Vol. 31, No. 4 (2019)
Synthesis of Benzofuran-Oxadiazole Conjugates as Potential Antitubercular Agents 967
for C12H10N2O3; C, 62.60; H, 4.38; N, 12.17; Found: C, 62.54;
H, 4.38; N, 12.16.
7.52-7.55 (t, J = 7.5 Hz, 1H, Ar-H), 7.78-7.80 (d, J = 9.0 Hz,
1H, Ar-H), 7.86-7.88 (d, J = 9.0 Hz, 1H, Ar-H), 8.05-8.10 (m,
2H, oxadiazole-H and Ar-H), 8.10 (s, 1H, C2-H), 8.14-8.15
(d, J = 8.5 Hz, 1H, Ar-H); 13C NMR (125 MHz, DMSO-d6): δ
22.56, 114.12, 114.64, 121.28, 123.87, 126.44, 126.82, 127.60,
127.98, 129.87, 131.74, 145.33, 154.82, 164.74, 172.10;
GCMS m/z: 250 [M+]; Anal. calcd. for C15H10N2O2; C, 71.99;
H, 4.03; N, 11.19; Found: C, 71.97; H, 4.03; N, 11.18.
2-(Naphtho[1,2-b]furan-3-ylmethyl)-1,3,4-oxadiazole
(7o): Brown solid; m.p. 161-162 °C; yield (70 %); IR (KBr,
2-((6-Methoxybenzofuran-3-yl)methyl)-1,3,4-oxadia-
zole (7i): Grey solid; m.p. 171-172 °C; yield (80 %); IR (KBr,
ν
max, cm–1): 1627 (C=N); 1H NMR (500 MHz, DMSO-d6): δ
3.59 (s, 3H, 6-OCH3), 3.89 (s, 2H, C3-CH2), 6.86 (dd, J = 9.0
Hz, 2.0 Hz, 1H, C5-H), 7.14 (d, J = 2.0 Hz, 1H, C7-H), 7.44
(d, J = 9.0 Hz, 1H, C4-H), 7.61 (s, 1H, oxadiazole-H), 7.78
(s, 1H, C2-H); 13C NMR (125 MHz, DMSO-d6): δ 21.70, 56.14,
104.55, 105.34, 112.98, 114.14, 125.38, 144.17, 144.54,
169.05, 172.06; GCMS m/z: 230 [M+]; Anal. calcd. for
C12H10N2O3; C, 62.60; H, 4.38; N, 12.17; Found: C, 62.58; H,
4.38; N, 12.16.
ν
max, cm–1): 1652 (C=N); 1H NMR (500 MHz, DMSO-d6): δ
3.86 (s, 2H, C3-CH2), 7.46-7.49 (m, 1H, Ar-H), 7.61-7.63 (m,
1H, Ar-H), 7.65-7.67 (d, J = 8.4 Hz, 1H, Ar-H), 7.70-7.72 (d,
J = 8.8 Hz, 1H, Ar-H), 8.02 (m, 3H, oxadiazole and Ar-H),
8.18 (d, J = 8.0 Hz, 1H, Ar-H); 13C NMR (125 MHz, DMSO-
d6): δ 29.68, 116.68, 119.82, 119.99, 121.82, 124.56, 124.18,
126.63, 128.10, 128.64, 133.18, 145.68, 149.98, 169.15,
172.44; GCMS m/z: 250 [M+]; Anal. calcd. for C15H10N2O2;
C, 71.99; H, 4.03; N, 11.19; Found: C, 71.98; H, 4.03; N,
11.19.
2-((5-Chlorobenzofuran-3-yl)methyl)-1,3,4-oxadiazole
(7j): Colourless solid; m.p. 149-150 °C; yield (69 %); IR (KBr,
ν
max, cm–1): 1639 (C=N); 1H NMR (500 MHz, DMSO-d6): δ
3.92 (s, 2H, C3-CH2), 7.36 (d, J = 9.0 Hz, 1H, C6-H), 7.59 (d,
J = 9.0 Hz, 1H, C7-H), 7.64 (s, 2H, C4-H and oxadiazole-H),
7.90 (s, 1H, C2-H); 13C NMR (125 MHz, DMSO-d6): 29.71,
114.18, 115.92, 121.44, 125.56, 128.01, 131.35, 145.98,
155.33, 168.12, 171.32; GCMS m/z: 234, 236 [M+, M+2];
Anal. calcd. for C11H7N2O2Cl; C, 56.31; H, 3.01; N, 11.94;
Found: C, 56.30; H, 3.01; N, 11.93.
Antitubercular activity: The antitubercular activity of
titled compounds 7(a-o) were performed against M. phlei and
M. tuberculosis H37RV using well known procedure microplate
alamar blue assay (MABA) [46]. This methodology is non-
toxic, uses stable reagents and shows good correlation with
proportional and BACTEC radiometric method. In brief, 200
µL of sterile deionized water was added to all outer perimeter
wells of sterile 96-well plate to minimize evaporation of medium
in the test wells during incubation. The 96-well plate received
100 µL of the Middlebrook 7H9 broth and serial dilution of
compounds was made directly on plate. The final drug concen-
trations tested were 100-0.1 µg/mL. Plates were covered and
sealed with parafilm and incubated at 37 °C for 5 days. After
this time, 25 µL of freshly prepared 1:1 mixture of Alamar
Blue reagent and 10 % Tween 80 were added to the plate and
incubated for 24 h. A blue colour in the well was interpreted
as no bacterial growth and pink colour was scored as growth.
