Synthesis of novel inhibitors of β-glucuronidase based on the benzothiazole skeleton and their molecular docking studies

Article abstract of DOI:10.1039/c5ra23072a

A series of benzothiazole based oxadiazole analogs 1-20 was synthesized by reacting intermediate sulfite adducts with 2-aminothiophenol and refluxing in DMF for 12 h to afford ester analog I which, on further refluxing in methanolic hydrazine hydrate solu

Full text of DOI:10.1039/c5ra23072a

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: M. Taha, N. I.
Ismail, S. Imran, M. Selvaraj and F. Rahim, RSC Adv., 2015, DOI: 10.1039/C5RA23072A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 28
RSC Advances
View Article Online
DOI: 10.1039/C5RA23072A
Synthesis of Novel Inhibitors of β-Glucuronidase Based on the Benzothiazole Skeleton and
their Molecular Docking Studies
Muhammad Tahaa,b, Nor Hadiani Ismaila,b, Syahrul Imrana,b, Manikandan Selvarajc,d, Fazal
Rahime
aAtta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM),
Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia
bFaculty of Applied Science UiTM, 40450 Shah Alam, Selangor, Malaysia
cIntegrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM),
Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia
dFaculty of Pharmacy, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300
Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia
eDepartment of Chemistry, Hazara University, Mansehra-21120, Pakistan
Abstract
A series of benzothiazole based oxadiazole analogs 1-20 was synthesized by reacting
intermediate sulfite adduct with 2-aminothiophenol upon refluxing in DMF for 12 h to afford
ester analog I which on further refluxing in methanolic hydrazine hydrate solution to afford
compound II. Compound II was then condensed with different aromatic carboxylic acids in
POCl3 to synthesize novel benzothiazole based oxadiaxole derivatives 1-20 in good yields. All
compounds were screened for β-glucuronidase inhibitory potential. Compounds 7, 14, 8 and 17
were found to be the most active analogs among the series with micromolar activities (IC50
=
2.16, 4.38, 7.20 and 8.56 µM respectively). While compounds 5, 10, 18, 16, 1, 2, 15, 11, and 20
showed moderate activity with IC50 value ranging between 14.12-75.14 µM), whereas
compounds 3, 12, 13, and 19 were found to be inactive. Further studies showed that they do not
possess any cytotoxic properties. Molecular docking studies were done to reveal the binding
modes of the synthetic benzothiazole derivatives 1-20 targeting the active site of β-glucuronidase
(PDB code: 1BHG).
Keywords: benzothiazole, β-glucuronidase, Oxadiazole, Docking studies
 Correspondence and reprints
E-mail: taha_hej@yahoo.com and muhamm9000@puncakalam.uitm.edu.my, Tel: 0060193098141
1

RSC Advances
Page 2 of 28
View Article Online
DOI: 10.1039/C5RA23072A
1. Introduction
-Glucuronidase enzyme is present in lysosomes and microsomes tissues, and excretes normally
in urine along with cells of the urinary tract [1]. -Glucuronidase is an exoglycosidase enzyme
related with breakage of glucuronosyl-O-bonds [2]. It is present in different body parts like, body
fluids, liver, spleen, kidney, gastric juice, blood cells, bile, lung, urine, muscle, and serum. [3,4].
In some diseases like hepatic diseases, cancer, inflammatory joint, and AIDS, activity of -
glucuronidase increases [5]. Endogenous biliary -glucuronidase is related with deconjugation of
glucuronides of bilirubin which in terns produce cholelithiasis in human bile [6]. Amplified level
of this enzyme has been related with different ailments of urinary tract, such as active
pyelonephritis, acute renal necrosis and cancer of the kidney and bladder [7]. In contrast to other
enzymes
E.
coli
-glucuronidase
has
higher
pH
[8].
Deficiency
of
-glucuronidase in humane has resulted in mucopolysaccharidosis type VII (MPS VII; Sly
syndrome), which is characterized by growth of glycosaminoglycans in cells of most tissues
[9,10]. Leprosy is a disease found in children of less than 15 years of age caused by -
glucuronidase.
The benzothiazole skeleton constitutes an important central template for a wide variety of
biologically active compounds, having many pharmacological functions. The benzothiazoles also
have immunosuppressive, antiviral properties [11,12], and calmodulin (CaM) antagonists activity
[13]. Extensive literature search reveals the antimalarial [14], antifungal [15], anti-inflammatory,
analgesic [16], anticandidous [17] and various CNS activities [18] of benzothiazoles.
Much attention had been paid to the chemistry and biological activities of 1,3,4-oxadiazole
nucleus. Several compounds possessing 1,3,4-oxadiazole scaffold have been recently reported as
potential antiproliferative agents [19-21]. Beside anticancer activity, other biological activities
have been reported for 1,3,4-oxadiazole derivatives such as antidiabetic [22], antitubercular [23],
antifungal [24], anti-inflammatory [25], and antibacterial activities [26]. Moreover, many
sulfonamide analogs have been reported as anticancer agents [27-29].
Here in this study we are reporting on synthesis of the hybrid molecule of benzothiazole and
oxadiazole, its characterization, -Glucuronidase inhibition and molecular docking studies.
2

Page 3 of 28
RSC Advances
View Article Online
DOI: 10.1039/C5RA23072A
2. Result discussion
2.1 Chemistry
A series of benzothiazole was synthesized according to literature protocol [30]. The intermediate
sulfite adduct was refluxed with 2-aminothiophenol in dimethylformamide for 12 h to afford
compound I. The compound I was refluxed in methanolic hydrazine hydrate solution to afford
compound II. Compound II was then condensed with different aromatic carboxylic acids in
POCl3 to synthesize novel benzothiazole derivatives 1-20 in good yields [31]. Spectral data
including 1H-NMR, 13C NMR, HR MS, elemental analysis and melting points of the synthesized
compounds were recorded Scheme-1.
Scheme-1 Synthesis of novel benzothiazole derivatives 1-20
3

RSC Advances
Page 4 of 28
View Article Online
DOI: 10.1039/C5RA23072A
Table 1. β-Glucuronidase inhibitory potential of novel benzothiazole derivatives 1-20.
Comp.
R
IC50 ± SEMa [M] Comp.
R
IC50 ± SEMa [M]
1
18.38 ± 0.60
31.21 ± 0.75
11
39.15 ± 1.25
2
3
12
13
N. A.b
N. A.b
N. A.b
4
5
14
15
14.12 ± 0.48
74.37 ± 1.68
4.38 ± 0.20
32.42 ± 1.10
6
7
16
17
24.17 ± 1.05
2.16 ± 0.25
17.30 ± 0.70
8.56 ± 0.49
4

Page 5 of 28
RSC Advances
View Article Online
DOI: 10.1039/C5RA23072A
8
9
18
19
7.20 ± 0.35
15.40 ± 0.75
19.68 ± 0.95
N. A.b
10
20
14.89 ± 0.46
75.14 ± 2.49
D-Saccharic acid 1,4-lactone
48.4 ± 1.25
aSEM is the standard error of the mean, bN.A. No activity
3.0. -Glucuronidase and pharmacokinetic properties evaluation
In the continuation of our effort for enzyme inhibition [32] we synthesized novel derivatives of
benzothiazole 1-20. All synthesized compounds were evaluated for β-glucuronidase inhibitory
potential. The β-glucuronidase inhibitory activity performed in this study involves mixing
synthesized compounds with substrate (p-nitrophenyl-β-D-glucuronide) and β-glucuronidase
enzyme to determine the ability of the compounds synthesized to prevent β-glucuronidase from
breaking down the substrate (p-nitrophenyl-β-D-glucuronide) into β-D-glucuronide. Compounds
7, 14, 8 and 17 were found to be the most active analogs among the series with IC50 ranging
2.16-8.56 µM respectively. Whereas compound 5, 10, 18, 16, 1, 11, 2, 15, and 20 showed good
to moderate activity with IC50 value ranging between 14.12-75.14 µM. On the other hand
compound 3, 12, 13, and 19 were found inactive (Table 1). Further studies showed that all
compounds were not cytotoxic.
The twenty benzothiazole derivatives 1-20 were optimized using Ligprep and their
pharmacokinetic properties were evaluation using QikProp for three descriptors: the predicted
aqueous solubility (QP log S), the predicted octanol/water partition coefficient (QP logP), and
5

RSC Advances
Page 6 of 28
View Article Online
DOI: 10.1039/C5RA23072A
the predicted Caco-2 cell permeability (QPPcaco) considering their recommended range (Table
2).
Table 2: Optimization of novel benzothiazole derivatives 1-20
[a]
[c]
Compounds
QPlog P o/w
4.501
4.204
3.888
4.319
4.843
4.168
3.622
3.664
3.664
3.722
3.569
5.141
5.083
QPlog S[b]
- 6.698
-5.942
-5.621
-6.541
-6.472
-5.544
-6.229
-6.199
-6.2
QP Pcaco [nms-1]
1
2
1027.072
1531.164
1310.952
733.849
2339.252
2180.364
265.417
312.746
312.305
375.562
223.569
2420.136
2375.661
3
4
5
6
7
8
9
10
11
12
13
-6.177
-6.253
-6.965
-6.835
6

