S. Vodela et al. / Chinese Chemical Letters 24 (2013) 625–628
627
2-(5-p-Tolyl-[1,3,4]oxadiazol-2-yl)benzoxazole (7a): Yellish
green solid, yield: 73%, mp: 163–165 8C; IR (KBr, cmꢁ1):
3040
(C–H, Ar), 1565 (C55C), 1435 (C55N), 1135 (C–O) cmꢁ1 1H NMR
(300 MHz, DMSO-d6): 7.62–7.45 (m, 4H, Ar–H), 3.45 (s, 1H, CH);
13C NMR (100 MHz, CDCl3):
155.3, 154.3, 152.0, 150.1, 141.5,
pharmaceutical and biological fields, and in continuation of our
research on biologically active heterocycles, we have introduced
oxadiazole moiety into the benzoxazole ring which leads to both
active pharmacophores in a single molecular frame work for the
intensified biological activities. Thus we have designed and
synthesized a series of novel 2-(5-substituted-[1,3,4]oxadiazol-
2-yl)-benzoxazoles (7a–h) from commercially available benzox-
azole-2-carboxylic acid (1). Benzoxazole-2-carbonyl chloride (2)
has been synthesized from compound 1 on reaction with thionyl
chloride in presence of ethanol solvent on constant stirring at room
temperature for 4 h. The intermediate benzoxazole-2-carboxylic
n
;
d
d
137.6, 134.2, 129.3, 129.0, 126.7, 126.5, 125.4, 123.0, 120.4, 110.5,
24.6; MS: m/z 187 (M+).
2-[5-(4-Chloro phenyl)-[1,3,4]oxadiazol-2-yl)benzoxazole (7b):
Pink solid, yield: 75%, mp: 125–127 8C; IR (KBr, cmꢁ1):
n
3035
(C–H, Ar), 2965 (C–H, CH3), 1560 (C55C), 1440 (C55N), 1130 (C–O)
cmꢁ1 1H NMR (300 MHz, DMSO-d6):
7.58–7.23 (m, 4H, Ar–H),
3.45 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3):
157.4, 155.3, 154.3,
;
d
d
acid methyl ester (3) was achieved form compound 2 on
151.0, 144.6, 139.8, 134.6, 131.0, 127.8, 127.6, 126.5, 126.2, 122.5,
121.5, 112.7; MS: m/z 201 (M+).
esterification with methanol in presence of triethyl amine under
reflux for 3 h. Compound 3 on reaction with hydrazine hydrates in
presence of ethanol solvent under reflux for 8 h was turned into the
key intermediate benzoxazole-2-carboxylic acid hydrazide (4).
Benzoxazole-2-carboxylic acid N0-acetyl hydrazides (5a–d) have
been prepared form compound 4 and different acid chlorides in
dioxane solvent at reflux temperature for 4–5 h. The subsequent
ring closure reaction of compounds 5a–d with POCl3 under reflux
for 4–5 h yielded the title compounds, 2-[1,3,4]oxadiazol-2-yl-
benzoxazoles (7a–d). Benzoxazole-2-carboxylic acid-ethylidene-
hydrazides (6a–d) were prepared form the reaction of same
intermediate 4 with suitable orthoforamtes under reflux for 10–
12 h. Finally 2-[1,3,4]-oxadiazol-2-yl-benzoxazoles (7e–h) have
been achieved from the reaction of 6 in refluxing pyridine for 4–
5 h. The chemical structures of all the newly synthesized
compounds were confirmed by their IR, 1H NMR, 13C NMR and
Mass spectral data and further the compounds 7a–h were used to
evaluate their antimicrobial activity.
The disc diffusion method [19] was used for the screening of
anti microbial activity. The in vitro antibacterial activity of the
synthesized compounds 7a–h was tested against three gram-
positive bacteria i.e. Staphylococcus aureus, Staphylococcus albus,
Streptococcus faecalis and against five Gram-negative bacteria i.e.,
Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeuroginosa,
Proteus mirabilis, Salmonella typhi using a nutrient agar medium.
