Hybrid benzothiazole analogs as antiurease agent: Synthesis and molecular docking studies

Article abstract of DOI:10.1016/j.bioorg.2016.03.010

Benzothiazole analogs (1-20) have been synthesized, characterized by EI-MS and ¹H NMR, and evaluated for urease inhibition activity. All compounds showed excellent urease inhibitory potential varying from 1.4 ± 0.10 to 34.43 ± 2.10 μM when compared with standard thiourea (IC₅₀ 19.46 ± 1.20 μM). Among the series seventeen (17) analogs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, and 18 showed outstanding urease inhibitory potential. Analogs 15 and 19 also showed good urease inhibition activity. When we compare the activity of N-phenylthiourea 20 with all substituted phenyl derivatives (1-18) we found that compound 15 showed less activity than compound 20 having 3-methoxy substituent. The binding interactions of these active analogs were confirmed through molecular docking.

Full text of DOI:10.1016/j.bioorg.2016.03.010

Accepted Manuscript
Hybrid Benzothiazole analogs as Antiurease Agent: Synthesis and Molecular
Docking Studies
Muhammad Taha, Nor Hadiani Ismail, Syahrul Imran, Abdul Wadood, Fazal
Rahim, Khalid Muhammad Khan, Muhammad Riaz
PII:
S0045-2068(16)30029-3
DOI:
http://dx.doi.org/10.1016/j.bioorg.2016.03.010
YBIOO 1897
Reference:
To appear in:
Bioorganic Chemistry
Received Date:
Revised Date:
Accepted Date:
9 November 2015
19 February 2016
23 March 2016
Please cite this article as: M. Taha, N.H. Ismail, S. Imran, A. Wadood, F. Rahim, K.M. Khan, M. Riaz, Hybrid
Benzothiazole analogs as Antiurease Agent: Synthesis and Molecular Docking Studies, Bioorganic Chemistry
(
2016), doi: http://dx.doi.org/10.1016/j.bioorg.2016.03.010
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Hybrid Benzothiazole analogs as Antiurease Agent: Synthesis and Molecular Docking
Studies
Muhammad Taha a,b, Nor Hadiani Ismail , Syahrul Imran , Abdul Wadood , Fazal Rahim ,
a,b
a,b
c
d
e
c
Khalid Muhammad Khan , Muhammad Riaz
a
Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM),
Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia
b
Faculty of Applied Science UiTM, 40450 Shah Alam, Selangor, Malaysia
c
Computational Medicinal Chemistry Laboratory, Department of Biochemistry, UCSS, Abdul
Wali Khan University, Mardan, Pakistan
d
Department of Chemistry, Hazara University, Mansehra, Pakistan
e
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi-75270, Pakistan.
Abstract:
Benzothiazole analogs (1-20) have been synthesized, characterized by EI-MS and 1H-NMR, and
evaluated for urease inhibition activity. All compounds showed excellent urease inhibitory
potential varying from 1.4 ± 0.10 to 34.43 ± 2.10 µM when compared with standard thiourea
(
IC50 19.46 ± 1.20 µM). Among the series seventeen (17) analogs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
2, 13, 14, 16, 17, and 18 showed outstanding urease inhibitory potential. Analogs 15 and 19 also
1
showed good urease inhibition activity. When we compare the activity of N-phenylthiourea 20
with all substituted phenyl derivatives (1-18) we found that compound 15 showed less activity
than compound 20 having 3-methoxy substituent. The binding interactions of these active
analogs were confirmed through molecular docking.
Keywords: Benzothiazole, Urease inhibitor, Synthesis, Molecular Docking

Correspondence and reprints
E-mail: taha_hej@yahoo.com and muhamm9000@puncakalam.uitm.edu.my, Tel: 0060193098141
1

1
. Introduction
Urease is an important enzyme that converts urea into ammonia. Its activity has been shown to
have link with a number of clinical conditions like development of gastrointestinal ulcers, kidney
stones and pyelonephritis. In gastrointestinal track, urease is excreted by bacterium helicobacter
pylori as a mechanism to survive in the acidic environment of the stomach. The enzyme
transforms urea into ammonia and neutralizes the acid around the microorganism. It has been
estimated that more than 80% of humanity in the developing nations and overall more than 50%
worldwide suffer from H. pylori infection [1]. By inhibiting urease activity, the infection by H.
pylori can, thus, be avoided. Urease inhibitors are therefore considered to be potential anti- ulcer
drugs [2, 3]. Another possible application of urease inhibitors is in the field of agriculture where
urea fertilizers are converted by microbial urease into ammonia. Abnormally enhanced release of
ammonia into atmosphere has adverse environmental and economic consequences which can be
minimized by the use of suitable urease inhibitors [4-6].
Natural and synthetic benzothiazoles derivatives, which had been used for a long time as
precursors for pharmaceutical agents, possess various biological activities. Benzothiazole is a
neuroprotective agent [7, 8], muscarinic receptor [9], Lck enzyme inhibitor [10], anti-bacterial
[
11] anti-allergic agents [12], antiglycation [13], antilieshmanial, [14] and β-glucuronidase [15].
With reference to its diverse bioactivity, benzothiazole skeleton is an important template for a
wide range of bioactive compounds, having many pharmacological functions. Its analogs, like
phenylbenzothiazoles are potent antitumour agents that have been used as prodrugs and chosen
for clinical evaluation [16-18]. Some benzothiazole derivatives having 2-(4-aminophenyl) and
quinol are found to be valuable anti-cancer agents for both in vitro and in vivo systems [19-22].
Recent study on fluorinated 2-arylbenzothiazole shows that it able to selectively suppress activity
of breast, lungs, and colon cancer cells [23]. Our research group is struggling continuously to
identify lead molecules for enzyme inhibition [24]. In this study, we are reporting synthesis and
urease inhibitory activity of benzothiazole analogs.
2