Page 7 of 28
RSC Advances
View Article Online
DOI: 10.1039/C5RA23072A
14
15
16
17
18
19
20
4.414
4.319
4.42
-6.484
-6.539
-6.839
-6.918
-7.312
-6.688
-5.618
1029.629
735.78
731.947
2422.332
2422.529
2421.15
1308.768
5.184
5.45
5.002
3.886
[a] Predicted octanol/water partition coefficient (QP log Po/w): range of recommended values= - 2.0 - + 6.5.
[b] Predicted aqueous solubility (QP log S): values less than -6 or greater than -1 are undesirable.
[c] Predicted apparent Caco-2 cell permeability (QP Pcaco): value < 25 is poor.
3.1. Molecular docking studies
Molecular docking studies were done to reveal the binding modes of the 1-20 synthetic
benzothiazole derivatives targeting the active site of β-glucuronidase (PDB code: 1BHG). In
compound 7 the hydroxyl group at meta and para position in the phenyl ring forms hydrogen
bond with Trp528, Gln524 and Asn486 respectively. While the ring forms hydrophobic
interaction with Tyr487 and Leu501. The phenyl-oxadiazole group forms hydrophobic
interaction via weak van der Waals interactions with side chains non-polar group of His509,
Tyr505, Tyr508, Asn484, Ser503 and Asn502. The thiazole group of the benzothiazole ring
forms π- π interaction with Tyr504, while the benzene ring forms cation-π interaction with
7

RSC Advances
Page 8 of 28
View Article Online
DOI: 10.1039/C5RA23072A
Lys606. Additionally, the benzothiazole ring forms hydrophobic mediated van der Waals
contact with side chains of Arg600, Asp207, Glu451 and Glu540 (Figure-1a).
Compound 14 being the second most active compound, forms stable interaction with active site
residues of β-D-glucuronidase. Where, the benzene ring of the benzothiazole ring and the
benzene ring of the other end of the compound 14 form π- π interaction with Tyr505 and Trp587,
respectively. While the hydroxyl group attached to the benzene ring forms hydrogen bond
interaction with Tyr508 and non-polar side chains of Lys606, Glu451, Asn450, Asp207, His385,
Asn604 and Glu540 form albeit weak van der Waals interactions with phenyl-oxadiazole.
Similar hydrophobic interactions are also found between the benzothiazole ring and with side
chains of Gln524, Ser503, His509, Ser503 Asn484, Asn502 and Tyr504 as in Figure-1b.
Compound 8 is the third most active compound among the benzothiazole-phenyl-oxadiazole
derivatives and the predicted preferred bind pose of compound 8 in the active site of β-D-
glucuronidase showed that the benzothiazole ring system forms π-π interaction with Tyr504,
while the same ring system forms van der Waals interaction with non-polar side chains of
residues such as Tyr508, Arg600, Asp207, Lys606, Trp587, Glu540, Glu451, Asn484.
Additionally, the middle benzene ring of the compound 8 forms similar van der Waals
interaction with side chains of Ser503, His509, Asn502, and Tyr508. The phenyl-oxadiazole
group at the other end forms non-polar contacts through weak van der Waals interactions with
side chains of Leu501, Tyr487 and Tyr505.While the meta hydroxyl group forms hydrogen bond
interaction with Gln524 and Trp528 (Figure-1c).
8

Page 9 of 28
RSC Advances
View Article Online
DOI: 10.1039/C5RA23072A
Compound 17 is the fourth most active compound among the synthesized benzothiazole-phenyl-
oxadiazole derivatives. The predicted binding mode of compound 17 showed that the
flurophenyl oxadiazole forms weak hydrophobic interaction with Leu501, Tyr505, Trp528,
Tyr487 and van der Waals interactions with Gln524, Asn486, Ser485, Asn484, Ser505 and
Asn502. The thiazole group of the benzothiazole ring forms π-π interaction with Tyr504, while
the benzene ring forms cation-π interaction with Lys606 similar as that observed in compound 7.
Furthermore, the central benzene ring forms van der Waals interaction with non-polar part of
Glu451 and Tyr508. While the benzothiazole ring system was involved in weak hydrophobic
contacts with side chains of Arg600, Glu540 and Asp207 as shown in Figure-1d.
Binding mode analysis shows that the inactivity of these compounds largely depends on the
hydrophobic substituted group, while the active site residues are of hydrophilic in nature. The
binding mode of the potent compounds illuminates the activity profile, where the hydrophilic
nature of these compounds form stable hydrogen bond network with the key hydrophilic residues
in the active site. Consistently, the activity profile of the compounds directly depends on
magnitude of hydrogen bonding.
9

RSC Advances
Page 10 of 28
View Article Online
DOI: 10.1039/C5RA23072A
Figure1: Graphical illustration of predicted binding modes of active benzothiazole derivatives.
Binding modes of a. compound 7 shown in stick form, b. Compound 14, c. Compound 8 and d.
Compound 17. Key residues are represented in spear and labeled. The hydrogen bond
interactions are represented by magenta arrow, π-π interactions are shown in green color lines
and cation-π interactions are shown in red color lines. Compounds are represented in line form.
Conclusions
Successively, our molecular docking studies evidently demonstrate the interaction pattern of our
synthetic compounds in correspondence with β-glucuronidase inhibitory assay. Analysis of the
binding mode clearly shows the presence of hydrophilic group i.e. hydroxyl moiety plays a key
10

Page 11 of 28
RSC Advances
View Article Online
DOI: 10.1039/C5RA23072A
role in the activity data. Additionally, π-π and cation-π interaction along with hydrophobic
interaction do also influence the activity profile. The compounds were not showing any
cytotoxicity activity.
3. Experimental
3.1 General
NMR experiments were performed on UltraShield Bruker FT NMR 500 MHz, CHN analyses
were performed on a Carlo Erba Strumentazion-Mod-1106, Italy. Thin layer chromatography
(TLC) was performed on pre-coated silica gel aluminum plates (Kieselgel 60, 254, E. Merck,
Germany). Chromatograms were visualized by UV at 254 and 365 nm.
3.2 β-glucuronidase inhibition activity
β-glucuronidase (E.C. 3.2.1.31 from bovine liver, G-0251) inhibition activity of the compounds
had been evaluated by using method as reported in [33]. In this study, D-saccharic acid 1,4-
lactone had been used as a standard drug [34].
3.3 Cytotocity
In vitro cytotoxicity assays were performed as described by Taha et al. (2015)[35]. Briefly, the
cells (1x104/well) were seeded in 96-well microtiter plates (Nunc) and allowed to grow for 24 h
before treatment. After 24 h of incubation, the cells were treated with six different concentrations
(0.1-100 µg/mL) of test compounds, in three replicates. The plates were incubated for 72 h at
37°C in a 5% CO2 incubator. A stock solution was obtained by dissolving the test compounds in
DMSO. Further dilution to different tested concentrations were then carried out ensuring that the
final concentration of DMSO in the test and control wells was not in excess of 1% (v/v). No
effect due to the DMSO was observed. Doxorubicin was used as the positive control. The well
containing untreated cells was the negative control. At the end of the incubation period, the
media were replaced with medium containing 50 µg/mL of Neutral Red. The plates were
incubated for another 3 h to allow for uptake of the vital dye into the lysosomes of viable and
injured cells. After the incubation period, the media were removed and cells were washed with
the neutral red washing solution. The dye was eluted from the cells by adding 200 µL of Neutral
Red resorb solution and incubated for 30 min at room temperature with rapid agitation on a
11

RSC Advances
Page 12 of 28
View Article Online
DOI: 10.1039/C5RA23072A
microtiter plate shaker. Dye absorbance was measured at 540 nm using a spectrophotometer
ELISA plate reader.
3.4 Protein Preparation for Docking
The human β-D-glucuronidase structure (PDB code: 1BHG) [36] was downloaded from the PDB
database and optimized using protein preparation wizard in Maestro [37]. The initial crystal
structure were preprocessed for assigning bond order, addition of hydrogen, adding missing
disulfide bonds and deleting B-chain, co-factors and water molecules. Further the structure was
refined by minimizing hydrogens of altered species, pH 7 was set and a restrained energy
minimization was done with converge heavy atoms to RMSD 0.30 Å.
3.5 Ligand Preparation
All the twenty benzothiazole-phenyl-oxadiazole derivatives 3D structures were sketched using
the Schrodinger Maestro [37] using build option and the structure were further optimized using
Ligprep application with OPLS_2005 forcefield, generation of possible states of pH 7.0 ±
2.0.Generating possible tautomers, with all combinations of stereoisomer and with lowest energy
conformation.
3.6 Rapid pharmacokinetic predictions of Benzothiazole-phenyl-oxadiazole derivatives
In silico pharmacokinetic properties were evaluated for the twenty benzothiazole derivatives
using the QikProp program, implemented in Maestro [38]. Particular, three descriptors were
taken into consideration for evaluation: the predicted aqueous solubility (QP log S), the predicted
octanol/water partition coefficient (QP logP), and the predicted Caco-2 cell permeability
(QPPcaco).
3.7 Docking studies
Docking studies were performed using Glide: A complete solution for ligand-receptor docking in
small molecule drug discovery suite [37]. Initially, receptor grid generation was used to generate
grid on the β-D-glucuronidase protein structure were the grid box was centered on catalytic
residue Glu540 by supplying X,Y,Z coordinates: 81.875, 81.601 and 88.010 of β-D-
glucuronidase with 12 Å radius respectively. The standard precision (SP) mode was chosen
12