The antifungal activity of the compounds was screened against
Candia albicans and Aspergillus fumigatus using Sabouraded
dextrose agar medium. The sterilized medium (autoclaved at
121 8C for 15 min) was inoculated with the suspension of the micro
organisms and poured into a Petri dish to give a depth of 3–4 mm.
The paper impregnated with the synthesized compounds 7a–h
2-[5-(4-Bromo phenyl)-[1,3,4]oxadiazol-2-yl)benzoxazole (7c):
Yellow solid, yield: 71%, mp: 136–138 8C; IR (KBr, cmꢁ1):
n
;
3042 (C–H, Ar), 1570 (C55C), 1448 (C55N), 1146 (C–O) cmꢁ1
1H NMR (300 MHz, DMSO-d6):
7.78–7.25 (m, 4H, Ar–H), 4.05
(q, 2H, CH2), 1.31 (t, 3H, CH3); 13C NMR (100 MHz, CDCl3):
156.6,
d
d
154.4, 153.8, 152.5, 145.4, 138.6, 135.3, 132.5, 128.6, 128.2, 125.6,
125.1, 123.4, 120.8, 114.6; MS: m/z 215 (M+).
2-[5-(4-Nitro phenyl)-[1,3,4]oxadiazol-2-yl)benzoxazole (7d):
Pale yellow solid, yield: 70%, mp: 147–149 8C; IR (KBr, cmꢁ1):
n
3045 (C–H, Ar), 1562 (C55C), 1442 (C55N), 1140 (C–O); 1H NMR
(300 MHz, DMSO-d6): 8.45 (dd, 1H, J = 7.7, 1.5 Hz, Ar–H), 7.89 (d,
d
1H, J = 8.0 Hz, Ar–H), 7.80 (dd, 1H, J = 7.7, 1.5 Hz, Ar–H), 7.53 (d, 1H,
J = 7.8 Hz, Ar–H), 7.42–7.25 (m, 5H, Ar–H); 13C NMR (100 MHz,
CDCl3):
d 157.6, 155.4, 154.6, 150.2, 147.8, 136.7, 135.5, 133.2,
129.4, 129.3, 126.7, 126.0, 125.2, 122.4, 118.3; MS: m/z 263 (M+).
2-[1,3,4]Oxadiazol-2-yl-benzoxazole (7e): Brown solid, yield:
71%, mp: 128–130 8C; IR (KBr, cmꢁ1):
n
3055 (C–H, Ar), 1570 (C55C),
1445 (C55N), 1138 (C–O); 1H NMR (300 MHz, DMSO-d6):
d
8.42 (dd,
1H, J = 7.7, 1.4 Hz, Ar–H), 7.85 (d, 1H, J = 8.2 Hz, Ar–H), 7.74 (d, 2H,
J = 7.8 Hz, Ar–H), 7.65 (dd, 1H, J = 7.7, 1.4 Hz, Ar–H), 7.54 (d, 2H,
J = 7.8 Hz, Ar–H), 7.52 (d, 1H, J = 7.8 Hz, Ar–H), 2.80 (s, 3H, CH3); 13
C
NMR (100 MHz, CDCl3):
122.0, 118.6, 112.0; MS: m/z 277 (M+).
2-(5-Methyl-[1,3,4]oxadiazol-2-yl)benzoxazole (7f): Pale yellow
solid, yield: 73%, mp: 131–133 8C; IR (KBr, cmꢁ1):
3060 (C–H, Ar),
1562 (C55C), 1440 (C55N), 1128 (C–O) cmꢁ1 1H NMR (300 MHz,
DMSO-d6): 8.32 (dd, 1H, J = 7.3, 1.7 Hz, Ar–H), 8.21 (d, 1H,
d 158.6, 155.6, 152.4, 148.7, 142.0, 127.6,
n
;
d
J = 8.2 Hz, Ar–H), 7.84 (d, 2H, J = 7.4 Hz, Ar–H), 7.78 (dd, 1H, J = 7.3,
1.7 Hz, Ar–H), 7.65 (d, 2H, J = 7.4 Hz, Ar–H), 7.42 (d, 1H, J = 7.8 Hz,
Ar–H); 13C NMR (100 MHz, CDCl3):
d
156.4, 153.2, 150.3, 147.5,
(300 mg/mL in DMF) was placed on the solidified medium. The
plates were preincubated for 1 h at room temperature and
incubated at 378 for 24 h and 48 h for antibacterial and antifungal
144.5, 129.4, 125.3, 121.1, 116.5, 18.6; MS: m/z 297 (M+).
