Evaluation of bisindole as potent β-glucuronidase inhibitors: Synthesis and in silico based studies

Article abstract of DOI:10.1016/j.bmcl.2014.02.015

Bisindole analogs 1-17 were synthesized and evaluated for their in vitro β-glucuronidase inhibitory potential. Out of seventeen compounds, the analog 1 (IC₅₀ = 1.62 ± 0.04 μM), 6 (IC₅₀ = 1.86 ± 0.05 μM), 10 (IC₅₀ = 2.80 ± 0.29 μM), 9 (IC₅₀ = 3.10 ± 0.28 μM), 14 (IC₅₀ = 4.30 ± 0.08 μM), 2 (IC₅₀ = 18.40 ± 0.09 μM), 19 (IC₅₀ = 19.90 ± 1.05 μM), 4 (IC₅₀ = 20.90 ± 0.62 μM), 7 (IC₅₀ = 21.50 ± 0.77 μM), and 3 (IC₅₀ = 22.30 ± 0.02 μM) showed superior β-glucuronidase inhibitory activity than the standard (d-saccharic acid 1,4-lactone, IC₅₀ = 48.40 ± 1.25 μM). In addition, molecular docking studies were performed to investigate the binding interactions of bisindole derivatives with the enzyme. This study has identified a new class of potent β-glucouronidase inhibitors.

Full text of DOI:10.1016/j.bmcl.2014.02.015

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1825–1829
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Evaluation of bisindole as potent b-glucuronidase inhibitors:
Synthesis and in silico based studies
b
c
Khalid Mohammed Khan a, , Fazal Rahim , Abdul Wadood , Muhammad Taha d,e, Momin Khan f,
⇑
Shagufta Naureen a, Nida Ambreen a, Shafqat Hussain a, Shahnaz Perveen g, Mohammad Iqbal Choudhary a
a H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
b Department of Chemistry, Hazara University, Mansehra, Pakistan
c Computational Medicinal Chemistry Laboratory, Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
d Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia
e Faculty of Applied Science UiTM, 40450 Shah Alam, Selangor, Malaysia
f Department of Chemistry, Abdul Wali Khan University, Mardan, Mardan 23200, Pakistan
g PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan
a r t i c l e i n f o
a b s t r a c t
Article history:
Bisindole analogs 1–17 were synthesized and evaluated for their in vitro b-glucuronidase inhibitory
Received 21 November 2013
Revised 28 January 2014
Accepted 6 February 2014
Available online 14 February 2014
potential. Out of seventeen compounds, the analog 1 (IC50 = 1.62 0.04
10 (IC50 = 2.80 0.29 M), 9 (IC50 = 3.10 0.28 M), 14 (IC50 = 4.30 0.08
19 (IC50 = 19.90 1.05 M), 4 (IC50 = 20.90 0.62 M), 7 (IC50 = 21.50 0.77
0.02 M) showed superior b-glucuronidase inhibitory activity than the standard (
1,4-lactone, IC50 = 48.40 1.25 M). In addition, molecular docking studies were performed to investigate
l
M), 6 (IC50 = 1.86 0.05
l
l
M),
M),
l
l
lM), 2 (IC50 = 18.40 0.09
l
l
l
M), and 3 (IC50 = 22.30
-saccharic acid
l
D
l
Keywords:
Bisindole
b-Glucuronidase inhibition
Molecular docking
SAR
the binding interactions of bisindole derivatives with the enzyme. This study has identified a new class of
potent b-glucouronidase inhibitors.
Ó 2014 Elsevier Ltd. All rights reserved.
The indole analogs are frequently encountered and are consid-
ered to be an important scaffold in medicinal chemistry.1 Variety
of compounds having indole moiety, exhibited antitumor activity.2
Bis(indolyl)methanes is the important class of heterocyclic com-
pounds with a variety of pharmacological activities, some of them
play a key role in the treatment of chronic fatigue, fibromyalgia
and irritable bowel syndrome.3,4 Some of these are responsible
for beneficial estrogen metabolism, and induce apoptosis in cancer
cells of human.5 The bis(indolyl)alkanes from marine and terres-
trial sources are found to posses diverse activities, like coronary
dilatory properties, antibacterial activity and genotoxicity.6 Some
bisindole alkaloids, such as macrocarpamine, macralstonine ace-
tate and villastonine possess significant antiprotozoal activity
in vitro against Plasmodium falciparum and Entamoeba histolytica.7,8
Some bis(indolyl)methane derivatives are also used as dietary
supplements for humans.9 They exhibit inhibitory activity against
bladder cancer,10 and renal cell carcinoma growth,11 and inhibit
lung12 and colon cancers.13,14 Bis(indolyl)methanes have inhibitory
activity on phenobarbital-induced hepatic CYP mRNA expression15
and also act as cytodifferentiating agents.16 Some bis
(indolyl)methanes derivatives have DDPH radical scavenging,17
antimetastatic18,19 and analgesic activities.20
In present study the synthesis of bis(indolyl)methane analogs
1–17 and their in vitro b-glucuronidase inhibition activity has been
achieved. b-Glucuronidase is an enzyme which catalyze the glucur-
onosyl-O-bonds cleavage.21 This is also up regulated in different
pathological conditions, such as infection of urinary tract22–25 renal
disease26 rejection of transplantation27 epilepsy28 larynx and
breast.29 Besides, this enzyme is also involved in inflammatory
joint diseases, like rheumatoid arthritis30,31 Some hepatic diseases
and AIDS is also reported due to over-expression of the enzyme.
Literature report showed that the bacterial b-glucuronidase inhib-
itor lead to a decrease in carcinogen induced colonic tumors.32 The
current study is focused on the discovery of b-glucuronidase inhib-
itors of pharmacological importance.
Our current research group is continuously working on the
chemistry and biological of new heterocyclic compounds,33 sulfur
containing compounds34 and hydrazones.35 Recently we have pub-
lished benzothiazole as potent inhibitor of b-glucuronidase. Due to
close resemblance of indole moiety with benzothiazole we envis-
aged that bis(indolyl)methanes may have b-glucuronidase inhibi-
tory and observed results proved our hypothesis.
⇑
Corresponding author. Tel.: +92 2134824910; fax: +92 2134819018.
E-mail addresses: khalid.khan@iccs.edu, hassaan2@super.net.pk (K.M. Khan).
http://dx.doi.org/10.1016/j.bmcl.2014.02.015
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

