New s-block complexes of 1,10-phenanthroline and 1,3-benzothizole-2-thiolate inhibit urease in silico and in vitro

Article abstract of DOI:10.1002/aoc.5842

The coordination chemistry of 1,10-phenanthroline (phen) and sodium 1,3-benzothiazole-2-thiolate (SBT) with selected s-block elements has been investigated. Four metal complexes were prepared and their structures were characterized using a variety of analytical techniques including infrared, UV–visible, ¹H NMR and ¹³C NMR spectroscopies, elemental analysis, mass spectrometry and single-crystal X-ray diffraction. The reactions of phen and SBT with M(X)_n (M = K(I), Cs(I), Mg(II), Sr(II); X = OH^?, CO₃^?, Cl^?; n = 1, 2) in MeOH–H₂O yielded one-dimensional chains of both potassium [K₂(phen)₂(BT)₂(H₂O)₄]_n (1) and caesium [Cs(phen)(BS)(H₂O)]_n (2) (where BT = 1,3-benzthiazole-2-thiolate and BS = 1,3-benzthiazole-2-sulfinothiolate) and mononuclear complexes of both magnesium {[Mg(phen)(H₂O)₄](BT)₂·phen} (3) and strontium {[Sr(phen)₂(H₂O)₄](BT)₂} (4). In these complexes, phen binds via an N,N′ chelate pocket, while the monoanonic BT^? ligands either coordinate in a bidentate fashion (in the case of 1) or remain uncoordinated (in the case of 3 and 4). In complex 2, SBT ligand was oxidized in situ into a new BS ligand. The sulfinothiolate oxygen atoms in BS coordinate with caesium in a tridentate fashion. Complexes 1–4 were evaluated against urease for enzyme inhibition. The complexes displayed significant inhibition with IC₅₀ values in the range 10.8–45.8 μM. In order to examine the structure–activity relationship, the complexes were docked at the active site of urease. Docking results clearly demonstrate the binding of each complex within the active site of the enzyme.

Full text of DOI:10.1002/aoc.5842

Received: 2 April 2020
DOI: 10.1002/aoc.5842
Revised: 8 May 2020
Accepted: 9 May 2020
F U L L P A P E R
New s-block complexes of 1,10-phenanthroline and
1,3-benzothizole-2-thiolate inhibit urease in silico and
in vitro
Syed Raza Shah1,2 | Zarbad Shah2 | Mohammed Khiat1 | Sobia A. Halim1
Ajmal Khan1 | Javid Hussain3 | Rene Csuk4 | Muhammad U. Anwar1
Ahmed Al-Harrasi1
|
|
1Natural and Medical Sciences Research
The coordination chemistry of 1,10-phenanthroline (phen) and sodium
1,3-benzothiazole-2-thiolate (SBT) with selected s-block elements has been
investigated. Four metal complexes were prepared and their structures were
characterized using a variety of analytical techniques including infrared, UV–
visible, 1H NMR and 13C NMR spectroscopies, elemental analysis, mass
spectrometry and single-crystal X-ray diffraction. The reactions of phen and
SBT with M(X)n (M = K(I), Cs(I), Mg(II), Sr(II); X = OH−, CO3−, Cl−; n = 1, 2)
in MeOH–H2O yielded one-dimensional chains of both potassium
[K2(phen)2(BT)2(H2O)4]n (1) and caesium [Cs(phen)(BS)(H2O)]n (2) (where
BT = 1,3-benzthiazole-2-thiolate and BS = 1,3-benzthiazole-2-sulfinothiolate)
and mononuclear complexes of both magnesium {[Mg(phen)(H2O)4]
(BT)2ꢀphen} (3) and strontium {[Sr(phen)2(H2O)4](BT)2} (4). In these com-
plexes, phen binds via an N,N0 chelate pocket, while the monoanonic BT−
ligands either coordinate in a bidentate fashion (in the case of 1) or remain
uncoordinated (in the case of 3 and 4). In complex 2, SBT ligand was oxidized
in situ into a new BS ligand. The sulfinothiolate oxygen atoms in BS coordinate
with caesium in a tridentate fashion. Complexes 1–4 were evaluated against
urease for enzyme inhibition. The complexes displayed significant inhibition
with IC50 values in the range 10.8–45.8 μM. In order to examine the structure–
activity relationship, the complexes were docked at the active site of urease.
Docking results clearly demonstrate the binding of each complex within the
active site of the enzyme.
Centre, University of Nizwa, Birkat
Almouz 616, Birkat Almouz, Oman
2Department of Chemistry, Bacha Khan
University Charsadda, Charsadda, Khyber
Pakhtunkhwa, 24420, Pakistan
3Department of Biological Sciences and
Chemistry, University of Nizwa, Birkat
Almouz, Oman
4Organic Chemistry, Martin-Luther-
University Halle-Wittenberg, Kurt-
Mothes-Strasse 2, Halle (Saale), 06120,
Germany
Correspondence
Muhammad U. Anwar and Ahmed Al-
Harrasi, Natural and Medical Sciences
Research Centre, University of Nizwa,
Birkat Almouz 616, University of Nizwa,
Birkat Almouz, Oman.