2
2
. Chemistry
.1.Result discussion
The general synthetic pathway for the preparation of novel 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-
N-phenylhydrazinecarbothioamides 1-19 are shown in Scheme 1 and 2. The scheme 1 involves
synthesis of benzothiazole having benzohydrazide through a series of reactions as reported [25].
Methyl 4-(benzo[d]thiazol-2-yl)benzoate III was achieved by reacting 2-aminothiophenol I with
methyl 4-formylbenzoate II. The methyl 4-(benzo[d]thiazol-2-yl)benzoate III was then
converted into benzothiazole having benzohydrazide IV (scheme 1).
Scheme 1. Synthesis of 4-(benzo[d]thiazol-2-yl)benzohydrazide IV
Scheme 2. Synthesis of benzothiazole analogs 1-19
The
2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-phenylhydrazinecarbothioamides
1-20
were
synthesized by mixing the equal amount of benzothiazole benzohydrazide IV and a variety of
isothiocyanates in the presence of triethylamine and refluxed for 6 hours. The completion of
3

reaction was confirmed by thin layer chromatography. The crude products were further
recrystallized from methanol to afford pure compounds with the yield between 72-92 %. The
structures of the 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-phenylhy-drazinecarbothioamides 1-20
were determined using spectroscopic techniques such as NMR, MS, and were further confirmed
using CHN analysis.
3
. Urease Inhibition
Benzothiazole analogs (1-20) have been evaluated for urease activity. All compounds showed
excellent urease inhibitory potential varying from 1.4 ± 0.10 to 34.43 ± 2.10 µM when compared
with standard thiourea (IC50 19.46 ± 1.20 µM) (Table-1). Among the series eighteen (18) analogs
1
-14, 16-18, 20, showed better urease inhibitory potential with IC50 values ranges 1.4 and 19.14
µM, respectively, better than the standard thiourea. On the other hand the analogs 15 and 19 also
showed good urease inhibitory potential. The most interesting thing, to note that compounds 1-
1
4, 16-18 having phenyl substituted derivatives showed better activity then unsubstituted phenyl
analog 20 except analog 15 which showed less activity.
Table-1. Urease inhibition activity and docking score (S) of benzothiazole derivatives 1-19
IC50 (μM
IC50(μM±SE
S.No
1
R
S
S.No
11
R
S
a
a
±
SEM )
M )
7.4 ± 0.46
-8.1536
18.7 ± 1.10
6.3 ± 0.42
-7.8867
2
3
4
3.4 ± 0.26
4.3 ± 0.29
6.9 ± 0.38
-8.8940
-8.8220
-8.2645
12
13
-8.3245
-8.1023
-8.6234
11.4 ± 0.70
5.7 ± 0.36
1
4
4

5
10.4 ± 0.58
-
8.1131
15
16
28.12 ± 1.45
-7.5773
6
7
8
9
2.5 ± 0.10
13.7 ± 0.65
5.5 ± 0.27
13.6 ± 0.76
1.4 ± 0.10
-8.9262
-8.0321
-8.6564
-8.0521
2.1 ± 0.24
-8.9951
9.6975
1
7
1.60 ± 0.10
-
18
19
20
17.60 ± 0.98
-7.8998
34.43 ± 2.10 -7.4373
1
0
-9.8669
19.14 ± 1.10
-7.7967
Thiourea (Standard Drug)
19.46 ± 1.20 µM
4
.0 Docking studies
All the above compounds (1-20) were docked into the binding cavity of Urease (PDB ID:
UBP). From the docking studies a good agreement was observed between the docking and
4
experimental results. The results show that the molecular docking approach is reliable and
produces a good correlation coefficient (r² = 0.912) between p-docking score and IC50 values of
the ligands as shown in Figure 1.
5

Fig.1. Correlation graph of docking scores and IC50 values of the ligands.
On the basis of IC50 values, the top compounds 2 3, 6, 10, 16, and 17 were found to show
considerable interaction with target protein. The most active compound 10, as shown in Figure
2
a, binds deeply into the binding cavity of urease and interacts with the residues His 324, Gly
2
80, Ala 170 and Ni ion of the binding cavity. Basic His 324 showed arene-cation interaction
with the benzothiazole ring. Ala 170 and Gly 280 were found inside chain acceptor interaction
with the hydrogen of different NH group. The S group showed interaction with the Ni ion of the
binding cavity. The important feature observed in the structure of this ligand regarding
interaction was the nitro group which has an electron withdrawing effect that enhances the
polarizability of molecule as a whole.
6