Page 13 of 28
RSC Advances
View Article Online
DOI: 10.1039/C5RA23072A
during the Glide docking process and Glide gscore was considered during analysis. While,
GOLD (Genetic Optimization for Ligand Docking) version 5.1 [39] was used as docking
validation tool. Gold scoring function was chosen as a fitness function. The genetic algorithm
(GA) with search efficiency of 100% was set. The specified centroid (x, y, z coordinates: 80.43,
84.41, 90.48) with a cavity 12 Å radius was defined as active site. Results divergent by less than
1.5 Å in ligand-all atom RMSDs were clustered together. Best clusters and top rank scored
binding mode analyzed in Pymol [40].
3.8 Synthesis of methyl 4-(benzo[d]thiazol-2-yl)benzoate (I)
2-aminobenzenethiol (6.63 g, 53 mmol) and 4-formylbenzoic acid methyl ester (6.73 g, 41
mmol) were dissolved in DMF (40 mL). Sodium metabisulfite (7.79 g, 41 mmol) was added and
reaction mixture was refluxed 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 (I) and yielded 10.20 g (92.5 %) of White solid, Rf = 0.57 (ethyl
1
acetate:hexane 2:8); M.p. 228 °C; H-NMR (500 MHz, DMSO-d6): δ 8.26 (d, 2H, J = 8.5 Hz),
8.21 (d, 2H, J = 8.5 Hz), 8.10 (d, 1H, J = 8.0 Hz), 8.08 (d, 1H, J = 8.0 Hz), 7.61 (dt,1H, J = 6.5,
J = 1.5 Hz), 7.45 (dt,1H, J = 8.0, J = 1.0 Hz), 3.98 (s, 3H, CH3); 13C-NMR (DMSO-d6, 125
MHz): δ 52.88, 122.99, 123.71, 126.53, 127.41, 127.41, 127.95, 130.63, 130.63, 132.17, 135.25,
137.24, 153.98, 166.09, 166.45; Anal. Calcd for C15H11NO2S, C = 66.89; H = 4.12; N 5.20;
found C = 66.87; H = 4.13; N 5.22; EI MS m/z (% rel. abund.): 269.
3.9 Synthesis of 4-(benzo[d]thiazol-2-yl)benzohydrazide (II)
Mixture of compound I (8.07 g, 30 mmol) and hydrazine hydrate (10 mL, 95%) in ethanol (50
mL) was refluxed for 12 h. The solvent and excess of hydrazine hydrate were evaporated and the
residue (II) was washed with water, filtered, dried, and then crystallized from ethanol and
1
yielded White solid, Rf = 0.32 (ethyl acetate:hexane 9:1); (7.35 g, 91%). m.p. 325 °C; H-NMR
(500 MHz, DMSO-d6): δ 9.82 (s, 1H, NH), 8.28 (d, 2H, J = 8.5 Hz), 8.25 (d, 2H, J = 8.0 Hz),
8.11 (d, 1H, J = 8.0 Hz), 8.06 (d, 1H, J = 8.0 Hz), 7.64 (dt,1H, J = 6.5, J = 2.0 Hz), 7.52 (dt,1H, J
13
= 8.0, J = 1.0 Hz), 3.91 (br. s, 2H, NH2); C-NMR (DMSO-d6, 150 MHz): δ 122.93, 123.56,
126.33, 127.31, 127.31, 127.62, 128.48, 128.48, 135.13, 135.42, 136.05, 153.99, 165.44, 166.87;
13

RSC Advances
Page 14 of 28
View Article Online
DOI: 10.1039/C5RA23072A
Anal. Calcd for C14H11N3OS, C = 62.43; H = 4.12; N 15.60; found C = 62.44; H = 4.13; N 15.62;
EI MS m/z (% rel. abund.):269.
3.9.1 General procedure for synthesis of oxadiazole benzohydrazones (1-20)
A mixture of compound (II) (0.25 mmol) and various aromatic acid (0.25 mmol) in POCl3 (5
ml) was refluxed for 8-14 h at 120 ᶛC. The mixture was cooled and poured onto crushed ice.
It was neutralized with NaHCO3 solution and the resulting solid mass precipitated out was
filtered, dried, and crystallized [17].
3.9.1.1 2-(5-(4-(benzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-4-methoxyphenol (1)
1
Yellow solid. Yield: 85.1%. m.p.: 279-280 °C; HNMR (500 MHz, DMSO-d6): δ 10.26 (s, 1H,
OH), 8.29 (d, 2H, J2ʹ,6ʹ/5ʹ,3ʹ = 8.0 Hz, H-2ʹ,H-6ʹ), 8.20 (d, 1H, J4,5 = 8.0 Hz, H-4), 8.15 (d, 2H,
J3ʹ,5ʹ/2ʹ,6ʹ = 8.0 Hz, H-3ʹ,H-5ʹ), 8.10 (d, 1H, J7,6 = 7.5 Hz, H-7), 7.63 (dt, 1H, J5,7 = 2.0, J5(4,6) = 7.5
Hz, H-5), 7.55 (dt, 1H, J6,4 = 2.0, J6(5,7) = 7.5 Hz, H-6), 7.11 (d, 1H, J6ʹʹ,4ʹʹ = 2.0 Hz, H-6ʹʹ), 6.90
(dd,1H, J4ʹʹ,6ʹʹ = 2.0, J4ʹʹ,3ʹʹ = 8.0 Hz, H-4ʹʹ), 6.84 (d, 1H, J3ʹʹ,4ʹʹ = 8.0 Hz, H-3ʹʹ), 3.77 (s, 3H, OCH3);
13C-NMR (150 MHz, DMSO-d6): δ 165.37, 162.52, 154.38, 154.25, 152.79, 152.38, 137.23,
136.39, 128.47, 128.47, 126.72, 126.72, 126.54, 126.24, 125.31, 123.47, 122.60, 118.16, 116.72,
114.81, 110.68, 56.23; HREI-MS: m/z calcd for C22H15N3O3S [M]+ 401.0834; Found 401.0838;
Anal. Calcd for C22H15N3O3S, C, 65.82; H, 3.77; N, 10.47; found C, 65.81; H, 3.79; N, 10.45;
3.9.1.2 2-(4-(benzo[d]thiazol-2-yl)phenyl)-5-(pyridin-2-yl)-1,3,4-oxadiazole (2)
1
Brown solid. Yield: 83.3%. m.p.: 281-282 °C; H-NMR (500 MHz, DMSO-d6): δ 8.69 (d, 1H,
J6ʹʹ,5ʹʹ = 6.0 Hz, H-6ʹʹ), 8.30 (d, 2H, J2ʹ,6ʹ/5ʹ,3ʹ = 8.5 Hz, H-2ʹ,H-6ʹ), 8.20 (d, 1H, J4,5 = 8.5 Hz, H-4),
8.17 (d, 2H, J3ʹ,5ʹ/2ʹ,6ʹ = 8.5 Hz, H-3ʹ,H-5ʹ), 8.10 (d, 1H, J7,6 = 8.5 Hz, H-6), 8.00 (d, 1H, J3ʹʹ,4ʹʹ = 7.0
Hz, H-3ʹʹ), 7.91 (t, 1H, J5ʹʹ(6ʹʹ,4ʹʹ) = 7.0 Hz, H-5ʹʹ), 7.64 (t, 1H, J5(4,6) = 6.5 Hz, H-5), 7.52 (t, 1H,
13
J6(5,7) = 7.0 Hz, H-6), 7.49 (t, 1H, J4ʹʹ(3ʹʹ,5ʹʹ) = 7.0 Hz, H-4ʹʹ); C-NMR (150 MHz, DMSO-d6): δ
167.20, 165.47, 162.42, 152.48, 148.46, 142.01, 139.58, 137.43, 136.29, 128.50, 128.50, 128.50,
126.92, 126.92, 126.59, 126.44, 125.48, 123.70, 122.70, 119.84; HREI-MS: m/z calcd for
14