Email: usman.anwar@unizwa.edu.om;
aharrasi@unizwa.edu.om
K E Y W O R D S
alkali/alkaline earth metal complexes, enzyme inhibition, molecular docking, single-crystal X-
ray diffraction, urease
1 | INTRODUCTION
the conversion of urea into ammonia and carbon diox-
ide.4 Urease accelerates the rate of urea hydrolysis by
Urease is widely distributed in plants,1 bacterial cultures2
and soil.3 It is a binuclear Ni(II) enzyme, which catalyses
1014 times compared to natural degradation.5 This rapid
decomposition of urea has adverse effects on humans,
Appl Organomet Chem. 2020;e5842.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
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SHAH ET AL.
animals and plant life.6 It can cause various diseases in
humans such as peptic ulcers, stomach cancer, gastric
infections, dental plaque, kidney stone formation and
pyelonephritis.5,7 In soils, it affects the efficiency of nitro-
gen fertilization, ammonia volatilization and root dam-
age.8 Urease inhibitors can be used to prevent the activity
of this enzyme. Urease inhibitors, including synthetic
organic compounds, plant extracts and metal salts,
reduce the activity of the urease enzyme; however, most
of these inhibitors are associated with toxicity and
side/slow effects.9–14 An alternative strategy is to use
metal complexes as enzyme inhibitors. In this respect,
various V(IV), Ni(II), Cu(II), Zn(II), Cd(II), Sn(IV) and
Bi(III) complexes have been extensively investigated.15
Bismuth complexes, in particular, are used as the first-
line treatment in many countries.16,17 Among the coordi-
nation complexes, Schiff base complexes have been
widely studied for their urease inhibition.15,18,19 While
first-row transition metal complexes have received more
attention, the urease inhibition of cheaper alkali/alkaline
earth metal complexes has remained unexplored. This
can be attributed to difficulties encountered in crystalli-
zation and unpredictable coordination numbers and
geometries associated with these metals.20 Alkali/alkaline
earth metals play a critical role in cellular pathways. For
example, potassium is essential for maintaining the total
body fluid volume, electrolyte balance and normal cell
function.21 Dietary potassium intake exerts a protective
effect against stroke and cardiovascular disease. An
increase in K+ intake per day results in alleviation of
blood pressure.21 Among alkaline earth metals, the
importance of Mg2+ in the body can be realized due to its
necessity in over 325 enzymes.22 It promotes specific
structural or catalytic activities of proteins and
enzymes.23 In humans, a dietary deficiency of Mg2+ can
cause various types of heart diseases such as heart failure
and ischemic heart disease.24 The heavier alkali/alkaline
earth metals such as Cs+ and Sr2+ have received less
attention, due the fact that they have no known biologi-
cal functions in the human body.25
FIGURE 1 Structural representations of the ligands
The complexes of phen with O-donor co-ligands have
been studied for their enzyme inhibition and some of
them have been found to be active against urease.36–38
The s-block complexes of phen with S-donor co-ligands
are rare; a CSD search (2019) resulted in only five
hits.39–43
1,3-Benzothiazole-2-thiol (BT-H; Figure 1) is a natural
product and was first isolated from a fermentation cul-
ture of a Micrococcus sp. bacterial symbiont of the marine
sponge Tedania ignis.44,45 In industry, it is used in the
vulcanization of rubber.45 The coordination chemistry of
BT-H is also well established.40,46–48 In the BT-H ligand,
there are three potential donor atoms, i.e. two sulfur and
one nitrogen. The coordination, however, takes place via
sulfur (located at 1-position) and nitrogen atoms only,
while the sulfur atom, located in the ring, does not take
part in coordination with metals.
In continuation of the search for new bioactive coor-
dination compounds,49,50 we have sought to combine the
well-known enzyme inhibition properties of phen and
develop structurally well-defined alkali and alkaline
earth metal complexes of phen/BT as potential urease
inhibitors. We recently reported alkali and alkaline earth
metal complexes of phen with 2-(3,4-dichlorophenyl)
acetic acid (dcf)50 and diclofenac (dcf) as co-ligands.49
The complexes of phen/dcf showed cytotoxic activity
against lung and oral cancer cell lines. In the study
reported here, we investigated the reactions of phen and
sodium 1,3-benzothiazole-2-thiolate (SBT; Figure 1) with
selected s-block metals and determined the structures of
the polymeric chains of both K2(phen)2(BT)2(H2O)4]n (1)
and [Cs(phen)(BS)(H2O)2n (2) and of two mononuclear
complexes of both magnesium {[Mg(phen)(H2O)4]
(BT)2ꢀphen} (3) and strontium {[Sr(phen)2(H2O)4](BT)2}
(4) (Figure 2). The structures of 1–4 were analysed using
single-crystal X-ray diffraction. Bulk composition was
confirmed using 1H NMR, 13C NMR, UV–visible and
infrared (IR) spectroscopies, mass spectrometry and ele-
mental analysis. In vitro urease enzyme inhibition and
molecular docking studies were conducted to evaluate
the mode of interaction.
1,10-Phenanthroline (phen) is a rigid and coplanar
bidentate ligand (Figure 1). It offers an N,N0 chelate
pocket for cation binding in which the two N-donor
atoms offer a rigid bidentate coordination environment.
The complexes of phen and its derivatives are reported to
cleave DNA and RNA backbones.26,27 They are also
extensively studied for their antibacterial,28 cytotoxic29
and anticancer30 properties. The aromaticity in phen
involves the σ/π-donor and π*-acceptor orbitals31 which
enhances the electronic interaction with metal centres to
create supramolecular architectures with interesting
electrochemical,32 photoluminescent33 and magnetic
properties.33 Phen is a well-known enzyme inhibitor.34,35

SHAH ET AL.