Fig. 2a. 2D molecular docking conformation of Compound 10 in the catalytic cavity of Urease
enzyme.
These interactions confirmed that active compounds are interacting through non-covalent
interactions so these compounds are competitive inhibitors.
The second most active compound 17, having a trifluoromethyl benzene substituent and the third
most active compound 16, having dichlorobenzene group were found making similar interactions
with the residues Gly 280 and Ni ion of the binding cavity as shown in Figure 2b and 2c. Gly
2
80 was found inside chain acceptor interaction with the hydrogen of NH group. The S group
showed interaction with the Ni ion of the binding cavity. The presence of trifluoromethyl
benzene group in compound 17 and dichlorobenzene in 16 resulted in a similar behavior
regarding interactions. Both the groups have atoms with high electronegativity which may
enhance the activity of rest of the molecules by making them polarized.
7

Fig. 2. Molecular interactions of the benzothiazole derivatives in the active site of Urease
enzyme: compound 10 (2a), 17 (2b), 16 (2c) and compound 6 (2d). The ligand is shown in
Yellow stick (Molecular color).
Compound 6 substituted with para-fluorobenzene showed four important interactions with the
residues Asp 363, Gly 280 and Ni ion (Fig. 2d). A side chain hydrogen acceptor and a backbone
hydrogen acceptor interaction were found for the Asp 363 and Gly 280, respectively, with the
two different NH group of the ligand.
8

Fig. 3. Molecular docking conformation of Compound 2 (3a), 3 (3b), and least active compounds
9 (3c) and 15 (3d) in the catalytic cavity of Urease enzyme. The ligand is shown in Yellow stick
Molecular color).
1
(
Compound 2 (Fig. 3a), the o-flourobenzene derivative and compound 3 (Fig. 3b), the o-
chlorobenzene derivative showed similar interactions with the active site residues. In both the
compounds S is coordinated to Ni ion of the cavity while the thiazole moieties are involved in
cation-arene interactions with the His 324.
From the structural differences of compounds and their docking studies, we can conclude that
compounds having a substituent that are highly electronegative, polarizable and possess electron
withdrawing inductive effect may enhance the activity and interactions. On the other hand,
ligands with non-polar moiety like methyl or benzene and bulky groups showed poor interactions.
This correlates well with their low inhibition activity, which had been determined experimentally.
It can be verified from the inferior activity of compound 15 and 19 (Table-1) and their
9

interactions as shown in Figure 3c and 3d. Compound 15 made a single interaction with Ni ion
while compound 19 is only bonded to Ala 366.
In this study we synthesized novel derivatives of benzothiazole and tested them for Urease
inhibition. We identify some new urease inhibitors and also confirmed our results with docking
studies further we tested our compounds for toxicity and they were found to be non toxic.
4
4
. Experimental
.1. Urease Inhibition
The reaction mixtures, comprising 25 μL of enzyme (jack bean urease, Sigma aldrich) solution
and 55 μL of buffers containing 100 mM urea, were incubated with 5 μL of the test compounds
°
(
0.5 mM concentration) at 30 C for 15 minutes in 96-well plates. For the kinetics assessment the
urea concentrations were changed from 2-24 mM. Urease activity was determined by measuring
ammonia production using the indophenol method as described by Weatherburn. Briefly, 45 μL
of phenol reagent (1% w/v phenol and 0.005% w/v sodium nitroprusside (Sigma Aldrich)) and,
7
0 μL of alkali reagent (0.5% w/v NaOH (Sigma Aldrich) and 0.1% active chloride NaOCl
(
Sigma Aldrich)) were added to each well. The increasing absorbance at 630 nm was measured
after 50 minutes, using a microplate reader (Molecular Device, USA). All reactions were
performed in triplicate in a final volume of 200 μL. The results (change in absorbance per min)
were processed by using SoftMaxPro software (molecular Device, USA). The entire assays were
performed at pH 6.8. Percentage inhibition was calculated from the formula 100-(ODtest
well/ODcontrol)×100. Thiourea was used as the standard inhibitor for urease [26].
4
.2. Methyl 4-(benzo[d]thiazol-2-yl)benzoate (III)
4
-Formylbenzoic acid methyl ester (8.2 g, 50 mmol) and sodium metabisulfite (4.75 g, 25 mmol)
°
were dissolved in 50 mL of aqueous EtOH (80% ) and stirred for 1 hour at 0-5 C, then kept in a
fridge for several hours. Precipitate formed was filtered and dried to give 12.6 g (94%) of sulfite
adduct . The mixture of sulfite adduct (10.72 g, 40 mmol) and o-aminothiophenol (6.25 g, 40
mmol) in DMF (40 mL) was heated 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
10

