Synthesis of 2-(2-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole derivatives and evaluation of their antiglycation potential

Article abstract of DOI:10.1007/s00044-015-1476-8

In the search of potent antidiabetic drug, we synthesized 1-25 2-(2-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole derivatives. First, we synthesized 2-methoxybenzohydrazide from methyl 2-methoxybenzoate which was treated with different arylaldehydes to afford 1-25 compounds. The synthesized compounds were evaluated for antiglycation activity. We found that 1-6 and 8 showed potent activity ranging from 160.2 to 290.17 μM better than standard drug rutin (IC₅₀ = 295.09 ± 1.04 μM). All the synthesized compounds were characterized by different spectroscopy methods. These compounds can further be studied to develop lead antidiabetic compounds.

Full text of DOI:10.1007/s00044-015-1476-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1476-8
ORIGINAL RESEARCH
Synthesis of 2-(2-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole
derivatives and evaluation of their antiglycation potential
1
,2
1,2
3
1,2
•
Muhammad Taha
4
•
Nor Hadiani Ismail
4
Syed Muhammad Kashif
•
Waqas Jamil
Mohd Zulkefeli
•
Syahrul Imran
1,5
Fazal Rahim
•
•
Received: 12 May 2015 / Accepted: 27 October 2015
Ó Springer Science+Business Media New York 2015
Abstract In the search of potent antidiabetic drug, we
synthesized 1–25 2-(2-methoxyphenyl)-5-phenyl-1,3,4-
oxadiazole derivatives. First, we synthesized 2-methoxy-
benzohydrazide from methyl 2-methoxybenzoate which
was treated with different arylaldehydes to afford 1–25
compounds. The synthesized compounds were evaluated
for antiglycation activity. We found that 1–6 and 8 showed
potent activity ranging from 160.2 to 290.17 lM better
than standard drug rutin (IC50 = 295.09 ± 1.04 lM). All
the synthesized compounds were characterized by different
spectroscopy methods. These compounds can further be
studied to develop lead antidiabetic compounds.
Introduction
Oxidative stress and chronic hyperglycemia produce
advanced glycation end-products. Amadori products for-
mation starts by glycation process by the reaction of the
amino group of proteins and sugar molecules. (Rojas
and Morales, 2004). Carboxyl-methyllysine and car-
boxymethyl-hydroxylysine are AGEs formed through
oxidative cleavage of Amadori adducts, while pentosidine
results by crosslinking of lysine and arginine. It was
observed that high level of glycation process occurs at
aging and hyperglycemic patient as compared to healthy
persons (Baral et al., 2000). AGEs formation is further
enhanced with oxidative stress (Wu and Yen, 2005). Dia-
betic complication like retinopathy, neuropathy,
atherosclerosis and cataract has direct relevance with
AGEs (Ahmed, 2005).
Keywords
2
-(2-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole Á
Antiglycation activity Á Rutin Á Diabetic
Some molecules have been reported that can break
AGEPs crosslinks and possibly open the opportunity of
reversing the slow process of diabetic complications
(
Vasan et al., 2003). It has been found that AGE inhibits
&
Muhammad Taha
taha_hej@yahoo.com;
muhamm9000@puncakalam.uitm.edu.my
the formation of AGEPs in vitro and stops the formation of
glycation-derived free radicals. S-Allylcysteine is an
important component of AGE that acts as a potent
antioxidant and thus inhibits the AGEPs formation (Hunt
et al., 1993; Ahmed and Ahmed, 2006). Aminoguanidine,
an inhibitor of AGEPs formation, was found to prevent
retinopathy in diabetic animals and protect them from
developments of diabetic vascular complications. How-
ever, aminoguanidine has encountered some toxicity
problems in phase III clinical trials (Gugliucci, 2000).
Great struggles have been made nowadays to develop new
and safe synthetic antiglycation agents (Singh et al., 2001).
The heterocyclic compounds have wide range of bio-
logical application (Rahim et al., 2015; Khan et al., 2014,
1
Atta-ur-Rahman Institute for Natural Product Discovery,
Universiti Teknologi MARA (UiTM), Puncak Alam Campus,
4
2300 Bandar Puncak Alam, Selangor, Malaysia
2
3
4
5
Faculty of Applied Science, UiTM, 40450 Shah Alam,
Selangor, Malaysia
Department of Chemistry, Hazara University, Mansehra,
Pakistan
Institute of Advance Research Studies in Chemical Sciences,
University of Sindh Jamshoro, Hyderabad 76080, Pakistan
Faculty of Pharmacy, Universiti Teknologi MARA (UiTM),
Puncak Alam Campus, 42300 Bandar Puncak Alam,
Selangor Darul Ehsan, Malaysia
123

Med Chem Res
2
015; Imran et al., 2014, 2015a, b; Taha et al., 2014a, b;
methoxyphenyl)-5-phenyl-1,3,4-oxadiazole derivatives 1–25
Scheme 1. All the synthesized compounds 1–25 were char-
Zawawi et al., 2015). Great attention has been paid to the
chemistry and biological activities of 1,3,4-oxadiazole
nucleus. Numerous compounds having 1,3,4-oxadiazole
scaffold have been freshly reported as potential antipro-
liferative agents (Gudipati et al., 2011; Rashid et al., 2012).
Besides from anticancer potential, other biological activi-
ties have been reported for 1,3,4-oxadiazole derivatives
such as antidiabetic (Hadady et al., 2004), antitubercular
1
acterized by diverse spectroscopy methods: HNMR, EI, MS
and elemental analysis (Table 1). The compounds 1–16, 18,
21 and 24 are new, and compounds 17, 19, 20, 22, 23 and 25
are known (Wang et al., 2006; Khan et al., 2005; Biju et al.,
2012; Roy et al., 2005; Yi-Ming et al., 2014).
(
Ahsan et al., 2011), antifungal (Liu et al., 2008), anti-
inflammatory (Jakubkiene et al., 2002) and antibacterial
activities (Desai et al., 2013). 1,3,4-Oxadiazole, a fortunate
structure, showed a key motif in heterocyclic chemistry and
attracts a lot of interest in the fields of medicinal chemistry
and synthetic study due to their competence to exhibit a
wide range of pharmacological activities, such as
antianxiety (Harfenist et al., 1996) and antitubercular
activities (Ahsan et al., 2011). Literature survey revealed
that minor modification in the structure of 1,3,4-oxadia-
zole/thiadiazole can lead to quantitative as well as quali-
tative changes in the biological activity (Aziz-Ur-Rehman
Biological activity
It is reported that a Schiff base adduct between pyridoxal
and aminoguanidine is responsible for inhibiting advanced
glycation end-product (AGEPs) formation. In continuation
of our study on activity of heterocyclic compounds bearing
oxadiazole ring (Taha et al., 2015a), we have synthesized
2-(2-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole derivatives
1–25 to analyze for their antiglycation potential.
Bovine serum albumin, methyl glyoxal, various con-
centrations of the compounds and phosphate buffer (pH
7.4) containing sodium azide were mixed and incubated
under aseptic conditions at 37 °C for 9 days. After 9 days,
each sample was examined for the development of specific
fluorescence. Rutin was used as a positive control (Khan
et al., 2011a, 2013a, b; Taha et al., 2014a, b, 2015b; Khan
et al., 2009; Jamil et al., 2015).
