Synthesis of novel inhibitors of α-glucosidase based on the benzothiazole skeleton containing benzohydrazide moiety and their molecular docking studies

Article abstract of DOI:10.1016/j.ejmech.2015.01.009

In an effort to design and synthesize a new class of α-glucosidase inhibitor, we synthesized benzothiazole hybrid having benzohydrazide moiety (5). Compound 5 was reacted with various substituted aryl aldehyde to generate a small library of compounds 6-35

Full text of DOI:10.1016/j.ejmech.2015.01.009

European Journal of Medicinal Chemistry 92 (2015) 387e400
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of novel inhibitors of a-glucosidase based on the
benzothiazole skeleton containing benzohydrazide moiety and their
molecular docking studies
a
,
b
,
*
, Nor Hadiani Ismail a , Salima Lalani , Muhammad Qaiser Fatmi ,
,
b
c
d
Muhammad Taha
c
c
c
a, b
Atia-tul-Wahab , Salman Siddiqui , Khalid Mohammed Khan , Syahrul Imran
Muhammad Iqbal Choudhary
Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor,
Malaysia
Faculty of Applied Science UiTM, 40450 Shah Alam, Selangor, Malaysia
,
c
a
b
c
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
Department of Biosciences, COMSATS Institute of Information Technology (CIIT), Park Road, Chak Shahzad, Islamabad 45600, Pakistan
d
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 May 2014
Received in revised form
In an effort to design and synthesize a new class of a-glucosidase inhibitor, we synthesized benzothiazole
hybrid having benzohydrazide moiety (5). Compound 5 was reacted with various substituted aryl
aldehyde to generate a small library of compounds 6e35. Synthesis of compounds was confirmed by the
28 November 2014
spectral information. These compounds were screened for their
varying degree of -glucosidase inhibition with IC50 values ranging between 5.31 and 53.34
pounds 6, 7, 9e16, 19, 21e30, 32e35 showed superior activity as compared to standard acarbose
M). This has identified a new class of -glucosidase inhibitors. The predicted physico-
a
-glucosidase activity. They showed a
Accepted 6 January 2015
Available online 9 January 2015
a
m
M. Com-
(
IC50 ¼ 906 ± 6.3
m
a
Keywords:
Benzothiazole derivatives
chemical properties indicated the drug appropriateness for most of these compounds, as they obey
Lipinski's rule of five (RO5). A hybrid B3LYP density functional theory (DFT) was employed for energy,
minimization of 3D structures for all synthetic compounds using 6-311 þ G(d,p) basis sets followed by
a-Glucosidase
DFT calculations
Docking studies
molecular docking to explore their interactions with human intestinal C- and N-terminal domains of a-
Physico-chemical properties
glucosidase. All compounds bind to the prospective allosteric site of the C- terminal domain, and
consequently, may be considered as mixed inhibitors. It was hypothesized that both the dipole moment
and H-bond interactions govern the biological activation of these compounds.
©
2015 Elsevier Masson SAS. All rights reserved.
1
. Introduction
aminophenyl) are found to be the most valuable anticancer
agents for both in vivo and in vitro systems [12e15]. Recently,
fluorinated 2-arylbenzothiazole derivatives have been reported to
show selective and potent inhibitory activity against colon, lung
and breast cancer cells [16]. The study suggests that some amino-
benzothiazole derivatives possess the mutagenic potency
depending on either metabolic activation [17] or by inducing DNA
damage [18]. Benzohydrazides are reported to possess a wide va-
riety of biological activities like antiglycation [19e22], antioxidant
Benzothiazole derivatives have been reported as precursors for
pharmacological agents. Their biological activities reported as
neuroprotective agents [1,2], b-glucuronidase [3], p56 lck enzyme
inhibitor [4], antibacterial [5] and anti-allergic agents [6]. The
phenylbenzothiazole derivatives are reported as powerful anti-
tumor agents and chosen for clinical evaluation [7e11]. Several
derivatives of benzothiazole especially quinol and 2-(4-
[23e25], antileishmanial [26], antibacterial [27], antifungal [28],
antitumor [29] and anticonvulsant [30]. Benzothiazole Schiff bases
have also been reported with various biological activities [31].
*
Corresponding author. Atta-ur-Rahman Institute for Natural Product Discovery,
Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak
Alam, Selangor, Malaysia.
E-mail addresses: taha_hej@yahoo.com, muhamm9000@puncakalam.uitm.edu.
my (M. Taha).
a
-Glucosidase (EC 3.2.1.20, maltase) is a glucosidase that acts
upon 1,4- bonds [32,33] in contrast to -glucosidase. -Glucosi-
dase breaks down starch and disaccharides to glucose.
a
b
a
a-
http://dx.doi.org/10.1016/j.ejmech.2015.01.009
0223-5234/© 2015 Elsevier Masson SAS. All rights reserved.

388
M. Taha et al. / European Journal of Medicinal Chemistry 92 (2015) 387e400
Glucosidase hydrolyzes terminal, non-reducing 1-4 linked
glucose residues to release a single -glucose molecule [34]. Two
proposed mechanisms for hydrolysis include nucleophilic
displacement and an oxocarbenium ion intermediate [35]. Rhodnius
prolixus, a bloodsucking insect, uses -glucosidase to convert he-
moglobin to hemozoin. It is proposed that -glucosidase in the
a
-
3. In vitro a-glucosidase activity
a
a
In an ongoing project which is aimed to develop new enzyme
inhibitors [44], we screened a large number of benzothiazole
compounds, including its ester 4 and hydroxide 5 derivatives, both
a
a
exhibited potent a-glucosidase inhibitory activity. On the basis of
glucosidic path plays an important role in liver's metabolic
response to the energy demands of exercise [36]. Alglucosidase alfa,
luteolin and acarbose are drugs which are currently used to inhibit
that we decided to synthesize hydrazones of benzothiazole ben-
zohydrazide 5. Synthetic compounds 6e35 showed a varying de-
gree of
5.31 and 53.34
Compounds 6, 7, 9e16, 19, 21-30, and 32e35 showed superior
M).
a-glucosidase inhibition with IC50 values ranging between
a
-glucosidase activity [37e40]. In the quest to find better drugs for
mM (Table 2).
diabetes, we have previously reported benzothiazole as -glucu-
b
ronidase [3] and benzohydrazide as antiglycation agent [19e22]. In
the current work, we have subjected these synthesized molecules
activity as compared to the standard acarbose (IC50 ¼ 906 ± 6.3
m
The compounds 8, 17, 18, 20, and 31 showed less than 50% in-
hibition therefore, they were not further evaluated for their IC50
values (Table 2).
for the
a-glucosidase inhibition activity by keeping in mind the
biological importance of benzothiazole as well as benzohydrazide.
To understand the mechanism of
binding mode of these novel derivatives of benzothiazole inside the
binding pocket of -glucosidase and to confirm the experimental
results, molecular docking studies were performed.
a-glucosidase inhibition and
2
. Results and discussion
a
2.1. Chemistry
The synthesis of benzothiazole hybrid having benzohydrazide
3
.1. Molecular docking
moiety (5) was established with the conversion of aldehyde (1) to
its sulfite adduct (2) on treatment with sodium metabisulfite as
reported [41]. The resulting sulfite adduct (2) was refluxed with o-
aminothiophenol (3) in DMF for 6 h to afford arylester substituted
benzothiazole (4). The benzothiazole hybrid (5) was afforded by
refluxing compound (4) with hydrazine hydrate in methanol for
The substrate-protein association is a key step in protein func-
tion. An intrusion in the substrate-protein binding process or pre-
vention of the complex formation can lead to the attenuate protein
activity or impaired protein function. The mechanism of inhibition
depends on several factors, including the types of inhibitor as well
as the nature of the protein. In general, the allosteric inhibitors
function through mixed or non-competitive binding. The molecular
docking study can provide a significant insight into ligand-protein
binding strengths as well as ligand binding mode and mecha-
nism. The current docking studies of compounds 6e35 clearly
indicate that these new scaffolds bind well with the prospective
1
2 h (Scheme 1).
The synthesis of benzothiazole benzohydrazide Schiff bases
6e35) were carried out by treating compound (5) with different
aldehydes in the presence of catalytic amount of acetic acid (Table 1
Scheme 2). The compounds 18, 19, 21, 23 and 32 were reported
previously by El-Hamouly and co-workers [42].
(
allosteric site of the C-terminal domain of
a-glucosidase protein
2
.2. Configuration (Z/E)
(Fig.1) with higher affinity than that of the substrate and, therefore,
may be classified as mixed inhibitors. Several theoretical as well as
experimental studies have also confirmed the existence of allosteric
The stereochemical configuration of the double bond (eN]CH-
R) in benzothiazole 6e35 (Scheme 2) may be assigned as Z or E. We
have reported that the E/Z isomer can be distinguished on the basis
sites in a-glucosidase and in other related enzymes such as a-
amylase. Brindis et al. [45] reported (Z)-3-butilidenephthalide as an
allosteric non-competitive inhibitor, which showed significant
anti-hyperglycemic effect by inhibiting the activity of intestinal and
of IR [43]. Comparison between the peak of
in all compounds (6e35), IR spectra showed that only compounds 7
and 14 CH (CH in eN]CH-R) are close to 3000 which is for Z
nCH (CH in eN]CH-R)
n
yeast
demonstrated that N-acetylcysteine (NAC), a known pharmaceu-
tical drug, is a novel allosteric chaperone for lysosomal -glucosi-
a-glucosidases both in vivo and in vitro. Porto et al. [46]
isomer. Therefore, compounds 6, 8e13 and 15e35 are E isomers
while compounds 7 and 14 are Z isomers. The stability of the Z
configuration in 7 and 18 with respect to E is due to the formation of
hydrogen bonding with the nitrogen (7) and oxygen (14) respec-
tively, with the substituted amide (eCONHe) group.
a
dase. They proposed that NAC and it's derivatives bind reversibly to
allosteric sites, remote from the catalytic site and act by perturbing
conformational dynamics of a-glucosidase leading to a destabilized
2 5 2
Scheme 1. Synthesis of Novel Benzothiazole compound having benzohydrazide moiety 5 Scheme 1: a) NaS O , MeOH:H O 80%, b) DMF, Reflux 6 h, c) Hydrazine hydrate, methanol,
Reflux 12 h.

M. Taha et al. / European Journal of Medicinal Chemistry 92 (2015) 387e400
389
Table 1
Synthesis of benzothiazole benzoylhydrazones derivatives 6e35.
Comp. No.
R
Yield (%)
88
Comp. No.
R
Yield (%)
6
21
86
1
"
1"
6
"
OH
6"
2"
3"
5
"
3
"
H CO
3
4"
F
7
8
9
85
82
84
22
23
24
89
87
83
1
"
1"
6
"
6
"
2"
N
5
5
"
3"
H CO
OCH3
3
4"
4"
1
"
1"
6
"
2"
6
"
"
2
"
5
"
3
"
N
4
"
4
"
1
"
1"
6
"
2"
6"
5"
2"
5
"
3
"
Br
OH
F
10
85
25
85
1
"
1
"
S
6"
2"
5
"
2
"
5
"
3"
3
"
4
"
OCH3
1
1
1
2
82
86
26
27
84
85
1
"
1"
6
"
"
OH
HO
OH
5
"
5"
3
"
OH
4
"
OH
1
"
1 "
6
OH
6 "
2 "
5"
5 "
3"
B r
OCH3
O H
1"
1
1
3
4
83
87
28
29
86
1
"
6
"
OH
6"
2"
3"
5
"
5"
3
"
4
"
Cl
88
1
"
1
"
O
6"
2"
5
"
2
"
5"
3
"
4
"
OCH3
4"
(
continued on next page)