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FIGURE 2 Synthesis of
K2(phen)2(BT)2(H2O)4]n (1), [Cs
(phen)(BS)(H2O)]n (2), {[Mg
(phen)(H2O)4](BT)2ꢀphen} (3)
and {[Sr(phen)2(H2O)4](BT)2} (4)
2 | EXPERIMENTAL
(2) K using graphite-monochromated Mo-Kα radiation
(λ = 0.71073 Å). Data were collected using APEX-II
software,51 integrated using SAINT52 and corrected for
absorption using a multi-scan approach (SADABS).53
Final cell constants were determined from full least-
squares refinement of all observed reflections. The struc-
ture was solved using intrinsic phasing (SHELXT).54 All
non-hydrogen atoms were located in subsequent differ-
ence maps and refined anisotropically with SHELXL-
2016/6. Hydrogen atoms were added at calculated posi-
tions and refined with a riding model. The structures of
1–4 have been deposited with the CCDC (deposition
numbers 1976335–1976338). The carbons in phen in 1–4
have slightly elongated displacement parameters
suggesting some slight disorder but these were insuffi-
cient to merit splitting and modelling the atomic posi-
tions over two sites.
2.1 | General considerations
Solvents, ligands and metal salts were obtained from
commercial suppliers and used without further
purification.
2.2 | Physical measurements
Melting points were determined using a Stanford
Research Systems MPA120 EZ-Melt automated melting
point apparatus. Elemental compositions were deter-
mined with a PerkinElmer 2400 Series II CHNS/O ana-
lyser. UV–visible spectra were measured with an Agilent
8453 spectrophotometer using 1 × 10−6–10−4 M solutions
in water in the range 200–700 nm. IR spectra were
obtained using a Bruker Alpha FT-IR spectrometer
equipped with a platinum single reflection diamond ATR
module. The 1H NMR (600 MHz) and 13C NMR
(151 MHz) spectra were run on a Bruker spectrometer.
Molar conductivities of complexes 1–4 (1 x 10−3 M, H2O)
were measured using a HI-5521-02 conductivity meter.
2.4 | Preparation of complexes
2.4.1 | Preparation of
[K2(phen)2(BT)2(H2O)4]n (1)
SBT (0.167 g, 1.0 mmol) and KOH (0.0561 g, 1.0 mmol)
were refluxed in MeOH–H2O (1:1) mixture for 1 h. Phen
(0.198 g, 1.0 mmol) in 4 mL of MeOH were added
dropwise and the reaction mixture was further refluxed
for an additional hour. The solution was then filtered and
left undisturbed for crystallization at room temperature.
Colourless crystals suitable for X-ray diffraction were col-
lected after one week. Yield: 0.303 g, 75%. Melting point:
2.3 | X-ray crystallography
Crystal data are summarized in Table 1. Single crystals of
1–4 were mounted on a MiTeGen loop with grease and
examined using a Bruker D8 Venture APEX diffractome-
ter equipped with a Photon 100 CCD area detector at 296

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SHAH ET AL.
TABLE 1
Crystal data for complexes 1–4
1
2
3
4
Formula
Mr (g mol−1
K2C38H28N6O2S4
807.10
CsC19H14N3O3S2
529.36
MgC38H32N6O4S4
789.24
SrC38H32N6O4S4
852.55
)
Crystal system, space group
Monoclinic, P21/
Monoclinic, P21/
Monoclinic, Pn
Orthorhombic,
c
c
Pbcn
Temperature (K)
296
296
296
296
a (Å)
b (Å)
c (Å)
β (ꢁ)
V (Å3)
Z
7.1488 (3),
10.7884 (5),
24.4437 (11)
97.174 (2)
1870.44 (14)
2
7.5599 (5),
25.4640 (17)
10.8014 (7)
100.837 (2)
2042.2 (2)
4
12.9911 (7),
7.2821 (3)
19.9000 (13)
101.808 (5)
1842.75 (18)
2
24.5733 (12),
10.9415 (5)
14.4062 (5)
90
3873.4 (3)
4
μ (mm−1
)
0.52
2.04
0.33
1.66
Tmin, Tmax
0.626, 0.745
0.5251, 0.7454
0.6519, 0.7451
0.528, 0.745
51 157, 3957, 3279
No. measured, independent and observed [I > 2σ
(I)] reflections
32 222, 3810,
3227
33 795, 4196,
3739
12 103, 12 103,
7629
Rint
0.035
0.626
0.041
0.627
0.1036
0.597
0.058
(sin θ/λ)max (Å−1
)
0.626
R[F2 > 2σ(F2)], wR(F2), S
0.046, 0.136, 0.95 0.036, 0.088, 1.25 0.075, 0.127, 1.03
0.036, 0.133, 1.08
No. reflections
3810
4196
12 103
503
3957
No. parameters
241
259
252
No. restraints
2
3
10
5
Δρmax, Δρmin (e Å−3
)
0.41, −0.36
1976335
0.62, −0.83
1976336
0.32, −0.37
1976337
0.55, −0.65
1976338
CCDC
205–210ꢁC. Selected IR data (cm−1): νOH = 3668–3050,
νC=S = 1669, νC=C = 1560s, νC=N = 1504s. UV–visible
(1.0 × 10−5 M, H2O; λmax, nm (ε, M−1 cm−1)):
227 (6.6 × 104), 264 (4.4 × 104), 319 (2.3 × 104),
ethyl acetate. Colourless transparent crystals suitable for
X-ray diffraction were formed in three days. Yield:
0.380 g, 74.3%. Melting point: 300ꢁC (decomposed).