Ò
et al., 2012). There are several examples like, Raltegravir ,
Ò
an antiretroviral drug and Zibotentan an anticancer agent,
while this scaffold, also a part of antibiotics such as
furamizole etc. (Musmade et al., 2015) (Fig. 1).
Results and discussion
The current study is planned to explore potent antigly-
cating agents: Out of twenty-five (25) compounds, fourteen
(14) analogs showed variable degree of antiglycation
activities with IC50 values ranging between 160.2 ± 0.50
and 668.25 ± 3.74 lM, if compared with standard rutin
(IC50 = 295.09 ± 1.04 lM) (Table 1). The standard
The 2-(2-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole deriva-
tives synthesis begins with the synthesis of 2-methoxyben-
zohydrazide and then 2-methoxybenzohydrazide was
treated with different arylaldehydes to produce 2-(2-
Fig. 1 Oxadiazole ring
containing commercially
available drugs
O
N
OH
N
MeO
O
H
N
N
N
N
N N
O
H
N
O
O S NH
F
N
O
O
N
Raltegravir
Zibotentan
NH2
N
MeO
MeO
SCH Cl
2
N
N
O
N
N
N
O
Tidozosin
1
23

Med Chem Res
Scheme 1 Synthesis of oxadiazole 1–25
(
rutin) is the choice because it is potent natural product.
compounds. Out of twenty-five compounds, 19 compounds
are new.
Compounds 1 (IC50 = 160.2 ± 0.50 lM), 6 (IC50
=
1
65.23 ± 0.33 lM),
5
(IC50 = 185.41 ± 0.43 lM),
4
(IC50 = 232.22 ± 0.78 lM), 2(IC50 = 236.29 ± 0.67
lM), 3 (IC50 = 280.24 ± 0.88 lM) and 8 (IC50 = 290.17
1.05 lM) showed excellent antiglycation potential,
much better to the standard rutin (IC50 = 295.09 ±
.04 lM). Compounds 12 (IC50 = 331.56 ± 1.32 lM)
and 7 (IC50 = 390.32 ± 1.10 lM) showed moderate to
good antiglycation activity. However, compound 9 (IC50
06.07 ± 1.55 lM), 23 (IC50 = 475.89 ± 1.89 lM), 11
IC50 = 480.49 ± 2.23 lM), 10 (IC50 = 495.26 ± 2.04
lM) and 14 (IC50 = 668.25 ± 3.74 lM) are the weakly
active among the series. Moreover, remaining compounds
showed less than 50 % inhibition and were therefore not
evaluated for IC50 values (Table 2).
Materials and methods
Experimental
±
1
General experimental
=
4
NMR experiments were performed on UltraShield Bruker
FT NMR 500 MHz. IR experiments were performed on
Perkin Elmer FT-IR and UV, Perkin Elmer Lambda 35
UV–Vis Spectrometer. CHN analysis was performed on a
Carlo Erba Strumentazion-Mod-1106, Italy. Ultraviolet
Electron impact mass spectra (EI MS) were recorded on a
Finnigan MAT-311A, Germany. Thin layer chromatogra-
phy (TLC) was performed on pre-coated silica gel alu-
minum plates (Kieselgel 60, 254, E. Merck, Germany).
Chromatograms were visualized by UV at 254 and 365 nm.
(
Compound 1, having a trihydroxyl group on the phenyl
residue, is the most active analog of the series. Activity
related to this compound may be due to the acetal forma-
tion by the reaction of hydroxy groups of this compound
and the carbonyl group of methylglyoxal.
Compound 6 is the second most active compound
among the series. It is a dihydroxylated analog. The minor
differences in activity are due to the difference in number
of the hydroxyl groups on the phenyl ring. Compounds 2,
Assay protocol
Bovine serum albumin (BSA) was purchased from Merck
Marker Pvt. Ltd. (Germany), rutin and methylglyoxal (MG)
(40 % aqueous solution) were purchased from Sigma-
Aldrich (Japan), sodium dihydrogen phosphate (NaH PO ),
3
, 4 and 5 are the dihydroxylated analogs showing potent
activities. There is a slight activity among these com-
pounds. The activity difference among these compounds
might be due to the position difference of hydroxyl group
on the phenyl ring. The decline in activity is observed in
compounds having single hydroxyl group. Finally, it
becomes obvious from the experimental data that all
compounds having hydroxyl group showed anti-glycation
potential.
2
4
disodium hydrogen phosphate (Na HPO ) and sodium azide
4
2
(NaN ) were purchased from Scharlau Chemie, S. A.
3
(Spain), while dimethyl sulphoxide (DMSO) was purchased
from Fischer Scientific (UK). Bovine serum albumin
(10 mg/mL), methyl glyoxal (14 mM), various concentra-
tions of the compounds (prepared in DMSO, 10 % final
concentration) and 0.1 M phosphate buffer (pH 7.4) con-
taining sodium azide (30 mM) were incubated under aseptic
conditions at 37 °C for 9 days. After 9 days, each sample
was examined for the development of specific fluorescence
Conclusion
(excitation, 330 nm; emission, 440 nm) against sample
We synthesized 1–25 oxadiazole derivatives and evaluated
antiglycation potential. Out of twenty-five compounds,
only seven compounds 1–6 and 8 showed better activity
than standard drug which can further be studied for lead
blank. Rutin was used as a positive control. The percent
inhibition of AGE formation in the test sample versus control
was calculated for each inhibitor compound by using the
following formula: % inhibition = (1 - fluorescence of test
123

Med Chem Res
Table 1 Synthesis of 2-(2-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole 1–25 and their % yields
Comp. No.
R
Yield (%)
28
Comp. No.
R
Yield (%)
45
1
14
HO
OH
I
OH
OH
O
O
2
3
4
5
6
7
34
37
36
34
42
44
15
16
17
18
19
20
60
67
68
54
52
57
OH
OH
O
OH
O
O
OH
OH
OH
HO
HO
O
N
N
OH
OH
OH
N
1
23

Med Chem Res
Table 1 continued
Comp. No.
R
Yield (%)
45
Comp. No.
R
Yield (%)
70
8
21
S
OH
9
47
50
59
54
52
22
23
24
25
51
48
60
65
–
OH
OH
O
O
1
1
1
1
0
1
2
3
O
NO2
OH
O
Br
F
OH
Br
O
F
–
OH
sample/Fluorescence of the control group) 9 100 (Khan
et al., 2013a; Taha et al., 2014a; Khan et al., 2013c, 2011b).
temperature. The solvent was evaporated and the residue
was washed with diethyl ether, filtered, dried and then
crystallized from ethanol to afford desired compounds 1–
25.
Synthesis 2-(2-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole
(
1–25)
2
-(5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)benzene-1,3,5-
1
triol (1) Yield: 0.084 g (28 %); H NMR (500 MHz,
A mixture of 2-methoxybenzohydrazide and benzaldehyde
derivatives (1 mmol) each and equivalent amount of
DMSO-d ): d 9.15 (s, 2H, -OH), 8.60 (s, 1H, -OH) 7.62
6
(dd, 1H, J = 8.5, 2.2 Hz, H-4), 7.50–7.46 (m, 1H, H-2),
PhI(OAc) was stirred in dichloromethane (10 ml) at room
2
123

Med Chem Res
Table 2 Evaluation of antiglycation potential of 2-(2-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole derivatives 1–25
a
a
a
Comp.
IC50 (lM ± SEM )
Comp.
IC50 (lM ± SEM )
Comp.