The MIC was defined as the lowest drug concentration that
prevented the colour change from blue to pink.
2-((6-Chlorobenzofuran-3-yl)methyl)-1,3,4-oxadiazole
(7k): Colourless solid; m.p. 158-159 °C; yield (67 %); IR (KBr,
ν
max, cm–1): 1631 (C=N); 1H NMR (500 MHz, DMSO-d6): δ
3.90 (s, 2H, C3-CH2), 7.09-7.11 (d, J = 8.0 Hz, 1H, C5-H),
7.42 (s, 1H, C7-H), 7.44-7.46 (d, J = 8.0 Hz, 1H, C4-H), 7.51
(s, 1H, oxadiazole-H), 7.76 (s, 1H, C2-H); 13C NMR (125 MHz,
DMSO-d6): δ 29.98, 115.33, 116.54, 121.98, 125.74, 128.45,
132.44, 147.58, 156.10, 166.41, 172.43; GCMS m/z: 234, 236
[M+, M+2]; Anal. calcd. for C11H7N2O2Cl; C, 56.31; H, 3.01;
N, 11.94; Found: C, 56.30; H, 3.01; N, 11.93.
2-((5-Bromobenzofuran-3-yl)methyl)-1,3,4-oxadiazole
(7l): Colourless solid; m.p. 168-169 °C; yield (66 %); IR (KBr,
ν
max, cm–1): 1635 (C=N); 1H NMR (500 MHz, DMSO-d6): δ
3.91 (s, 2H, C3-CH2), 7.41-7.44 (dd, J = 9.0 Hz, 2.0 Hz, 1H,
C6-H), 7.53 (d, J = 9.0 Hz, 1H, C7-H), 7.86 (d, J = 2.0 Hz,
13
1H, C4-H), 7.88-7.90 (m, 2H, oxadiazole-H and C2-H); C
NMR (125 MHz, DMSO-d6): δ 29.52, 114.04, 115.98, 116.07,
124.53, 128.33, 132.84, 146.78, 155.62, 164.47, 172.14;
GCMS m/z: 277, 279 [M+, M+2]; Anal. calcd. for
C11H7N2O2Br; C, 47.34; H, 2.53; N, 10.04; Found: C, 47.33;
H, 2.53; N, 10.04.
RESULTS AND DISCUSSION
The concise synthetic route used to synthesize the inter-
mediates and titled compounds 7(a-o) are outlined in Schemes
I and II. Benzofuran-3-yl-acetic acids 5(a-o) were converted
into corresponding ethyl esters by refluxing with absolute ethanol
in presence of conc. sulphuric acid. The resulting mixture, was
converted into the acid hydrazides 6(a-o) by the reaction with
hydrazine hydrate at reflux temperature [45]. Further, these
acid hydrazides 6(a-o) were reacted with triethyl orthoformate
in toluene at reflux temperature for 15 h afforded title compounds
7(a-o). All the synthesized compounds 7(a-o) were charac-
terized by elemental analysis, IR, 1H NMR, 13C NMR and mass
spectral data.
The IR spectrum of an intermediate (6-methyl-benzo-
furan-3-yl)-acetic acid hydrazide (6b), showed a strong peak
at 1643 cm-1 for carbonyl group whereas 3303 cm-1 for NHNH2
stretching. The 1H NMR spectrum exhibited δ 2.41 (s, 3H, 6-
CH3), 3.63 (d, J = 1.0 Hz, 2H, C3-CH2), 4.22 (s, br, 2H, NH2,
2-((6-Bromobenzofuran-3-yl)methyl)-1,3,4-oxadiazole
(7m): Colourless solid; m.p. 134-135 °C; yield (60 %); IR
(KBr, νmax, cm–1): 1629 (C=N); 1H NMR (500 MHz, DMSO-
d6): δ 3.91 (s, 2H, C3-CH2), 7.08-7.10 (d, J = 8.0 Hz, 1H, C5-
H), 7.39 (s, 1H, C7-H), 7.42-7.44 (d, J = 8.0 Hz, 1H, C4-H),
7.60 (s, 1H, oxadiazole-H), 7.75 (s, 1H, C2-H); 13C NMR (125
MHz, DMSO-d6): 29.98, 115.11, 116.47, 121.52, 127.45,
129.82, 135.84, 148.44, 156.87, 169.33, 172.70; GCMS m/z:
277, 279 [M+, M+2];Anal. calcd. for C11H7N2O2Br; C, 47.34;
H, 2.53; N, 10.04; Found: C, 47.32; H, 2.53; N, 10.04.
2-(Naphtho[2,1-b]furan-1-ylmethyl)-1,3,4-oxadiazole
(7n): Beige solid; m.p. 201-202 °C; yield (72 %); IR (KBr,
ν
max, cm–1): 1618 (C=N); 1H NMR (500 MHz, DMSO-d6): δ
3.81 (s, 2H, C3-CH2), 7.46-7.49 (t, J = 7.5 Hz, 1H, Ar-H),