390
M. Taha et al. / European Journal of Medicinal Chemistry 92 (2015) 387e400
Table 1 (continued )
Comp. No.
R
Yield (%)
80
Comp. No.
R
Yield (%)
84
15
16
17
30
1
"
1"
6
"
"
2"
6"
5"
2"
5"
OH
OH
4"
OH
82
85
31
32
82
85
1
"
1"
6
OH
6"
5"
2"
3"
5"
3"
N
OH
1
"
1"
6
"
2"
6"
5"
2"
5
"
3
"
OCH3
OH
O
H CO
3
1
1
2
8
9
0
88
81
84
33
34
35
86
84
85
1
"
1"
6
"
2"
6"
I
5
"
5"
OCH3
OCH3
OH
3
OCH
1
"
1"
6
"
"
2"
6"
OH
5
"
3
"
3"
HO
HO
4"
NO2
1
"
1"
6
2"
6"
2"
5
"
OH
OCH3
4" OH
Scheme 2. Synthesis of novel benzothiazole Shiff bases was achieved by treated compound 5 with various aryl-aldehydes to get final products 6e35.
non-functional state of the protein. Liu et al. [47] proposed the
similar mode of action for xanthone inhibitors (1,3,7-
tridroxyxanthone and 1,3-dihydroxybenzoxanthone) against yeast
favorable for these compounds bind with (Table 3). A kinetic study
is, however, required to validate this hypothesis.
Although no specific coherence has been observed between IC50
and binding energy values of these compounds (Fig. 2), they show
a
-glucosidase. Oben patented a composition contains flavonoids
and/or indanes to inhibit lipase, -amylase and -glucosidase ac-
tivity in mammals [48]. They proposed that quercitrin and quer-
a
a
strong binding affinities with the C-terminal domain of a-glucosi-
dase protein as compared to that of acarbose (Table 3). The
important binding site residues which are involved in H-bond in-
teractions with the ‘variable moieties’ of the compounds 6e35
include: Lys1460, Asn1429, Arg1455, Ser1426, and Phe1427; where
the latter two interact through backbone atoms. The other inter-
acting residues notable for the ‘common moieties’ are: Arg1510 and
Asp1157 which form H-bonds; Trp1369, Phe1560, Tyr1251,
Phe1559, His1584, Trp1523, Trp1418, Trp1355 and Phe1427 which
are involved in aromaticearomatic interactions; Pro1159 and
0
0
citrin-3-O acetate display
a-glucosidase inhibitory activity by
binding to allosteric sites of the enzyme. Likewise, Liu et al. [49]
observed that 'diboside A' binds to two allosteric binding sites of
a
-amylase (starch hydrolase) using in silico studies.
In our study, the possible reason for these synthetic compounds
to be allosteric inhibitors is due to their smaller polar surface area
2
2
(
(
PSA) ranging from 54 Å to 115 Å as compared to acarbose
2
321 Å ). This makes the orthosteric site about a-glucosidase less

M. Taha et al. / European Journal of Medicinal Chemistry 92 (2015) 387e400
391
Table 2
In vitro
contour fields of protein residues, calculated by solving the non-
linear Poisson-Boltzmann equation, are also given in Fig. 3(e)
showing the complementarity between protein and ligand 28. All
compounds, including the top three active compounds (IC50 values
a-glucosidase activities of benzothiazole benzoylhydrazones derivatives
6
e35.
Comp. No.
IC50
(
m
M ± SEMa)
Comp. No.
IC50 (m
M ± SEMa)
6
7
8
9
6.50 ± 0.07
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
7.12 ± 0.39
16.17 ± 0.29
8.05 ± 0.13
28.02 ± 1.8
18.33 ± 0.9
8.37 ± 0.29
8.07 ± 0.13
5.31 ± 0.03
11.09 ± 0.14
9.21 ± 0.13
(5.5
m
M) in the series, i.e. 13, 16 and 28 bind relatively stronger with
10.23 ± 1.014
the C-terminal domain of
domain. The acarbose, however, exhibits fairly similar but consid-
erably lower affinity for both domains (especially for C-terminal),
which corroborates with its high IC50 value i.e. 906 mM.
We hypothesized that compounds with higher dipole moment
and/or with weakly contributed H-bonds tend to be less active.
Compounds 17, 20 and 31 are examples of experimental non-active
compounds possessing relatively high dipole moments (ꢀ6.2
Debye). Other examples of non-active compounds include 8 and 18,
which exhibit moderate dipole moment (3.6 and 4.1 Debye,
respectively) but showed either no H-bond interaction at all or
weak interaction with the protein residues (H-bond distances are
a-glucosidase than to the N-terminal
b
N.A
11.29 ± 0.45
8.48 ± 0.25
11.22 ± 0.35
6.97 ± 0.52
5.55 ± 0.09
12.75 ± 0.46
15.09 ± 0.50
5.58 ± 0.6
10
11
12
13
14
15
16
17
18
19
20
b
N.A
b
N.A
N.A
53.34 ± 1.21
44.8 ± 0.73
11.85 ± 0.81
11.12 ± 0.2
b
26.38 ± 3.4
b
N.A
Acarbose
906 ± 6.3
3.6 and 4.35 Å, respectively). It is noteworthy that these are not the
a
SEM is the standard error of the mean.
N.A ¼ not active, acarbose is the standard.
only parameters that determine the activity of a compound;
therefore, exceptions to these observations cannot be overruled.
Compounds with halogen substituent's at ortho- or para-positions
such as 21, 24, 28, and 33 displayed higher dipole moments (ꢀ5
Debye). Nonetheless, they are still biologically active even though
the variable moieties do not contribute in H-bond interactions
b
Met1421 which contribute through hydrophobic interactions; as
well as Asp1420, Asp1279 and Asp1526 which develop a rare but
interesting anionearomatic interactions (Fig. 3). The electrostatic
Fig. 1. (a) Docked conformations of compounds 6e35 in the allosteric site of C-terminal of
a-glucosidase forming a cluster (b) The binding site has been zoomed out; and the protein
residues forming H-bonds with the ligands have been labeled in yellow. It can be clearly observed that the common moiety of all ligands significantly overlaps with other. (c)
Illustration for allosteric and orthosteric binding sites embed in the C-terminal of -glucosidase. Compound 28, a representative docked conformation, has been highlighted as
a
green. The acarbose bound to the orthosteric site is shown in red licorice. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version
of this article.)

392
M. Taha et al. / European Journal of Medicinal Chemistry 92 (2015) 387e400
Table 3
Summarizing the electronic properties of compounds 6e35 as well as their experimental IC50 values and docking results with C- and N-terminal of
moments have been calculated at B3LYP level using 6-311 þ G (d,p) basis sets. The H-bond and halogen-bond distances have been measured between heavy atoms.
a-glucosidase. Dipole
Compound no. Dipole Moment Polar surface Binding energy (kcal/mol) Hydrogen/Halogen bond interactions of Variable groups of ligands with protein
2
(
Debye)
area (Å )
C-terminal
N-terminal
(3L4T.pdb)
Interacting residues
of protein
Interacting groups
of ligands
Distance between
heavy atoms (Å)
(3TOP.pdb)
6
5.01
83.81
ꢁ9.6
ꢁ7.3
Lys1460
Asn1429
Lys1460
No Bond
Arg1455
Asn1429
Lys1460
Lys1460
Lys1460
Asn1429
Ser1426
Phe1427
Lys1460
Arg1455
Asn1429
Phe1427
Lys1460
Asn1429
Arg1455
Arg1455
Asn1429
Asn1429
Arg1455
Arg1455
Asn1429
Arg1455
Asn1429
Asn1429
Phe1427
Asn1429
Arg1455
Asn1429
No Bond
Asn1429
Arg1455
Asn1429
Arg1455
Lys1460
Phe1427
Ser1426
Arg1455
Asn1429
Arg1455
Asn1429
Asn1429
Arg1455
Asn1429
Asn1429
Asn1429
Arg1455
Asn1429
Lys1460
Asn1429
Arg1455
Lys1460
Asn1429
Phe1427
Asn1429
Phe1427
OH
OCH3
N
3.01
3.39
3.25
7
8
9
2.17
3.62
2.74
67.24
67.24
74.58
ꢁ9.4
ꢁ9.4
ꢁ9.7
ꢁ7.9
ꢁ8.1
ꢁ7.7
a
OH
OH
S
o-OH
OH
OCH3
OH
OH
O
PeO
m-O
m-O
o-OH
p-OH
p-OH
O
4.28
3.36/3.99
3.68
3.09
3.01
3.25
3.93
3.65
3.2
4.29
3.05/3.62/3.45
3.14
3.02
3.22/3.87
4.19
3.13
3.05
3.6
4.35
3.21
3.01
4.36
3.3
2.99/3.65
3.16
3.54
4.35
3.68
1
1
1
0
1
2
4.56
4.37
5.15
54.35
94.81
83.81
ꢁ9
ꢁ7.9
ꢁ8.5
ꢁ7.3
ꢁ9.97
ꢁ9.7
1
3
4.67
74.58
ꢁ9.3
ꢁ9.1
ꢁ8.8
1
1
4
5
4.77
5.11
67.49
94.81
ꢁ8
ꢁ10
ꢁ7.7
1
6
4.82
94.81
ꢁ9.7
ꢁ7.6
1
1
1
2
7a
8a
9
6.20
4.14
8.95
6.34
80.65
72.81
97.49
83.81
ꢁ9.8
ꢁ9.3
ꢁ7.4
ꢁ7.2
ꢁ7.3
ꢁ7.3
O
p-OCH3
p-OCH3
O
ꢁ10
O
0a
ꢁ9.9
OCH3
OCH3
OH
OH
F
2
1
5.05
54.35
ꢁ9.8
ꢁ7.7
F
2
2
2
2
3
4
4.90
4.10
5.05
72.81
54.35
54.35
ꢁ9.5
ꢁ9.7
ꢁ9.9
ꢁ7.4
ꢁ8.3
ꢁ7.9
m-OCH3
F
F
3.67
4.34
3.35
4.39
3.19
3.25
4.01
3.96
3.95/4.72
4.29
3.72/4.37
3.58
4.03
3.7
3.61/3.16
4.47
4.26
3.41/4.04
3.92
4.17
2
5
6
2.67
6.10
63.58
ꢁ9.6
ꢁ9.1
ꢁ7.3
ꢁ7.5
OCH3
OCH3
o-OH
o-OH
o-OH
p-OH
p-OH
OH
OH
Cl
Cl
OCH3
OH
N
OH
OH
I
OCH3
OCH3
o-OH
m-OH
m-OH
m-OH
m-OH
2
115.04
2
7
8
2.31
5.19
74.58
54.35
ꢁ9.6
ꢁ9.8
ꢁ9.8
ꢁ7.9
ꢁ7.3
2
2
3
3
3
9
0
1
2
3.52
4.30
6.23
4.36
63.58
74.58
67.24
83.81
ꢁ7.4
ꢁ8.6
ꢁ7.7
ꢁ7.6
ꢁ10
a
ꢁ9.4
ꢁ9.4
3
3
3
7.39
4.32
5.64
83.81
94.81
94.81
ꢁ9.6
ꢁ9.9
ꢁ9.8
ꢁ7.5
ꢁ8.9
ꢁ8.4
3.13
3.07
3.69/3.25
3.11
3.12/3.64
3.15
4
5
3
a
Indicates non-active compounds.
(
except compound (33) which shows weak H-bond interactions).
This clearly highlights the crucial role of halogen bonds (range from
.54 to 4.35 Å) in the binding of the ligands. On the other hand,
this context where, despite carrying higher dipole moments (ꢀ5
Debye), these compounds are active possibly due to the strong
binding contributed by H-bonds (H-bond lengths vary from 3.01 to
3.39 Å; the distances have been measured between heavy atoms).
The calculated physico-chemical properties (Fig. 4) indicate that
most of these compounds are more likely to be membrane
permeable and can be easily absorbed by the body. The number of
3
compound 27, which is a meta-substituted halogenated compound
with low dipole moment and exhibits weak H-bond interaction; it
is an active compound as well which further supports our hy-
pothesis. Compounds 6, 12, 15, 19, and 35 are few more examples in