Page 15 of 28
RSC Advances
View Article Online
DOI: 10.1039/C5RA23072A
C20H12N4OS [M]+ 356.0732; Found 356.0735; Anal. Calcd for C20H12N4OS, C, 67.40; H, 3.39;
N, 15.72; Found C, 67.41; H, 3.40; N, 15.70;
3.9.1.3 2-(4-(benzo[d]thiazol-2-yl)phenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole (3)
1
Light brown solid. Yield: 75.3%. m.p.: 275-266 °C; H-NMR (500 MHz, DMSO-d6): δ 8.96 (s,
1H, H-2ʹʹ), 8.60 (d, 1H, J6ʹʹ,5ʹʹ = 5.0 Hz, H-6ʹʹ), 8.24 (d, 2H, J2ʹ,6ʹ/5ʹ,3ʹ = 8.5 Hz, H-2ʹ,H-6ʹ), 8.19 (d,
1H, J4,5 = 8.5 Hz, H-4), 8.15 (d, 1H, J5ʹʹ,6ʹʹ = 5.0 Hz, H-5ʹʹ), 8.11 (d, 2H, J3ʹ,5ʹ/2ʹ,6ʹ = 8.5 Hz, H-3ʹ,H-
5ʹ ), 8.09 (d, 1H, J7,6 = 7.0 Hz, H-7), 7.60 (t, 1H, J5(4,6) = 7.0 Hz, H-5), 7.51 (t, 1H, J6(5,7) = 7.0
Hz, H-6 ), 7.45 (t, 1H, J4ʹʹ(3ʹʹ,5ʹʹ) = 7.0 Hz, H-4ʹʹ); 13C-NMR (150 MHz, DMSO-d6): δ 165.38,
162.39, 156.14, 152.49, 149.27, 148.44, 137.53, 136.49, 135.71, 128.48, 128.48, 128.24, 126.87,
126.87, 126.49, 126.32, 125.38, 123.67, 123.61, 122.56; HREI-MS: m/z calcd for C20H12N4OS
[M]+ 356.0732; Found 356.0729; Anal. Calcd for C20H12N4OS, C, 67.40; H, 3.39; N, 15.72;
Found C, 67.41; H, 3.41; N, 15.71;
3.9.1.4 4-(5-(4-(benzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)phenol (4)
1
Red solid. Yield: 80.2%. m.p.: 288-289 °C; H-NMR (500 MHz, DMSO-d6): δ 10.60 (s, 1H,
OH), 8.26 (d, 2H, J2ʹ,6ʹ
/3ʹ,5ʹ = 7.5 Hz, H-2ʹ,H-6ʹ), 8.20 (d, 1H, J4,5 = 8.0 Hz, H-4), 8.10 (d, 2H, J3ʹ,5ʹ
/
= 7.5 Hz, H-3ʹ,H-5ʹ), 8.08 (d, 1H, J7,6 = 8.0 Hz, H-7), 7.60-7.56 (m, 3H, H-5, H-2ʹʹ, H-6ʹʹ ),
2ʹ,6ʹ
7.51 (t, 1H, J6(5,7) = 7.5 Hz, H-6), 6.89 (d, 2H, J3ʹʹ,5ʹʹ/2ʹʹ,6ʹʹ = 7.5 Hz, H-3ʹʹ,H-5ʹʹ); 13C-NMR (150
MHz, DMSO-d6): δ 165.49, 165.49, 162.32, 160.76, 152.43, 137.48, 136.39, 128.69, 127.42,
126.72, 126.54, 126.41, 125.49, 123.60, 122.68, 117.38, 115.78; HREI-MS: m/z calcd for
C21H13N3O2S [M]+ 371.0728; Found 371.0736; Anal. Calcd for C21H13N3O2S, C, 67.91; H, 3.53;
N, 11.31; Found C, 67.89; H, 3.52; N, 11.30;
3.9.1.5 2-(4-(benzo[d]thiazol-2-yl)phenyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (5)
1
Dark brown solid. Yield: 78.4%. m.p.: 276-278 °C; H-NMR (500 MHz, DMSO-d6): δ 8.29 (d,
2H, J2ʹ,6ʹ/3ʹ,5ʹ = 8.0 Hz, H-2ʹ, H-6ʹ), 8.19 (d, 1H, J4,5 = 7.0 Hz, H-4), 8.12 (d, 2H, J3ʹ,5ʹ /2ʹ,6ʹ = 8.0 Hz,
H-3ʹ,H-5ʹ), 8.08 (d, 1H, J7,6 = 8.0 Hz, H-7), 7.69(d, 1H, J3ʹʹ,5ʹʹ = 6.0 Hz, H-3ʹʹ), 7.63 (dt, 1H, J5,7
=
2.0, J5(4,6) = 7.5 Hz, H-5), 7.51-7.48 (m, 2H, H-6, H-5ʹʹ), 7.16 (dd, 1H, J4ʹʹ,5ʹʹ = 4.5 Hz, J4ʹʹ,3ʹʹ = 6.0
Hz, H-4ʹʹ); 13C-NMR (150 MHz, DMSO-d6): δ 165.92, 162.36, 160.37, 152.31, 137.53, 136.49,
131.39, 130.53, 130.14, 128.30, 128.30, 127.47, 126.62, 126.62, 126.19, 126.42, 125.48, 123.68,
15

RSC Advances
Page 16 of 28
View Article Online
DOI: 10.1039/C5RA23072A
122.57; HREI-MS: m/z calcd for C19H11N3OS2 [M]+ 361.0344; Found 361.0347; Anal. Calcd
for C19H11N3OS2, C, 63.14; H, 3.07; N, 11.63; Found C, 63.13; H, 3.08; N, 11.65;
3.9.1.6 2-(4-(benzo[d]thiazol-2-yl)phenyl)-5-(furan-2-yl)-1,3,4-oxadiazole (6)
Brown solid. Yield: 79.7%. m.p.: 289-290 °C; 1H-NMR (500 MHz, DMSO-d6): δ 8.30 (d, 2H,
J2ʹ,6ʹ/3ʹ,5ʹ = 8.0 Hz, H-2ʹ, H-6ʹ), 8.18 (d, 1H, J4,5 = 7.0 Hz, H-4), 8.14 (d, 2H, J3ʹ,5ʹ /2ʹ,6ʹ = 8.0 Hz, H-
3ʹ,H-5ʹ), 8.10 (d, 1H, J7,6 = 8.0 Hz, H-7), 7.72 (d, 1H, J3ʹʹ,5ʹʹ = 6.5 Hz, H-3ʹʹ), 7.60 (dt, 1H, J5,7
=
2.0, J5(4,6) = 7.0 Hz, H-5), 7.54-7.51 (m, 2H, H-6, H-5ʹʹ), 7.19 (dd, 1H, J4ʹʹ,5ʹʹ = 4.0 Hz, J4ʹʹ,3ʹʹ = 6.0
13
Hz, H-4ʹʹ); C-NMR (150 MHz, DMSO-d6): δ 165.96, 162.85, 162.36, 152.42, 149.83, 144.02,
137.53, 136.37, 128.51, 128.51, 126.98, 126.62, 126.62, 126.43, 125.68, 123.62, 122.86, 112.61,
111.18; HREI-MS: m/z calcd for C19H11N3O2S [M]+ 345.0572; Found 345.0575; Anal. Calcd
for C19H11N3O2S, C, 66.07; H, 3.21; N, 12.17; Found C, 66.08; H, 3.19; N, 12.16;
3.9.1.7 4-(5-(4-(benzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzene-1,2-diol (7)
Light brown solid. Yield: 91.3%. m.p.: 294-295 °C; 1H-NMR (500 MHz, DMSO-d6): δ 11.02 (s,
2H, 2xOH), 8.26 (d, 2H, J2ʹ,6ʹ/3ʹ,5ʹ = 8.0 Hz, H-2ʹ, H-6ʹ), 8.20 (d, 1H, J4,5 = 8.0 Hz, H-4), 8.11 (d,
2H, J3ʹ,5ʹ /2ʹ,6ʹ = 8.0 Hz, H-3ʹ,H-5ʹ), 8.08 (d, 1H, J7,6 = 8.0 Hz, H-7), 7.60 (dt, 1H, J5,7 = 2.0, J5(4,6)
=
7.5 Hz, H-5), 7.51 (dt, 1H, J6,4 = 2.0, J6(5,7) = 7.5 Hz, H-6), 7.02 (d, 1H J3ʹʹ,4ʹʹ = 8.0 Hz, H-4ʹʹ),
6.89 (d, J6ʹʹ,5ʹʹ = 8.0 Hz, H-6ʹʹ), 6.76 (t, 1H, J5ʹʹ (4ʹʹ,6ʹʹ) = 7.5 Hz, H-5ʹʹ); 13C-NMR (150 MHz,
DMSO-d6): δ 165.89, 165.48, 162.52, 152.37, 148.27, 148.12, 137.53, 136.19, 128.47, 128.47,
126.98, 126.98, 126.50, 126.41, 125.43, 123.60, 122.63, 121.44, 119.17, 117.62, 112.30; HREI-
MS: m/z calcd for C21H13N3O3S [M]+ 387.0678; Found 387.0685; Anal. Calcd for C21H13N3O3S,
C, 65.11; H, 3.38; N, 10.85; Found C, 65.13; H, 3.36; N, 10.84;
3.9.1.8 2-(5-(4-(benzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzene-1,4-diol (8)
Pale yellow solid, Yield: 76.5%. m.p.: 287-289 °C; 1H-NMR (500 MHz, DMSO-d6): δ 10.20 (s,
1H, OH), 9.25 (s, 1H, OH), 8.25 (d, 2H, J2ʹ,6ʹ/3ʹ,5ʹ = 8.0 Hz, H-2ʹ,H-6ʹ), 8.18 (d, 1H, J4,5 = 8.0 Hz,
H-4), 8.11 (d, 2H, J3ʹ,5ʹ /2ʹ,6 = 8.0 Hz, H-3ʹ,H-5ʹ), 8.07 (d, 1H, J7,6 = 7.5 Hz, H-7), 7.60 (t, 1H,
J5(4,6) = 7.5 Hz, H-5), 7.51 (dt, 1H, J6(5,7) = 7.0 Hz, H-6), 7.0 (d, 1H, J6ʹʹ,4ʹʹ = 2.0 Hz, H-6ʹʹ), 6.76-
13
6.73 (m, 2H, H-3ʹʹ, H-4ʹʹ); C-NMR (150 MHz, DMSO-d6): δ 165.57, 162.48, 154.25, 153.11,
152.49, 152.19, 137.33, 136.32, 128.48, 128.48, 126.97, 126.97, 126.31, 126.14, 125.68, 123.73,
16