2-(5-Ethyl-[1,3,4]oxadiazol-2-yl)benzoxazole (7g): Yellowish
green solid, yield: 75%, mp: 143–145 8C; IR (KBr, cmꢁ1):
n
3038
(C–H, Ar), 1568 (C55C), 1446 (C55N), 1140 (C–O); 1H NMR (300 MHz,
DMSO-d6): 8.43 (dd, 1H, J = 8.0, 1.5 Hz, Ar–H), 8.05 (d, 1H,
activity respectively. Amicacin (300
terial activity studies, whereas fluconazole (300
m
g/mL) was used in antibac-
g/mL) was used
m
d
in antifungal activity studies as reference compounds. After
incubation, the relative susceptibility of the micro organisms to
the potential antimicrobial agent is demonstrated by a clear zone
of growth inhibition around the disc. The lowest concentration
(highest dilution) of the compounds at which there was no visually
detectable bacterial growth was taken as minimum inhibitory
concentration (MIC) and it was determined for the compounds 7a–
h. The inhibition zone caused by the various compounds on the
micro organisms was measured and the activity rated on the basis
of the size of the inhibition zone. The observed zone of inhibition in
mm is presented in Table 1.
J = 8.1 Hz, Ar–H), 7.81 (dd, 1H, J = 8.0, 1.5 Hz, Ar–H), 7.74 (d, 2H,
J = 7.0 Hz, Ar–H), 7.65 (d, 2H, J = 7.0 Hz, Ar–H), 7.36 (d, 1H, J = 7.8 Hz,
Ar–H); 13C NMR (100 MHz, CDCl3):
d 155.3, 152.5, 151.7, 146.4,
145.6, 131.5, 127.4, 126.3, 119.8, 21.2, 16.3; MS: m/z 340 (M+).
2-(5-Phenyl-[1,3,4]oxadiazol-2-yl)benzoxazole (7h): Yellow solid,
yield: 70%, mp: 150–152 8C; IR (KBr, cmꢁ1):
n
3028, (C–H, Ar), 1572
(C55C), 1442(C55N), 1143 (C–O);1HNMR(300 MHz, DMSO-d6):
d
8.32
(dd, 1H, J = 8.2, 1.6 Hz, Ar–H), 8.12 (d, 1H, J = 8.2 Hz, Ar–H), 7.89 (dd,
1H, J = 8.2, 1.6 Hz, Ar–H), 7.69 (d, 2H, J = 7.4 Hz, Ar–H), 7.58 (d, 2H,
J = 7.4 Hz, Ar–H), 7.42 (d, 1H, J = 8.2 Hz, Ar–H); 13C NMR (100 MHz,
CDCl3):
d
159.3, 156.7, 154.0, 150.2, 141.7, 136.8, 129.7, 129.4, 128.4,
The results of the antimicrobial screening of the tested
compounds revealed that, all the tested compounds exhibited
antimicrobial activity comparable with that of reference com-
pounds. Most of the compounds showed significant activity
against both bacteria and fungi. Some of the compounds showed
high activity against both the bacteria and fungi. Most of the
compounds showed highly to moderate activity against bacteria
127.6, 127.2, 125.4, 124.0, 120.8, 110.5; MS: m/z 308 (M+).
3. Results and discussion
Based on these observations, inspired by the biological profile of
benzoxazoles and oxadiazoles, their increasing importance in