M. Taha et al. / European Journal of Medicinal Chemistry 92 (2015) 387e400
393
4.2. Synthesis of sulfite adducts (2)
4-Formylbenzoic acid methyl ester (1) (8.2 g, 50 mmol) and
sodium metabisulfite (4.75 g, 25 mmol) were dissolved in 50 mL of
ꢂ
aqueous EtOH (80%) and stirred for 1 h at 0e5 C, then kept in a
fridge for several hours. Precipitate formed was filtered and dried to
give 12.6 g (94%) of sulfite adduct (2) [40].
4.3. Methyl 4-(benzo[d]thiazol-2-yl)benzoate (4)
The mixture of sulfite adduct (2) (10.72 g, 40 mmol) and o-
aminothiophenol (3) (6.25 g, 40 mmol) in DMF (40 mL) was heated
ꢂ
at 130 C for 6 h. Then reaction mixture was poured into ice water
and the solid product was filtered, crystallization of crude product
from ethanol gave methyl 4-(benzo[d]thiazol-2-yl)benzoate (4)
and yielded (9.15 g, 85%). White solid, R
f
¼ 0.57 (ethyl acetate:-
hexane 2:8); M.p. 228 C. H NMR (500 MHz, DMSO-d ): 8.26 (d,
H, J ¼ 8.5 Hz), 8.21 (d, 2H, J ¼ 8.5 Hz), 8.10 (d, 1H, J ¼ 8.0 Hz), 8.08
ꢂ
1
6
d
2
(
d, 1H, J ¼ 8.0 Hz), 7.61 (dt,1H, J ¼ 6.5, J ¼ 1.5 Hz), 7.45 (dt,1H, J ¼ 8.0,
13
J ¼ 1.0 Hz), 3.98 (s, 3H, CH
3 6
); C NMR (DMSO-d ,125 MHz): d 52.88,
1
22.99, 123.71, 126.53, 127.41, 127.41, 127.95, 130.63, 130.63, 132.17,
2
135.25, 137.24, 153.98, 166.09, 166.45; Anal. Calcd for C15H11NO S,
C ¼ 66.89; H ¼ 4.12; N 5.20; found C ¼ 66.87; H ¼ 4.13; N 5.22; EI
MS m/z (% rel. abund.): 269.
4.4. 4-(Benzo[d]thiazol-2-yl)benzohydrazide (5)
Mixture of compound 4 (8.07 g, 30 mmol) and hydrazine hy-
Fig. 2. (a) A comparison of ligands' binding energy between C-terminal (red lines and
green circles) and N-terminal (blue lines and pink circles) -glucosidase. (b) A plot of
IC50 values (orange lines and blue circles). Orange circles represent non-active (NA)
compounds. Compound 36 indicates the properties of acarbose. The value ‘906’ rep-
resents the IC50 of acarbose. (For interpretation of the references to colour in this
figure legend, the reader is referred to the web version of this article.)
drate (10 mL, 95%) in ethanol (50 mL) was refluxed for 12 h. The
solvent and excess of hydrazine hydrate were evaporated and the
residue (5) was washed with water, filtered, dried, and then crys-
a
tallized from ethanol and yielded White solid, R
f
¼ 0.32 (ethyl
acetate:hexane 9:1); (7.35 g, 91%). m.p. 325 C. H NMR (500 MHz,
DMSO-d ):
9.82 (s, 1H, NH), 8.28 (d, 2H, J ¼ 8.5 Hz), 8.25 (d, 2H,
ꢂ
1
6
d
J ¼ 8.0 Hz), 8.11 (d, 1H, J ¼ 8.0 Hz), 8.06 (d, 1H, J ¼ 8.0 Hz), 7.64
H-bond donor and acceptor atoms in all molecules range from 1 to
(
2
1
1
dt,1H, J ¼ 6.5, J ¼ 2.0 Hz), 7.52 (dt,1H, J ¼ 8.0, J ¼ 1.0 Hz), 3.91 (br. s,
4
and 3e6, respectively, which are safely below the threshold
values as set by Lipinski in the rule of 5 (Ro5). However, molecules
7, 19, 21, 23, 24, 27 and 28 possess slightly higher values for log P as
.1, 5.1, 5.3, 5.1, 6.0, 5.6 and 5.7, respectively. Despite being biolog-
13
2 6
H, NH ); C NMR (DMSO-d , 150 MHz): d 122.93, 123.56, 126.33,
27.31, 127.31, 127.62, 128.48, 128.48, 135.13, 135.42, 136.05, 153.99,
65.44, 166.87; Anal. Calcd for C14
OS, C ¼ 62.43; H ¼ 4.12; N
5.60; found C ¼ 62.44; H ¼ 4.13; N 15.62; EI MS m/z (% rel.
abund.):269.
1
5
11 3
H N
1
ically active, compound 33 violates two criteria for Lipinski's rule,
i.e. log P > 5 and molecular weight >500 Da and, therefore, may
exhibit poor oral bioavailability.
4.4.1. Benzothiazole Schiff bases (6e35)
Equimolar quantities (0.269 g, 1 mmol) of benzothiazole ben-
zoylhydrazide (5) and substituted benzaldehydes (6e35) (1 mmol)
in n-butanol (25 mL) were refluxed for 3 h, in the presence of
catalytic amount of glacial acetic acid. The resulting solid was
filtered and recrystallized from n-butanol in good yields.
4
. Experimental
4.1. Assay for -glucosidase inhibitory activity
a
0
1
35
the 96 well plate and 20
added into the wells. 20
m
L of 50 mM phosphate saline buffer pH (6.8) was added in
L of the test sample with 70% DMSO
L of enzyme was added to each well and
4.4.1.1. (E)-N -(2-Hydroxy-5-methoxybenzylidene)-4-(benzo[d]thia-
m
zol-2-yl)benzohydrazide (6). Orange solid, R
te:hexane 7:3); m.p. 270 C. Yield: (0.354 g, 88%); HNMR
f
¼ 0.45 (ethyl aceta-
ꢂ
1
m
the plate was incubated for 15 min. After incubation, pre-read of
the plate was taken by using SpectraMax Microplate reader. Af-
(500 MHz, DMSO-d
(s,1H, CH]N), 8.26 (d, 2H, J
6
): d 11.10 (s, 1H, NH), 10.10 (s, 1H, OH), 8.65
0
0
0
0
0
0
¼ 8.5 Hz, H-2 ,H-6 ), 8.22 (d, 1H,
2
,6
/5
,3
,5
0
0
terward 25
mL of the substrate (pNPG) was added and reading was
J
4,5 ¼ 7.5 Hz, H-4), 8.16 (d, 2H, J
3
0
0
/2
0
,6
0
¼ 8.5 Hz, H-3 ,H-5 ), 8.13 (d,
taken using SpectraMax Microplate reader at 400 nm for 30 min.
The normal reading was taken and the percent inhibition was
calculated [50e52].
1H, J7,6 ¼ 7.0 Hz, H-7), 7.61 (dt, 1H, J5,7 ¼ 2.0, J5(4,6) ¼ 7.0 Hz, H-5),
7.53 (dt, 1H, J6,4 ¼ 2.0, J6(5,7) ¼ 7.0 Hz, H-6), 7.14 (d, 1H, J6ʺ,4ʺ ¼ 3.0 Hz,
0
0
00
H-6 ), 6.92 (dd,1H, J4ʺ,6ʺ ¼ 3.0, J4ʺ,3ʺ ¼ 9.0 Hz, H-4 ), 6.87 (d, 1H,
0
0
13
Chemicals:
J
d
3ʺ,4ʺ ¼ 9.0 Hz, H-3 ), 3.75 (s, 3H, OCH
): 56.04, 112.74, 117.80, 118.88, 119.46, 122.95, 123.63, 126.42,
127.36, 127.77, 127.77, 129.20, 129.20, 135.21, 135.59, 136.14, 148.47,
152.03, 152.60, 154.01, 162.58, 166.71; Anal. Calcd for C22 S,
3
); C NMR (125 MHz, DMSO-
6
d
Substrate: p-Nitrophenyl-
a-
D
-glucopyranoside. Lot
#
(
BCBD7865V) CAS #3767-28-0 SigmaeAldrich
17 3 3
H N O
Enzyme:
a
-Glucosidase from Saccharomyces cerevisiae recom-
C ¼ 65.49, H ¼ 4.25, N ¼ 10.42, Found C ¼ 65.48, H ¼ 4.26,
binant, G0660-750UN CAS9001-42-7 SigmaeAldrich.
N ¼ 10.44; EI MS m/z (% rel. abund.): 403.

394
M. Taha et al. / European Journal of Medicinal Chemistry 92 (2015) 387e400
Fig. 3. Ligand-protein interactions for top three active compounds 13, 16 and 28. (a) Docked conformations involved in variety of aromaticearomatic interactions with protein
aromatic rings (red bipyramid rings) as well as in van der Waal's interactions with Pro1560 (orange bipyramid ring with blue outline). These interactions are common for all
synthetic compounds. Insets (b, c and d) display H-bonds (black dotted lines), halogen bonds (orange dotted lines) as well as anionearomatic interactions (commonly contributed
through Asp1526, Asp1279 and Asp1420 for all synthetic compounds) for compounds 13, 16 and 28, respectively. (e) Electrostatic maps of the prospective allosteric site of the
protein. The maps have been generated using the non-linear Poisson-Boltzmann equation. The red and blue contour plots indicate hydrophilic preferences (positive and negative,
respectively) while the white contour represents hydrophobic preferences. The most active compound 28 shown in CPK is located in the allosteric site. (For interpretation of the
references to colour in this figure legend, the reader is referred to the web version of this article.)
0
00
4
.4.1.2. (Z)-4-(Benzo[d]thiazol-2-yl)-N -((pyridin-2-yl)methylene)
8.22 (d, 1H, J4,5 ¼ 8.0 Hz, H-4), 8.18 (d, 1H, J5ʺ,6ʺ ¼ 4.0 Hz, H-5 ), 8.14
0
0
benzohydrazide (7). Light orange solid, R
hexane 8:2); m.p. 278 C. Yield: (0.304 g, 85%); HNMR (500 MHz,
f
¼ 0.64 (ethyl acetate:-
(d, 2H, J
3
0
,5
0
/2
0
,6
0
¼ 8.0 Hz, H-3 ,H-5 ), 8.12 (d, 1H, J7,6 ¼ 8.0 Hz, H-7),
ꢂ
1
7.62 (t, 1H, J5(4,6) ¼ 7.0 Hz, H-5), 7.54 (t, 1H, J6(5,7) ¼ 7.0 Hz, H-6), 7.48
0
0
13
DMSO-d
6
):
d
12.25 (s,1H, NH), 8.65 (d, 1H, J6ʺ,5ʺ ¼ 6.5 Hz, H-6 ), 8.52
(t, 1H, J4ʺ(3ʺ,5ʺ) ¼ 7.0 Hz, H-4ʺ); C NMR (125 MHz, DMSO-d
6
):
0
0
(
s,1H, CH]N), 8.29 (d, 2H, J
2
0
,6
0
/5
0
,3
,5
0
¼ 8.0 Hz, H-2 ,H-6 ), 8.22 (d, 1H,
d
67.84, 122.97, 123.63, 124.52, 126.43, 127.37, 127.76, 127.76, 129.23,
129.23, 130.76, 132.14, 134.07, 135.20, 136.13, 146.10, 149.27, 154.01,
162.96, 166.74; Calcd for C20
0
0
J
1
4,5 ¼ 8.0 Hz, H-4), 8.15 (d, 2H, J
3
0
0
/2
0
,6
0
¼ 8.0 Hz, H-3 ,H-5 ), 8.13 (d,
H, J7,6 ¼ 8.0 Hz, H-6), 8.03 (d, 1H, J3ʺ,4ʺ ¼ 7.5 Hz, H-3ʺ), 7.93 (t, 1H,
H
14
N
4
OS, C ¼ 67.02, H ¼ 3.94,
J
J
(
1
1
C
5ʺ(6ʺ,4ʺ) ¼ 7.0 Hz, H-5ʺ), 7.62 (t, 1H, J5(4,6) ¼ 7.0 Hz, H-5), 7.54 (t, 1H,
N ¼ 15.63, Found C ¼ 67.01, H ¼ 3.95, N ¼ 15.63; EI MS m/z (% rel.
13
6(5,7) ¼ 7.5 Hz, H-6), 7.46 (t, 1H, J4ʺ(3ʺ,5ʺ) ¼ 7.5 Hz, H-4ʺ); C NMR
125 MHz, DMSO-d ): 120.53, 122.95, 123.63, 124.98, 126.42,
27.36, 127.77, 127.77, 129.27, 129.27, 135.21, 135.78, 136.21, 137.39,
49.00, 150.02, 153.65, 154.01, 163.11, 166.68; Anal. Calcd for
abund.): 358.
6
d
0
4.4.1.4. (E)-N -(4-Hydroxybenzylidene)-4-(benzo[d]thiazol-2-yl)ben-
zohydrazide (9). White solid, R ¼ 0.43 (ethyl acetate:hexane 7:3);
f
ꢂ
1
H
20 14
N
4
OS, C ¼ 67.02, H ¼ 3.94, N ¼ 15.63, Found C ¼ 67.02,
m.p. 298 C. Yield: (0.313 g, 84%); HNMR (500 MHz, DMSO-d ):
6
H ¼ 3.94, N ¼ 15.63; EI MS m/z (% rel. abund.): 358.
d 11.85 (s, 1H, NH), 10.11 (s, 1H, OH), 8.38 (s,1H, CH]N), 8.28 (d, 2H,
0
0
J
2
0
,6
0
/3
0
,5
,5
0
¼ 8.0 Hz, H-2 ,H-6 ), 8.22 (d, 1H, J4,5 ¼ 8.0 Hz, H-4), 8.13 (d,
0
0
0
4
.4.1.3. (E)-4-(Benzo[d]thiazol-2-yl)-N -((pyridin-3-yl)methylene)
2H, J
3
0
0
/2
0
,6
0
¼ 8.0 Hz, H-3 ,H-5 ), 8.11 (d, 1H, J7,6 ¼ 8.0 Hz, H-7),
benzohydrazide (8). White solid, R
8
d
f
¼ 0.54 (ethyl acetate:hexane
7.62e7.58 (m, 3H, H-5, H-2ʺ, H-6ʺ), 7.54 (t, 1H, J6(5,7) ¼ 7.0 Hz, H-6),
ꢂ
1
13
:2); m.p. 272 C. Yield: (0.293 g, 82%); HNMR (500 MHz, DMSO-
6.87 (d, 2H, J3ʺ,5ʺ/2ʺ,6ʺ ¼ 7.5 Hz, H-3ʺ,H-5ʺ); C NMR (125 MHz,
0
0
6
):
d
12.23 (s, 1H, NH), 8.99 (s, 1H, H-2 ), 8.64 (d, 1H, J6ʺ,5ʺ ¼ 4.0 Hz,
6
DMSO-d ): d 116.23, 116.23, 122.93, 123.60, 125.71, 126.37, 127.33,
0
0
H-6ʺ), 8.55 (s,1H, CH]N), 8.28 (d, 2H, J
2
0
,6
0
/5
0
,3
0
¼ 8.0 Hz, H-2 ,H-6 ),
127.69, 127.69, 129.08, 129.08, 129.45, 129.45, 135.18, 135.84, 136.31,

