-
amine hydrochloride in equimolar amounts were added
to sodium acetate (25 mL) in a round bottom flask and
refluxed for 8 h. The mixture was then poured into ice
cold water upon stirring. The corresponding product
was formed.
EXPERIMENTAL
4-Acetylbenzenesulfonamide, substituted aldehydes
and other chemicals were purchased from Sigma-
Aldrich and purified if needed. Melting points of the
synthesized compounds 1–6 were recorded on an
instrument Melt-Temp and reported as received.
Heraeus Vario EL III analyzer was used to obtain the
4-[3-(4-Methoxyphenyl)-1,2-oxazol-4-yl]benzene-
sulfonamide (1). Yield 94%, mp 132–134°C. FT-IR
spectrum, ν, cm−1: 1044 (SO2, sym.), 1565 (SO2,
asym.), 1588 (C=C), 1611 (C=N), 2966 (CH-Ar), 3280
1 The text was submitted by the author in English.
1886

SYNTHESIS, CHARACTERIZATION, AND ANTIMICROBIAL ASSESSMENT
1887
Scheme 1. Synthesis of 1,2-oxazoles 1–6.
O
R1
R3
R1
O
S−ΝΗ2
NaOH, ethanol
O
H3COC
R2
CHO
+
reflux
R2
S
NH2
R3
O
O
Chalcones
.
NH2OH HCl,
CH3COONa
O
O
S−ΝΗ2
N
O
R3
R1
R2
1−6
R1 = R3 = H, OCH3, OH; R2 = OCH3, OH.
1
(NH2). H NMR spectrum, δ, ppm: 3.714 s (3H,
OCH3), 7.045–7.112 d (2H, CH-Ar), 7.312–7.363 d
(2H, CH-Ar), 7.572 s (2H, SO2NH2), 7.656–7.713 d
(2H, CH-Ar), 7.790–7.837 d (2H, CH-Ar), 8.163 s
(1H, =C=CH, oxazole nucleus). Found, %: C 58.38, H
4.21, N 8.59. C16H14N2O4S. Calculated, %: C 58.17, H
4.27, N 8.48.MS: m/z: 331.07.
nucleus). Found, %: C 55.42, H 4.58, N 7.34. C18H18N2O6S.
Calculated, %: C 55.38, H 4.65, N 7.18. MS: m/z: 391.09.
4-[3-(4-Hydroxyphenyl)-1,2-oxazol-4-yl]benzene-
sulfonamide (4). Yield 90%, mp 137–139°C. FT-IR
spectrum, ν, cm−1: 1044 (SO2, sym.), 1568 (SO2, asym.),
1592 (C=C), 1614 (C=N), 2970 (CH-Ar), 3293 (NH2),
1
3434 (OH). H NMR spectrum, δ, ppm: 5.510 s (1H,
OH), 6.928-6.963 d (2H, CH-Ar), 7.238–7.270 d (2H,
CH-Ar), 7.588 s (2H, SO2NH2), 7.714–7.746 d (2H,
CH-Ar), 7.808–7.839 d (2H, CH-Ar), 8.159 s (1H,
=C=CH, oxazole nucleus). Found, %: C 57.03, H 3.78,
N 8.82. C15H12N2O4S. Calculated, %: C 56.95, H 3.82,
N 8.86. MS: m/z: 317.06.
4-[3-(3,4-Dimethoxyphenyl)-1,2-oxazol-4-yl]benzene-
sulfonamide (2). Yield 88%, mp 135–137°C. FT-IR
spectrum, ν, cm−1: 1049 (SO2, sym.), 1562 (SO2,
asym.), 1592 (C=C), 1610 (C=N), 2973 (CH-Ar), 3314
1
(NH2). H NMR spectrum, δ, ppm: 3.732 s (3H,
OCH3), 3.818 s (3H, OCH3), 7.144–7.192 d (2H, CH-
Ar), 7.279 s (1H, CH-Ar), 7.510 s (2H, SO2NH2),
7.713–7.770 d (2H, CH-Ar), 7.822–7.881 d (2H, CH-
Ar), 8.182 s (1H, =C=CH, oxazole nucleus). Found,
%: C 57.02, H 4.41, N 7.72. C17H16N2O5S. Calculated,
%: C 56.66, H 4.47, N 7.77. MS: m/z: 361.08.
4-[3-(3,4-Dihydroxyphenyl)-1,2-oxazol-4-yl]-
benzenesulfonamide (5). Yield 93%, mp 134–136°C.