methyl 4-(benzo[d]thiazol-2-yl)benzoate and yielded ( 9.15 g, 85%). White solid, R = 0.57
f
1
(
ethyl acetate:hexane 2:8); M.p. 228 °C. H NMR (500 MHz, DMSO-d
6
):  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 =
1
3
6
.5, J = 1.5 Hz), 7.45 (dt,1H, J = 8.0, J = 1.0 Hz), 3.98 (s, 3H, CH
MHz): δ 52.88, 122.99, 123.71, 126.53, 127.41, 127.41, 127.95, 130.63, 130.63, 132.17, 135.25,
37.24, 153.98, 166.09, 166.45; Anal. Calcd for C15 S, 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 [25].
.3. 4-(Benzo[d]thiazol-2-yl)benzohydrazide (IV)
3
); C-NMR (DMSO-d , 125
6
1
H
11NO
2
4
Mixture of compound 4 (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 (5) was washed with water, filtered, dried, and then crystallized from ethanol and yielded
1
White solid, R
MHz, DMSO-d
H, 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 = 8.0, J
f
= 0.32 (ethyl acetate:hexane 9:1); (7.35 g, 91%). m.p. 325 °C. H NMR (500
6
):  9.82 (s, 1H, NH), 8.28 (d, 2H, J = 8.5 Hz), 8.25 (d, 2H, J = 8.0 Hz), 8.11 (d,
1
1
3
=
1.0 Hz), 3.91 (br. s, 2H, NH
27.31, 127.31, 127.62, 128.48, 128.48, 135.13, 135.42, 136.05, 153.99, 165.44, 166.87; Anal.
Calcd for C14 OS, 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 [1].
.4. Synthesis of 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-phenylhydrazinecarbothioamides
1-19)
2
); C-NMR (DMSO-d , 150 MHz): δ 122.93, 123.56, 126.33,
6
1
H
11
N
3
4
(
Equal amount of benzothiazole hydrazide IV (1 mmole) and isothiocyanates (1 mmole) were
mixed in the presence of ethanol (20 mL) and catalytic amount of triethylamine and refluxed for
6
hours. The completion of reaction was confirmed by TLC. The crude products were further
recrystallized from methanol to afford pure compounds with the yield between 72-92 %.
4
.5. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(o-tolyl)hydrazinecarbothioamide (1)
1
White solid. Yield: 83.2%. m.p.: 273-274 °C, H NMR (500 MHz, DMSO-d
6
): δ 12.23 (s, 1H) 10
.
60 (s, 1H), 10.34 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 8.5 Hz, 3H), 7.56 (t, J = 7.0 Hz,
1
3
1
H), 7.44-7.50 (m, 5H), 7.38 (d, J = 3.5 Hz, 2H), 2.07 (s, 3H); C NMR (150 MHz, DMSO-d6):
δ 180.81, 166.92, 162.45, 152.42, 138.44, 138.01, 136.32, 133.71, 132.73, 129.97, 128.59, 128.5
, 127.73, 127.25, 127.25, 126.95, 125.44, 124.68, 123.71, 123.07, 122.76, 17.3; Anal. Calcd for
9
11

C
22
H
18
N
4
OS
2
, C = 63.13; H = 4.33; N = 13.39, Found C = 63.14; H = 4.35; N = 13.40; EI MS m/
z (% rel. abund.): 418.2
4
.6. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(2-fluorophenyl)hydrazinecarbothioamide (2)
1
Yellow solid. Yield: 74.8%. m.p.: 267-268 °C. H NMR (500 MHz, DMSO-d
6
): δ 10.62 (s, 1H),
9
7
.94 (s, 1H), 9.68 (s, 1H), 8.23 (d, J = 8.0 Hz, 2H), 8.19 (d, J = 8.0 Hz, 2H), 7.67-7.59 (m, 3H),
1
3
.51-7.40 (m, 3H), 7.24 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H); C NMR (150 MHz, DMS
O-d6): δ 180.89, 166.92, 162.45, 159.01 (d, J = 262.3 Hz), 152.45, 138.41, 136.24, 133.73, 128.
5
2
8, 128.58, 127.85, 127.31, 127.31, 126.97, 125.74, 125.43, 124.48, 123.90, 123.76, 122.70, 117.
5, 117.04; Anal. Calcd for C21 OS , C = 59.70; H = 3.58; N = 13.26; Found C = 59.69; H
3.59; N = 13.24; EI MS m/z (% rel. abund.): 422.3
H15FN
4
2
=
4
.7. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(2-chlorophenyl)hydrazinecarbothioamide (3)
White solid. Yield: 92.5%. m.p.: 271-273 °C. 1H NMR (500 MHz, DMSO-d6): δ 10.90 (s, 1H),
9
7
1
1
1
.94 (s, 1H), 9.78 (s, 1H), 8.18 (d, J = 8.5 Hz, 2H), 8.10 (d, J = 8.0 Hz, 2H), 7.58-7.44 (m, 3H),
.46-7.27 (m, 5H); 13C NMR (150 MHz, DMSO-d6): δ 180.82, 166.92, 162.40, 152.49, 138.46,
36.25, 134.77, 133.73, 129.77, 129.33, 128.58, 128.58, 127.71, 127.23, 127.23, 126.91, 125.45,
25.42, 125.06, 123.73, 122.71; Anal. Calcd for C21H15ClN4OS2, C = 57.46; H = 3.44; N =
2.76, Found C = 57.47; H = 3.43; N = 12.74; EI MS m/z (% rel. abund.): 439.1
4
.8. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(2-bromophenyl)hydrazinecarbothioamide (4)
1
White solid. Yield: 86.5%. m.p.: 278-280 °C. H NMR (500 MHz, DMSO-d
6
): δ 10.56 (s, 1H), 9.
):
δ 180.81, 166.94, 162.44, 152.46, 138.52, 136.48, 136.33, 133.78, 132.71, 128.72, 128.58, 128.5
1
3
9
0 (s, 1H), 9.74 (s, 1H), 8.11-8.22 (m, 7H), 7.39-7.65 (m, 5H); C NMR (150 MHz, DMSO- d
6
8
, 127.31, 127.31, 126.93, 125.51, 125.31, 124.01, 123.75, 122.72, 117.48; Anal. Calcd for C21
BrN OS
rel. abund.): 483.6
H
1
5
4
2
, C = 52.18; H = 3.13; N = 11.59; Found C = 52.20; H = 3.14; N = 11.60; EI MS m/z (
%
4
.9. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(p-tolyl)hydrazinecarbothioamide (5)
Pale yellow solid. Yield: 85.7%. m.p.: 269-270 °C. 1H NMR (500 MHz, DMSO- d
6
): δ 10.60 (s,
1
H), 9.78 (s, 2H) 8.23 (d, J = 8.5 Hz, 2H), 8.20 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 8.5 Hz, 1H), 8.06
(
d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.47-7.52 (m, 2H), 2.38 (s,
12