IC50 (lM ± SEM )
1
2
3
4
5
6
7
8
9
a
160.2 ± 0.50
236.29 ± 0.67
280.24 ± 0.88
232.22 ± 0.78
185.41 ± 0.43
165.23 ± 0.33
390.32 ± 1.10
290.17 ± 1.05
406.07 ± 1.55
10
11
12
13
14
15
16
17
18
495.26 ± 2.04
480.49 ± 2.23
331.56 ± 1.32
N.A.
19
N.A.
20
N.A.
21
N.A.
22
N.A.
668.25 ± 3.74
N.A.
23
475.89 ± 1.89
N.A.
24
N.A.
25
N.A.
N.A.
Standard drug rutin
295.09 ± 1.04 lM
N.A.
SEM is the standard error of the mean; rutin is the standard drug
7
6
.18 (d, 1H, J = 8.0 Hz, H-1), 7.02–6.96 (m, 1H, H-3),
0
2-(5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)benzene-1,4-
1
diol (4) Yield: 0.102 g (36 %); H NMR (500 MHz,
0
.67 (s, 2H, H-2 , H-4 ), 3.88 (s, 3H, -OCH ); C-NMR:
3
0
0
(
75 MeOD-d ): 164.4 (C, 3 ), 162.1 (C, 1 ), 160.4 (C, 2),
4
DMSO-d ): d 10.41 (s, 1H, -OH), 9.01 (s, 1H, -OH) 7.65
6
0
0
00
00
1
1
1
60.0 (C, 4 ), 158.4 (C, 2 ), 158.3 (CH, 6 ), 129.2 (CH, 4),
(dd, 1H, J = 7.5, 2.0 Hz, H-4), 7.50–7.46 (m, 1H, H-2),
28.2 (CH, 6), 122.2 (CH, 1), 121.5 (CH, 4), 116.5 (CH, 3),
00
7.15 (d, 1H, J = 8.0 Hz, H-1), 7.08–7.02 (m, 1H, H3), 6.90
0
0
0
00
0
0
03.4 (C, 1 ), 98.4 (CH, 3 ), 98.4 (CH, 5 ), 56.2 (OCH ),
3
(d, 1H, J = 2.0 Hz, H-1 ), 6.74–6.70 (m, 2H, H-3 , H-4 ),
3.88 (s, 3H, -OCH ); C-NMR: (75 MeOD-d ): d 164.4 (C,
Anal. Calcd for C H N O , C = 60.00, H = 4.03,
5
1
5
12
2
3
4
0 0 00 00
N = 9.33, Found C = 60.02, H = 4.04, N = 9.34; EI MS
m/z (% rel. abund.): 300.
3 ), 162.1 (C, 1 ), 160.4 (C, 2), 150.2 (C, 3 ), 148.5 (C, 6 ),
0
0
129.6 (CH, 4), 128.2 (CH, 6), 125.2 (C, 1 ), 122.5 (C, 1),
00 00
1
2
21.2 (CH, 5), 117.4 (CH, 5 ), 117.3 (CH, 4 ), 115.4 (CH,
0
3
-(5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)benzene-1,2-
0
), 114.2 (CH, 3), 56.2 (OCH ), Anal. Calcd for
1
diol (2) Yield: 0.097 g (34 %); H NMR (500 MHz,
3
C H N O , C = 63.38, H = 4.25, N = 9.85, Found
15 12 2 4
DMSO-d ): d 11.42 (s, 1H, -OH), 8.23 (s, 1H, -OH), 7.96
6
C = 62.37, H = 4.27, N = 9.84; EI MS m/z (% rel.
(
dd, 1H, J = 8.5, 2.0 Hz, H-4), 7.61–7.54 (m, 1H, H-2),
abund.): 284.
7
6
3
3
2
5
.26 (d, 1H, J = 8.5 Hz, H-1), 7.14–7.09 (m, 1H, H-3),
0
0
0
.94–6.89 (m, 2H, H-2 , H-3 ), 6.82–6.75 (m, 1H, H-1 ),
5-(5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)benzene-1,3-
1
Yield: 0.098 g (34 %), H NMR (500 MHz,
.87 (s, 3H, -OCH ); C-NMR: (75 MeOD-d ): d 164.4 (C,
diol (5)
DMSO-d ): d 9.60 (s, 2H, -OH) 7.94 (dd, 1H, J = 8.0,
J = 2.0 Hz, H-1), 7.55–7.51 (m, 1H, H-2), 7.23 (d, 1H,
3
4
0
0
0
0
00
), 162.1 (C, 1 ), 160.4 (C, 2), 145.2 (C, 3 ), 143.4 (C,
00
0
6
0
),129.3 (CH, 4), 128.1 (CH, 6), 125.2 (C, 1 ), 123.1 (CH,
00
), 122.2 (CH, 1), 121.3 (CH, 6 ), 121.5 (CH, 5), 117.2
0
J = 8.0 Hz, H-1), 7.14–7.09 (m, 1H, H-3), 6.75 (d, 2H,
0
0
0
0
(
CH, 3 ), 114.7 (CH, 3), 56.2 (OCH ), Anal. Calcd for
3
J = 2.0 Hz, H-1 , H-5 ), 6.30–6.26 (m, 1H, H-3 ), 4.03 (s,
0
C H N O , C = 63.38, H = 4.25, N = 9.85, Found
4
3H, -OCH ); C-NMR: (75 MeOD-d ): d 164.4 (C, 3 ),
1
5
12
2
3
4
0
00
00
C = 63.41, H = 4.27, N = 9.87; EI MS m/z (% rel.
162.1 (C, 1 ), 160.1 (C, 2), 159.5 (C, 5 ), 159.3 (C, 3 ),
00
abund.): 284.
139.2 (C, 1 ), 129.6 (CH, 4), 128.2 (CH, 6), 122.2 (C, 1),
00
21.4 (CH, 5), 114.5 (CH, 3), 106.5 (CH, 6 ), 106.4 (CH,
1
2
4
-(5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)benzene-1,2-
0
0
00
), 102.5 (CH, 4 ), 56.1 (OCH ), Anal. Calcd for
3
1
diol (3) Yield: 0.105 g (37 %), H NMR (500 MHz,
C H N O , C = 63.38, H = 4.25, N = 9.85, Found
15 12 2 4
DMSO-d ): d 11.24 (s, 2H, -OH), 7.61 (dd, 1H, J = 7.5,
6
C = 62.39, H = 4.24, N = 9.87; EI MS m/z (% rel.
2
.0 Hz, H-4), 7.55–7.49 (m, 1H, H-4, H-2), 7.42 (d, 1H,
0
abund.): 284.