M. Taha et al. / European Journal of Medicinal Chemistry 92 (2015) 387e400
395
Fig. 4. Physico-chemical properties of compounds 6e35 represented as purple circles. The pink circles indicate the properties of acarbose. It is very obvious that the acarbose, a
medically relevant secondary metabolite produced by strains of the genera Actinoplanes and Streptomyces, remarkably violets the Lipinski's rule of five (RO5), Most of the synthetic
compounds, however, obey RO5. Compound 36 (pink circles) indicates the properties of acarbose. (For interpretation of the references to colour in this figure legend, the reader is
referred to the web version of this article.)
1
49.17, 154.02, 160.02, 162.53, 166.76; Anal. Calcd for C21
H
15
N
3
O
2
S,
H ¼ 3.89, N ¼ 10.80; EI MS m/z (% rel. abund.): 389.
C ¼ 67.54, H ¼ 4.05, N ¼ 11.25 Found C ¼ 67.53, H ¼ 4.07, N ¼ 11.24,
EI MS m/z (% rel. abund.): 373.
0
4
.4.1.7. (E)-N -(2-Hydroxy-4-methoxybenzylidene)-4-(benzo[d]thia-
zol-2-yl)benzohydrazide (12). Light yellow solid, R
acetate:hexane 7:3); m.p. 256 C. Yield: (0.347 g, 86%); HNMR
f
¼ 0.51 (ethyl
0
ꢂ
1
4
.4.1.5. (E)-4-(Benzo[d]thiazol-2-yl)-N -((thiophen-2-yl)methylene)
benzohydrazide (10). Orange solid, R
f
¼ 0.71 (ethyl acetate:hexane
(500 MHz, DMSO-d
(s,1H, CH]N), 8.28 (d, 2H, J
4,5 ¼ 8.0 Hz, H-4), 8.14 (d, 2H, J
6
): d 12.18 (s, 1H, NH), 11.61 (s, 1H, OH), 8.60
ꢂ
1
0
0
8
:2); m.p. 254 C. Yield: (0.308 g, 85%); HNMR (500 MHz, DMSO-
2
0
,6
0
/3
0
,5
,5
0
¼ 8.0 Hz, H-2 ,H-6 ), 8.22 (d, 1H,
0
0
d
6
):
d
12.00 (s, 1H, NH), 8.70 (s,1H, CH]N), 8.27 (d, 2H, J
2
0
,6
0
/
J
3
0
0
/2
0
,6 ¼ 8.0 Hz, H-3 ,H-5 ), 8.13 (d,
0
0
0
0
¼ 7.5 Hz, H-2 , H-6 ), 8.22 (d, 1H, J ¼ 7.5 Hz, H-4), 8.14 (d, 2H,
1H, J ¼ 7.0 Hz, H-7), 7.61 (t, 1H, J
¼ 7.5 Hz, H-5), 7.53 (t,
3
,5
4,5
7,6
5(4,6)
0
0
J
3
0
,5
0
/2
0
,6
0
¼ 7.5 Hz, H-3 ,H-5 ), 8.11 (d, 1H, J7,6 ¼ 8.0 Hz, H-7), 7.71 (d,
J
6(5,7) ¼ 7.0 Hz, H-6), 7.48 (d, 1H, J6ʺ,5ʺ ¼ 8.0 Hz, H-6ʺ), 6.56 (dd,1H,
0
0
1
H, J3ʺ,5ʺ ¼ 5.0 Hz, H-3ʺ), 7.61 (dt, 1H, J5,7 ¼ 2.0, J5(4,6) ¼ 7.0 Hz, H-5),
J
5ʺ,3ʺ ¼ 2.0, J5ʺ,6ʺ ¼ 8.0 Hz, H-5 ), 6.52 (d, 1H, J3ʺ,500 ¼ 2.0 Hz, H-3ʺ),
13
7
.54e7.51 (m, 2H, H-6, H-5ʺ), 7.18 (dd, 1H, J4ʺ,5ʺ ¼ 3.5 Hz,
3 6
3.79 (s, 3H, OCH ); C NMR (125 MHz, DMSO-d ): d 55.80, 101.69,
13
J
4ʺ,3ʺ ¼ 5.0 Hz, H-4ʺ); C NMR (125 MHz, DMSO-d
23.61, 126.39, 127.34, 127.73, 127.73, 128.38, 129.11, 129.60, 129.60,
31.58, 135.20, 136.03, 139.48, 143.93, 149.46, 154.01, 162.67, 166.72;
Anal. Calcd for C19 OS
6
):
d
122.93,
107.01, 112.25, 122.94, 123.61, 126.40, 127.35, 127.35, 127.76, 129.11,
129.11, 131.65, 135.21, 135.56, 136.08, 149.72, 154.01, 159.96, 162.29,
162.70, 166.71; Anal. Calcd for C22
1
1
H
17
N
3
O
3
S, C ¼ 65.49, H ¼ 4.25,
H
13
N
3
2
, C ¼ 62.79, H ¼ 3.61, N ¼ 11.56, Found
N ¼ 10.42, Found C ¼ 65.48, H ¼ 4.26, N ¼ 10.44; EI MS m/z (% rel.
C ¼ 62.80, H ¼ 3.62, N ¼ 11.57; EI MS m/z (% rel. abund.): 363.
abund.): 403.
0
0
4
.4.1.6. (E)-N -(2,3-Dihydroxybenzylidene)-4-(benzo[d]thiazol-2-yl)
4.4.1.8. (E)-N -(2-Hydroxybenzylidene)-4-(benzo[d]thiazol-2-yl)ben-
benzohydrazide (11). White solid, R
f
¼ 0.60 (ethyl acetate:hexane
zohydrazide (13). Light orange solid, R
ane 7:3); m.p. 276 C. Yield: (0.31 g, 83%); HNMR (500 MHz,
f
¼ 0.32 (ethyl acetate:hex-
ꢂ
1
ꢂ
1
7:3); m.p. 285 C. Yield: (0.319 g, 82%); HNMR (500 MHz, DMSO-
d
6
):
d
12.25 (s, 1H, NH), 11.02 (s, 2H, 2ꢃOH), 8.64 (s,1H, CH]N), 8.29
DMSO-d
8.27 (d, 2H, J
4), 8.15 (d, 2H, J
6
): d 12.28 (s, 1H, NH), 11. 26 (s, 1H, OH), 8.70 (s,1H, CH]N),
0
0
0
0
(
d, 2H, J
2
0
,6
0
/3
0
,5
0
¼ 7.5 Hz, H-2 , H-6 ), 8.22 (d, 1H, J4,5 ¼ 8.0 Hz, H-4),
2
0
,6
0
/3
0
0
,5
0
0
¼ 8.5 Hz, H-2 ,H-6 ), 8.22 (d, 1H, J4,5 ¼ 7.5 Hz, H-
0
0
0
0
8
.15 (d, 2H, J
3
0
,5
0
/2
0
,6
0
¼ 7.5 Hz, H-3 ,H-5 ), 8.13 (d, 1H, J7,6 ¼ 8.0 Hz, H-
3
,5
/2
0
,6 ¼ 8.5 Hz, H-3 ,H-5 ), 8.12 (d, 1H, J7,6 ¼ 8.0 Hz,
7
), 7.62 (dt, 1H, J5,7 ¼ 2.0, J5(4,6) ¼ 7.0 Hz, H-5), 7.54 (dt, 1H, J6,4 ¼ 2.0,
H-7), 7.62e7.59 (m, 2H, H-6, H-5ʺ), 7.54 (dt, 1H, J6,4 ¼ 2.0,
J
J
6(5,7) ¼ 7.0 Hz, H-6), 7.01 (d, 1H J3ʺ,4ʺ ¼ 8.0 Hz, H-4ʺ), 6.87 (d,
J
6(5,7) ¼ 7.0 Hz, H-6), 7.34 (t, 1H, J4ʺ(5ʺ,3ʺ) ¼ 2.0 Hz, H-4ʺ), 6.97e6.92
13
13
6ʺ,5ʺ ¼ 8.0 Hz, H-6ʺ), 6.78 (t, 1H, J5ʺ (4ʺ,6ʺ) ¼ 8.0 Hz, H-5ʺ); C NMR
125 MHz, DMSO-d ): 118.01, 119.25, 119.68, 120.59, 122.92,
23.62, 126.40, 127.34, 127.34, 127.78, 129.18, 129.18, 135.22, 135.41,
36.19, 146.10, 146.66, 129.96, 154.01, 162.48, 166.67; Anal. Calcd for
S, C ¼ 64.77, H ¼ 3.88, N ¼ 10.79, Found C ¼ 64.76,
(m, 2H, H-3ʺ, H-6ʺ), H-5ʺ); C NMR (125 MHz, DMSO-d
6
):
d
116.92,
(
1
1
6
d
119.16, 119.87, 122.94, 123.63, 126.41, 127.35, 127.35, 127.78, 129.18,
129.18, 129.99, 132.01, 135.22, 135.45, 136.18, 149.21, 154.01, 157.98,
162.51, 166.68; Anal. Calcd for C21
N ¼ 11.25, Found C ¼ 67.55, H ¼ 4.07, N ¼ 11.25; EI MS m/z (% rel.
H
15
N
3
O
2
S, C ¼ 67.54, H ¼ 4.05,
21 15 3 3
C H N O