3
1
1
H); 13C NMR (150 MHz, DMSO- d
36.23, 133.73, 132.76, 130.32, 130.32, 128.53, 128.53, 127.31, 127.31, 126.96, 125.44, 123.74,
22.71, 120.89, 120.89, 21.15; Anal. Calcd for C22 OS , C = 63.13; H = 4.33; N = 13.39,
6
): δ 179.34, 166.93, 162.43, 152.42, 138.47, 137.69,
H
18
N
4
2
Found C = 63.12; H = 4.31; N = 13.44; EI MS m/z (% rel. abund.): 418.1
4
.10. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(4-fluorophenyl)hydrazinecarbothioamide (6)
White solid. Yield: 92.5%. m.p.: 270-271 °C. 1H NMR (500 MHz, DMSO-d ): δ 10.62 (s, 1H), 9
94 (s, 1H), 9.68 (s, 1H), 8.23 (d, J = 8.0 Hz, 2H), 8.19 (d, J = 8.0, 2H), 8.16 (s, 1H), 8.11 (d, J =
6
.
8
.0, 2H), 7.60 (t, J = 7.5, 1H), 7.51 (t, J = 8.0, 1H), 7.24 (t, J = 8.5, 1H), 7.17(d, J = 8.0, 2H); 13C
): δ 179.33, 166.96, 162.45, 159.47 (d, J = 262.3 Hz), 152.43, 138.4
, 136.27, 135.63, 133.78, 128.54, 128.54, 127.31, 127.31, 126.95, 125.44, 123.75, 122.71, 122.7
, 122.47, 115.42, 115.42; Anal. Calcd for C21 OS , C = 59.70; H = 3.58; N = 13.26; Foun
NMR (150 MHz, DMSO-d
6
2
1
H15FN
4
2
d C = 59.71; H = 3.57; N = 13.25; EI MS m/z (% rel. abund.): 422.3
4
.11. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(4-bromophenyl)hydrazinecarbothioamide (7)
1
White solid. Yield: 86.3%. m.p.: 264-265 °C. H NMR (500 MHz, DMSO-d
6
): δ 10.99 (s, 1H), 9.
9
8
1
1
8 (s, 1H), 9.88 (s, 1H), 8.31 (d, J = 8.0 Hz, 2H), 8.23 (d, J = 8.0, 2H), 8.19 (d, J = 8.0 Hz, 2H),
1
3
.06 (d, J = 7.5, 1H), 7.55-7.63 (m, 3H), 7.49-7.52 (m, 2H); C NMR (150 MHz, DMSO- d
79.35, 166.93, 162.41, 152.45, 138.47, 138.06, 136.22, 133.78, 131.22, 131.22, 128.56, 128.56,
27.24, 127.24, 126.90, 125.46, 123.72, 123.15, 123.15, 122.78, 114.73; Anal. Calcd for C21
OS , C = 52.18; H = 3.13; N = 11.59; Found C = 52.19; H = 3.15; N = 11.58; EI MS m/z (%
rel. abund.): 483.6
6
): δ
H
15
BrN
4
2
4
.11.1. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(4-chlorophenyl)hydrazinecarbothioamide (8)
1
Light yellow. Yield: 91.2%. m.p.: 277-278 °C. H NMR (500 MHz, DMSO-d
6
): δ 10.80 (s, 1H),
9
.89 (s, 2H), 8.24 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.0, 2H), 8.10 (t, J = 8.0 Hz, 2H), 7.49-7.68 (
1
3
m, 5H), 7.39-7.34 (m, 2H); C NMR (150 MHz, DMSO- d
6
): δ 179.33, 166.96, 162.41, 152.45,
39.93, 138.45, 136.21, 133.74, 129.39, 129.39, 128.54, 128.54, 128.14, 127.27, 127.27, 126.93,
25.45, 123.71, 122.74, 121.94, 121.94; Anal. Calcd for C21 OS , C = 57.46; H = 3.44; N
1
1
H
15ClN
4
2
=
12.76, Found C = 57.45; H = 3.45; N = 12.76; EI MS m/z (% rel. abund.): 439.2
4
.11.2. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(4-methoxyphenyl)hydrazinecarbothioamide
(
9)
13