0
J = 2.0 Hz, H-5 ), 7.25 (d, 1H, J = 8.0 Hz, H-2 ),
7
1
.13–7.08 (m, 1H, H-1), 7.05–6.99 (m, 1H, H-3), 6.80 (d,
0
4-(5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)benzene-1,3-
1
diol (6) Yield: 0.119 g (42 %); H NMR (500 MHz,
H, J = 7.5 Hz, H-1 ), 3.87 (s, 3H, -OCH ); C-NMR: (75
3
0
0
MeOD-d ): d 164.4 (C, 3 ), 162.1 (C, 1 ), 160.4 (C, 2),
DMSO-d ): d 10.41 (s, 1H), 9.02 (s, 1H), 7.64 (dd, 1H,
4
6
0
0
00
00
1
1
1
45.1 (C, 3 ), 144.4 (C, 4 ), 130.2 (C, 1 ), 129.5 (CH, 4),
J = 7.0, 2.0 Hz, H-4), 7.50–7.47 (m, 1H, H-4, H-2), 7.29
0
00
28.3 (CH, 6), 122.2 (C, 1), 121.5 (CH, 6 ), 121.4 (CH, 5),
0
(d, 1H, J = 8.0 Hz, H-4 ), 7.20 (d, 1H, J = 8.0 Hz, H-1),
0
00
17.5 (CH, 5 ), 115.4 (CH, 2 ), 114.7 (CH, 3), 56.2
7.08–7.04 (m, 1H, H-3), 6.35 (dd, 1H, J = 8.0,
0
0
(
OCH3), Anal. Calcd for C H N O , C = 63.38,
15 12 2 4
J = 2.0 Hz, H-2 ), 6.29 (d, 1H, J = 2.0 Hz, H-1 ), 3.88 (s,
0
H = 4.25, N = 9.85, Found C = 62.39, H = 4.27,
N = 9.86; EI MS m/z (% rel. abund.): 284.
3H, -OCH ); C-NMR: (75 MeOD-d ): 164.4 (C, 3 ), 162.1
3
4
0
00
00
(C, 1 ), 160.4 (C, 2), 158.5 (C, 4 ), 157.4 (C, 2 ), 129.5
1
23

Med Chem Res
0
0
0
0
(
CH, 4), 129.4 (CH, 6 ), 128.1 (CH, 6), 122.5 (C, 1), 121.5
00
3.89 (s, 3H, -OCH ), 3.79 (s, 3H, -OCH ); C-NMR: (75
3 3
0 00 0
00 00
(
CH, 5), 116.2 (C, 1 ), 114.5 (CH, 3), 108.5 (CH, 5 ),
0
MeOD-d ): d 164.4 (C, 3 ), 163.5 (C, 4 ), 162.1 (C, 1 ),
4
0
1
03.3 (CH, 3 ), 56.1 (OCH ), Anal. Calcd for C H N O ,
3 15 12 2 4
160.5 (C, 2), 156.4 (C, 2 ), 129.5 (CH, 4), 129.4 (CH, 6 ),
00
128.1 (CH, 6), 122.5 (C, 1), 121.5 (CH, 5), 116.2 (C, 1 ),
C = 63.38, H = 4.25, N = 9.85, Found C = 62.36,
H = 4.26, N = 9.86; EI MS m/z (% rel. abund.): 284.
0
0
00
114.5 (CH, 3), 107.5 (CH, 5 ), 101.3 (CH, 3 ), 56.1
OCH3), Anal. Calcd for C H N O , C = 64.42,
(
16
14 2 4
3
-(5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)phenol (7) Yield:
1
H = 4.73, N = 9.39, Found C = 64.44, H = 4.72,
N = 9.38,; EI MS m/z (% rel. abund.): 298.
0.118 g (44 %), H NMR (500 MHz, DMSO-d ): d 8.22 (s,
1
6
H, -OH), 7.60 (dd, 1H, J = 8.0, 2.0 Hz, H-4), 7.51–7.49
(
m, 1H, H-2), 7.27–7.23 (m, 1H, H-3), 7.17–7.11 (m, 4H,
0
4-Methoxy-2-(5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl)phe-
1
nol (11) Yield: 0.176 (59 %), H NMR (500 MHz,
0
0
H-1, H-2 , H-3 , H-5 ), 6.80 (dd, 1H, J = 7.0, 2.0 Hz,
0
H-1 ), 4.03 (s, 3H, -OCH ); C-NMR: (75 MeOD-d ): d
DMSO-d ): d 8.48 (s, 1H, -OH), 7.92 (dd, 1H, J = 8.0,
3
4
6
0
0
00
1
1
6
1
64.4 (C, 3 ), 162.1 (C, 1 ), 160.4 (C, 2), 157.3 (C, 3 ),
0
J = 2.0 Hz, H-4), 7.58–7.56 (m, 1H, H-2), 7.20 (d, 1H,
0
30.5 (CH, 5 ), 129.5 (CH, 4), 128.3 (CH, 6), 119.4 (CH,
J = 8.5 Hz, H-1), 7.11–7.09 (m, 1H, H-3), 7.08 (d, 1H,
0
0
0
0
0
00
0
), 122.4 (C, 1), 121.5 (CH, 5), 115.5 (CH, 4 ), 114.6 (C,
00
J = 2.0 Hz, H-4 ), 6.91 (dd, 1H, J = 8.0, 2.0 Hz, H-3 ),
0
), 114.4 (CH, 2 ), 114.5 (CH, 3), 56.1 (OCH ), Anal.
3
6.84 (d, 1H, J = 8.0 Hz, H-5 ), 3.90 (s, 3H, -OCH ), 3.84
3
0
Calcd for C H N O , C = 67.16, H = 4.51, N = 10.44,
3
(s, 3H, -OCH ); C-NMR: (75 MeOD-d ): d 164.4 (C, 3 ),
1
5
12
2
3
4
0 00 00
Found C = 67.15, H = 4.52, N = 10.43; EI MS m/z (%
162.2 (C, 1 ), 160.6 (C, 2), 155.5 (C, 5 ), 148.4 (C, 6 ),
00
148.4 (C, 2 ), 129.6 (CH, 4), 128.1 (CH, 6), 122.4 (C, 1),
rel. abund.): 268.
0
0
0
0
1
4
24.2 (C, 1 ), 121.5 (CH, 5), 117.3 (CH, 3 ), 115.5 (CH,
0
4
-(5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)phenol (8) Yield:
1
0
), 114.5 (CH, 3), 56.1 (OCH ), Anal. Calcd for
3
0
.121 g (45 %); H NMR (500 MHz, DMSO-d ): d 9.93 (s,
6
C H N O , C = 64.42, H = 4.73, N = 9.39, Found
16 14 2 4
1
H, -OH), 7.60 (dd, 1H, J = 7.0, J = 2.0 Hz, H-4), 7.50
0
C = 64.43, H = 4.71, N = 9.36; EI MS m/z (% rel.
0
(
d, 2H, J = 8.5 Hz, H-2 , H-4 ), 7.46 (ddd, 1H, J = 7.0,
abund.): 298.
6
1
3
3
1
1
.0, 2.0 Hz, H-2), 7.14 (d, 1H, J = 8.0 Hz, H-1), 7.03 (t,
0
0
H, J = 5.0 Hz, H-3), 6.81 (d, 2H J = 8.5 Hz, H-1 , H-5 ),
.87 (s, 3H, -OCH ); C-NMR: (75 MeOD-d ): d 164.4 (C,
2-Methoxy-5-(5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl)phenol
1
(12) Yield: 0.161 g (54 %), H NMR (500 MHz, DMSO-
3
4
0
0
00
00
), 162.1 (C, 1 ), 160.6 (C, 2), 157.5 (C, 4 ), 116.3 (C, 3 ),
d ): d 9.33 (s, 1H), 7.60 (dd, 1H, J = 7.0, 2.0 Hz, H-4),
7.53–7.51 (m, 1H, H-2), 7.24 (d, 1H, J = 2.0 Hz, H-5 ),
6
00
0
29.5 (CH, 4), 128.3 (CH, 6), 128.5 (CH, 6 ), 129.6 (C,
0
0
00
), 128.4 (CH, 2 ), 122.2 (C, 1), 121.5 (CH, 5), 116.3
0
7.15 (d, 1H, J = 8.0 Hz, H–H-1), 7.06–7.04 (m, 2H, H-3,
0
0
0
(
CH, 5 ), 114.5 (CH, 3), 56.1 (OCH ), Anal. Calcd for
3
H-2 ), 6.96 (d, 1H, J = 8.0 Hz, H-1 ), 3.89 (s, 3H,
-OCH ), 3.85 (s, 3H, OCH ); C-NMR: (75 MeOD-d ): d
C H N O , C = 67.16, H = 4.51, N = 10.44, Found
1
5
12
2
3
3
3
4
0
0
0
0
C = 67.14, H = 4.50, N = 10.45; EI MS m/z (% rel.