1826
K. M. Khan et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1825–1829
R1
our bioassay result either its due to aggregate formation or by
R1
R1
R2
O
compounds themselves.38
NaBrO3 /NaHSO3
H2O
+
R2
H
In order to study the binding affinity of bisindole derivatives
N
H
HN
NH
within the b-
their structure–activity relationship, in silico study was performed.
In this study, 3D structure of human b- -glucuronidase (having
80% sequence similarity with bovine b- -glucuronidase) was used,
as 3D structure of bovine b- -glucuronidase has not been reported
yet. The sequence similarity of bovine b- -glucuronidase was
D-glucuronidase binding pocket and to understand
Scheme 1. Synthesis of bis(indolyl)methane derivatives 1–17.
D
D
D
D
Bis(indolyl)methane analogs 1–17 were synthesized by treating
commercially available substituted indole with different aldehydes
in water. In a typical reaction, to a stirring mixture of substituted
indole (3 mmol) and different substituted aromatic aldehydes
(3 mmol) in water, the 10 mol % of sodium bromate and sodium
hydrogen sulfite was added for 2 h.36 The reaction completion
was monitored by TLC. The bis(indolyl)methane derivatives 1–17
are obtained in good yields after completion of the reaction. By
washing through hot n-hexane or in some cases through column
chromatography (silica gel) using 3:7 acetone and n-hexane as elu-
ent afforded pure products. The structures of compounds 1–17
were deduced by using various spectroscopic techniques, including
1H NMR and EI mass spectroscopy (Scheme 1).
b-Glucuronidase belong to the glycosidase family of enzymes
which catalyzes this breakdown of complex molecules of carbohy-
drates. Enzyme inhibition is one of the most significant tools in
pharmaceutical research as well as in the field of drugs discovery.
During this study, we have synthesized seventeen (17) derivatives
and evaluated their b-glucuronidase enzyme inhibition activity.
Out of seventeen (17), ten (10) compounds showed a potent inhi-
bition superior to standard inhibitor of b-glucuronidase.
searched by online server Blastp (http://blast.ncbi.nlm.nih.gov/),
the obtained results showed 80% sequence similarity with human
b-
D-glucuronidase and thus 3D structure of human b-D-glucuroni-
dase can be used for molecular docking. From the Protein Data
Bank the X-ray crystallographic structure of human b-D-glucuron-
idase was retrieved39 (PDB Code 1BHG)40 for the docking
simulation.41
Docking simulation indicated that the top ranked conformation
of the most active compound 1 (Fig. 1A) from three hydrogen
bonds between the phenolic group of the compound and the active
site residues (His 385, Asp 207, and Tyr 508) of the enzymes. Addi-
tionally the indole moiety of the compound forms arene-arene
interactions with the phenyl ring of the active site residue (Tyr
504). Glu 540, Glu 541, His 509, Trp 587, and Lys 606 are the other
remains that alleviate the requisite of the compound 1 in the active
site of b-D-glucuronidase. The strong hydrogen bonding network
formed by the phenolic groups of the compound 1 and the active
site residues might be the reason for the highest activity of com-
pound 1 in the series (Table 1). For example, if we compare the ob-
served activities (Table 1) and predicted interactions of compounds
1, 2, 4, 6, 7, and 9, the compounds having phenolic moiety showed
more activity (compounds 1, 6 and 9), as compared to those lacking
this group (compounds 2, 3, 4, and 7). This difference in activities
might be due to additional hydrogen bonding between phenolic
compounds with active site residues of the enzyme as observed
in docking simulation (Fig. 1A and B).
When the activities (Table 1) and predicted binding modes
(Fig. 2A and B) of compounds 10, 14 and 17 was compared, it
was observed that the methoxy group might play an important
role in their activities and binding interactions. From the docked
conformations of compounds 10 and 14 with phenolic groups, it
was observed that these compounds form strong hydrogen
Compounds 1–17 exhibited a varying degree of b-glucuronidase
inhibitory activity with IC50 values between 1.62 0.04 and
22.30 0.02
1,4-lactone (IC50 = 48.40 1.25). Compound 1 (IC50 = 1.62 0.040 -
M), (IC50 = 1.86 0.05 M), 10 (IC50 = 2.80 0.29 M),
(IC50 = 3.10 0.28 M), 14 (IC50 = 4.30 0.08 M), 2 (IC50 = 18.40
0.09 M), 19 (IC50 = 19.90 1.05
(IC50 = 21.50 0.77
excellent b-glucuronidase inhibitory activity higher than the stan-
dard ( -saccharic acid 1,4-lactone, IC50 = 48.40 1.25
M).37 More-
lM when compared with standard D-saccharic acid
l
6
l
l
9
l
l
l
l
M), 4 (IC50 = 20.90 0.62 lM), 7
l
M), and 3 (IC50 = 22.30 0.02 lM) showed
D
l
over the remaining compounds showed less than 50% inhibition
and thus were not further evaluated for IC50 values. We checked
Figure 1. Predicted binding interactions of bisindoles (1) and (17) in the active site of human b-D-glucuronidase.