396
M. Taha et al. / European Journal of Medicinal Chemistry 92 (2015) 387e400
abund.): 373.
.4.1.9. (Z)-4-(Benzo[d]thiazol-2-yl)-N -((furan-2-yl)methylene)ben-
DMSO-d
6
):
d 11.93, (s, 1H, NH), 8.41 (s,1H, CH]N), 8.27 (d, 2H, J
2 ,6 /
0 0
0
0
0
0
¼ 8.0 Hz, H-2 ,H-6 ), 8.22 (d, 1H, J ¼ 8.0 Hz, H-4), 8.14 (d, 2H,
3
J
,5
0
4,5
0
0
0
4
3
,5
0
/2
0
,6 ¼ 8.0 Hz, H-3 ,H-5 ), 8.11 (d, 1H, J7,6 ¼ 8.0 Hz, H-7), 7.62 (t,
zohydrazide (14). Light orange solid, R
ane 8:2); m.p. 243 C. Yield: (0.302 g, 87%); HNMR (500 MHz,
f
¼ 0.62 (ethyl acetate:hex-
1H, J5(4,6) ¼ 7.0 Hz, H-5), 7.54 (t, 1H, J6(5,7) ¼ 7.0 Hz, H-6), 7.39 (d, 1H,
ꢂ
1
00
J
J
2ʺ,6ʺ ¼ 2.0 Hz, H-2 ), 7.25 (d, 1H, J6ʺ,5ʺ ¼ 7.5 Hz, H-6ʺ), 7.06 (d, 1H,
0
0
13
DMSO-d
6
):
d
11.98 (s, 1H, NH), 8.38 (s,1H, CH]N), 8.27 (d, 2H, J
2
0
,6
0
/
5ʺ,6ʺ ¼ 7.5 Hz, H-5 ) 3.84 (s, 3H, OCH
3 3
), 3.83 (s, 3H, OCH ); C NMR
0
0
0
0
¼ 8.0 Hz, H-2 ,H-6 ), 8.22 (d, 1H, J ¼ 8.0 Hz, H-4), 8.14 (d, 2H,
(125 MHz, DMSO-d ):
d
55.99, 56.07, 108.94, 112.03, 122.53, 122.92,
3
,5
4,5
6
0
0
J
3
0
,5
0
/2
0
,6 ¼ 8.0 Hz, H-3 ,H-5 ), 8.11 (d, 1H, J7,6 ¼ 8.0 Hz, H-7), 7.88 (s,
123.60, 126.37, 127.33, 127.33, 127.44, 127.70, 129.10, 129.10, 135.19,
135.91, 136.23, 149.07, 149.61, 151.40, 154.02, 162.67, 166.75; Anal.
Calcd for C23
C ¼ 66.18, H ¼ 4.60, N ¼ 10.08; EI MS m/z (% rel. abund.): 417.
1
J
(
1
H, H-3ʺ) 7.61 (dt, 1H, J5,7 ¼ 2.0, J5(4,6) ¼ 7.0 Hz, H-5), 7.54 (dt, 1H,
6,4 ¼ 2.0, J6(5,7) ¼ 7.0 Hz, H-6), 6.98 (d, 1H, J4ʺ,5ʺ ¼ 3.5 Hz, H-4ʺ), 6.67
H
19
N
3
O
3
S, C ¼ 66.17, H ¼ 4.59, N ¼ 10.07, Found
13
d, H, J5ʺ,4ʺ ¼ 3.5 Hz, H-5ʺ); C NMR (125 MHz, DMSO-d
14.23, 122.96, 123.61, 126.41, 127.36, 127.36, 127.74, 129.13, 129.13,
35.20, 135.97, 138.70, 145.78, 150.04, 154.01, 161.10, 162.77, 166.77;
Anal. Calcd for C19
6
):
d
112.76,
0
1
4.4.1.14. (E)-N -(4-Nitrobenzylidene)-4-(benzo[d]thiazol-2-yl)benzo-
hydrazide (19). White solid, R
m.p. 265 C. Yield: (0.326 g, 81%); HNMR (500 MHz, DMSO-d
13
H N
3
O
2
S, C ¼ 65.69, H ¼ 3.77, N ¼ 12.10, Found
f
¼ 0.47 (ethyl acetate:hexane 8:2);
ꢂ
1
C ¼ 65.70, H ¼ 3.78, N ¼ 12.11; EI MS m/z (% rel. abund.): 347.
6
):
d
11.30 (s,1H, NH), 8.60 (s,1H, CH]N), 8.34 (d, 2H, J2ʺ,6ʺ/3ʺ,5ʺ ¼ 8.5 Hz,
0
0
0
0
4
.4.1.10. (E)-N -(3,4-Dihydroxybenzylidene)-4-(benzo[d]thiazol-2-yl)
H-2ʺ,H-6ʺ), 8.29 (d, 2H, J
2
0
,6
0
/3
0
,5
0
¼ 8.5 Hz, H-2 ,H-6 ), 8.22 (d, 1H,
0
benzohydrazide (15). Yellow solid, R
f
¼ 0.35 (ethyl acetate:hexane
J
4,5 ¼ 7.5 Hz, H-4), 8.15 (d, 2H, J
3
0
,5
0
/2
0
,6 ¼ 8.5 Hz, H-3 ,H-5 ), 8.12 (d,
ꢂ
1
7:3); m.p. 295 C. Yield: (0.311 g, 80%); HNMR (500 MHz, DMSO-
1H, J7,6 ¼ 7.5 Hz, H-7), 8.04 (d, 2H, J3ʺ,5ʺ/2ʺ,6ʺ ¼ 8.5 Hz, H-3ʺ,H-5ʺ), 7.62
13
d
6
):
d
11.89 (s, 1H, NH), 11.23 (s, 2H, 2ꢃOH), 8.30 (s,1H, CH]N), 8.26
(t, 1H, J5(4,6) ¼ 7.0 Hz, H-5), 7.54 (t, 1H, J6(5,7) ¼ 7.0 Hz, H-6); C NMR
(125 MHz, DMSO-d ): 122.93, 123.65, 126.40, 127.39, 127.39,
0
0
(
d, 2H, J
2
0
,6
0
/3
0
,5
0
¼ 8.5 Hz, H-2 , H-6 ), 8.22 (d, 1H, J4,5 ¼ 8.0 Hz, H-4),
6
d
0
0
8
.14 (d, 2H, J
3
0
,5
0
/2
0
,6 ¼ 8.5 Hz, H-3 , H-5 ), 8.11 (d, 1H, J7,6 ¼ 8.0 Hz, H-
127.78, 129.16, 129.16, 132.12, 132.12, 133.84, 135.15, 135.94, 136.53,
140.45, 140.45, 145.04, 148.91, 154.02, 162.77, 166.70; Anal. Calcd for
7
), 7.62 (dt, 1H, J5,7 ¼ 2.0, J5(4,6) ¼ 7.0 Hz, H-5), 7.54 (dt, 1H, J6,4 ¼ 2.0,
00
J
6(5,7) ¼ 7.0 Hz, H-6), 7.27 (d, 1H, J2ʺ,6ʺ ¼ 2.0 Hz, H-2 ), 6.97 (dd, 1H,
C
21
H
14
N
4
O
3
S, C ¼ 62.68, H ¼ 3.51, N ¼ 13.92, Found C ¼ 62.67,
0
0
J6ʺ,2ʺ ¼ 2.0 Hz, J6ʺ,5ʺ ¼ 8.0 Hz, H-6ʺ), 6.81 (d, 1H, J5ʺ,6ʺ ¼ 8.0 Hz, H-5 );
H ¼ 3.52, N ¼ 13.93; EI MS m/z (% rel. abund.): 402.
1
3
C NMR (125 MHz, DMSO-d
23.59, 126.18, 126.37, 127.33, 127.33, 127.68, 129.06, 129.06, 135.18,
35.82, 136.34, 146.23, 148.60, 149.37, 154.01, 162.48, 166.77; Anal.
Calcd for C21
6
): d 113.31, 116.09, 121.19, 122.93,
0
1
1
4.4.1.15. (E)-N -(3-Hydroxy-4-methoxybenzylidene)-4-(benzo[d]
thiazol-2-yl)benzohydrazide (20). Yellow solid, R
acetate:hexane 7:3); m.p. 252 C. Yield: (0.339 g, 84%); HNMR
(500 MHz, DMSO-d
f
¼ 0.55 (ethyl
ꢂ
1
H
15
N
3
O
3
S, C ¼ 64.77, H ¼ 3.88, N ¼ 10.79, Found
C ¼ 64.77, H ¼ 3.89, N ¼ 10.81; EI MS m/z (% rel. abund.): 389.
6
): d 11.87, (s, 1H, NH), 9.31 (s, 1H, OH), 8.34
0
0
(s,1H, CH]N), 8.27 (d, 2H, J
2
0
,6
0
/3
0
,5
,5
0
¼ 8.0 Hz, H-2 ,H-6 ), 8.22 (d, 1H,
0
0
0
4
.4.1.11. (E)-N -(2,4-Dihydroxybenzylidene)-4-(benzo[d]thiazol-2-yl)
J
4,5 ¼ 8.0 Hz, H-4), 8.14 (d, 2H, J
3
0
0
/2
0