1
Light yellow. Yield: 81.6%. m.p.: 267-269 °C. H NMR (500 MHz, DMSO-d
0.42 (s, 1H), 9.72 (s, 1H), 8.16 (d, J = 7.5 Hz, 2H), 8.08 (d, J = 7.5, 2H), 8.06 (d, J = 8.0 Hz, 2H
, 8.01 (d, J = 7.5 Hz, 2H), 7.52 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 7.0 Hz, 1H), 7.06 (d, J = 8.0 Hz,
6
): δ 10.60 (s, 1H),
1
)
1
3
2
H), 3.81 (s, 3H); C NMR (150 MHz, DMSO- d
38.42, 136.24, 133.71, 133.13, 128.51, 128.51, 127.32, 127.32, 126.98, 125.42, 123.68, 122.69,
22.21, 122.21, 114.11, 114.11, 56.04; Anal. Calcd for C22 , C = 60.81; H = 4.18; N =
2.89; Found C = 60.82; H = 4.19; N = 12. 90; EI MS m/z (% rel. abund.): 434.6
6
): δ 179.33, 166.92, 162.46, 154.87, 152.44,
1
1
1
H
18
N
4
O S
2 2
4
.11.3. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(4-nitrophenyl)hydrazinecarbothioamide (10)
1
White. Yield: 85.6%. m.p.: 275-276 °C. H NMR (500 MHz, DMSO-d
6
): δ 10.98 (s, 2H), 9.18 (s,
1
2
H), 8.24 (d, J = 7.5 Hz, 2H), 8.22 (d, J = 9.0, 1H), 8.19 (d, J = 7.5 Hz, 2H), 8.12 (d, J = 8.0 Hz,
1
3
H), 7.90-7.82 (m, 3H), 7.59 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H); C NMR (150 MHz,
): δ 166.93, 162.45, 152.42, 143.61, 143.28, 138.43, 136.27, 133.72, 128.53, 128.53, 1
7.21, 127.21, 126.97, 125.45, 125.02, 125.02, 123.73, 122.78, 120.93, 120.93; Anal. Calcd for
, C = 56.11; H = 3.36; N = 15.58; Found C = 56.13; H = 3.38; N = 15.60; EI MS m
z (% rel. abund.): 450.1
DMSO- d
6
2
C
21
H
15
N
5
O S
3 2
/
4
.11.4. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(m-tolyl)hydrazinecarbothioamide (11)
1
White solid. Yield: 83.7%. m.p.: 269-271 °C. H NMR (500 MHz, DMSO-d
6
): δ 10.71 (s, 1H), 9.
7
9 (s, 1H), 9.73 (s, 1H), 8.24 (d, J = 8.5 Hz, 2H), 8.21 (d, J = 8.0, 1H), 8.11-8.18 (m, 3H), 7.55-7
.
61 (m, 2H), 7.51 (d, J = 7.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.19-7.30 (m, 2H), 6.98 (d, J = 7.0
1
3
Hz, 1H), 2.25 (s, 3H); C NMR (150 MHz, DMSO- d
6
): δ 179.34, 166.96, 162.47, 152.42, 140.
4, 138.46, 138.32, 136.23, 133.71, 128.65, 128.58, 128.58, 127.23, 127.23, 126.96, 126.64, 125.
3, 123.76, 122.74, 121.56, 120.62, 21.22; Anal. Calcd for C22 OS , C = 63.13; H = 4.33; N
2
4
H
18
N
4
2
=
13.39, Found C = 63.15; H = 4.32; N = 13.41; EI MS m/z (% rel. abund.): 418.1
4
.11.5. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(3-fluorophenyl)hydrazinecarbothioamide (12)
1
Light yellow. Yield: 78.9%. m.p.: 267-268 °C. H NMR (500 MHz, DMSO-d
6
): δ 10.65 (s, 1H),
9
,
.93 (s, 1H), 9.14 (s, 1H), 8.25 (d, J = 8.0 Hz, 2H), 8.19 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0, 2H)
1
3
7.59-7.51 (m, 5H), 7.35-7.28 (m, 2H); C NMR (150 MHz, DMSO- d ): δ 179.35, 166.93, 162
6
.
46, 160.07 (d, J = 262.3 Hz), 152.42, 140.13, 138.51, 136.27, 133.73, 129.52, 128.57, 128.57, 1
7.23, 127.23, 126.95, 125.43, 123.72, 122.71, 118.45, 112.28, 111.43; Anal. Calcd for C21
OS , C = 59.70; H = 3.58; N = 13.26; Found C = 59.68; H = 3.61; N = 13.25; EI MS m/z (% r
2
15
H F
N
4
2
14