FT-IR spectrum, ν, cm−1: 1049 (SO2, sym.), 1573
(SO2, asym.), 1594 (C=C), 1619 (C=N), 2977 (CH-
1
Ar), 3297 (NH2), 3748 (OH), 3819 (OH). H NMR
spectrum, δ, ppm: 5.275 s (1H, OH), 5.391 s (1H, OH),
6.994–7.132 d (2H, CH-Ar), 7.275 s (1H, CH-Ar), 7.
577 s (2H, SO2NH2), 7.759–7.797 d (2H, CH-Ar),
7.917–7.971 d (2H, CH-Ar), 8.163 s (1H, =C=CH,
oxazole nucleus). Found, %: C 54.58, H 3.58, N 8.29.
C15H12N2O5S. Calculated, %: C 54.21, H 3.64, N 8.43.
MS: m/z: 333.05.
4-[3-(3,4,5-Trimethoxyphenyl)-1,2-oxazol-4-yl]-
benzenesulfonamide (3). Yield 92%, mp 133–135°C.
FT-IR spectrum, ν, cm−1: 1055 (SO2, sym.), 1581
(SO2, asym.), 1578 (C=C), 1615 (C=N), 2966 (CH-
1
Ar), 3218 (NH2). H NMR spectrum, δ, ppm: 3.539 s
(3H, OCH3), 3.637 s (3H, OCH3), 3.747 s (3H, OCH3),
7.235 s (1H, CH-Ar), 7.298 s (1H, CH-Ar), 7.607 s
(2H, SO2NH2), 7.755–7.613 d (2H, CH-Ar), 7.914–
7.973 d (2H, CH-Ar), 8.177 s (1H, =C=CH, oxazole
4-[3-(3,4,5-Trihydroxyphenyl)-1,2-oxazol-4-yl]-
benzenesulfonamide (6). Yield 95%, mp 137–139°C.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

1888
ARSHAD
O
O
N
O
O
H3CO
H3CO
H3CO
H3CO
N
N
N
H3CO
HO
H3CO
O S O
O S O
O S O
O S O
NH2
NH2
NH2
NH2
1
2
3
4
O
N
O
HO
HO
HO
N
HO
O
N
HO
HO
N
NH
O S O
O
O S O
F
NH2
NH2
Ciproflocaxin
5
6
The structures of 1,2-oxazole derivatives and their bioactivity score.
Parameter
Ciptoflocaxin
0.12
1
2
3
4
5
6
GPCR ligand
–0.02 –0.01 –0.02
0.09
0.08
–0.03
0.21
0.08
0.11
0.24
0.07
–0.02
0.23
0.06
0.13
0.27
Ion channel modulator
Kinase inhibitor
–0.14 –0.14 –0.14 –0.02
–0.04
0.13
0.13 0.13
0.18
0.10
0.12
0.24
–0.07
Nuclear receptor ligand
Protease inhibitor
Enzyme inhibitor
–0.12 –0.07 –0.12
–0.19
0.02
0.11
0.04 0.02
0.12 0.11
– 0.20
0.28
FT-IR spectrum, ν, cm−1: 1069 (SO2, sym.), 1597
(SO2, asym.), 1678 (C=C), 1618 (C=N), 2987 (CH-
Ar), 3334 (NH2), 3378 (OH), 3798 (OH), 3976 (OH).
1H NMR spectrum, δ, ppm: 5.413 s (1H, OH), 5.498 s
(1H, OH), 5.527 s (1H, OH), 7.130 s (1H, CH-Ar),
7.263 s (1H, CH-Ar), 7.597 s (2H, SO2NH2), 7.690–
7.739 d (2H, CH-Ar), 7.817–7.877 d (2H, CH-Ar),
8.154 s (1H, =C=CH, oxazole nucleus). Found, %: C
51.83; H 3.38; N 8.12. C15H12N2O6S. Calculated, %: C
51.72; H 3.47; N 8.04. MS: m/z: 349.04.
used as a reference and DMSO as negative control in
the experiment.
RESULTS AND DISCUSSION
Structures of the 1,2-oxazoles were drawn and
calculated for the bioactivity score and physico-
chemical properties by utilizing the online available
software (www.molinspiration.com). Results of com-
putational screening revealed that all the components
were in compliance with the Lipinski rule of five’s and
possessed very significant good bioactivity score (see
figure and Table 1). Preparation of 1,2-oxazole nucleus
was achieved by two step synthetic procedure (Scheme 1).