,6 ¼ 8.0 Hz, H-3 ,H-5 ), 8.11 (d,
benzohydrazide (16). Light orange solid, R
hexane 7:3); m.p. 299 C. Yield: (0.319 g, 82%); HNMR (500 MHz,
f
¼ 0.47 (ethyl acetate:-
1H, J7,6 ¼ 8.0 Hz, H-7), 7.62 (t, 1H, J5(4,6) ¼ 7.0 Hz, H-5), 7.54 (t, 1H,
ꢂ
1
00
J
6(5,7) ¼ 8.0 Hz, H-6), 7.30 (d, 1H, J2ʺ,6ʺ ¼ 2.0 Hz, H-2 ), 7.11 (dd, 1H,
0
0
00
DMSO-d
8
1
6
):
.55 (s,1H, CH]N), 8.28 (d, 2H, J
H, J4,5 ¼ 7.5 Hz, H-4), 8.14 (d, 2H, J
d
12.11 (s, 1H, NH), 11.44 (s, 1H, OH), 10.05 (s, 1H, OH),
J6ʺ,2ʺ ¼ 2.0 Hz, J6ʺ,5ʺ ¼ 8.0 Hz, H-6 ), 7.01 (d, 1H, J5ʺ,6ʺ ¼ 7.5 Hz, H-5 ),
0
0
13
0
0
0
0
¼ 8.5 Hz, H-2 ,H-6 ), 8.22 (d,
3.82 (s, 3H, OCH
); C NMR (125 MHz, DMSO-d
):
d
112.41, 112.96,
2
,6
/3
,5
,5
3
6
0
0
0
0
0
,6 ¼ 8.5 Hz, H-3 ,H-5 ), 8.11
120.89, 122.91, 123.60, 126.34, 127.31, 127.31, 127.39, 127.61, 127.68,
129.09, 129.09, 135.19, 135.88, 136.27, 147.41, 149.00, 150.41, 154.02,
162.55, 166.74; Anal. Calcd for C22
3
/2
(
7
d, 1H, J7,6 ¼ 7.5 Hz, H-7), 7.62 (dt, 1H, J5,7 ¼ 2.0, J5(4,6) ¼ 7.0 Hz, H-5),
.54 (dt, 1H, J6,4 ¼ 2.0, J6(5,7) ¼ 7.0 Hz, H-6), 7.36 (d, 1H, J6ʺ,5ʺ ¼ 8.5 Hz,
H-6ʺ), 6.97 (dd, 1H, J5ʺ,3ʺ ¼ 2.0 Hz, J5ʺ,6ʺ ¼ 8.5 Hz, H-5ʺ), 6.34 (d, 1H,
H
17
N
3
O
3
S, C ¼ 65.49, H ¼ 4.25,
N ¼ 10.42, Found C ¼ 65.50, H ¼ 4.24, N ¼ 10.44; EI MS m/z (% rel.
0
0
13
J
1
1
1
3ʺ,5ʺ ¼ 2.0 Hz, H-3 ); C NMR (125 MHz, DMSO-d
08.28, 111.02, 122.88, 123.60, 126.35, 127.30, 127.30, 127.72, 129.06,
29.06, 131.91, 135.21, 135.63, 136.03, 150.19, 154.01, 160.07, 161.36,
62.18, 166.69; Anal. Calcd for C21
6
):
d
103.21,
abund.): 403.
0
4.4.1.16. (E)-N -(4-Fluorobenzylidene)-4-(benzo[d]thiazol-2-yl)ben-
zohydrazide (21). White solid, R
m.p. 215 C. Yield: (0.322 g, 86%); HNMR (500 MHz, DMSO-d
H
15
N
3
O
3
S, C ¼ 64.77, H ¼ 3.88,
f
¼ 0.63 (ethyl acetate:hexane 5:5);
ꢂ
1
N ¼ 10.79 Found C ¼ 64.77, H ¼ 3.89, N ¼ 10.81; EI MS m/z (% rel.
6
):
abund.): 389.
d
12.08 (s, 1H, NH), 8.48 (s,1H, CH]N), 8.27 (d, 2H,
0
0
J
2
0
,6
0
¼ J
6
0
,2
,5
0
¼ 7.5 Hz, H-2 ,H-6 ), 8.22 (d, 1H, J4,5 ¼ 7.5 Hz, H-4), 8.14
0
0
4.4.1.12. Methyl
4-((E)-(4-(benzo[d]thiazol-2-yl)benzoylimino)
(d, 2H, J
3
0
0
¼ J
3
0
,5
0
¼ 8.0 Hz, H-3 ,H-5 ), 8.11 (d,1H, J7,6 ¼ 8.0 Hz, H-7),
methyl)benzoate (17). White solid, R
f
¼ 0.45 (ethyl acetate:hexane
7.71 (dd, 2H, J3ʺ,5ʺ/2ʺ,6ʺ ¼ 6.0 Hz, J3ʺ,5ʺ/F ¼ 6.0 Hz, H-3ʺ H-5ʺ), 7.62 (t,
1H, J5(4,6) ¼ 7.0 Hz, H-5), 7.54 (t, 1H, J6(5,7) ¼ 7.0 Hz, H-6), 7.71 (dd,
ꢂ
1
8
:2); m.p. 281 C. Yield: (0.353 g, 85%); HNMR (500 MHz, DMSO-
d
6
):
d
12.20 (s, 1H, NH), 8.55 (s,1H, CH]N), 8.29 (d, 2H, J
2
0
,6
0
/
2H, J3ʺ,5ʺ/2ʺ,6ʺ ¼ 6.0 Hz, J3ʺ,5ʺ/F ¼ 6.0 Hz, H-3ʺ H-5ʺ), 7.34 (t, 2H, J2ʺ,6ʺ/
0
0
13
0
0
¼ 8.5 Hz, H-2 ,H-6 ), 8.22 (d, 1H, J ¼ 8.0 Hz, H-4), 8.14 (d, 2H,
¼ 7.5 Hz, H-2ʺ,H-6ʺ); C NMR (125 MHz, DMSO-d ):
d 116.32,
3
,5
4,5
3ʺ,5ʺ,F
6
0
0
J
3
0
,5
0
/2
0
,6 ¼ 8.5 Hz, H-3 ,H-5 ), 8.11 (d, 1H, J7,6 ¼ 7.5 Hz, H-7), 8.07 (d,
116.50, 116.50, 122.96, 123.61, 126.42, 127.37, 127.37, 127.74, 129.17,
129.17, 129.89, 129.89, 135.19, 136.03, 136.80, 147.72, 154.01, 159.52
2
3
H, J2ʺ,6ʺ/3ʺ,5ʺ ¼ 8.5 Hz, H-2ʺ,H-6ʺ), 7.92 (d, 2H, J3ʺ,5ʺ/2ʺ,6ʺ ¼ 8.5 Hz, H-
ʺ,H-5ʺ), 7.62 (t, 1H, J5(4,6) ¼ 7.0 Hz, H-5), 7.54 (t, 1H, J6(5,7) ¼ 7.0 Hz,
(d, J ¼ 223.75 Hz), 162.97, 166.94; Anal. Calcd for C21
3
H14FN OS,
13
H-6), (s, 3H, OCH
3
); C NMR (125 MHz, DMSO-d
6
):
d
68.27, 108.31,
C ¼ 67.18, H ¼ 3.76, N ¼ 11.19, Found C ¼ 67.20, H ¼ 3.77, N ¼ 11.20;
1
1
1
22.97, 123.68, 126.42, 127.33, 127.33, 127.74, 129.10, 129.10, 130.15,
30.15, 132.50, 132.50, 135.23,135.99, 136.28, 138.70, 149.23,154.02,
62.37, 166.80, 176.75; Anal. Calcd for C23
S, C ¼ 66.49,
EI MS m/z (% rel. abund.): 375.
0
H
17
N
3
O
3
4.4.1.17. (E)-N -(3,5-Dimethoxybenzylidene)-4-(benzo[d]thiazol-2-
yl)benzohydrazide (22). Light yellow solid, R
te:hexane 5:5); m.p. 235 C. Yield: (0.371 g, 89%); HNMR
H ¼ 4.12, N ¼ 10.11, Found C ¼ 66.48, H ¼ 4.13, N ¼ 10.12; EI MS m/z
f
¼ 0.51 (ethyl aceta-
ꢂ
1
(
% rel. abund.): 415.
(
500 MHz, DMSO-d
6
):
d 12.07 (s, 1H, NH), 8.42 (s,1H, CH]N), 8.28
0
0
0
4
.4.1.13. (E)-N -(3,4-Dimethoxybenzylidene)-4-(benzo[d]thiazol-2-
(d, 2H, J
8.13 (d, 2H, J
2
0
,6
0
/3
0
,5
0
¼ 8.0 Hz, H-2 ,H-6 ), 8.22 (d, 1H, J4,5 ¼ 8.0 Hz, H-4),
0
0
yl)benzohydrazide (18). Yellow solid, R
ane 8:2); m.p. 224 C. Yield: (0.367 g, 88%); HNMR (500 MHz,
f
¼ 0.52 (ethyl acetate:hex-
3
0
,5
0
/2
0
,6 ¼ 8.0 Hz, H-3 ,H-5 ), 8.11 (d, 1H, J7,6 ¼ 8.0 Hz, H-
ꢂ
1
7), 7.62 (dt, 1H, J5,7 ¼ 2.0 Hz, J5(4,6) ¼ 7.0 Hz, H-5), 7.54 (dt, 1H,