K. M. Khan et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1825–1829
1827
M)
Table 1
Table 1 (continued)
In vitro b-glucuronidase of bis(indolyl)methanes 1–17
Compound no.
R1
R2
IC50 SEMa
(l
Compound no.
R1
R2
IC50 SEMa
1.62 0.04
(lM)
HO
15
5-CN
NAb
1
5-Br
Cl
Cl
OH
NO2
16
17
5-Br
NAb
F
2
3
5-Br
5-Br
18.40 0.09
22.30 0.02
NO2
5-CN
—
19.90 1.05
48.40 1.25
—
D-Saccharic acid 1,4-lactone
Cl
a
SEM is the standard error of the mean.
NA not active, D-saccharic acid 1,4-lactone standard inhibitor for b-glucouo-
Me
b
4
5
5-Br
5-Br
20.90 0.62
NAb
ronidase activity.
OMe
bonding with active site residues Asp 484, and two hydrophobic
interactions with residues Asp 207 and Tyr 508, whereas the com-
pound 17 lacking methoxy group was unable to make hydrogen
bond with the active site residues, and developed only the hydro-
phobic interaction with active site residues Tyr 508 as shown in
Figure 2B. This lack of hydrogen bonding might be one of the rea-
sons of low activity of compound 17, as compared to compounds
10 and 14 (Fig. 2A and B).
6
7
8
5-Br
5-Br
5-Br
1.86 0.05
21.50 0.77
NAb
OH
The top ranked docked conformations of inactive compound 15
is shown in Figure 3. From the analysis of the predicted binding
interactions of inactive compounds it was observed that these
compounds do not form hydrogen bonds with the important active
site residues of the enzyme, as observed in our previous study.41
This lack of hydrogen bonding might be one of the reasons for their
low activity.
Cl
Cl
NO2
X-ray crystallographic structure of human b-D
-glucuronidase39
OH
was recovered from the protein data bank. In docking procedure,
the way for receptor and ligands structures, was used, as explain
in our earlier publication.41 Structure of protein was checked for
missing atoms, contacts and bonds. The B-chain of protein and het-
ero-atoms, together with co-factors was distant from the original
file of protein data bank. Hydrogen atoms then added to the pro-
tein structure by means of the biopolymer module in SYBYL7.3
software package.42 All the docking simulation studies were
performed on IntelÒ XeonÒ Quad™ Core processor 3.0 GHz Linux
workstation running under open SUSE11.3, equipped with
GOLD3.0 as the docking software.
Molecular docking studies were carried out via GOLD software
version 3.0 from the Cambridge Crystallographic Data Centre.43
Gold Score was selected as a fitness score and the standard default
settings were utilized in all docking calculations. The configuration
file was defined by the following process: docking site contains all
the atoms within 10 Å of a specified centroid (x, y, z coordinates:
80.43, 84.41, 90.48). For each of the 100 independent genetic algo-
rithm runs, a default maximum of 100,000 genetic operations was
performed by using the default operator weights and a population
size of 100 chromosomes. Operator weights for cross over, muta-
tion and migration were set to 100 and 0, respectively. To allow
poor non-bonded contacts at the start of each GA run, the maxi-
mum distance between hydrogen donors and fitting points were
set to 5.0 Å, and non-bonded VdW energies were selected at
cut-off value of 10 Å. All single bonds were treated as rotatable.
Results differing by less than 1.5 Å in ligand-all atom RMSDs were
9
5-Br
3.10 0.28
2.80 0.29
Cl
OH
10
5-CN
OMe
11
12
13
14
5-Br
5-Br
5-CN
5-CN
NAb
S
Me
NAb
OMe
OH
S
NAb
Me
4.30 0.08
OMe
OH