164.4 (C, 3 ), 162.2 (C, 1 ), 160.6 (C, 2), 116.5 (CH, 5 ),
00 00
120.4 (CH, 6 ), 115.4 (CH, 2 ), 129.6 (CH, 4), 128.1 (CH,
abund.): 268.
0
0
0
0
6
1
), 122.4 (C, 1), 130.1 (C, 1 ), 121.4 (CH, 5), 143.3 (C, 3 ),
0
2
-(5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)phenol (9) Yield:
1
0
49.5 (C, 4 ), 114.5 (CH, 3), 56.1 (OCH ), Anal. Calcd for
3
0
.126 g (47 %); H NMR (500 MHz, DMSO-d ): d 11.27
6
C H N O , C = 64.42, H = 4.73, N = 9.39, Found
16 14 2 4
(
s, 1H, -OH), 7.60 (dd, 1H, J = 7.0, 2.0 Hz, H-4),
C = 64.40, H = 4.72, N = 9.37; EI MS m/z (% rel.
0
0
7
7
6
.52–7.50 (m, 2H, H-2, H-4 ), 7.42–7.40 (m, 1H, H-3 ),
abund.): 298.
.16 (d, 1H, J = 8.0 Hz, H-1), 7.04–7.02 (m, 1H, H-3),
0
0
.90–6.88 (m, 2H, H-1 , H-2 ), 3.88 (s, 3H, -OCH );
3
2
-Bromo-4-(5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)phenol
0
0
C-NMR: (75 MeOD-d ): d 164.4 (C, 3 ), 162.1 (C, 1 ),
1
1
13) Yield: 0.180 g (52 %); H NMR (500 MHz, DMSO-
4
(
00 00
60.4 (C, 2), 155.4 (CH, 2 ), 121.5 (CH, 5 ), 129.4 (CH,
00
0
d ): d 11.39 (s, 1H, -OH), 7.80 (d, 1H, J = 2.0 Hz, H-5 ),
6
0
0
4
), 6 ), 129.5 (CH, 4 ), 128.6 (CH, 6), 128.5 (CH, 123.6
00
7
.61 (dd, 1H, J = 7.0, 2.0 Hz, H-4), 7.52 (dd, 1H, J = 8.0,
0
0
0
(
C, 1 ), 122.6 (C, 1), 121.5 (CH, 5), 116.3 (CH, 3 ), 114.5
CH, 3), 56.2 (OCH ), Anal. Calcd for C H N O ,
J = 2.0 Hz, H-1 ), 7.50–7.48 (m, 1H, H-2), 7.14 (d, 1H,
(
3
15 12 2 3
J = 8.0 Hz, H-1), 7.04–7.01 (m, 1H, H-3), 6.98 (d, 1H,
0
C = 67.16, H = 4.51, N = 10.44, Found C = 67.17,
H = 4.52, N = 10.46; EI MS m/z (% rel. abund.): 268.
J = 8.0 Hz, H-2 ), 3.88 (s, 3H, -OCH ); C-NMR: (75
3
0
0
00
MeOD-d ): d 164.4 (C, 3 ), 162.2 (C, 1 ), 160.5 (C, 4 ),
4
00 00
5
-Methoxy-2-(5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl)phenol
160.4 (C, 2), 131.4 (CH, 2 ), 131.1 (C, 1 ), 129.6 (CH, 4),
1
10) Yield: 0.148 g (50 %); H NMR (500 MHz, DMSO-
00 00
128.1 (CH, 6),118.5 (CH, 5 ), 127.5 (CH, 6 ), 122.4 (C, 1),
(
0
0
d6): d 11.57 (s, 1H, -OH) 7.60 (dd, 1H, J = 8.0,
J = 2.0 Hz, H-4), 7.51–7.49 (m, 1H, H-2), 7.37 (d, 1H,
121.5 (CH, 5), 114.5 (CH, 3), 110.3 (C, 3 ), 56.1 (OCH
),
3
Anal. Calcd for C15H11BrN O , C = 51.90, H = 3.19,
2 3
0
J = 8.0 Hz, H-1 ), 7.16 (d, 1H, J = 8.0 Hz, H-1),
0 0
N = 8.07, Found C = 51.92, H = 3.18, N = 8.09; EI MS
m/z (% rel. abund.): (M ? 2) 348, 346.
7
.05–7.03 (m, 1H, H-3), 6.51–6.48 (m, 2H, H-2 , H-4 ),
123

Med Chem Res
0
d ): d 8.60–8.58 (m, 1H, H-4 ), 7.96 (d, 1H, J = 8.5 Hz,
H-3 ), 7.88–7.86 (m, 1H, H-2 ), 7.62 (dd, 1H, J = 8.5,
2
2
-Iodo-6-methoxy-3-(5-(2-methoxyphenyl)-1,3,4-oxadiazol-
1
-yl)phenol (14) Yield: 0.191 g (45 %), H NMR
6
0
0
(
500 MHz, DMSO-d ): d 11.65 (s, 1H, -OH), 7.51 (dd,
2.0 Hz, H-4), 7.50–7.47 (m, 1H, H-2), 7.30–7.28 (m, 1H,
0
6
0
1
H, J = 7.0, 2.0 Hz, H-4), 7.50–7.48 (m, 1H, H-2), 7.43
0
H-1 ), 7.16 (d, 1H, J = 8.0 Hz, H-1 ), 7.08–7.06 (m, 1H,
H-3), 3.89 (s, 3H, -OCH ); C-NMR: (75 MeOD-d ): d 164.4
(
d, 1H, J = 8.0 Hz, H-2 ), 7.13 (d, 1H, J = 8.0 Hz, H-1),
0
3
4
0
0
0
0
7
.04 (d, 1H, J = 8.0 Hz, H-1 ), 7.05–7.02 (m, 1H, H-3),
.89 (s, 3H, -OCH ), 3.87 (s, 3H, -OCH ); C-NMR: (75
(C, 3 ), 162.1 (C, 1 ), 160.5 (C, 2), 157.5 (C, 1 ), 150.3 (CH,
0
0
00
00
3
3 ), 136.3 (CH, 5 ), 129.4 (CH, 4), 128.3 (CH, 6), 122.5 (CH,
00
3
3
0
0
MeOD-d ): d 164.5 (C, 3 ), 162.1 (C, 1 ), 160.5 (C, 2),
6 ), 122.4 (C, 1), 121.4 (CH, 5), 120.6 (CH, 4 ), 114.4 (CH,
4
0
0
00
00
1
1
1
5
52.3 (C, 3 ), 150.5 (C, 4 ), 139.5 (C, 1 ), 129.4 (CH, 4),
3), 56.6 (OCH ), Anal. Calcd for C H N O , C = 66.40,
3 14 11 3 2
00
28.3 (CH, 6), 122.5 (CH, 6 ), 122.6 (C, 1), 121.5 (CH, 5),
0
H = 4.38, N = 16.59, Found C = 66.42, H = 4.39,
N = 16.60; EI MS m/z (% rel. abund.): 253.