Selected IR data (cm−1): νOH = 3510–3000, νS=O = 1680,
νC=C = 1588, νC=N = 1520. UV–visible (1.0 × 10−5 M,
H2O; λmax, nm (ε, M−1 cm−1)): 224 (4.6 × 104),
263 (2.9 × 104), 319 (3.0 × 103). Elemental analysis: calcd
for C19H13CsN3O3S2 (%): C, 43.19; H, 2.48; N, 7.95. Found
(%): C, 43.12; H, 2.38; N, 7.93. 1H NMR (600 MHz,
DMSO-d6, δH, ppm): 9.09 (d, 2H), 8.49 (d, 2H), 8.02 (d,
1H), 7.98 (s, 2H), 7.89 (d, 1H), 7.75–7.77 (q, 2H), 7.43 (t,
1H), 7.36 (t, 1H). 13C NMR (151 MHz, DMSO-d6, δC,
ppm): 155.4, 154.3, 153.4, 150.3, 145.9, 136.6, 135.3, 133.9,
128.9, 127.1, 126.6, 126, 125.9, 125.2, 123.7, 123.4, 123.3,
123.
1
541 (5.6 × 103). H NMR (600 MHz, DMSO-d6, δH, ppm):
9.09 (d, 2H), 8.49 (d, 2H), 7.98 (s, 2H), 7.75–7.77 (q, 2H),
7.36 (d, 1H), 7.22 (d, 1H), 7.04 (t, 1H), 6.87 (t, 1H). 13C
NMR (151 MHz, DMSO-d6, δC, ppm): 184.9, 156.07,
149.9, 145.5, 137.1, 136.2, 128.4, 126.7, 124, 123.3, 120.1,
118.8,
116.8.
Elemental
analysis:
calcd
for
C38H32K2N6O2S4ꢀ2H2O (%): C, 54.14; H, 3.83; N, 9.97.
Found (%): C, 53.83; H, 3.61; N, 9.69.
2.4.2 | Preparation of [Cs(phen)(BS)
(H2O)]n (2)
Cs2CO3 (0.325 g, 1.0 mmol) and SBT (0.334 g, 2.0 mmol)
were refluxed in MeOH–H2O (1:1) mixture for 1 h. To
this mixture, 10 mL of MeOH solution of phen (0.396 g,
2.0 mmol) was added dropwise. The resultant reaction
mixture was refluxed for an additional hour. The solvent
was evaporated and white solid was recrystallized from
2.4.3 | Preparation of {[Mg(phen)(H2O)4]
(BT)2ꢀphen} (3)
MgCl2ꢀ6H2O (0.203 g, 1.0 mmol) and SBT (0.378 g,
2.0 mmol) were refluxed for 1 h in MeOH–H2O (1:1) mix-
ture. To this mixture, 10 mL of MeOH solution of phen

SHAH ET AL.
5 of 12
(0.198 g, 1.0 mmol) was added dropwise. The resultant
reaction mixture was further refluxed for 1 h. The solu-
tion was then filtered and left undisturbed for crystalliza-
tion at room temperature. Colourless crystals suitable for
X-ray diffraction were collected after two days. Yield:
0.482 g, 61%. Melting point: 220–224ꢁC. Selected IR data
(cm−1): νOH = 3683–2940, νC=S = 1661, νC=C = 1586,
plates. Afterwards, 45 μL of phenol–sodium nitroprusside
mixture (1% w/v; 0.005% w/v) and 70 μL of NaOH–
NaOCl alkali mixture (0.5% w/v; 0.1% w/v) were added
and the urease activity was measured using the indophe-
nols method as described by Weatherburn.55 All reactions
were performed in phosphate buffer of pH 6.8 and
changes in absorbance were measured at 630 nm with a
microplate reader (xMark™ Microplate Spectrophotome-
ter, BIO-RAD) for 50 min. Assays were replicated three
times and thiourea was used as a positive control.56 The
results were processed using MS-Excel and Ez-fit pro-
grams. The IC50 values were calculated using the EZ-Fit
Enzyme Kinetics program (Perrella Scientific Inc.,
Amherst, USA). The inhibition was calculated from the
formula given below:
ν
C=N = 1530. UV–visible (1.0 × 10−5 M, H2O; λmax, nm (ε,
M−1 cm−1)): 228 (4.5 104), 262 (2.6 104),
×
×
321 (2.0 × 104). Elemental analysis: calcd for air-dried
sample C38H32MgN6O4S4ꢀH2O (%): C, 56.54; H, 4.25; N,
10.41. Found (%): C, 56.50; H, 3.83; N, 10.39.1H NMR
(600 MHz, DMSO-d6, δH, ppm): 9.08 (broad singlet, 4H),
8.85 (broad singlet, 1H), 8.49 (broad singlet, 3H), 8.23
(broad singlet, 1H), 8.07 (broad singlet, 2H), 7.98 (s, 3H),
7.76 (broad singlet, 3H), 7.38 (d, 2H), 7.23 (2H), 7.05 (t,
2H), 6.89 (t, 2H). 13C NMR (151 MHz, DMSO-d6, δC,
ppm): 185, 155.4, 150, 149.5, 145.5, 141.3, 139.3, 136.8,
136.2, 128.5, 127, 126.7, 125.3, 124.1, 123.3, 120.3,
119, 116.6.