The first step was the preparation of chalcone by
mixing an aldehyde and a ketone in eqimolar amounts
in 10% NaOH solution. In the second step formation
Antimicrobial activity. 1,2-Oxazole derivatives
were assessed for antibacterial effects on gram +ve and
gram –ve pathogens according to the protocol employ-
ing the disc diffusion method [28, 29]. Minimum
inhibitory concentration was calculated by using serial
dilutions from the stock solution. Ciprofloxacin was
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

SYNTHESIS, CHARACTERIZATION, AND ANTIMICROBIAL ASSESSMENT
1889
Table 1. Physicochemical properties of 1, 2-oxazole derivatives 1–6 and Ciprofloxacin
Components
Physicochemical
property score
1
2.57
95.43
23
2
2.16
104.67
25
3
2.14
113.90
27
4
2.03
106.42
22
5
1.54
126.65
23
6
1.25
146.88
24
standard
log P
TPSA
Natoms
Mw
–0.071
74.569
24.0
330.37
6
360.39
7
390.42
8
316.34
6
332.34
7
348.34
8
331.347
Non
6
nOHNH
Nviolations
Nrotb
2
2
2
3
4
5
2
0
0
0
0
0
0
0
3
4
5
6
3
3
3
Volume
272.54
298.08
323.63
255.01
263.03
271.05
285.460
Table 2. Zones of inhibition and minimum inhibitory concentration of 1,2-oxazole derivatives 1–6 and ciprofloxacin
Zones of inhibition, mm
Compound
gram positive
S. aureus
gram negative
S. epidermidis
21.26±0.32
21.44±0.20
22.17±0.33
22.36±0.24
22.55±0.17
23.18±0.34
22.87±0.37
E. coli
P. mirabilis
20.12±0.19
22.21±0.25
20.43±0.30
20.66±0.37
21.74±0.26
22.24±0.20
22.34±0.21
1
20.45±0.20
22.32±0.26
20.25±0.28
21.64±0.17
21.81±0.24
22.22±0.33
21.39±0.21
23.58±0.23
23.66±0.32
23.64±0.18
24.75±0.24
23.80±0.26
24.32±0.30
23.69±0.81
2
3
4
5
6
Ciprofloxacin
Minimum inhibitory concentration, µg/mL
1
6.25
6.25
6.25
6.25
6.25
6.25
6.25
3.125
3.125
3.125
3.125
3.125
3.125
3.125
6.25
6.25
6.25
6.25
6.25
6.25
6.25
12.5
12.5
12.5
12.5
12.5
12.5
12.5
2
3
4
5
6
Ciprofloxacin
of 1,2-oxazole nucleus was achieved by the reaction of
chalcone with hydroxylamine hydrochloride in
presence of sodium acetate. FT-IR and NMR spectra
confirmed the structures. In FT-IR spectra absence of
the band of C=O at ca. 1700 cm–1 confirmed formation
of the oxazole nucleus. The bands in the range of 1610–
1618 cm–1 (C=N) in the spectra of the synthesized
compounds also supported formation of the products.
1H NMR spectra of 1,2-oxazoles 1–6 contained the
singlet in the range of 8.157–8.182 ppm attributed to
the HC=C proton of the oxazole nucleus of the
synthesized compounds. This was supported by the
absence of a singlet in the ranges of 7.453–7.512 and
7.882–7.998 of HC=CH α,β-unsaturated protons of the
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1890
ARSHAD
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j.ejmech.2017.12.006
chalcone. 1,2-Oxazoles were tested for their antibact-
erial activity (Table 2). The accumulated data were in
accord with the computational results. All six products
exhibited the higher activity and lower minimum
inhibitory concentration than the standard drug.
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CONCLUSIONS
A sequence of six 1,2-oxazole derivatives was
designed and calculated computationally for drug
potential and physicochemical properties. The findings
demonstrated that all the derivatives possessed high
bioactivity score and were in compliance with the
Lipinski Rule of Five. All potentially bioactive 1,2-
oxazole derivatives 1–6 were then synthesized and
tested for their antibacterial activity. The experimental
data of antibacterial activity matched well with the
computational results. The compounds 2, 4–6
exhibited the highly significant antibacterial potential.
12. Jie, Z., Jing, J., Yi, Z., Yuwen, Y., Xiaoguang, C., and
Bailing, X., Eur. J. Med. Chem., 2013, vol. 68, p. 222.
doi 10.1016/j.ejmech.2013.08.006
ACKNOWLEDGMENTS
13. Chun-Liang, C., Fei-Lan, L., Chia-Chung, L., Tsung-
Chih, C., Wen-Wei, C., Jih-Hwa, G., Ahmed, A.A.A.,
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p. 4890. doi 10.1016/j.ejmech.2010.07.061
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p. 109. doi 10.1016/j.ejmech.2008.03.009
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Dr. M. Arshad, is highly thankful to Dr. Feras Al-
Marshad, the Dean College of Medicine Al-Dawadmi,
Shaqra University, Kingdom of Saudi Arabia for his
cooperation.
CONFLICT OF INTERESTS
No conflict of interest was declared by the authors.
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