0
00
14.5 (CH, 5 ), 114.4 (CH, 3), 84.2 (C, 2 ), 56.6 (OCH ),
3
6.4 (OCH ), Anal. Calcd for C H IN O , C = 45.30,
2 4
3
16 13
2
-(2-Methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole (19) M.p.
1
H = 3.09, N = 6.60, Found C = 45.31, H = 3.08,
N = 6.62; EI MS m/z (% rel. abund.): 424.
2
60 °C. H NMR (500 MHz, DMSO-d ): d 8.60 (d, 1H,
6
0
J = 6.0 Hz, H-5 ), 7.97 (d, 1H, J = 8.0 Hz, H-3),
0
2
-(3,4-Dimethoxyphenyl)-5-(2-methoxyphenyl)-1,3,4-oxadi-
7.93–7.91 (m, 1H, H-2 ), 7.61 (dd, 1H, J = 7.5, 2.0 Hz,
0
1
azole (15) Yield: 0.187 g (60 %), H NMR (500 MHz,
H-4), 7.56–7.54 (m, 1H, H-2), 7.47–7.44 (m, 1H, H-1 ),
0
DMSO-d ): d 7.92 (dd, 1H, J = 7.0, J = 2.0 Hz, H-1 ),
7.19 (d, 1H, J = 8.0 Hz, H-1), 7.11–7.09 (m, 1H, H-3),
6
7
.74 (d, 1H, J = 2.0 Hz, H-4), 7.55–7.53 (m, 1H, H-2),
0
3.88 (s, 3H, -OCH ); [20].
3
7
.20–7.18 (m, 2H, H-1, H-5 ), 7.11–7.08 (m, 1H, H-3), 6.98
0
2
-(2-Methoxyphenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazole (20) M.p.
1
(
d, 1H, J = 8.5 Hz, H-2 ), 3.92 (s, 3H, -OCH ), 3.90 (s,
3
280 °C. H NMR (500 MHz, DMSO-d ): d 8.60 (d, 2H,
6
3
H, -OCH ), 3.89 (s, 3H, -OCH ); C-NMR: (75 MeOD-
3 3
0
0
0
J = 5.5 Hz, H-2 , H-4 ), 7.62 (d, 2H, J = 6.0 Hz, H-1 ,
0
0
0
d ): d 164.4 (C, 3 ), 162.1 (C,1 ), 160.5 (C, 2), 148.3 (C,
4
H-5 ), 7.60 (dd, 1H, J = 7.5, 1.5 Hz, H-4), 7.54–7.52 (m,
0
0
00 00
3
6
5
), 147.5 (C, 4 ), 129.5 (C, 1 ), 129.3 (CH, 4), 128.1 (CH,
1H, H-2), 7.19 (d, 1H, J = 8.0, H-1), 7.11–7.08 (m, 1H,
0
0
), 120.5 (CH, 6 ), 122.6 (C, 1), 121.4 (CH, 5), 115.5 (CH,
0
H-3), 3.88 (s, 3H, -OCH ); [20].
3
0
00
), 114.4 (CH, 3), 113.4 (C, 2 ), 56.6 (OCH ), 56.6
3
(
OCH ), 56.3 (OCH ) Anal. Calcd for C H N O ,
3
2-(2-Methoxyphenyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole
1
(21) Yield: 0.183 g (70 %); H NMR (500 MHz, DMSO-
3
17 16 2 4
C = 65.38, H = 5.16, N = 8.97, Found C = 65.39,
H = 5.15, N = 8.99; EI MS m/z (% rel. abund.): 312.
0
d ): d 7.64 (d, 1H, J = 5.5 Hz, H-3 ), 7.56 (dd, 1H,
6
J = 7.0, 2.0 Hz, H-4), 7.50–7.48 (m, 1H, H-2), 7.41–7.38
0
2
-(3,5-Dimethoxyphenyl)-5-(2-methoxyphenyl)-1,3,4-oxa-
(d, 1H, J = 3.0 Hz, H-2 ), 7.14 (d, 1H, J = 8.0, H-1),
1
diazole (16) Yield: 0.210 g (67 %), H NMR (500 MHz,
0
7
3
1
1
1
.14–7.16 (m, 1H, H-1 ), 7.05–7.02 (m, 1H, H-3), 3.89 (s,
0
DMSO-d ): d 7.60 (dd, 1H, J = 7.0, 2.0 Hz, H-4),
6
H, -OCH ); C-NMR: (75 MeOD-d ): d 164.4 (C, 3 ),
3
4
7
.51–7.49 (m, 1H, H-2), 7.16 (d, 1H, J = 8.0 Hz, H-1),
0
00
62.1 (C, 1 ), 160.4 (C, 2), 142.5 (C, 1 ), 129.4 (CH, 4),
0
7
.02 (t, 1H, J = 7.0 Hz, H-3), 6.87 (d, 2H, J = 2.0 Hz,
0
0
00
28.3 (CH, 6), 127.6 (CH, 4 ), 125.4 (CH, 3 ), 122.4 (C,
00
0
H-1 , H-5 ), 6.56–6.53 (m, 1H), 3.89 (s, 3H, -OCH ), 3.84
3
), 122.3 (CH, 5 ), 121.4 (CH, 5), 114.4 (CH, 3), 56.6
0
(
s, 6H, OCH ); C-NMR: (75 MeOD-d ): d 164.4 (C, 3 ),
3
4
(OCH ), Anal. Calcd for C H N O S, C = 60.45,
3 13 10 2 2
00 00 0
1
1
1
2
63.3 (C, 3 ), 163.3 (C, 5 ), 162.1 (C, 1 ), 160.5 (C, 2),
H = 3.90, N = 10.85, Found C = 60.46, H = 3.92,
N = 10.84; EI MS m/z (% rel. abund.): 258.
0
0
38.5 (C, 1 ), 129.3 (CH, 4), 128.1 (CH, 6), 122.6 (C, 1),
00
21.4 (CH, 5), 114.4 (CH, 3), 104.5 (CH, 6 ), 104.5 (CH,
0
0
00
), 99.5 (CH, 4 ), 56.6 (OCH ), 56.6 (OCH ), 56.4
3
3
Methyl 4-(5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl)ben-
zoate (22) M.p. 290 °C. 1H NMR (500 MHz, DMSO-
(
OCH3) Anal. Calcd for C H N O , C = 65.38,
17 16 2 4
H = 5.16, N = 8.97, Found C = 65.37, H = 5.17,
N = 8.96; EI MS m/z (% rel. abund.): 312.
0
0
d ): d 8.10 (d, 2H, J = 8.0 Hz, H-2 , H-4 ), 7.97 (d, 2H,
6
0
0
J = 8.0 Hz, H-1 , H-5 ), 7.92 (dd, 1H, J = 7.5, 2.0 Hz,
H-4), 7.57 (ddd, 1H, J = 7.5, 6.5, 2.0 Hz, H-2), 7.24 (d,
1H, J = 8.5 Hz, H-1), 7.09 (t, 1H, J = 8.5, H-3), 3.89 (s,
2
-(2-Methoxyphenyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole
1
(
17) M.p. 262 °C. H NMR (500 MHz, DMSO-d ): d
6
7
.94 (dd, 1H, J = 7.5, 2.0 Hz, H-4), 7.81 (dd, 2H,
0
3H, -OCH
-(2-Methoxyphenyl)-5-(4-nitrophenyl)-1,3,4-oxadiazole
23) M.p. 285 °C. 1H NMR (500 MHz, DMSO-d ): d
3 3
), 3.86 (s, 3H, -COOCH ); [20].