Inhibition ð%Þ = 100−ðOD test=OD controlÞ × 100
2.6 | Statistical analysis
2.4.4 | Preparation of {[Sr(phen)2(H2O)4]
(BT)2} (4)
The IC50 values were calculated using the EZ-Fit Enzyme
Kinetics program (Perrella Scientific Inc., Amherst,
USA).
SrCl2ꢀ6H2O (0.266 g, 1.0 mmol) and SBT (0.378 g,
2.0 mmol) were refluxed in MeOH–H2O (1:1) mixture for
1 h. To this mixture, 10 mL of MeOH solution of phen
(0.198 g, 1.0 mmol) was added dropwise. The resultant
reaction mixture was further refluxed for 1 h. The solu-
tion was then filtered and left undisturbed for crystalliza-
tion at room temperature. Colourless crystals suitable for
X-ray diffraction were collected after two weeks. Yield:
0.580 g, 68%. Melting point: 130–135ꢁC. Selected IR data
(cm−1): νOH = 3600–2900, νC=S = 1669, νC=C = 1586,
νC=N = 1511. UV–visible (1.0 × 10−5 M, H2O; λmax, nm (ε,
2.7 | Molecular docking protocol
The three-dimensional structure of urease in complex
with its inhibitor (PDB code 4UBP, resolution 1.55 Å)
was used in docking experiments. Docking was con-
ducted using Molecular Operating Environment software
(MOE 2014.09).57 Using the Protonate3D command of
MOE, hydrogens were added on protein and partial char-
ges were applied based on the OPLSAA force field. Nickel
parameters were set as mass = 58.6930, r = 1.170 Å,
M−1 cm−1)): 228 (6.1
× ×
104), 261 (3.7 104),
321 (3.8 × 104), 541 (7.3 × 103). Elemental analysis: calcd
for air-dried sample of C38H32N6O4S4SrꢀH2O (%): C,
52.43; H, 3.94; N, 9.65. Found (%): C, 52.01; H, 3.48; N,
q = +2.0 and van der Waals well depth = 0.100 kcal mol−1
.
Heteroatoms other than the ligands were removed. The
carboxylate group of carbamylated lysine (KCX220) in
the active site of urease was deprotonated. To release the
strain, protein was minimized at RMSD gradient of
0.1RMS kcal mol−1 Å−1. The coordinates of each complex
(ligand) was taken from the crystal information file (cif)
and converted into mol2 format using Avogadro version
1.2.0 (http://avogadro.cc/).58 Avogadro determined the
specific atom types of each atom in complexes 1–4. Dur-
ing docking, OPLSAA force field parameters were set for
K (mass = 39.0980, r = 2.76920 Å, q = +1.0 and van der
1
9.49. H NMR (600 MHz, DMSO-d6, δH, ppm): 9.11 (d,
2H), 8.52 (d, 2H), 8.0 (s, 2H), 7.78–7.80 (q, 2H), 7.43 (d,
1H), 7.25 (d, 1H), 7.11 (t, 1H), 6.96 (t, 1H). 13C NMR
(151 MHz, DMSO-d6, δC, ppm): 186, 152.8, 150.1, 145.3,
136.5, 135.4, 128.5, 126.7, 124.7, 123.4, 121.0, 119.5, 115.9.
2.5 | Assay for urease inhibition
In 200 μL of reaction mixture, 25 μL of urease enzyme
from Canavalia ensiformis (Jack bean), 5 μL of samples
with different concentrations and 55 μL of urea
(100 mM) were incubated for 15 min at 30ꢁC in 96-well
Waals well depth
(mass = 132.9050, r = 3.7690 Å, q = +1.0 and van der
Waals well depth
0.0001 kcal mol−1), Mg
(mass = 24.3050, r = 0.9230 Å, q = +2.0 and van der
=
0.0003 kcal mol−1), Cs
=

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SHAH ET AL.
Waals well depth
=
0.8750 kcal mol−1
)
and Sr
reflected in
a
series of peaks in the range
(mass = 87.6200, r = 1.7410 Å, q = +2.0 and van der
Waals well depth = 0.1182 kcal mol−1) ions. Hydrogens
were added and partial charges of each complex were cal-
culated using the OPLSAA force field. For docking, the
Alpha Triangle docking algorithm and London dG scor-
ing function59,60 were applied. As a default parameter,
thirty docked solutions were set. However, different num-
bers of docked solutions were obtained for each complex
based on their chemical structures. All docked solutions
were analysed, and the best docked pose was selected on
the basis of docking rank, score and binding interactions
of complexes 1–4 to analyse their structure–activity
relationship.
1514–1520 cm−1.61 Multiple peaks appeared in the range
1689–1560 cm−1 which indicate C=C aromatic ring
stretching, while the peaks in range 998–945 cm−1 are
due to C&bond;S and C=S stretching.62 In the spectrum
of 2, a strong distinctive peak appeared at 1075 cm−1
,
which indicates the presence of S=O bond.62 Attempts to
measure the UV–visible data for complexes 1–4 in non-
coordinating CH2Cl2 were hampered by insolubility. As a
consequence, the UV–visible data for the complexes were
measured in water. The UV–visible spectra of 1–4 are
dominated by a series of intense (ε = 102–107 M−1 cm−1
)
π–π* ligand-centred absorption bands in the range
224–319 nm (Figure S2). These assignments were corrob-
orated by the fact that the absorption profiles for the
complexes match the absorption spectra of the free
ligands. In the case of 1 and 4, there was an additional
lower intensity absorption band at 540 nm which is
absent in the spectra of free ligands and, based on the
absorption coefficients, can be attributed to a metal–
ligand charge transfer/ligand–metal charge transfer tran-
sition. The increase of absorption coefficient (ε) of 1–4
compared to the free ligands supports the suggestion that
these ligands remained coordinated in solution, with
metal coordination enhancing the extinction coefficient.