Page 17 of 28
RSC Advances
View Article Online
DOI: 10.1039/C5RA23072A
122.50, 120.15, 118.16, 115.58, 111.13; HREI-MS: m/z calcd for C21H13N3O3S [M]+ 528.2161;
Found 528.2167; Anal. Calcd for C21H13N3O3S, C, 65.11; H, 3.38; N, 10.85; Found C, 65.09; H,
3.40; N, 10.84;
3.9.1.9 4-(5-(4-(benzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzene-1,3-diol (9)
Light brown solid. Yield: 86.3%. m.p.: 297-298 °C; 1H-NMR (500 MHz, DMSO-d6): δ 11.20 (s,
1H, OH), 10.15 (s, 1H, OH), 8.25 (d, 2H, J2ʹ,6ʹ/3ʹ,5ʹ = 8.0 Hz, H-2ʹ,H-6ʹ), 8.19 (d, 1H, J4,5 = 7.5 Hz,
H-4), 8.14 (d, 2H, J3ʹ,5ʹ /2ʹ,6 = 8.0 Hz, H-3ʹ,H-5ʹ), 8.09 (d, 1H, J7,6 = 7.5 Hz, H-7), 7.60 (dt, 1H, J5,7
= 2.0, J5(4,6) = 7.5 Hz, H-5), 7.51 (dt, 1H, J6,4 = 2.0, J6(5,7) = 7.5 Hz, H-6), 7.32 (d, 1H, J6ʹʹ,5ʹʹ = 8.5
Hz, H-6ʹʹ), 6.94 (dd, 1H, J5ʹʹ,3ʹʹ = 2.0 Hz, J5ʹʹ,6ʹʹ = 8.5 Hz, H-5ʹʹ), 6.31 (d, 1H, J3ʹʹ,5ʹʹ = 2.0 Hz, H-3ʹʹ);
13C-NMR (150 MHz, DMSO-d6): δ 165.51, 162.51, 159.43, 159.17, 155.85, 152.49, 137.45,
136.32, 129.78, 128.56, 128.56, 126.94, 126.94, 126.63, 126.47, 125.31, 123.58, 122.72, 109.19,
105.18, 104.26; HREI-MS: m/z calcd for C21H13N3O3S [M]+ 387.0678; Found 387.0682; Anal.
Calcd for C21H13N3O3S, C, 65.11; H, 3.38; N, 10.85; Found C, 65.12; H, 3.39; N, 10.83;
3.9.1.10 3-(5-(4-(benzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzene-1,2-diol (10)
Pale yellow solid. Yield: 89.3%. m.p.: 298-299 °C; 1H-NMR (500 MHz, DMSO-d6): δ 11.29 (s,
1H, OH), 11.20 (s, 1H, OH), 8.26 (d, 2H, J2ʹ,6ʹ/3ʹ,5ʹ = 8.0 Hz, H-2ʹ, H-6ʹ), 8.21 (d, 1H, J4,5 = 8.0
Hz, H-4), 8.12 (d, 2H, J3ʹ,5ʹ /2ʹ,6 = 8.0 Hz, H-3ʹ, H-5ʹ), 8.09 (d, 1H, J7,6 = 8.0 Hz, H-7), 7.60 (dt, 1H,
J5,7 = 2.0, J5(4,6) = 7.5 Hz, H-5), 7.52 (dt, 1H, J6,4 = 2.0, J6(5,7) = 7.5 Hz, H-6), 7.29 (d, 1H, J2ʹʹ,6ʹʹ
=
2.0 Hz, H-2ʹʹ), 6.96 (dd, 1H, J6ʹʹ,2ʹʹ = 2.0 Hz, J6ʹʹ,5ʹʹ = 7.5 Hz, H-6ʹʹ), 6.79 (d, 1H, J5ʹʹ,6ʹʹ = 7.5 Hz, H-
5ʹʹ);13C-NMR (150 MHz, DMSO-d6): δ 165.51, 162.39, 155.78, 152.31, 148.84, 147.47, 137.49,
136.31, 128.36, 128.36, 126.95, 126.95, 126.69, 126.24, 125.58, 123.80, 122.75, 121.91, 120.87,
118.12, 112.53; HREI-MS: m/z calcd for C21H13N3O3S [M]+ 387.0678; Found 387.0681; Anal.
Calcd for C21H13N3O3S, C, 65.11; H, 3.38; N, 10.85; Found C, 65.10; H, 3.36; N, 10.87;
3.9.1.11 5-(5-(4-(benzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzene-1,3-diol (11)
1
White solid. Yield: 92.6%. m.p.: 295-296 °C; H-NMR (500 MHz, DMSO-d6): δ 9.30 (s, 2H,
2xOH), 8.28 (d, 2H, J2ʹ,6ʹ/3ʹ,5ʹ = 8.0 Hz, H-2ʹ,H-6ʹ), 8.20 (d, 1H, J4,5 = 8.0 Hz, H-4), 8.12 (d, 2H,
J3ʹ,5ʹ/2ʹ,6 = 8.5 Hz, H-3ʹ,H-5ʹ), 8.09 (d, 1H, J7,6 = 8.0 Hz, H-7), 7.60(t, 1H, J5(4,6) = 7.5 Hz, H-5 ),
7.52 (t, 1H, J6(5,7) = 7.5 Hz, H-6), 6.60 (d, 2H, J2ʹʹ,6ʹʹ/4ʹʹ = 2.0 Hz, H-2ʹʹH-6ʹʹ), 6.26 (s, 1H, H-4ʹʹ);
17

RSC Advances
Page 18 of 28
View Article Online
DOI: 10.1039/C5RA23072A
13C-NMR (150 MHz, DMSO-d6): δ 165.49, 164.54, 162.41, 161.68, 161.68, 152.44, 137.63,
136.22, 128.70, 128.70, 126.72, 126.72, 126.50, 126.32, 126.16, 125.39, 123.69, 122.52, 109.75,
109.75, 103.87; HREI-MS: m/z calcd for C21H13N3O3S [M]+ 387.0678; Found 387.0675; Anal.
Calcd for C21H13N3O3S, C, 65.11; H, 3.38; N, 10.85; Found C, 65.09; H, 3.40; N, 10.84;
3.9.1.12 2-(4-(benzo[d]thiazol-2-yl)phenyl)-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole (12)
Brown solid m.p.: 276-277 °C; 1H-NMR (500 MHz, DMSO-d6): δ 8.25 (d, 2H, J2ʹ,6ʹ/3ʹ,5ʹ = 8.0 Hz,
H-2ʹ,H-6ʹ), 8.20 (d, 1H, J4,5 = 8.0 Hz, H-4), 8.12 (d, 2H, J3ʹ,5ʹ /2ʹ,6 = 8.0 Hz, H-3ʹ,H-5ʹ), 8.09 (d,
1H, J7,6 = 8.0 Hz, H-7), 7.60 (t, 1H, J5(4,6) = 7.0 Hz, H-5), 7.52 (t, 1H, J6(5,7) = 7.0 Hz, H-6), 7.37
(d, 1H, J2ʹʹ,6ʹʹ = 2.0 Hz, H-2ʹʹ), 7.28 (d, 1H, J6ʹʹ,5ʹʹ = 7.0 Hz, H-6ʹʹ), 7.09 (d, 1H, J5ʹʹ,6ʹʹ = 7.0 Hz, H-
5ʹʹ) 3.86 (s, 3H, OCH3), 3.82 (s, 3H, OCH3); 13C-NMR (150 MHz, DMSO-d6): δ 165.81, 165.48,
162.32, 152.28, 152.16, 151.48, 137.47, 136.39, 128.51, 128.51, 126.94, 126.94, 126.69, 126.41,
125.58, 123.78, 122.60, 121.21, 120.15, 115.53, 107.69, 56.79, 56.72; HREI-MS: m/z calcd for
C23H17N3O3S [M]+ 415.0991; Found 415.0987; Anal. Calcd for C23H17N3O3S, C, 66.49; H, 4.12;
N, 10.11; Found C, 66.51; H, 4.14; N, 10.13;
3.9.1.13 2-(4-(benzo[d]thiazol-2-yl)phenyl)-5-(2,5-dimethoxyphenyl)-1,3,4-oxadiazole (13)
1
Orange solid. Yield: 81.7%. m.p.: 274-275 °C; H-NMR (500 MHz, DMSO-d6): δ 8.26 (d, 2H,
J2ʹ,6ʹ/3ʹ,5ʹ = 8.5 Hz, H-2ʹ,H-6ʹ), 8.20 (d, 1H, J4,5 = 8.5 Hz, H-4), 8.14 (d, 2H, J3ʹ,5ʹ /2ʹ,6 = 8.0 Hz, H-
3ʹ,H-5ʹ), 8.10 (d, 1H, J7,6 = 8.0 Hz, H-7), 7.61 (dt, 1H, J5,7 = 2.0 Hz, J5(4,6) = 7.5 Hz, H-5), 7.52
(dt, 1H, J6,4 = 2.0 Hz, J6(5,7) = 7.5 Hz, H-6), 6.90 (d, 2H, J2ʹʹ,6ʹʹ,/ 4ʹʹ = 2.0 Hz, H-2ʹʹ, H-6ʹʹ), 6.62 (d,
1H, J4ʹʹ/ 6ʹʹ,2ʹʹ = 2.0 Hz, H-4ʹʹ), 3.83 (s, 6H, 2xOCH3); 13C-NMR (150 MHz, DMSO-d6): δ 165.49,
162.41, 156.17, 155.25, 152.49, 151.34, 137.33, 136.32, 128.48, 128.48, 126.94, 126.94, 126.61,
126.46, 125.58, 123.71, 122.54, 118.12, 117.47, 115.65, 115.38, 56.72, 56.01; HREI-MS: m/z
calcd for C23H17N3O3S [M]+ 415.0991; Found 415.0996; Anal. Calcd for C23H17N3O3S, C,
66.49; H, 4.12; N, 10.11; Found C, 66.47; H, 4.14; N, 10.09;
3.9.1.14
2-(5-(4-(benzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)phenol (14)
1
Brownish solid. Yield: 96.2%. m.p.: 265-266 °C; H-NMR (500 MHz, DMSO-d6): δ 10.56 (s,
1H, OH), 8.29 (d, 2H, J2ʹ,6ʹ/3ʹ,5ʹ = 8.0 Hz, H-2ʹ,H-6ʹ), 8.20 (d, 1H, J4,5 = 7.5 Hz, H-4), 8.13 (d, 2H,
J3ʹ,5ʹ /2ʹ,6 = 8.0 Hz, H-3ʹ,H-5ʹ), 8.10 (d, 1H, J7,6 = 8.0 Hz, H-7), 7.60-7.56 (m, 2H, H-6, H-5ʹʹ), 7.52
18