M. Taha et al. / European Journal of Medicinal Chemistry 92 (2015) 387e400
397
0
0
J
6,4 ¼ 2.0 Hz, J6(5,7) ¼ 8.0 Hz, H-6), 6.92 (d, 2H, J2ʺ,6ʺ,/4ʺ ¼ 2.0 Hz, H-2 ,
(500 MHz, DMSO-d
6
):
d
11.97 (s, 1H, NH), 8.35 (s,1H, CH]N), 8.26
0
0
13
0
0
H-6 ), 6.60 (d, 1H, J4ʺ/6ʺ,2ʺ ¼ 2.0 Hz, H-4ʺ), 3.81 (s, 6H, 2ꢃOCH
NMR (125 MHz, DMSO-d ): 55.84, 55.84, 102.94, 105.46, 105.46,
22.93, 123.61, 126.39, 127.34, 127.34, 127.72, 129.17, 129.17, 135.20,
36.03, 136.03, 136.74, 148.77, 154.02, 161.21, 161.21, 162.88, 166.72;
Anal. Calcd for C23
3
);
C
(d, 2H, J
8.14 (d, 2H, J
2
0
,6
0
/3
0
,5
0
0
¼ 8.0 Hz, H-2 ,H-6 ), 8.22 (d, 1H, J4,5 ¼ 8.0 Hz, H-4),
0
0
d
3
,5
0
/2
0
,6 ¼ 8.0 Hz, H-3 ,H-5 ), 8.11 (d, 1H, J7,6 ¼ 8.0 Hz, H-
6
1
1
7), 7.90 (d, 1H, J2ʺ,6ʺ ¼ 2.0 Hz, H-2ʺ), 7.61e7.58 (m, 2H, H-5, H-5ʺ),
13
7.54 (t, 1H, J6(5,7) ¼ 8.0 Hz, H-6), 7.05 (d, 1H, J6ʺ,5ʺ ¼ 8.5 Hz, H-6ʺ);
NMR (125 MHz, DMSO-d ): 56.52, 110.39, 117.07, 122.93, 123.60,
126.38, 127.34, 127.34, 127.70, 128.50, 129.12, 129.12, 131.93, 135.19,
35.94, 136.12, 147.50, 154.01, 156.48, 162.68, 166.73; Anal. Calcd for
14BrN
C
H
19
N
3
O
3
S, C ¼ 66.17, H ¼ 4.59, N ¼ 10.07, Found
6
d
C ¼ 66.19, H ¼ 4.60, N ¼ 10.06; EI MS m/z (% rel. abund.): 417.
1
0
4
(
.4.1.18. (E)-4-(Benzo[d]thiazol-2-yl)-N -benzylidenebenzohydrazide
21
C H
3
O
2
S, C ¼ 55.76, H ¼ 3.12, N ¼ 9.29, Found C ¼ 55.75,
23). White crystalline solid, R
f
¼ 0.55 (ethyl acetate:hexane 5:5);
H ¼ 3.13, N ¼ 9.30; EI MS m/z (% rel. abund.): 451.
ꢂ
1
m.p. 274 C. Yield: (0.311 g, 87%); HNMR (500 MHz, DMSO-d
12.05 (s,1H, NH), 8.50 (s,1H, CH]N), 8.28 (d, 2H, J
¼ 8.5 Hz,
H-2 ,H-6 ), 8.22 (d, 1H, J4,5 ¼ 8.0 Hz, H-4), 8.14 (d, 2H, J
6
):
0
d
2
0
,6
0
/3
0
,5
0
4.4.1.23. (E)-N -(4-Chlorobenzylidene)-4-(benzo[d]thiazol-2-yl)ben-
0
0
0
0
zohydrazide (28). White solid, R
¼ 0.58 (ethyl acetate:hexane 5:5);
3
,5
/
f
0
0
ꢂ
1
0
¼ 8.5 Hz, H-3 ,H-5 ), 8.11 (d, 1H, J ¼ 8.0 Hz, H-7), 7.78 (m, 2H,
m.p. 245 C. Yield: (0.336 g, 86%); HNMR (500 MHz, DMSO-d ):
2
,6
7,6
6
H-2ʺ,H-6ʺ), 7.61 (t, 1H, J5(4,6) ¼ 7.0 Hz, H-5), 7.54e7.47 (m, 4H, H-6,
H-3ʺ, H-4ʺ, H-5ʺ); 13C NMR (125 MHz, DMSO-d
): 122.96, 123.61,
26.41, 127.36, 127.36, 127.66, 127.73, 128.97, 129.18, 129.18, 129.35,
30.70, 132.15, 133.27, 134.70, 135.19, 136.01, 148.87, 154.01, 163.02,
66.85; Anal. Calcd for C21
d
12.12 (s, 1H, NH), 8.48 (s,1H, CH]N), 8.28 (d, 2H, J
2
0
,6
0
/3
0
,5
0
¼ 8.5 Hz,
0
0
d
H-2 ,H-6 ), 8.22 (d, 1H, J4,5 ¼ 8.0 Hz, H-4), 8.14 (d, 2H, J
0 0
3 ,5 /
6
0
0
1
1
1
2
0
,6 ¼ 8.5 Hz, H-3 ,H-5 ), 8.12 (d, 1H, J7,6 ¼ 7.5 Hz, H-7), 7.80 (d, 2H,
J
2ʺ,6ʺ/3ʺ,5ʺ ¼ 8.0 Hz, H-2ʺ,H-6ʺ), 7.62 (t, 1H, J5(4,6) ¼ 7.0 Hz, H-5), 7.56
00
H
15
N
3
OS, C ¼ 70.57, H ¼ 4.23, N ¼ 11.76,
(t, 1H, J6(5,7) ¼ 7.0 Hz, H-6), 7.51 (d, 2H, J3ʺ,5ʺ/2ʺ,6ʺ ¼ 8.5 Hz, H-3 ,H-
0
0
13
Found C ¼ 70.58, H ¼ 4.24, N ¼ 11.75; EI MS m/z (% rel. abund.): 357.
5 ); C NMR (125 MHz, DMSO-d
27.75, 129.28, 129.28, 129.44, 132.15, 135.20, 135.97, 136.91, 139.87,
139.87, 147.53, 148.86, 153.98, 160.63, 160.63, 162.85, 166.52; Anal.
Calcd for C21 14ClN
6
): d 122.95, 123.61, 126.43, 127.75,
1
0
4
2
.4.1.19. (E)-N -(3-Bromo-4-fluorobenzylidene)-4-(benzo[d]thiazol-
-yl)benzohydrazide (24). White solid, R
f
¼ 0.55 (ethyl acetate:-
H
3
OS, C ¼ 64.36, H ¼ 3.60, N ¼ 10.72, Found
ꢂ
1
hexane 5:5); m.p. 262 C. Yield: (0.375 g, 83%); HNMR (500 MHz,
C ¼ 64.37, H ¼ 3.61, N ¼ 10.73; EI MS m/z (% rel. abund.): 391.
DMSO-d
6
):
d 12.19 (s, 1H, NH), 8.45 (s,1H, CH]N), 8.28 (d, 2H, J
2 ,6 /
0 0
0
0
0
0
0
¼ 8.5 Hz, H-2 ,H-6 ), 8.22 (d, 1H, J ¼ 8.0 Hz, H-4), 8.14e8.09
4.4.1.24. (E)-N -(3-Methoxybenzylidene)-4-(benzo[d]thiazol-2-yl)
3
,5
4,5
0
0
(
(
(
1
1
m, 4H, H-3 ,H-5 , H-4, H-2ʺ), 7.84 (t, 1H, J5ʺ(6ʺ,F) ¼ 6.0 Hz, H-5ʺ), 7.61
benzohydrazide (29). White solid, R
f
¼ 0.55 (ethyl acetate:hexane
13
ꢂ
1
t, 1H, J5(4,6) ¼ 7.0 Hz, H-5), 7.54e7.48 (m, 2H, H-6, H-6ʺ); C NMR
125 MHz, DMSO-d ): 109.29,117.65,117.83,122.90,123.61,126.37,
27.32, 127.32, 127.70, 129.19, 129.19, 132.14, 133.06, 135.19, 135.80,
36.09, 146.09, 154.00, 158.59 (d, J ¼ 250 Hz), 162.92, 166.67; Anal.
Calcd for C21 13BrFN
5:5); m.p. 225 C. Yield: (0.341 g, 88%); HNMR (500 MHz, DMSO-
6
d
6 2 ,6 /
d ): d 12.06 (s, 1H, NH), 8.47 (s,1H, CH]N), 8.27 (d, 2H, J
0 0
0
0
0
0
¼ 8.0 Hz, H-2 ,H-6 ), 8.22 (d, 1H, J4,5 ¼ 7.5 Hz, H-4), 8.15 (d, 2H,
3
J
,5
0
0
0
0
0
,6 ¼ 8.0 Hz, H-3 ,H-5 ), 8.12 (d, 1H, J7,6 ¼ 8.0 Hz, H-7), 7.62 (dt,
3
,5
/2
H
3
OS, C ¼ 55.52, H ¼ 2.88, N ¼ 9.25, Found
1H, J5,7 ¼ 2.0, J5(4,6) ¼ 7.5 Hz, H-5), 7.54 (dt, 1H, J6,4 ¼ 2.0 Hz,
C ¼ 55.53, H ¼ 2.89, N ¼ 9.24,; EI MS m/z (% rel. abund.): 452.
J
6(5,7) ¼ 8.0 Hz, H-6), 7.42 (t,1H, J5ʺ(4ʺ,6ʺ) ¼ 7.50 Hz, H5ʺ), 7.3e7.27 (m,
2
H, H-2ʺ,H-4ʺ), 7.05 (dd, 1H, J6ʺ,2ʺ ¼ 2.0 Hz, J6ʺ,5ʺ ¼ 7.5 Hz, H-6ʺ), 3.83
0
13
4
.4.1.20. (E)-N -(4-Methoxybenzylidene)-4-(benzo[d]thiazol-2-yl)
(s, 3H, OCH
3
); C NMR (125 MHz, DMSO-d
6
):
d
55.68, 111.83,
benzohydrazide (25). Light yellow solid, R
hexane 5:5); m.p. 239 C. Yield: (0.329 g, 85%); HNMR (500 MHz,
f
¼ 0.46 (ethyl acetate:-
116.84, 120.64, 122.93, 123.61, 126.39, 127.34, 127.34, 127.72, 129.17,
129.17, 130.45, 135.20, 136.03, 136.15, 146.84, 148.76, 154.01, 160.06,
ꢂ
1
DMSO-d
6
):
d
11.92 (s, 1H, NH), 843 (s,1H, CH]N), 8.27 (d, 2H, J
2
0
,6
0
/
162.87, 166.72; Anal. Calcd for C22
H
17
N
3
O
2
S, C ¼ 68.20, H ¼ 4.42,
0
0
0
0
¼ 8.0 Hz, H-2 ,H-6 ), 8.22 (d, 1H, J ¼ 8.0 Hz, H-4), 8.14 (d, 2H,
N ¼ 10.85, Found C ¼ 68.21, H ¼ 4.43, N ¼ 10.85; EI MS m/z (% rel.
3
,5
4,5
0
0
J
3
0
,5
0
/2
0
,6 ¼ 8.0 Hz, H-3 ,H-5 ), 8.11 (d, 1H, J7,6 ¼ 7.5 Hz, H-7), 7.72 (d,
abund.): 387.
2
7
3
1
1
1
H, J2ʺ,6ʺ/3ʺ,5ʺ ¼ 8.5 Hz, H-2ʺ,H-6ʺ), 7.62 (t, 1H, J5(4,6) ¼ 7.5 Hz, H-5),
0
.54 (t, 1H, J6(5,7) ¼ 8.0 Hz, H-6), 7.06 (d, 2H, J3ʺ,5ʺ/2ʺ,6ʺ ¼ 8.5 Hz, H-
ʺ,H-5ʺ); 13C NMR (125 MHz, DMSO-d
): 55.80, 114.87, 114.87,
22.95, 123.60, 126.41, 127.26, 127.26, 127.72, 129.11, 129.11, 129.31,
29.31, 135.18, 135.89, 136.26, 148.78, 154.01, 161.47, 161.47, 162.68,
66.78; Anal. Calcd for C22
4.4.1.25. (E)-N -(3-Hydroxybenzylidene)-4-(benzo[d]thiazol-2-yl)
6
d
benzohydrazide (30). White solid, R
f
¼ 0.55 (ethyl acetate:hexane
ꢂ
1
7:3); m.p. 265 C. Yield: (0.313 g, 84%); HNMR (500 MHz, DMSO-
d
6
):
2H, J
(d, 2H, J
.62 (t, 1H, J5(4,6) ¼ 7.5 Hz, H-5), 7.54 (t, 1H, Hz, J6(5,7) ¼ 8.0 Hz, H-6),
7.30 (t, 1H, J5ʺ(4ʺ,6ʺ) ¼ 7.50 Hz, H-5ʺ), 7.23 (s, 1H, H-2ʺ), 7.14 (d, 1H,
4ʺ,5ʺ ¼ 7.0 Hz, H-4ʺ), 6.87 (dd,1H, J6ʺ,2ʺ ¼ 2.0 Hz, J6ʺ,5ʺ ¼ 7.5 Hz, H-6ʺ);
d 11.99 (s, 1H, NH), 9.70 (s, 1H, OH), 8.40 (s,1H, CH]N), 8.27 (d,
0
0
H
17
N
3
O
2
S, C ¼ 68.20, H ¼ 4.42, N ¼ 10.85,
2
0
,6
0
/3
0
,5
,5
0
¼ 8.0 Hz, H-2 ,H-6 ), 8.22 (d, 1H, J4,5 ¼ 8.0 Hz, H-4), 8.14
0
0
Found C ¼ 68.22, H ¼ 4.43, N ¼ 10.86; EI MS m/z (% rel. abund.): 387.
3
0
0
/2
0
,6 ¼ 8.0 Hz, H-3 ,H-5 ), 8.12 (d, 1H, J7,6 ¼ 8.0 Hz, H-7),
7
0
4
.4.1.21. (E)-N -(2,4,6-Trihydroxybenzylidene)-4-(benzo[d]thiazol-2-
yl)benzohydrazide (26). Brown solid, R
f
¼ 0.48 (ethyl acetate:hex-
J
ꢂ
1
13
ane 7:3); m.p. 305 C. Yield: (0.340 g, 84%); HNMR (500 MHz,
6
C NMR (125 MHz, DMSO-d ): d 113.31, 118.08, 119.40, 122.84,
DMSO-d
8
1
6
):
.84 (s,1H, CH]N), 8.27 (d, 2H, J
H, J4,5 ¼ 8.0 Hz, H-4), 8.13 (d, 2H, J
d
12.08 (s, 1H, NH), 11.14 (s, 2H, 2ꢃOH), 9.92 (s, 1H, OH),
123.48, 123.60, 126.32, 127.16, 127.27, 127.27, 127.68, 129.13, 129.13,
130.36, 135.20, 136.01, 148.98, 154.01, 158.19, 162.81, 166.69; Anal.
0
0
0
0
0
0
¼ 8.0 Hz, H-2 ,H-6 ), 8.22 (d,
2
,6
/3
,5
,5
0
0
0
0
0
,6 ¼ 8.0 Hz, H-3 ,H-5 ), 8.11
Calcd for C21
H
N
O
S, C ¼ 67.54, H ¼ 4.05, N ¼ 11.25, Found
3
/2
15
3
2
(
5
d, 1H, J7,6 ¼ 7.5 Hz, H-7), 7.62 (dt, 1H, J5,7 ¼ 2.0 Hz, J5(4,6) ¼ 7.5 Hz, H-
C ¼ 67.53, H ¼ 4.08, N ¼ 11.24; EI MS m/z (% rel. abund.): 373.
), 7.54 (t, 1H, J6,4 ¼ 2.0 Hz, J6(5,7) ¼ 8.0 Hz, H-6), 7.06 (s, 2H, H-3ʺ,H-
13
0
5
1
1
ʺ); C NMR (125 MHz, DMSO-d
26.39, 127.34, 127.34, 127.75, 129.04, 129.04, 135.20, 135.55, 136.00,
47.80, 154.01, 160.27, 160.27, 161.80, 161.80, 162.19, 166.74; Anal.
Calcd for C21
6
):
d
94.92, 99.57, 122.93, 123.61,
4.4.1.26. (E)-4-(Benzo[d]thiazol-2-yl)-N -((pyridin-4-yl)methylene)
benzohydrazide (31). White solid, R
8:2); m.p. 285 C. Yield: (0.293 g, 82%); HNMR (500 MHz, DMSO-
f
¼ 0.68 (ethyl acetate:hexane
ꢂ
1
H
15
N
3
O
4
S, C ¼ 62.21, H ¼ 3.73, N ¼ 10.36, Found
d
6
):
d
12.32 (s, 1H, NH), 8.69 (d, 2H, J2ʺ,6ʺ/3ʺ,5ʺ ¼ 5.0 Hz, H-2ʺ,H-6ʺ),
0
0
C ¼ 62.22, H ¼ 3.74, N ¼ 10.38; EI MS m/z (% rel. abund.): 405.
8.48 (s,1H, CH]N), 8.29 (d, 2H, J
2
0
,6
0
/3
0
,5
,5
0
¼ 8.0 Hz, H-2 ,H-6 ), 8.22 (d,
0
0
1
H, J4,5 ¼ 8.0 Hz, H-4), 8.14 (d, 2H, J
3
0
0
/2
0
,6 ¼ 8.0 Hz, H-3 ,H-5 ), 8.11
0
4
.4.1.22. (E)-N -(3-Bromo-4-hydroxybenzylidene)-4-(benzo[d]thia-
(d, 1H, J7,6 ¼ 7.5 Hz, H-7), 7.72 (d, 2H, J3ʺ,5ʺ/2ʺ,6ʺ ¼ 5.0 Hz, H-3ʺ,H-5ʺ),
zol-2-yl)benzohydrazide (27). Yellow solid, R
te:hexane 7:3); m.p. 275 C. Yield: (0.383 g, 85%); HNMR
f
¼ 0.45 (ethyl aceta-
7.62 (dt, 1H, J5,7 ¼ 2.0 Hz, J5(4,6) ¼ 7.0 Hz, H-5), 7.56 (dt, 1H,
ꢂ
1
13
J6,4 ¼ 2.0 Hz, J6(5,7) ¼ 7.0 Hz, H-6); C NMR (125 MHz, DMSO-d
6
):