0
J = 8.5 Hz, H-1 , H-5 ), 7.60–7.58 (m, 1H, H-2), 7.21 (dd,
2
1
2
3
H, J = 8.5 Hz, H-1), 7.16–7.14 (m, 1H, H-3), 7.02 (dd,
0
(
0
6
H, J = 8.5 Hz, H-2 , H-4 ), 4.03 (s, 3H, OCH ), 3.87 (s,
3
0 0
8
.30 (d, 2H, J = 8.5 Hz, H-2 , H-4 ), 7.92 (d, 2H,
H, OCH ); [20].
3
0
0
J = 8.5 Hz, H-1 , H-5 ), 7.62 (dd, 1H, J = 7.5, 1.5 Hz,
H-4), 7.54 (m, 1H, H-2), 7.19 (d, 1H, J = 8.5 Hz, H-1),
2
-(2-Methoxyphenyl)-5-(pyridin-2-yl)-1,3,4-oxadiazole
1
18) Yield: 0.137 g (54 %); H NMR (500 MHz, DMSO-
(
7.09 (m, 1H, H-3), 3.88 (s, 3H, -OCH ); [20].
3
1
23

Med Chem Res
2
-(3-Bromo-4-fluorophenyl)-5-(2-methoxyphenyl)-1,3,4-oxadia-
Gugliucci AJ (2000) Glycation as the glucose link to diabetic
complications. Am Osteopath Assoc 100:621–634
Hadady Z, Toth M, Somsak L (2004) C-(b-D-Glucopyranosyl)
heterocycles as potential glycogen phosphorylase inhibitors.
Arkivoc 7:140–149
zole (24) Yield: 0.208 g (60 %); 1H NMR (500 MHz,
0
DMSO-d ): d 8.20 (d, 1H, J = 2.0 Hz, H-5 ), 7.90 (dd, 1H,
6
0
0
J = 8.0, 2.0 Hz, H-1 ), 7.82–7.79 (m, 1H, H-2 ), 7.54–7.51
(
m, 1H, H-4), 7.29–7.26 (m, 1H, H-2), 7.22 (d, 1H,
Harfenist M, Heuser DJ, Joyner CT, Batchelor JF, White HL (1996)
Selective inhibitors of monoamine oxidase. 3. Structure-activity
relationship of tricyclics bearing imidazoline, oxadiazole, or
tetrazole groups. J Med Chem 39:1857–1863
Hunt JV, Bottoms MA, Mitchinson MJ (1993) Oxidative alterations
in the experimental glycation model of diabetes mellitus are due
to protein-glucose adduct oxidation. Some fundamental differ-
ences in proposed mechanisms of glucose oxidation and oxidant
production. Biochem J 291:529–535
J = 8.0 Hz, H-1), 7.17–7.15 (m, 1H, H-3), 3.90 (s, 3H,
0
-
OCH ); C-NMR: (75 MeOD-d ): d 164.4 (C, 3 ), 162.1
3
4
0
00
00
(
C,1 ), 160.5 (C, 2), 165.5 (C, 4 ), 134.5 (C, 1 ), 131.4 (C,
0
0
00
2
), 129.4 (CH, 4), 128.2 (CH, 6), 127.5 (CH, 6 ), 122.6
00
(
(
C, 1), 121.4 (CH, 5), 115.5 (CH, 5 ), 114.4 (CH, 3), 110.3
0
0
C, 3 ), 56.6 (OCH ), Anal. Calcd for C H BrFN O ,
3
15 10
2 2
C = 51.60, H = 2.89, N = 8.02, Found C = 51.61,
H = 2.90, N = 51.61; EI MS m/z (% rel. abund.): 350
Imran S, Taha M, Ismail NH, Khan KM, Naz F, Hussain M, Tauseef S
(2014) Synthesis of novel bisindolylmethane Schiff bases and
their antibacterial activity. Molecules 19:11722–11740
Imran S, Taha M, Ismail NH, Kashif SM, Rahim F, Jamil W, Wahab
H, Khan KM (2015a) Synthesis, in-vitro, and docking studies of
new flavone ethers as a-glucosidase inhibitors. Chem Biol Drug
Des. doi:10.1111/cbdd.12666
Imran S, Taha M, Ismail NH, Kashif SM, Rahim F, Jamil W, Hariono
M, Yusuf M, Wahab H (2015b) Synthesis of novel flavone
hydrazones: in-vitro evaluation of a-glucosidase inhibition,
QSAR analysis and docking studies. Eur J Med Chem 105:
?
?
M ? 2, 30), 348 (M , 28).
(
2
-(4-Fluorophenyl)-5-(2-methoxyphenyl)-1,3,4-oxadiazole
(
25) M.p. 265 °C. 1H NMR (500 MHz, DMSO-d ): d
6
0
0
7
.82–7.79 (m, 2H, H-2 , H-4 ), 7.64 (dd, 1H, J = 7.5,
0
1
.5 Hz, H-4), 7.56–7.53 (m, 1H, H-2), 7.32 (m, 2H, H-1 ,
0
H-5 ), 7.18 (d, 1H, J = 7.5 Hz, H-1), 7.10–7.08 (m, 1H,
H-3), 3.88 (s, 3H, -OCH ) [20].
3
1
56–170
Jakubkiene V, Burbuliene MM, Udrenaite E, Garaliene V, Vainilavi-
cius P (2002) (6-methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-
pyrimidinyl)acetic acid and related compounds exhibiting anti-
inflammatory activity. Pharmazie 57:610–613
Jamil W, Solangi S, Ali M, Khan KM, Taha M, Khuhawar MY (2015)
Syntheses, characterization, in vitro antiglycation and DPPH
radical scavenging activities of isatin salicylhydrazidehydrazone
and its Mn (II), Co (II), Ni (II), Cu (II), and Zn (II) metal
complexes. Arab J Chem. doi:10.1016/j.arabjc.2015.02.015
Khan MTH, Choudhary MI, Khan KM, Rani M (2005) Structure-
activity relationships of tyrosinase inhibitory combinatorial
library of 2,5-disubstituted-1,3,4-oxadiazole analogues. Bioorg
Med Chem 13:3385–3395
Khan KM, Khan M, Ali M, Taha M, Rasheed S, Perveen S,
Choudhary MI (2009) Synthesis of bis-Schiff bases of isatins and
their antiglycation activity. Bioorg Med Chem 17:7795–7801
Khan KM, Shah Z, Ahmad VU, Khan M, Taha M, Rahim F, Jahun H,
Perveen S, Choudhary MI (2011a) Synthesis of 2,4,6-trichlor-
ophenyl hydrazones and their inhibitory potential against
glycation of protein. Med Chem 7:572–580
Khan KM, Khan M, Ali M, Taha M, Hameed A, Ali S, Perveen S,
Choudhary MI (2011b) Synthesis and DPPH radical scavenging
activity of 5-arylidene-N,N-dimethylbarbiturates. Med Chem
7:231–236
Acknowledgments Authors would like to acknowledge Research
Management Institute of UiTM for the financial support under Dana
Kecemerlangan Grant Scheme [Grant No. 600-RMI/DANA 5/3 RIF
(
143/2012)].