Page 19 of 28
RSC Advances
View Article Online
DOI: 10.1039/C5RA23072A
(dt, 1H, J6,4 = 2.0, J6(5,7) = 7.5 Hz, H-6), 7.31 (t, 1H, J4ʹʹ(5ʹʹ,3ʹʹ) = 2.0 Hz, H-4ʹʹ), 6.95-6.90 (m, 2H,
H-3ʹʹ, H-6ʹʹ), H-5ʹʹ); 13C-NMR (150 MHz, DMSO-d6): δ 165.57, 162.32, 158.48, 155.72, 152.52,
137.49, 136.19, 131.74, 130.01, 128.40, 128.40, 126.95, 126.95, 126.62, 126.47, 125.38, 123.60,
122.69, 119.84, 118.76, 111.62; HREI-MS: m/z calcd for C21H13N3O2S [M]+ 371.0728; Found
371.0722; Anal. Calcd for C21H13N3O2S, C, 67.91; H, 3.53; N, 11.31; Found C, 67.93; H, 3.51;
N, 11.32;
3.9.1.15 3-(5-(4-(benzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)phenol (15)
1
Dark brown solid. Yield: 76.2%. m.p.: 278-279 °C; H-NMR (500 MHz, DMSO-d6): δ 9.90 (s,
1H, OH), 8.29 (d, 2H, J2ʹ,6ʹ/3ʹ,5ʹ = 8.5 Hz, H-2ʹ,H-6ʹ), 8.21 (d, 1H, J4,5 = 8.5 Hz, H-4), 8.13 (d, 2H,
J3ʹ,5ʹ /2ʹ,6 = 8.0 Hz, H-3ʹ,H-5ʹ), 8.10 (d, 1H, J7,6 = 8.5 Hz, H-7), 7.60 (t, 1H, J5(4,6) = 8.0 Hz, H-5),
7.51 (t, 1H, Hz, J6(5,7) = 7.5 Hz, H-6), 7.32 (t, 1H, J5ʹʹ(4ʹʹ,6ʹʹ) = 7.0 Hz, H-5ʹʹ), 7.25 (s, 1H, H-2ʹʹ),
7.11 (d, 1H, J4ʹʹ,5ʹʹ = 7.5 Hz, , H-4ʹʹ), 6.89 (dd, 1H, J6ʹʹ,2ʹʹ = 2.0 Hz, J6ʹʹ,5ʹʹ = 7.0 Hz, H-6ʹʹ); 13C-NMR
(150 MHz, DMSO-d6): δ 165.87, 165.37, 162.49, 158.51, 152.38, 137.53, 136.28, 130.90,
128.30, 128.30, 126.72, 126.72, 126.94, 126.42, 126.25, 125.49, 123.71, 122.68, 121.13, 118.32,
114.27. HREI-MS: m/z calcd for C21H13N3O2S [M]+ 371.0728; Found 371.0731; Anal. Calcd for
C21H13N3O2S, C, 67.91; H, 3.53; N, 11.31; Found C, 67.92; H, 3.54; N, 11.32;
3.9.1.16 4-(5-(4-(benzo[d]thiazol-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)-2-methoxyphenol (16)
1
Dark brown solid. Yield: 88.4%. m.p.: 291-292 °C; H-NMR (500 MHz, DMSO-d6): δ 9.60 (s,
1H, OH), 8.29 (d, 2H, J2ʹ,6ʹ/3ʹ,5ʹ = 8.0 Hz, H-2ʹ,H-6ʹ), 8.20 (d, 1H, J4,5 = 8.0 Hz, H-4), 8.11 (d, 2H,
J3ʹ,5ʹ /2ʹ,6 = 8.0 Hz, H-3ʹ,H-5ʹ), 8.08 (d, 1H, J7,6 = 8.5 Hz, H-7), 7.64 (dt, 1H, J5,7 = 2.0 Hz, J5(4,6)
=
7.5 Hz, H-5), 7.53 (dt, 1H, J6,4 = 2.0 Hz, J6(5,7) = 7.5 Hz, H-6); 7.35 (d, 1H, J2ʹʹ,6ʹʹ = 2.0 Hz, H-2ʹʹ),
7.16 (dd, 1H, J6ʹʹ,2ʹʹ = 2.0 Hz, J6ʹʹ,5ʹʹ = 7.5 Hz, H-6ʹʹ), 6.90 (d, 1H, J5ʹʹ,6ʹʹ = 8.0 Hz, H-5ʹʹ), 3.82 (s, 3H,
OCH3); 13C-NMR (150 MHz, DMSO-d6): δ 165.95, 165.49, 162.38, 152.41, 150.82, 149.78,
137.53, 136.39, 128.40, 128.40, 126.82, 126.82, 126.49, 126.34, 125.47, 123.69, 122.87, 121.94,
117.50, 115.61, 111.78, 56.34; HREI-MS: m/z calcd for C22H15N3O3S [M]+ 401.0834; Found
401.0837; Anal. Calcd for C22H15N3O3S, C, 65.82; H, 3.77; N, 10.47; Found C, 65.83; H, 3.76;
N, 10.48.
19

RSC Advances
Page 20 of 28
View Article Online
DOI: 10.1039/C5RA23072A
3.9.1.17 2-(4-(benzo[d]thiazol-2-yl)phenyl)-5-(4-fluorophenyl)-1,3,4-oxadiazole (17)
1
Yellow solid. Yield: 86.4%. m.p.: 271-272 °C; H-NMR (500 MHz, DMSO-d6): δ 8.29 (d, 2H,
J2ʹ,6ʹ = J6ʹ,2ʹ = 8.0 Hz, H-2ʹ,H-6ʹ), 8.20 (d, 1H, J4,5 = 8.0 Hz, H-4), 8.12 (d, 2H, J3ʹ,5ʹ = J3ʹ,5ʹ = 8.0 Hz,
H-3ʹ,H-5ʹ), 8.09 (d, 1H, J7,6 = 8.0 Hz, H-7), 7.74 (dd, 2H, J3ʹʹ,5ʹʹ/2ʹʹ,6ʹʹ = 7.0 Hz, J3ʹʹ,5ʹʹ/F = 5.5 Hz, H-
3ʹʹ H-5ʹʹ), 7.60 (t, 1H, J5(4,6) = 7.5 Hz, H-5), 7.51 (t, 1H, J6(5,7) = 7.5 Hz, H-6 ), 7.71 (dd, 2H,
J3ʹʹ,5ʹʹ/2ʹʹ,6ʹʹ = 5.5 Hz, J3ʹʹ,5ʹʹ/F = 5.5 Hz, H-3ʹʹ H-5ʹʹ), 7.36 (t, 2H, J2ʹʹ,6ʹʹ/3ʹʹ,5ʹʹ,F = 7.0 Hz, H-2ʹʹ,H-6ʹʹ); 13C-
NMR (150 MHz, DMSO-d6): δ 166.37 (d, J = 223.2 Hz), 165.26, 162.45, 152.38, 137.53,
136.19, 129.82, 129.82, 128.60, 128.60, 126.82, 126.82, 126.60, 126.45, 125.47, 123.68, 123.51,
122.63, 116.23, 116.17, 116.17; HREI-MS: m/z calcd for C21H12FN3OS [M]+ 373.0685; Found
373.0690; Anal. Calcd for C21H12FN3OS, C, 67.55; H, 3.24; N, 11.25; Found C, 67.54; H, 3.22;
N, 11.28;
3.9.1.18 2-(4-(benzo[d]thiazol-2-yl)phenyl)-5-(4-chlorophenyl)-1,3,4-oxadiazole (18)
1
Brown solid, Yield: 78.7%. m.p.: 268-269 °C; H-NMR (500 MHz, DMSO-d6): δ 8.29 (d, 2H,
J2ʹ,6ʹ/3ʹ,5ʹ = 8.0 Hz, H-2ʹ,H-6ʹ), 8.20 (d, 1H, J4,5 = 8.0 Hz, H-4), 8.11 (d, 2H, J3ʹ,5ʹ /2ʹ,6 = 8.0 Hz, H-
3ʹ,H-5ʹ), 8.10 (d, 1H, J7,6 = 7.5 Hz, H-7), 7.77 (d, 2H, J2ʹʹ,6ʹʹ/ 3ʹʹ,5ʹʹ = 8.5 Hz, H-2ʹʹ,H-6ʹʹ), 7.60 (t,
1H, J5(4,6) = 7.5 Hz, H-5), 7.56 (t, 1H, J6(5,7) = 7.5 Hz, H-6), 7.52 (d, 2H, J3ʹʹ,5ʹʹ/ 2ʹʹ,6ʹʹ = 8.0 Hz, H-
13
3ʹʹ,H-5ʹʹ); C-NMR (150 MHz, DMSO-d6): δ 165.57, 162.48, 152.42, 137.53, 137.41, 136.31,
129.47, 129.47, 128.34, 128.34, 128.12, 127.79, 127.79, 126.93, 126.93, 126.49, 126.24, 125.38,
123.67, 122.54, 122.54; HREI-MS: m/z calcd for C21H12ClN3OS [M]+ 389.0390; Found
389.0395; Anal. Calcd for C21H12ClN3OS, C, 64.70; H, 3.10; N, 10.78; Found C, 64.71; H, 3.09;
N, 10.76;
3.9.1.19 2-(4-(benzo[d]thiazol-2-yl)phenyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole (19)
Light brown solid. Yield: 85.9%. m.p.: 285-286 °C; 1H-NMR (500 MHz, DMSO-d6): δ 8.29 (d,
2H, J2ʹ,6ʹ/3ʹ,5ʹ = 8.0 Hz, H-2ʹ,H-6ʹ), 8.20 (d, 1H, J4,5 = 8.0 Hz, H-4), 8.12 (d, 2H, J3ʹ,5ʹ/2ʹ,6 = 8.5 Hz,
H-3ʹ,H-5ʹ), 8.09 (d, 1H, J7,6 = 7.5 Hz, H-7), 7.70 (d, 2H, J2ʹʹ,6ʹʹ/ 3ʹʹ,5ʹʹ = 8.5 Hz, H-2ʹʹ,H-6ʹʹ), 7.64 (t,
1H, J5(4,6) = 7.0 Hz, H-5), 7.51 (t, 1H, J6(5,7) = 7.0 Hz, H-6), 7.08 (d, 2H, J3ʹʹ,5ʹʹ/2ʹʹ,6ʹʹ = 8.0 Hz, H-
3ʹʹ,H-5ʹʹ), 3.80 (s, 3H, OCH3); 13C-NMR (150 MHz, DMSO-d6): δ 165.47, 162.42, 162.19,
152.48, 137.43, 136.29, 128.50, 128.50, 127.07, 127.07, 126.92, 126.92, 126.59, 126.59, 126.44,
125.48, 123.70, 122.70, 121.54, 113.88, 113.88, 56.03; HREI-MS: m/z calcd for C22H15N3O2S
20