398
M. Taha et al. / European Journal of Medicinal Chemistry 92 (2015) 387e400
d
121.54, 121.54, 122.96, 123.63, 126.44, 127.38, 127.38, 127.78,
29.29, 129.29, 135.21, 135.64, 136.30, 141.87, 141.87, 146.39, 150.76,
54.00, 162.84, 166.68; Anal. Calcd for C20
OS, C ¼ 67.02,
4.5. Molecular docking
1
1
14
H N
4
Binding of prospective inhibitors with human intestinal a-
H ¼ 3.94, N ¼ 15.63, Found C ¼ 67.01, H ¼ 3.95, N ¼ 15.63; EI MS m/z
glucosidase and, thereby, inhibiting the hydrolysis of di- and
polysaccharides to glucose, is one of the potential approaches to
treat diabetes mellitus. To observe the binding strength and
pattern, a molecular docking study was performed, for which the
(
% rel. abund.): 358.
0
4
.4.1.27. (E)-N -(4-Hydroxy-3-methoxybenzylidene)-4-(benzo[d]
3D protein structures for both C- and N-terminal domains of hu-
thiazol-2-yl)benzohydrazide (32). White solid, R
acetate:hexane 7:3); m.p. 228 C. Yield: (0.342 g, 85%); H NMR
f
¼ 0.65 (ethyl
ꢂ
1
man intestinal -glucosidase (accession codes: 3TOP and 3L4T,
a
respectively) were retrieved from protein data bank (PDB). These
structures were selected after careful analysis of over 30 PDB
structures.
(
500 MHz, DMSO-d
6
):
d 11.87 (s, 1H, NH), 8.37 (s,1H, CH]N), 8.27
0
0
(
d, 2H, J
2
0
,6
0
/3
0
,5
0
0
¼ 8.5 Hz, H-2 ,H-6 ), 8.22 (d, 1H, J4,5 ¼ 8.0 Hz, H-4),
0
0
8
7
.14 (d, 2H, J
3
,5
0
/2
0
,6 ¼ 8.5 Hz, H-3 ,H-5 ), 8.11 (d, 1H, J7,6 ¼ 8.0 Hz, H-
The 2D structures of all compounds were prepared using Marvin
), 7.62 (dt, 1H, J5,7 ¼ 2.0 Hz, J5(4,6) ¼ 7.0 Hz, H-5), 7.56 (dt, 1H,
6.1.2, ChemAxon (http://www.chemaxon.com), and the physico-
J
7
6,4 ¼ 2.0 Hz, J6(5,7) ¼ 7.5 Hz, H-6); 7.37 (d, 1H, J2ʺ,6ʺ ¼ 2.0 Hz, H-2ʺ),
chemical properties such as number of hydrogen-bond doner and
acceptor (NHBD and NHBA, respectively), partition co-efficient
.13 (dd, 1H, J6ʺ,2ʺ ¼ 2.0 Hz, J6ʺ,5ʺ ¼ 7.5 Hz, H-6ʺ), 6.87 (d, 1H,
13
J
1
1
1
5ʺ,6ʺ ¼ 8.5 Hz, H-5ʺ); C NMR (125 MHz, DMSO-d
15.97, 122.81, 122.90, 123.59, 126.14, 126.35, 127.32, 127.32, 127.68,
29.08, 129.08, 135.18, 135.87, 136.28, 148.58, 149.44, 149.65, 154.01,
62.62, 166.75; Anal. Calcd for C22
6
): d 56.09, 109.66,
(logP), molecular weight (MW), and polar surface area (PSA) were
predicted through Calculator Plugins of Marvin 6.1.2.
The 3D structures of compounds 6e35 were built in Gabedit
H
17
N
3
O
3
S, C ¼ 65.49, H ¼ 4.25,
[53] followed by geometry optimizations at hybrid B3LYP density
N ¼ 10.42, Found C ¼ 65.50, H ¼ 4.25, N ¼ 10.43; EI MS m/z (% rel.
functional theory using 6-311 þ G(d,p) basis sets. The dipole
moment was also calculated at the same level of theory and basis
sets. These energy optimized structures were then subjected for
molecular docking studies. The Docking studies were carried out by
AutoDock Vina [54], using built-in Lamarckian genetic algorithm
method. A total of 20 runs were performed for each docking, and
the rest of the parameters were set to default values. Search space
was restricted to a grid box size of 35 each in x, y, and z dimensions,
which was centered on the binding sites of protein with x, y, and z
coordinates of ꢁ31.426, 35.7 and 26.324 Å, respectively, for C-ter-
minal domain while 44.631, 90.461 and 34.088 Å, respectively, in
abund.): 403.
0
4
.4.1.28. (E)-N -(3-Hydroxy-2-iodo-4-methoxybenzylidene)-4-
(
benzo[d]thiazol-2-yl)benzohyd-razide (33). Light yellow solid,
ꢂ
R
8
f
¼ 0.58 (ethyl acetate:hexane 7:3); m.p. 275 C. Yield: (0.455 g,
1
6%); H NMR (500 MHz, DMSO-d
6
): d 12.18 (s, 1H, NH), 9.98 (s, 1H,
0
0
OH) 8.74 (s,1H, CH]N), 8.27 (d, 2H, J
8
5
2
0
,6
0
/3
0
,5
0
0
¼ 8.0 Hz, H-2 ,H-6 ),
0
.21 (d, 1H, J4,5 ¼ 8.0 Hz, H-4), 8.14 (d, 2H, J
3
,5
0
/2
0
,6 ¼ 8.5 Hz, H-3 ,H-
0
), 8.11 (d, 1H, J7,6 ¼ 8.0 Hz, H-7), 7.62 (t, 1H, J5(4,6) ¼ 7.0 Hz, H-5),
7
.56 (t, 1H, J6(5,7) ¼ 7.5 Hz, H-6); 7.50 (d, 1H, J5ʺ,6ʺ ¼ 7.5 Hz, H-5ʺ), 7.13
13
(
d, 1H, J6ʺ,5ʺ ¼ 7.5 Hz, H-6ʺ), 3.89 (s, 3H, OCH
3
); C NMR (125 MHz,
the case of N-terminal domain of
a-glucosidase. The search
DMSO-d
6
):
d
56.69, 112.18, 119.03, 120.34, 122.95, 123.61, 126.41,
exhaustiveness was set to 60 in all dockings. VMD [55] and open-
office were used for snapshots, graphs and results analysis. Mo-
lecular Operating Environment (MOE) [56] suit has been used to
map the electrostatic fields of the protein.
1
1
C
27.36, 127.36, 127.67, 129.21, 129.21, 135.19, 135.99, 136.06, 146.59,
48.97, 152.43, 154.01, 155.02, 162.76, 166.77; Anal. Calcd for
22
H
16IN
3
O
3
S, C ¼ 49.92, H ¼ 3.05, N ¼ 7.94, Found C ¼ 49.93,
H ¼ 3.07, N ¼ 7.95; EI MS m/z (% rel. abund.): 529.
4.6. Conclusions
0
4
.4.1.29. (E)-N -(2,5-Dihydroxybenzylidene)-4-(benzo[d]thiazol-2-yl)
benzohydrazide (34). Dark brown solid, R
hexane 7:3); m.p. 292 C. Yield: (0.327 g, 84%); H NMR (500 MHz,
f
¼ 0.53 (ethyl acetate:-
The aim of the present work was to design, synthesize and
ꢂ
1
screen the
a-glucosidase activity of novel benzothiazole derivatives
DMSO-d
8
1
6
):
.62 (s,1H, CH]N), 8.28 (d, 2H, J
H, J4,5 ¼ 8.0 Hz, H-4), 8.14 (d, 2H, J
d 12.18 (s, 1H, NH), 10.39 (s, 1H, OH), 9.05 (s, 1H, OH),
in a quest to find out new structure leads as the most potent
a
-
0
0
0
0
0
0
¼ 8.5 Hz, H-2 ,H-6 ), 8.22 (d,
2
,6
/3
,5
,5
glucosidase inhibitors. Our target has been obtained by the syn-
thesis of small benzothiazole derivatives library of 30 compounds
with various functionalities. We synthesized novel derivatives of
benzothiazole with very simple and known chemistry route to
0
0
0
0
0
,6 ¼ 8.5 Hz, H-3 ,H-5 ), 8.11
3
/2
(
1
(
1
1
1
d, 1H, J7,6 ¼ 7.5 Hz, H-7), 7.62 (t, 1H, J5(4,6) ¼ 7.0 Hz, H-5), 7.54 (dt,
00
H, J6(5,7) ¼ 7.0 Hz, H-6), 7.0.2 (d, 1H, J6ʺ,4ʺ ¼ 2.0 Hz, H-6 ), 6.78e6.75
13
m, 2H, H-3ʺ H-4ʺ); C NMR (125 MHz, DMSO-d
19.48, 119.61, 122.93, 123.62, 126.41, 127.35, 127.35, 127.76, 129.16,
29.16, 135.21, 135.61, 136.11, 148.63, 150.37, 150.78, 154.01, 162.49,
66.71; Anal. Calcd for C21
6
): d 114.33, 117.60,
develop new inhibitors for
a-glucosidase activity. They showed 5 to
2
00 times better activity than the standard drug, and their activities
were further proved by docking studies. We believe that they can
be used as lead molecules for further study.
H
15
N
3
O
3
S, C ¼ 64.77, H ¼ 3.88, N ¼ 10.79,
Found C ¼ 64.75, H ¼ 3.88, N ¼ 10.81; EI MS m/z (% rel. abund.): 389.
Acknowledgment
0
4
.4.1.30. (E)-N -(3,5-Dihydroxybenzylidene)-4-(benzo[d]thiazol-2-yl)
benzohydrazide (35). White solid, R
f
¼ 0.43 (ethyl acetate:hexane
Authors would like to acknowledge The Ministry of Agriculture
(MOA) Malaysia and Universiti Teknologi MARA for the financial
support under MOA grant file No. 100-RMI/MOA 16/6/2 (1/2013)
and Atta-ur-Rahman Institute for Natural product Discovery (RiND)
to provide excellent designed lab and facility for the research and
all technical and non-technical staff for a lot of support for this
work. One of the co-authors, MQF, would like to thank Dr. Sobia
Ahsan Halim in Centre of Excellence in Molecular Biology (CEMB),
University of the Punjab, Lahore, Pakistan for providing the MOE
facility. This work was financially supported by the Higher Educa-
tion Commission (HEC) Pakistan, Project No. 20-2073 under the
National Research Program for Universities.
ꢂ
1
7:3); m.p. 297 C. Yield: (0.331 g, 85%); H NMR (500 MHz, DMSO-
d
6
):
d
11.93 (s, 1H, NH), 9.53 (s, 2H, 2ꢃOH), 8.29 (s,1H, CH]N), 8.27
0
0
(
d, 2H, J
2
0
,6
0
/3
0
,5
0
¼ 8.5 Hz, H-2 ,H-6 ), 8.22 (d, 1H, J4,5 ¼ 8.0 Hz, H-4),
0
0
8
7
6
.14 (d, 2H, J
3
0
,5
0
/2
0
,6 ¼ 8.5 Hz, H-3 ,H-5 ), 8.11 (d, 1H, J7,6 ¼ 8.0 Hz, H-
), 7.62 (t, 1H, J5(4,6) ¼ 7.0 Hz, H-5), 7.54 (t, 1H, J6(5,7) ¼ 8.0 Hz, H-6),
00
00
13
.63 (d, 2H, J2ʺ,6ʺ/4ʺ ¼ 2.0 Hz, H-2 H-6 ), 6.29 (s, 1H, H-4ʺ); C NMR
): 105.14, 105.14, 105.80, 122.94, 123.61,
26.39, 127.35, 127.35, 127.72, 129.14, 129.14, 135.19, 135.97, 136.11,
(
125 MHz, DMSO-d
6
d
1
136.38, 149.18, 154.01, 159.19, 159.19, 162.71, 166.74; Anal. Calcd for
C
21
H
15
N
3
O
3
S, C ¼ 64.77, H ¼ 3.88, N ¼ 10.79, Found C ¼ 64.75,
H ¼ 3.91, N ¼ 10.81; EI MS m/z (% rel. abund.): 389.

M. Taha et al. / European Journal of Medicinal Chemistry 92 (2015) 387e400
399
Appendix A. Supplementary data
benzophenonehydrazone Schiff bases and their in vitro antiglycating activ-
ities, Med. Chem. 9 (2013) 588e595.
[
[
21] M. Taha, H. Naz, S. Rasheed, N.H. Ismail, A.A. Rahman, S. Yousuf,
M.I. Choudhary, Synthesis of 4-methoxybenzoylhydrazones and evaluation of
their antiglycation activity, Molecules 19 (2014) 1286e1301.
22] M. Taha, N.H. Ismail, S. Imran, K.M. Khan, 4-[5-(2-methoxyphenyl)-1,3,4-
oxadiazol-2-yl]benzohydrazide, Molbank (2014) M826.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2015.01.009.
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