3 | RESULTS AND DISCUSSION
3.1 | Synthesis
The complexes of potassium, caesium, magnesium and
strontium were prepared from the corresponding metal
precursors by treatment with phen and SBT in either
MeOH or MeOH–H2O mixture (Scheme 1). The new
compounds 1–4 were soluble in water, DMSO and
MeOH. All four complexes were characterized using a
variety of analytical techniques including IR, UV–visible,
1H NMR and 13C NMR spectroscopies, elemental analy-
sis, mass spectrometry (ESI+) and single-crystal X-ray
diffraction. Single crystals were grown directly from the
mother liquor. The crystals of all four complexes proved
slightly hygroscopic, absorbing small quantities of water
upon standing, but otherwise appeared stable in air.
3.3 | Solution characterization
1
The H NMR and 13C NMR spectra of free ligands and
complexes 1–4 were recorded in DMSO-d6 (Figures S3
and S4). On comparing the peaks of free ligands and
those of 1–4, it was observed that all the signals of the
1
free ligands were present in the H NMR spectra of the
complexes, that is, four signals for the phen and four
more signals for the BT− and/or BS− protons. Integration
3.2 | Analytical data and spectral
characterization
1
assisted in the assignment of the H NMR resonances
and predicted that the ratio between phen and BT−/BS−
1
Complexes 1–4 were obtained in good yield (68–76%) in
an analytically pure form. The IR spectra of complexes 1–
4 are presented in Figure S1 of the supporting informa-
tion. In the IR spectra, peaks in the range
3500–3078 cm−1 attributed to O&bond;H stretching are
broadened due to hydrogen bonding. The heterocyclic
phen C=N stretching vibrations in these complexes were
is 1:1. In H NMR spectra of 1, 2 and 3, downfield shifts
in the range 0.3–0.1 ppm were observed when compared
with free ligands (Figure S3). In the case of 3, the
uncoordinated phen ligand exhibits πꢀꢀꢀπ interactions
with coordinated phen. In 1H NMR spectra, the signals of
both uncoordinated and coordinated phen appeared as
broad and downfield shifts of ca 0.03 ppm were observed
for phen protons while upfield shifts of 0.05 ppm were
observed for BT− protons. In 13C NMR spectra of 1, 3 and
4, downfield shifts of ca 1 ppm were observed, while in
the case of 2 a large downfield shift of 30.54 ppm was
observed for the carbon connected to O=S=O moiety.
The two-dimensional NMR spectra (ROESY) did not
show any coupling for complexes 1–4 indicating that the
coordination environment at the metal precludes the
SCHEME 1 Aerial in situ oxidation of sodium
1,3-benzothiazole-2-thiolate (SBT) to 1,3-benzothiazole-2-sulfinic
acid (BS−)

SHAH ET AL.
7 of 12
close approach between phen and BT−/BS− ligands nec-
essary to observe through-space interactions. ESI-MS
studies were conducted for all four complexes in MeOH
(Figures S4–S8). For 1 and 2 the MS data revealed ions
corresponding to phenH+, [M(phen)]+ and [M(phen)2]+,
while for 3 the data revealed ions corresponding to
phenH+ and [Mg(phen)2(BT)2] + Na]+. In the case of 4,
each other via alternating Owater (O1) and S (S1) bridges
resulting in a ladder-shaped arrangement (Figure 4). The
O1 water bridges to an inversion-related potassium atom,
so that a four-membered ring K(μ2-O2)2K is formed, in
which the distance between the two O1 atoms is 3.621
(2) Å. Similarly, S1 bridges to an inversion-related potas-
sium atom resulting in a four-membered ring K(μ2-S1)2K
in which the distance between the two S1 atoms is 4.796
(1) Å. The K1&bond;O1 and K1&bond;O1i distances
(symmetry code (i) = −x + 1, −y + 1, −z + 1) are 2.788
(2) and 2.828(2) Å. respectively. while K1&bond;O1/
O1i&bond;K1i angles are 99.70(6)ꢁ, leading to KꢀꢀꢀKi
(symmetry code (i) = −x + 1, −y + 1, −z + 1) separation
of 4.292(9) Å. The K1&bond;S1 and K1&bond;S1i (sym-
metry code (i) = −x, −y + 1, −z + 1) distances are 3.579
(9) and 3.354(1) Å, respectively, while K1ii&bond;S1/
S1i&bond;K1 angles are 92.54(2)ꢁ, leading to a K1ꢀꢀꢀK1ii
(symmetry code (ii) = −x, −y + 1, −z + 1) separation of
5.012(9) Å. The potassium complexes of phen with BT as
co-ligand are not known. A CSD search (2019) on potas-
sium complexes containing phen resulted in 23 hits
where the majority of the co-ligands used are O-donors
and only one example with S-donor ligand (ethyl xan-
thate) employed as co-ligand.39
Complex 2. The reaction of phen and SBT with KOH
in methanol afforded white crystals of 2 in 74% yield. The
synthesis involved an in situ oxidation of SBT into
1,3-benzothiazole-2-sulfinic acid (BS) (Scheme 1) in
which the S− atom undergoes aerial oxidation. The con-
version of sulfide into sulfinic acid is usually carried out
by the oxidation of thiols using oxidizing agents such as
H2O2. It is important to mention here that sulfinic acids
are inherently unstable and are usually prepared freshly
or in situ.65 To the best of our knowledge, we report here
for the first time the in situ conversion of SBT to BS and
successful trapping of an unstable BS intermediate in a
stable caesium complex (2).
peaks for [Sr(phen)(BT)2]
+
H]+ and [Sr
(phen)2(BT)2(H2O) + 3H]+ were observed in the mass
spectrum. The MS data clearly indicating that phen
remained bound to the metal in solution. Molar conduc-
tance measurements of 1–4 (Table S1) revealed that these
complexes were substantially ion-separated in solution
+
forming [M(phen)x(H2O)y]z ions and the corresponding
BT− or BS− anions.