el. abund.): 422.1
.11.6. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(3-methoxyphenyl)hydrazinecarbothioamide
15)
White solid. Yield: 79.1%. m.p.: 282-283 °C. H NMR (500 MHz, DMSO-d
.79 (s, 1H), 9.79 (s, 1H), 8.08-8.29 (m, 3H), 7.51-7.58 (m, 5H), 7.10-7.33 (m, 4H), 3.74 (s, 3H);
4
(
1
6
): δ 11.09 (s, 1H), 1
0
1
3
C NMR (150 MHz, DMSO-d
24, 133.75, 128.96, 128.51, 128.51, 127.24, 127.24, 126.93, 125.44, 123.75, 122.72, 112.47, 110
02, 109.12, 56.01; Anal. Calcd for C22 , C = 60.81; H = 4.18; N = 12.89; Found C = 6
.83; H = 4.17; N = 12.91; EI MS m/z (% rel. abund.): 434.6
6
): δ 179.31, 166.93, 162.47, 158.34, 152.41, 140.38, 138.41, 136
.
.
H
18
N
4
O S
2 2
0
4
.11.7. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(3,4-dichlorophenyl)hydrazinecarbothioamide
16)
Yellow solid. Yield: 74.6%. m.p.: 271-273 °C. H NMR (500 MHz, DMSO-d
(
1
6
): δ 10.82 (s, 1H),
1
8
6
5
0.06 (s, 1H), 9.98 (s, 1H), 8.25 (d, J = 8.5 Hz, 2H), 8.20 (d, J = 7.5 Hz, 1H), 8.18-8.13 (m, 3H),
1
3
.10-8.04 (m, 3H), 7.50-7.46 (m, 2H); C NMR (150 MHz, DMSO-d
, 152.44, 141.26, 138.43, 136.21, 133.73, 132.71, 131.87, 128.54, 128.54, 127.21, 127.21, 126.9
, 126.16, 125.45, 123.72, 123.55, 122.72, 120.01; Anal. Calcd for C21H14Cl OS , C = 53.28;
6
): δ 179.32, 166.94, 162.4
2
N
4
2
H = 2.98; N = 11.84; Found C = 53.29; H = 2.97; N = 11.82; EI MS m/z (% rel. abund.): 473.6
.11.8. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(4-(trifluoromethyl)phenyl)hydrazine-
carbothioamide (17)
White solid. Yield: 81.7%. m.p.: 268-269 °C. H NMR (500 MHz, DMSO-d
4
1
6
): δ 10.84 (s, 1H), 1
0
2
.05 (s, 1H), 9.98 (s, 1H), 8.25 (d, J = 8.5 Hz, 2H), 8.20 (d, J = 7.5 Hz, 1H), 8.18 (d, J = 8.0 Hz,
13
H), 8.13-8.06 (m, 3H), 7.78-7.70 (m, 2H), 7.60 (d, J = 7.5 Hz, 2H); C NMR (150 MHz, DMS
): δ 179.33, 166.96, 162.45, 152.43, 142.66, 138.41, 136.24, 133.73, 128.53, 128.53, 127.32,
27.32, 126.95, 126.47, 126.47, 126.02, 124.62 (d, J = 223.2 Hz), 123.45, 122.74, 121.36, 120.6
, 120.63; Anal. Calcd for C22 OS , C = 55.92; H = 3.20; N = 11.86; Found C = 55.93; H
3.21; N = 11.85; EI MS m/z (% rel. abund.): 472.5
.11.9. 2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-(2-methoxyphenyl)hydrazinecarbothio-amide
18)
Yellow solid. Yield: 92.3%. m.p.: 273-274 °C. H NMR (500 MHz, DMSO-d
0.35 (s, 1H), 9.85 (s, 1H), 8.24 (d, J = 8.0 Hz, 2H), 8.19 (d, J = 8.0 Hz, 2H), 8.06-8.16 (m, 2H),
O-d
6
1
3
H15F3N
4
2
=
4
(
1
6
): δ 10.79 (s, 1H),
1
15