References
Ahmed N (2005) Advanced glycation endproducts—role in pathology
of diabetic complications. Diabetes Res Clin Pract 67:3–21
Ahmed MS, Ahmed N (2006) Antiglycation properties of aged garlic
extract: possible role in prevention of diabetic complications.
J Nutr 136:796S–799S
Ahsan MJ, Samy JG, Khalilullah H, Nomani MS, Saraswat P, Gaur R,
Singh A (2011) Molecular properties prediction and synthesis of
novel 1,3,4-oxadiazole analogues as potent antimicrobial and
antitubercular agents. Bioorg Med Chem Lett 21:7246–7250
Aziz-Ur-Rehman SSZ, Abbasi MA, Abbas N, Khan KM, Shahid M,
Mahmood Y, Akhtar NM, Lajis NH (2012) Synthesis, antibac-
terial screening and hemolytic activity of S-substituted deriva-
tives of 5-benzyl-1,3,4-oxadiazole-2-thiol. Int J Pharm Pharm
Sci 4:676–680
Baral N, Koner BC, Karki P, Ramprasad C, Lamsal M, Koirala S
(2000) Evaluation of new WHO diagnostic criteria for diabetes
Khan KM, Rahim F, Ambreen N, Taha M, Khan M, Jahan H,
Najeebullah Shaikh A, Iqbal S, Perveen S, Choudhary MI
(2013a) Synthesis of benzophenonehydrazone Schiff bases and
their in vitro antiglycating activities. Med Chem 9:588–595
Khan KM, Taha M, Rahim F, Fakhri MI, Jamil W, Khan M, Rasheed
S, Karim A, Perveen S, Choudhary MI (2013b) Acylhydrazide
Schiff bases: synthesis and antiglycation activity. J Pak Chem
Soc 35:930–938
on the prevalence of abnormal glucose tolerance in a heteroge-
neous Nepali population—the implications of measuring gly-
cated hemoglobin. Singapore Med J 41:264–267
Biju CR, Ilango K, Prathap M, Rekha K (2012) Design and
microwave-assisted synthesis of 1,3,4-oxadiazole derivatives
for analgesic and anti-inflammatory activity. J Young Pharm
4
:33–37
Khan KM, Khan M, Ambreen N, Taha M, Rahim F, Rasheed S, Saied
S, Shafi H, Perveen S, Choudhary MI (2013c) Oxindole
derivatives: synthesis and antiglycation activity. Med Chem
9:681–688
Khan KM, Siddiqui S, Saleem M, Taha M, Saad SM, Perveen S,
Choudhary MI (2014) Synthesis of triazole Schiff bases: novel
inhibitors of nucleotide pyrophosphatase/phosphodiesterase-1.
Bioorg Med Chem 22:6509–6514
Desai NC, Bhatt N, Somani H, Trivedi A (2013) Synthesis,
antimicrobial and cytotoxic activities of some novel thiazole
clubbed 1,3,4-oxadiazoles. Eur J Med Chem 67:54–59
Gudipati R, Anreddy RNR, Manda S (2011) Synthesis, characteriza-
tion and anticancer activity of certain 3-{4-(5-mercapto-1,3,4-
oxadiazole-2-yl)phenylimino}indolin-2-one derivatives. Saudi
Pharm J 19:153–158
123

Med Chem Res
Khan KM, Irfan M, Ashraf M, Taha M, Saad SM, Perveen S,
Choudhary MI (2015) Synthesis of phenyl thiazole hydrazones
and their activity against glycation of proteins. Med Chem Res
Taha M, Ismail NH, Imran S, Khan KM (2014b) 4-[5-(2-Meth-
oxyphenyl)-1,3,4-oxadiazol-2-yl] benzohydrazide. Molbank
M826
2
4:3077–3085
Taha M, Ismail NH, Imran S, Rokei MQB, Saad SM, Khan KM
(2015a) Synthesis of new oxadiazole derivatives as a-glucosi-
dase inhibitors. Bioorg Med Chem 23:4155–4162
Taha M, Alkadi KA, Ismail NH, Imran S, Adam A, Kashif SM, Shah
SAA, Jamil W, Sidiqqui S, Khan KM (2015b) Antiglycation and
antioxidant potential of novel imidazo [4,5-b] pyridine benzo-
hydrazones. Arab J Chem. doi:10.1016/j.arabjc.2015.08.004
Vasan S, Foiles P, Founds H (2003) Therapeutic potential of breakers
of advanced glycation end product-protein crosslinks. Arch
Biochem Biophys 419:89–96
Wang Y, Sauer DR, Djuric SW (2006) A simple and efficient one step
synthesis of 1,3,4-oxadiazoles utilizing polymer-supported
reagents and microwave heating. Tetrahedron Lett 47:105–108
Wu CH, Yen GC (2005) Inhibitory effect of naturally occurring
flavonoids on the formation of advanced glycation endproducts.
J Agric Food Chem 53:3167–3173
Yi-Ming J, Wang CC, Xue LS, Li TY, Zhang S, Liu X, Liang X,
Zheng YX, Zuo JL (2014) Efficient organic light-emitting diodes
with low efficiency roll-off using iridium emitter with 2-(5-
phenyl-1,3,4-oxadiazol-2-yl) phenol as ancillary ligand.
J Organomet Chem 765:39–45
Liu F, Luo XQ, Song BA, Bhadury PS, Yang S, Jin LH, Xue W, Hu
DY (2008) Synthesis and antifungal activity of novel sulfoxide
derivatives containing trimethoxyphenyl substituted 1,3,4-thia-
diazole and 1,3,4-oxadiazole moiety. Bioorg Med Chem
1
6:3632–3640
Musmade DS, Pattan SR, Manjunath SY (2015) Oxadiazole a nucleus
with versatile biological behavior. Int J Pharm Chem. doi:10.
7
439/ijpc
Rahim F, Samreen M, Taha M, Saad SM, Perveen S, Alam MT, Khan
KM, Choudhary MI (2015) Antileishmanial activities of ben-
zothiazole derivatives. J Chem Soc Pak 37:157–161
Rashid M, Husain A, Mishra R (2012) Synthesis of benzimidazoles
bearing oxadiazole nucleus as anticancer agents. Eur J Med
Chem 54:855–866
Rojas A, Morales MA (2004) Advanced glycation and endothelial
functions: a link towards vascular complications in diabetes. Life
Sci 76:715–730
Roy RU, Desai ARR, Desai KR (2005) Synthesis and antimicrobial
activity of 1,2,4-triazoles. J Chem 2:1–5
Singh R, Barden A, Mori T, Beilin L (2001) Advanced glycation end-
products: a review. Diabetologia 44:129–146
Zawawi NKNA, Taha M, Ahmat N, Ismail NH, Wadood A, Rahim F,
Rehman AU (2015) Synthesis, in vitro evaluation and molecular
docking studies of biscoumarin thiourea as a new inhibitor of a-
glucosidases. Bioorg Chem 63:36–44
Taha M, Naz H, Rasheed S, Ismail NH, Rahman AA, Yousuf S,
Choudhary MI (2014a) Synthesis of 4-methoxybenzoylhydra-
zones and evaluation of their antiglycation activity. Molecules
1
9:1286–1301
1
23