3.4 | Crystal structure description
Complex 1. The asymmetric unit of 1 is shown in
Figure 3 and selected interatomic distances and angles
are listed in Table S2. The complex crystalizes in the
monoclinic space group P21/c, with one phen, a BT−, a
K+ cation and a coordinated water molecule in the asym-
metric unit. The K+ cation is charge-balanced by a BT−
anion, which satisfies the overall charge on complex 1.
The K+ ion adopts a distorted six-coordinate trigonal pris-
matic geometry (Figure S9, Table S3) comprising an
[N2O2S2] donor set. The phen ligand adopts an N,N0 che-
late mode through the N1 and N2 atoms, making a five-
membered ring, with K&bond;N bond distances of 2.816
(2) and 2.788(2) Å. The phen ligand molecules are virtu-
ally planar, and have similar bond distances and angles
comparable to those found in the structure of free phen.63
The K+ ion lies almost planar with the phen mean planes
(δK = 0.081 Å), and the phen ligand tilts with respect to
the K1–N1–N2 plane by a dihedral angle of 3.99ꢁ. The
K&bond;N bond lengths lie within the normal observed
range of 2.748(4)–2.872(2) Å for related potassium com-
plexes with phen ligands.64 The K+ ions are connected to
The complex crystallizes in the monoclinic space
group P21/c with one phen, a BS− and a Cs+ cation in the
asymmetric unit (Figure 5). The selected interatomic dis-
tances and angles are listed in Table S4. The fundamental
repeat unit in 2 is a binuclear [Cs2(phen)2(BS)2] motif
which are connected to each other via μ2-Owater bridging.
The Cs+ ion deviates from the phen mean planes by
0.425 Å, and the chelating phen ligand is tilted with
respect to the Cs1–N1–N2 plane by a dihedral angle of
8.60ꢁ.
The Cs+ ion is seven-coordinate and adopts a dis-
torted [N2O5] elongated triangular prismatic geometry
(Figure S10, Table S5) with one phen ligand acting as an
N2 donor (Cs&bond;Nphen (N1, N2) = 3.145(3) and 3.163
(3) Å) and two BS− ligands acting as O-donors, with one
O atom (O2) being μ-O (Cs1&bond;O2 = 3.477 Å) and
FIGURE 3 Asymmetric unit in 1. Thermal ellipsoids are
drawn at the 50% probability level

8 of 12
SHAH ET AL.
FIGURE 4 Sulfur/oxygen-bridged polymer
chain in 1
the other O atom (O1) being μ2-O adopting a 1,3 O:O0
bridging mode (Cs1&bond;O1 = 3.192(4) Å). The
remaining two coordination sites are occupied by water
molecules (Cs&bond;O6 = 3.128(3) Å and Cs&bond;
O7 = 3.298(3) Å). The Cs+ ions are connected to each
monoclinic space group Pn with one phen, one Mg2+
,
four water molecules, two uncoordinated BT− anions and
one co-crystallized uncoordinated phen in the asymmet-
ric unit. The Mg2+ ion adopts a distorted [N2O4] octahe-
dral geometry (Figure S11, Table S7) with one phen
ligand acting as am N2 donor (Mg&bond;Nphen (N1,
N2) = 2.213(3) and 2.264(3) Å) and the remaining site
occupied by four water molecules (Mg1&bond;
Owater = 2.033(9)–2.08(2) Å). The degree of the distortion
from ideal octahedral geometry of the Mg2+ ion is
reflected in the cis-oid (range 89.50(5)–97.5(5)ꢁ) and
trans-oid (range 165.2(6)–178.3(3)ꢁ) angles.
−
other via an alternating bridging of Owater and OBS
atoms resulting in a ladder-shaped arrangement similar
to that observed in 1 (Figure 6). The distance between the
two Cs+ ions, connected by water molecules, is 4.795
(4) Å which is slightly shorter than the distance between
two Cs+ ions that are linked via OBS (5.0562(4) Å). The
−
bond distances between sulfur and oxygen atoms are
1.451(3) and 1.486(4) Å which are slightly higher than
the uncoordinated S=O bond distances in related
ligands.66 The Cs+ coordination chemistry with phen
and/or BS ligands is unknown and 2 is the first example
containing phen and/or BS− ligands.
Complex 3. The molecular structure of 3 is shown in
Figure 7 and selected interatomic distances and angles
are listed in Table S6. The complex crystalizes in the
Complex 4. The reaction of phen and SBT with SrCl2
in methanol afforded white crystals of 4 in 68% yield. The
molecular structure of 4 is shown in Figure 8 and the
selected interatomic distances and angles are listed in
Table S8. The complex crystallizes in the orthorhombic
space group Pbcn with one phen, a Sr2+, two water mole-
cules and two BT− anions in the asymmetric unit
(Figure 9). Like in 3, the BT− ligands do not take part in
FIGURE 5 Asymmetric unit in 2. Thermal
ellipsoids are drawn at the 50% probability level

SHAH ET AL.