Page 21 of 28
RSC Advances
View Article Online
DOI: 10.1039/C5RA23072A
[M]+ 385.0885; Found 385.0880; Anal. Calcd for C22H15N3O2S, C, 68.55; H, 3.92; N, 10.90;
Found C, 68.56; H, 3.93; N, 10.91.
3.9.1.20
2-(4-(benzo[d]thiazol-2-yl)phenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazole (20)
1
Brown solid. Yield: 86.1%. m.p.: 280-281 °C; H-NMR (500 MHz, DMSO-d6): δ 8.67 (d, 2H,
J2ʹʹ,6ʹʹ/ 3ʹʹ,5ʹʹ = 6.0 Hz, H-2ʹʹ,H-6ʹʹ), 8.27 (d, 2H, J2ʹ,6ʹ/3ʹ,5ʹ = 8.5 Hz, H-2ʹ,H-6ʹ), 8.20 (d, 1H, J4,5 = 8.5
Hz, H-4), 8.11 (d, 2H, J3ʹ,5ʹ /2ʹ,6 = 8.5 Hz, H-3ʹ,H-5ʹ), 8.09 (d, 1H, J7,6 = 8.0 Hz, H-7), 7.71 (d, 2H,
J3ʹʹ,5ʹʹ/ 2ʹʹ,6ʹʹ = 6.0 Hz, H-3ʹʹ,H-5ʹʹ), 7.64 (dt, 1H, J5,7 = 2.0 Hz, J5(4,6) = 7.5 Hz, H-5), 7.53 (dt, 1H,
J6,4 = 2.0 Hz, J6(5,7) = 7.5 Hz, H-6); 13C-NMR (150 MHz, DMSO-d6): δ 165.48, 162.32, 152.49,
150.20, 137.45, 136.19, 133.37, 128.53, 128.53, 128.53, 126.96, 126.96, 126.50, 126.50, 126.21,
125.47, 123.75, 123.43, 122.61, 122.61; HREI-MS: m/z calcd for C20H12N4OS [M]+ 356.0732;
Found 356.0729; Anal. Calcd for C20H12N4OS, C, 67.40; H, 3.39; N, 15.72; Found C, 67.41; H,
3.38; N, 15.73.
Acknowledgment
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. The computational part of this project was funded through the
“TRGS” (grant no. 600-RMI/TRGS 5/3 (1/2014)-3) by the Ministry of Higher Education
Malaysia (MOHE).
References
1. Glaser, J. H.; Sly, W. S. b-Glucuronidase deficiency mucopolysaccharidosis: Methods for
enzymatic diagnosis. J. Lab. Clin. Med. 82 (1973) 969-977.
2. Sperker, B.; Backman, J. T.; Kromer, K. The role of β-glucuronidase in drug disposition
and drug targeting in humans. Clin. Pharmacokinet. 33 (1997) 18-24.
21

RSC Advances
Page 22 of 28
View Article Online
DOI: 10.1039/C5RA23072A
3. Fishman, W. H. Wakabayyashi, M. “Metabolic conjugation and metabolic hydrolysis”.
Academic Press, New York 1970, pp 519.
4. Paigen, K. Mammalian β-glucuronidase: genetics, molecular biology, and cell biology.
Progress in Nucleic Acid Res. Mol. Biol. 37 (1989) 155-205.
5. Holiman, P.C.H.; Hertog, M.G.L.; Katan, M.B. Analysis and health effects of flavonoids.
Food Chemistry 57 (1996) 43-46.
6. Ho, K. J.; Hsu, S. C.; Chen, J. S.; Ho, L. H. C. Human biliary glucuronidase: correlation
of its activity with deconjugation of bilirubin in the bile. Eur. J. Clin. Invest. 16
(1986) 361-367.
7. Gonick, H. C.; Kramer, H. J.; Schapiro, A. E. Urinary β-glucuronidase activity in renal
disease. Archives of Internal Medicine, 132 (1973) 63-69.
8. Ho, Y. C.; Ho, K. J. Differential quantitation of urinary β-glucuronidase of human and
bacterial origins. J. Urol. 134 (1985) 1227-1230.
9. Sly, W. S.; Quinton, B. A.; McAlister, W. H.; Rimoin, D. L. β-Glucuronidase deficiency:
report of clinical, radiologic, and biochemical features of
mucopolysaccharidosis. The Journal of Pediatrics 82 (1973) 249-257.
a
new
10. Hall, C.W.; Cantz, M.; Neufeld, E.F.
A
β-Glucuronidase deficiency
mucopolysaccharidosis: studies in cultured fibroblasts. Archives of Biochemistry and
Biophysics 155 (1973) 32-38.
11. Carroll, A.R.; Scheuer, P.J. Kuanoniamines A, B, C, and D: pentacyclic alkaloids from a
tunicate and its prosobranch mollusk predator Chelynotus semperi. Jounal of Organic
Chemistry 55 (1990) 4426-4431.
12. Gunawardana, G.P.; Kohmoto, S.; Gunasekera, S.P.; McConnell, O.J.; Koehn, F.E.
Dercitine, a new biologically active acridine alkaloid from a deep water marine
sponge, Dercitus sp. Journal of American Chemical Society 110 (1988) 4856-4858.
22

Page 23 of 28
RSC Advances
View Article Online
DOI: 10.1039/C5RA23072A
13. Tanaka, T.; Umekawa, H.; Saitoh, M.; Ishikawa, T.; Shin, T.; Ito, M.; Itoh, H.;
Kawamatsu, Y.; Sugihara, H.; Hidaka, H. Modulation of calmodulin function and of
Ca2+-induced smooth muscle contraction by the calmodulin antagonist, HT-74. Mol.
Pharmacol. 29 (1986) 264-269.
14. Bowyer, P.W.; Gunaratne, R.S.; Grainger, M.; Withers-Martinez, C.; Wickramsinghe, S.
R.; Tate, E.W.; Leatherbarrow, R.J.; Brown, K.A.; Holder, A.A.; Smith, D.F.
Molecules incorporating
a
benzothiazole core scaffold inhibit the N-
myristoyltransferase of Plasmodium falciparum. Biochem. J. 408 (2007) 173-180.
15. Mittal, S.; Samota, M.K.; Kaur, J.; Seth, G. Synthesis, spectral, and antifungal evaluation
of phosphorylated and thiophosphorylated benzothiazole derivatives. Phosphorus,
Sulfur and Silicon and the Related Elements 182 (2007) 2105-2113.
16. Gurupadayya, B.M.; Gopal, M.; Padmashali, B.; Manohara, Y.N. Synthesis and
pharmacological evaluation of azetidin-2-ones and thiazolidin-4-ones encompassing
benzothiazole. Indian J. Pharm. Sci. 70 (2008) 572-577.
17. Pozas, R.; Carballo, J.; Castro, C.; Rubio, J. Synthesis and in vitro antitrypanosomal
activity of novel nifurtimox analogues. Bioorg. Med. Chem. Lett. 15 (2005) 1417-
1421.
18. Rana, A.; Siddiqui, N.; Khan, S. A.; Ehtaishamul Haque, S.; Bhat, M. A. N-{[(6-
Substituted-1,
3-benzothiazole-2-yl)
amino]
carbonothioyl}-2/4-substituted
benzamides: Synthesis and pharmacological evaluation. Eur. J. Med. Chem. 43
(2008) 1114-1122.
19. Rashid, M.; Husain, A.; Mishra, R., Synthesis of benzimidazoles bearing oxadiazole
nucleus as anticancer agents. Eur. J. Med. Chem. 54 (2012) 855-866.
20. Husain, A.; Rashid, M.; Mishra, R.; Parveen S.; Shin, D.-S.; Kumar, D., Benzimidazole
bearing oxadiazole and triazolo-thiadiazoles nucleus: design and synthesis as
anticancer agents. Bioorg. Med. Chem. Lett. 22 (2012) 5438-5444.
23