7
3
.48-7.61 (m, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.15-7.19 (m, 2H), 7.06 (d, J = 9.0 Hz, 1H), 3.78 (s,
1
3
H); C NMR (150 MHz, DMSO-d
33.77, 132.15, 128.59, 128.59, 127.31, 127.31, 126.97, 125.46, 124.91, 123.74, 122.68, 122.56,
22.31, 111.04, 56.75; Anal. Calcd for C22 , C = 60.81; H = 4.18; N = 12.89; Found C
60.80; H = 4.17; N = 12. 88; EI MS m/z (% rel. abund.): 434.6
6
): δ 180.84, 166.95, 162.40, 152.45, 150.04, 138.51, 136.32,
1
1
H
18
N
4
O S
2 2
=
4
.11.10.
amide (19)
White solid. Yield: 72.5%. m.p.: 281-283°C. H NMR (500 MHz, DMSO-d
68 (s, 1H), 9.99 (s, 1H), 8.18 (s, J = 8.0 Hz 2H), 8.10 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 7.5 Hz, 1
H), 7.80 (d, J = 77.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 2.62 (m, 6H), 2.3
N-(adamantan-1-yl)-2-(4-(benzo[d]thiazol-2-yl)benzoyl)hydrazinecarbothio-
1
6
): δ 11.20 (s, 1H), 10
.
1
3
1
(m, 3H), 1.96 (m, 6H); C NMR (150 MHz, DMSO-d
51, 136.23, 133.74, 128.54, 128.54, 127.26, 127.26, 126.93, 125.50, 123.75, 122.73, 54.48, 43.6
, 43.65, 37.73, 37.73, 27.91, 27.91; Anal. Calcd for C25 OS , C = 64.90; H = 5.66; N = 12.
1; Found C = 64.91; H = 5.67; N = 12.10; EI MS m/z (% rel. abund.): 462.6
6
): δ 187.58, 166.94, 162.47, 152.41, 138
.
5
H
26
N
4
2
1
4
.11.11.
2-(4-(benzo[d]thiazol-2-yl)benzoyl)-N-phenylhydrazinecarbothioamide (20)
1
White solid. Yield: 82.0%. m.p.: 260-261 °C. H NMR (500 MHz, DMSO-d
6
): δ 10.81 (s, 1H), 9.
4
7 (s, 1H), 9.13 (s, 1H), 8.25 (d, J = 8.5 Hz, 2H), 8.20 (d, J = 8.0, 1H), 8.09-8.01 (m, 4H), 7.55-7
.
61 (m, 2H), 7.51 (d, J = 7.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.19-7.30 (m, 2H), 6.98 (d, J = 7.0
1
3
Hz, 1H); C NMR (150 MHz, DMSO- d
2.1, 130.1, 130.0, 129.2, 129.2, 128.2, 127.5, 127.5, 126.4, 126.4, 124.4, 121.6, 125.1, 121.5; A
nal. Calcd for C21 OS , C = 62.35; H = 3.99; N = 13.85, Found C = 62.34; H = 3.98; N = 1
.87; EI MS m/z (% rel. abund.): 404.0.
.12. Docking
6
): δ 181.0, 169.1, 164.6, 154.2, 146.4, 138.4, 133.7, 1
3
H
16
N
4
2
3
4
To understand the binding modes of the compounds given in Table-1, all ligands were docked
into the binding site of Urease enzyme. The top ranked conformations of each ligand were saved
in a separate database for further evaluation. The docking results well correlated with the
experimental results.
4
.13. Protein Preparation
16

Protein molecule included in our study; Urease (PDB ID 4ubp) was obtained from Protein Data
Bank. Water molecules were removed and the 3D protonation of the protein molecule was
carried out. Energy of the protein molecule was minimized with the help of Energy minimization
algorithm of MOE tool and the minimized structure was used for Docking.
4
.14. Ligands Preparation
The 3D structures of ligands were built using builder in MOE. The 3D protonation of ligands
were carried out and were energy minimized. These structures were saved in mdb file format as
input file for docking.
Acknowledgements
Authors would like to acknowledge Malaysia and Universiti Teknologi MARA for the financial
support under Listeri grant 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.
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19

Table-S. Urease % inhibition, IC50 and concentration of benzothiazole derivatives 1-19
IC50(μM
S.N
o
(Conc)
mM
%
IC50 (μM ±
(Conc)
mM
%
R
S.No
11
R
±
a
Inhib.
Inhib.
SEM )
a
SEM )
1
8.7 ±
.10
1
2
0.5
87
94
7.4 ± 0.46
3.4 ± 0.26
1.0
0.5
80
88
1
6
.3 ±
.42
0.125
12
0
1
1.4 ±
3
0.125
0.5
92
88
4.3 ± 0.29
13
0.5
0.5
86
90
0
.70
5
.7 ±
.36
4
5
6.9 ± 0.38
0
1
4
2
8.12 ±
.45
10.4 ± 0.58
0.5
85
95
82
15
16
1.0
76
94
1
2
.1 ±
.24
6
7
0.125
0.5
2.5 ± 0.10
0.125
0.125
0
1
.60 ±
0.10
1
7
13.7 ± 0.65
9
8
20

1
7.60 ±
.98
8
9
0.125
0.5
89
81
97
5.5 ± 0.27
13.6 ± 0.76
1.4 ± 0.10
18
19
20
0.75
1.0
78
70
76
0
3
4.43 ±
.10
2
1
9.14 ±
1
0
0.125
1.0
1
.10
21

*Graphical Abstract
Graphical Abstract
Hybrid Benzothiazole analogs as Antiurease Agent:
Synthesis and Molecular Docking Studies
Muhammad Taha, a,b Nor Hadiani Ismail , Syahrul Imran , Abdul Wadood , Fazal Rahim , Khalid
a,b
a,b
c
c
e
c
Muhammad Khan , Muhammad Riaz
a
Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar
Puncak Alam, Selangor, Malaysia
b
Faculty of Applied Science UiTM, 40450 Shah Alam, Selangor, Malaysia
c
Computational Medicinal Chemistry Laboratory, Department of Biochemistry, Abdul Wali Khan University, Mardan, Pakistan
d
Department of Chemistry, Hazara University, Mansehra, Pakistan
e
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi-75270, Pakistan
Synthesis of novel benzothiazole analogs (1-19) as potent urease inhibitors

Research Highlights
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Synthesis of 19 benzothiazole derivatives
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In-vitro urease inhibitory activity.
Most compounds are more active than standard drug
Docking studies were carried out to confirm binding of active compounds with enzyme
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