9 of 12
FIGURE 6 Oxygen-bridged
polymer chain in 2
phen mean planes by 1.313 Å, and the chelating phen
ligand is tilted with respect to the Sr1–N1–N2 plane by a
dihedral angle of 32.30ꢁ, which indicates the poor overlap
between the SrII ion atomic orbital and phen N atoms.
3.5 | In vitro urease inhibition
Complexes 1–4 were screened for their inhibitory poten-
tial against urease enzyme. All complexes showed signifi-
cant urease inhibition with IC50 values ranging from
10.8
standard thiourea (IC50 = 20.8
Complexes (IC50 10.8
4 (IC50 = 13.8
0.360 to 45.8
1.128 μM, when compared with
0.75 μM) (Table S10).
0.360 μM) and
3
=
0.980 μM) showed superior activities
when compared with the standard thiourea, while
1 (IC50 = 18.2 0.558 μM) showed comparable activity to
the standard. Complex 2 was the least active among the
series. The dose-dependent inhibition of 3 is presented in
Figure S13. In preliminary screening, the ligand phen
was found to be inactive having an inhibition of less than
50%. The ligand SBT showed good activity with IC50
value of 10.9 0.206 μM which is comparable to that of
3 (Table S10).
FIGURE 7 Molecular Structure of 3. Thermal ellipsoids are
drawn at the 50% probability level
coordination and remain as counter ions in balancing the
overall charge (+2) on 4. The Sr2+ ion is located on a two-
fold rotation axis and coordinated by two phen ligands
(Sr&bond;Nphen (N1, N2) = 2.743(2) and 2.766(2) Å) and
four water molecules (Sr&bond;Owater = 2.534(2) and
2.570(2) Å) in a distorted triangular dodecahedron coor-
dination geometry (Figure S12, Table S9). The Sr&bond;
N bond lengths lie within the normal observed range of
2.70–2.82 Å for related SrII complexes with phen
ligands.67 In 4, the SrII ion deviates markedly from the
3.6 | Molecular docking and predicted
structure–activity relationship
In order to gain some insight into the possible activity,
preliminary docking and binding studies were under-
taken for complexes 1–4. The exact nature of the complex
ions in solution is unknown although some evidence for
cation and anion dissociation is evident based on the con-
ductivity data while solution MS data point to retention
of phen coordination to the metal ions in 1 and 2, while

10 of 12
SHAH ET AL.
FIGURE 8 Molecular structure of 4.
Thermal ellipsoid are drawn at the 50%
probability level
complex interacts with the side chain of Lys169 at the
surface of the active site. This interaction is mediated by
both hydrogen bonding and ionic interactions. Addition-
ally, phen nitrogen atoms tend to form ionic interactions
with the carbonyl oxygen of Cys322. The docked view of
3 demonstrates that one of the BT− anions is fitted nicely
into the active site, while other is accommodated at the
surface of the groove. Both phen rings are accommodated
between two gatekeeping loops of the active site. The
binding mode of this complex is depicted in Figure S14.
The docking studies of complexes 1, 2 and 4 (Fig-
ures S15–S17, Table S10) are described in the supporting
information. The docking results clearly demonstrate that
the experimental results are in good agreement with the
computed docking scores.
FIGURE 9 Asymmetric unit in 4. Thermal ellipsoid are
drawn at the 50% probability level
coordination of both phen and BT− ligands in 3 and
4 can be surmised based on solution MS data.
4 | CONCLUSIONS
As a starting point to rationalize the biological activity
of these complexes, initial studies implementing the crys-
tallographic coordination geometry for 1–4 revealed that
experimental results are well correlated with the docking
scores. Complex 3 is the most active among the series
We have described the synthesis, structure and urease
inhibition activities of four new s-block complexes con-
taining phen, BT− and/or BS− ligands. Our investigations
of alkali/alkaline earth metal complexes have given rise
to a variety of structural variations. Complexes 1 and
2 are 1-dimensional polymeric chains while 3 and 4 are
both mononuclear. In all four complexes, the phen acts
as a bidentate ligand, while BT is either coordinated in
monodentate fashion (1) or remains uncoordinated
(3 and 4). In the synthesis of 2, SBT is oxidized in situ into
with IC50 value of 10.8
0.360 μM (Table S10). In 3,
three of the water molecules coordinated with the Mg2+
ion are bridging the complex with the side chain (&bond;
SH) of Cys322 and carbonyl oxygen of Ala170 via hydro-
gen bonding. Moreover, one of the BT− anions of the

SHAH ET AL.
11 of 12
BS− and resultant ligand is coordinated to the caesium
metal using both of its oxygen atoms. The complexes
showed significant urease inhibition with IC50 values
ranging from 10.8 0.360 to 45.8 1.128 μM. Complex
3 is the most active complex among the series with IC50
value of 10.8 0.360 μM. The reactions and the urease
inhibitory activities investigated in the present study have
opened up further possibilities of benzothiazole chemis-
try with other s-block metal ions. We are currently inves-
tigating these reactions.
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The authors thank University of Nizwa for the financial
support of this project and the scholarship of S.R.S.
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CONFLICT OF INTEREST
The authors declare no conflict of interest.
ORCID
Muhammad U. Anwar https://orcid.org/0000-0003-
4740-5737
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Additional supporting information may be found online
in the Supporting Information section at the end of this
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