RSC Advances
Page 24 of 28
View Article Online
DOI: 10.1039/C5RA23072A
21. Zhang, S.; Luo, Y.; He, L.-Q.; Liu, Z.-J.; Jiang, A.-Q.; Yang, Y.-H.; Zhu, H.-L.,
Synthesis, biological evaluation, and molecular docking studies of novel 1,3,4-
oxadiazole derivatives possessing benzotriazole moiety as FAK inhibitors with
anticancer activity. Bioorg. Med. Chem. 21 (2013) 3723-3729.
22. Hadady, Z.; Toth, M.; Somsak, L., C-(β-D-Glucopyranosyl) heterocycles as potential
glycogen phosphorylase inhibitors. ARKIVOC 7 (2004) 140-149.
23. Ahsan, M.J.; Samy, J.G.; Khalilullah, H.; Nomani, M.S.; Saraswat, P.; Gaur, R.; Singh,
A., Molecular properties prediction and synthesis of novel 1,3,4-oxadiazole analogues
as potent antimicrobial and antitubercular agents. Bioorg. Med. Chem. Lett. 21 (2011)
7246-7250.
24. Liu, F.; Luo, X.Q.; Song, B.A.; Bhadury, P.S.; Yang, S.; Jin, L.H.; Xue, W.; Hu, D.Y.,
Synthesis and antifungal activity of novel sulfoxide derivatives containing
trimethoxyphenyl substituted 1,3,4-thiadiazole and 1,3,4-oxadiazole moiety. Bioorg.
Med. Chem. 16 (2008) 3632-3640.
25. Jakubkiene, V.; Burbuliene, M.M.; Udrenaite, E.; Garaliene, V.; Vainilavicius, P., (6-
methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)acetic acid and related
compounds exhibiting anti-inflammatory activity. Pharmazie 57 (2002) 610-613.
26. Desai, N.C.; Bhatt, N.; Somani, H.; Trivedi A., Synthesis, antimicrobial and cytotoxic
activities of some novel thiazole clubbed 1,3,4-oxadiazoles. Eur. J. Med. Chem. 67
(2013) 54-59.
27. Ghorab, M.M.; Shaaban, M.A.; Refaat, H.M.; Heiba, H.I.; Ibrahim, S.S., Anticancer and
radiosensitizing evaluation of some new pyranothiazole-Schiff bases bearing the
biologically active sulfonamide moiety. Eur. J. Med. Chem. 53 (2012) 403-407.
28. Wang, X.-M.; Xu, J.; Li, Y.-P.; Li, H.; Jiang, C.-S.; Yang, G.-D.; Lu, S.-M.; Zhang, S.-
Q., Synthesis and anticancer activity evaluation of a series of [1,2,4]triazolo[1,5-
a]pyridinylpyridines in vitro and in vivo. Eur. J. Med. Chem. 67 (2013) 243-251.
24

Page 25 of 28
RSC Advances
View Article Online
DOI: 10.1039/C5RA23072A
29. Xu, F.; Xu, H.; Wang, X.; Zhang, L.; Wen, Q.; Zhang, Y.; Xu, W.; Discovery of N-(3-
((7H-purin-6-yl)thio)-4-hydroxynaphthalen-1-yl)-sulfonamide derivatives as novel
protein kinase and angiogenesis inhibitors for the treatment of cancer: Synthesis and
biological evaluation. Part III. Bioorg. Med. Chem. 22 (2014) 1487-1495.
30. Taha, M.; Ismail, N.H. ; Lalani, S.; Fatmi, M.Q.; Siddiqui, S.; Khan, K.M.; Imran, S.;
Choudhary, M. I.. Synthesis of novel inhibitors of α-glucosidase based on the
benzothiazole skeleton containing benzohydrazide moiety and their molecular
docking studies. Eur. J. Med. Chem. 92 (2015) 387-400.
31. Zawawi, N.K.N.A.; Taha, M.; Ahmat, N.; Wadood, A.; Ismail, N.H.; Rahim, F. ; Ali, M.;
Norishah, A.; Khan, K.M. Novel 2,5-disubtituted-1,3,4-oxadiazoles with
benzimidazole backbone: A new class of β-glucuronidase inhibitors and in silico
studies. Bioorg. Med. Chem. 23(2015) 3119-3125.
32. a) Taha, M.; Shah, S. A. A.; Khan, A.; Arshad, F.; Ismail, N. H.; Afifi, M.; Imran, S.;
Choudhary, M. I. Synthesis of 3, 4, 5-trihydroxybenzohydrazone and evaluation of
their urease inhibition potential. Arabian J. Chem. (2015); b) Imran, S.; Taha, M.;
Ismail, N. H.; Kashif, S. M.; Rahim, F.; Jamil, W.; Wahab, H.; Khan, K. M.
Synthesis, In vitro and Docking Studies of New Flavone Ethers as α‐Glucosidase
Inhibitors. Chem. Biol. Drug. Des. (2015); c) Imran, S.; Taha, M.; Ismail, N. H.;
Kashif, S. M.; Rahim, F.; Jamil, W.; Hariono, M.; Yusuf, M.; Wahab, H. Synthesis of
novel flavone hydrazones: in-vitro evaluation of α-glucosidase inhibition, QSAR
analysis and docking studies. European J. Med. Chem. 105 (2015) 156-170; d) Imran,
S.; Taha, M.; Ismail, N. H.; Fayyaz, S.; Khan, K. M.; Choudhary, M. I. Synthesis,
biological evaluation, and docking studies of novel thiourea derivatives of
bisindolylmethane as carbonic anhydrase II inhibitor. Bioorg. Chem 62 (2015) 83-93;
e) Taha, M.; Ismail, N. H.; Javaid, K., Imran, S.; Wadood, A., Ali, M.; Khan, K. M.;
Saad, S. M.; Rahim, F.; Choudhary, M. I. (2015). Evaluation of 2-
indolcarbohydrazones as potent α-glucosidase inhibitors, in silico studies and DFT
based stereochemical predictions. Bioorg. Chem. 63 (2015) 24-35; f) Taha, M.;
Ismail, N. H.; Khan, A., Shah, S. A. A.; Anwar, A.; Halim, S. A.; Fatmi, M. Q.;
Imran, S.; Rahim, F.; Khan, K. M. (2015). Synthesis of novel derivatives of oxindole,
25

RSC Advances
Page 26 of 28
View Article Online
DOI: 10.1039/C5RA23072A
their urease inhibition and molecular docking studies. Bioorg. Med. Chem. Lett.
25(2015) 3285-3289
33. Taha, M.; Ismail, N. H.; Imran, S.; Selvaraj, M.; Rashwan, H.; Farhanah, F. U.; Rahim,
F.; Kesavanarayanan, K. S.; Ali, M.. Synthesis of benzimidazole derivatives as potent
β-glucuronidase inhibitors. Bioorg. Chem. 61 (2015) 36-44.
34. Taha, M.; Ismail, N. H.; Imran, S.; Selvaraj, M.; Rahim, A.; Ali, M.; Siddiqui S.; Rahim
F.; Khan, K. M. Synthesis of novel benzohydrazone–oxadiazole hybrids as β-
glucuronidase inhibitors and molecular modeling studies. Bioorg. Med. Chem.
23(2015) 7394-7404.
35. Taha, M.; Ismail, N. H.; Imran, S.; Wadood, A., Rahim, F.; Ali, M.; Rehman, A. U.
(2015). Novel quinoline derivatives as potent in vitro α-glucosidase inhibitors: in
silico studies and SAR predictions. MedChemComm, 6(10), 1826-1836
36. Jain, S.; Drendel, W.B.; Chen, Z.W.; Mathews, F.S.; Sly, W.S.; Grubb, J.H. Structure of
human beta-glucuronidase reveals candidate lysosomal targeting and active-site
motifs. Nat. Struct. Biol., 3 (1996) 375-381.
37. Schrödinger Release 2015-1: Maestro, version 10.1, Schrödinger, LLC, New York, NY,
2015.
38. Maestro, Version 9.2, Schrodinger, LLC, New York, NY, USA, 2011.
39. Verdonk, M.L.; Cole, J.C.; Hartshorn, M.J.; Murray, C.W.; Taylor, R.D. Improved
protein-ligand docking using GOLD. Proteins 52 (2003) 609-623
40. PyMOL, Molecular Graphics System L, NY, USA, (2010) PyMOL New York, US:
Schrodinger] and Maestro visualization.
26

Page 27 of 28
RSC Advances
View Article Online
DOI: 10.1039/C5RA23072A
Captions for figures and tables
Scheme-1 Synthesis of novel benzothiazole derivatives 1-20
Figure1: Graphical illustration of predicted binding modes of active benzothiazole derivatives.
Binding modes of a. compound 7 shown in stick form, b. Compound 14, c. Compound 8 and d.
Compound 17. Key residues are represented in spear and labeled. The hydrogen bond
interactions are represented by magenta arrow, π-π interactions are shown in green color lines
and cation-π interactions are shown in red color lines. Compounds are represented in line form.
Table 1. β-Glucuronidase inhibitory potential of novel benzothiazole derivatives 1-20.
Table 2: Optimization of novel benzothiazole derivatives 1-20
27

RSC Advances
Page 28 of 28
View Article Online
DOI: 10.1039/C5RA23072A
Synthesis of Novel Inhibitors of βꢀGlucuronidase Based on the Benzothiazole
Skeleton and their Molecular Docking Studies
Muhammad Taha, Nor Hadiani Ismail, Syahrul Imran, Manikandan Selvaraj, Fazal
Rahim
Benzothiazole derivatives (1-20) evaluated for β-Glucuronidase inhibitory activity