1828
K. M. Khan et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1825–1829
Figure 2. Predicted binding interactions of bisindoles 10 and 17 in the active site of human b-D-glucuronidase.
Figure 3. Predicted binding interaction of bisindole derivatives having low % of inhibition (Compound 15) in the active site of human b-D-glucuronidase.
Table 2
clustered together. After docking, thirty poses were saved for each
ligand. On the basis of score, top scored docked poses were visually
inspected for each ligand. The molecular interactions were visual-
ized using LIGPLOT, implemented in Molecular Operating Environ-
ment (MOE).44
Synthesized compounds with b-D-glucuronidase inhibitory potential and docking
simulation
Compounds
Goldscore
IC50 SEMa
1.62 0.04
(lM)
p-Nitrophenyl-b-
1
2
3
4
5
6
7
D-glucuronidase
58.37
64.48
59.68
60.78
56.33
51.28
58.36
57.78
53.71
63.25
63.36
50.07
55.23
53.17
68.46
56.86
54.66
62.61
18.40 0.09
22.30 0.02
20.90 0.62
NAb
A reliable model of the complexed structure of b-D-glucuroni-
dase was prepared using the method mentioned in our previous
publication.41 The modeled structure was then used for the predic-
tion of favorable binding interaction of our new synthesized com-
NAb
pounds to b-D-glucuronidase by docking simulation (Table 2).
21.50 0.77
NAb
Three-dimensional (3D) structures of the ligands were modeled
by using standard bond lengths and angles from the SYBYL7.3 frag-
ment library. Partial charges were assigned according to the
Gasteiger–Hückel method.45 Geometry optimizations were carried
out using the Tripos force field with a distance-dependent dielec-
tric and the Powell conjugate gradient algorithm.
8
9
3.10 0.28
2.80 0.29
NAb
10
11
12
13
14
15
16
17
NAb
NAb
4.30 0.08
NAb
Bisindole analogs were synthesized and their inhibitory
NAb
potential was evaluated against b-
of seventeen (17) derivatives, ten (10) compounds showed
b- -glucuronidase inhibitory potential. Compounds 1, 6, 10, 9, 14,
2, 19, 4, 7 and 3 exhibited an excellent inhibition with IC50 values
D-glucuronidase enzyme. Out
19.90 1.05
48.40 1.25
D
a
SEM is the standard error of the mean.
NA Not active.
b

K. M. Khan et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1825–1829
1829
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the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.02.
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