Synthesis, antibacterial and anti-inflammatory activity of bis(indolyl)methanes

Article abstract of DOI:10.1016/j.cclet.2015.08.012

A series of bioactive bis(indolyl)methanes are synthesized by one-pot green reaction of indole with various substituted aldehydes by microwave irradiation under solvent free conditions. The antibacterial activity against Staphylococcus aureus and anti-inf

Full text of DOI:10.1016/j.cclet.2015.08.012

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Chinese Chemical Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
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Original article
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Synthesis, antibacterial and anti-inflammatory activity
of bis(indolyl)methanes
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Q1 Santhisudha Sarva a, Jayaprakash Soora Harinath a, Siva Prasad Sthanikam a,
Selvarajan Ethiraj b, Mohanasrinivasan Vaithiyalingam b, Suresh Reddy Cirandur a,
*
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a Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, India
b School of Biosciences and Technology, VIT University, Vellore 632014, India
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of bioactive bis(indolyl)methanes are synthesized by one-pot green reaction of indole with
various substituted aldehydes by microwave irradiation under solvent free conditions. The antibacterial
activity against Staphylococcus aureus and anti-inflammatory activity of the synthesized bis(indolyl)-
methanes are evaluated in vitro and compared to standard drugs tetracycline and diclofenac,
respectively. The majority of the compounds showed good antibacterial and anti-inflammatory activity.
Interestingly, compounds 3j, 3i, 3k and 3g exhibited much higher anti-inflammatory activity than the
standard diclofenac drug and thus qualify for clinical trials to be used as an anti-inflammatory
compound.
Received 15 January 2015
Received in revised form 21 May 2015
Accepted 21 July 2015
Available online xxx
Keywords:
Bis(indolyl)methanes
Microwave irradiation
Antibacterial activity
Anti-inflammatory activity
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
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1. Introduction
repertoire of effective antimicrobials that could combat/overcome 30
the problem of drug-resistance.
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Staphylococcus aureus, a gram-positive coccal bacterium, infects
tissues when the skin or mucosal barriers are breached. Its
infections spread through contact with pus from an infected
wound, skin-to-skin contact with an infected person by producing
hyaluronidase that destroys tissues and contact through the
objects used by an infected person. It is estimated that 20% of
human population are long term carriers of S. aureus [1]. It remains
still as one of the five most common causes of nosocomial
infections and is often the cause of post-surgical wound infections.
S. aureus, the chief culprit, is also a common source of community
acquired infections, and causes illnesses that range from minor
skin infections and abscesses to life-threatening diseases such as
severe pneumonia, meningitis, joint infections, and heart and
blood stream infections [2]. Most current bactericidal compounds
inhibit DNA, RNA, cell walls, and protein synthesis [3]. In the case
of S. aureus, infection occurs by inhibition of cell wall synthesis by
non-lytic cell death. Drug resistant bacterial infections are
becoming more prevalent and are a major challenging health
issue faced today. This rise of drug-resistance has limited our
Inflammation is a complex biological response of vascular 32
tissues to harmful stimuli like pathogens, cells, and irritants [4]. 33
The therapeutic anti-inflammatory effect of nonsteroidal anti- 34
inflammatory drugs (NSAIDs) occurs through inhibition of 35
prostaglandin biosynthesis and the selective inhibition of cyclo- 36
oxygenase. NSAIDs are able to overcome the side-effects of steroid 37
therapy through this mechanism [5,6]. Further, NSAIDs have many 38
drawbacks such as gastrointestinal toxicity, etc. [6]. In view of this, 39
a new generation of bis(indolyl)methanes as therapeutic agents 40
which nullify these drawbacks are developed. The indole is the 41
most ubiquitous heterocyclic moiety in many biological systems 42
that show pharmacological activity [7,8]. During the past few 43
years, a large number of natural products containing bis(indo- 44
lyl)methanes (BIM’s) and bis(indolyl)ethane’s (BIE’s) have been 45
isolated from marine sources. The BIM’s are highly beneficial in 46
promoting estrogen metabolism in women and men [9]. They also 47
exhibit antibacterial [10], cytotoxic [11], insecticidal [12], analge- 48
sic [13] and anti-inflammatory activities [13]. Due to this, special 49
interest has been focused on their synthesis [14].
50
Bis(indolyl)methanes are obtained by reactions of indoles with 51
various aldehydes via azafulvenium salt intermediate in the 52
presence of several Bronsted and Lewis acid catalysts such as 53
LiClO4 [15], CAN [16], ZrOCl2 [17], InCl3 [18], AlPW12O40 [19], ionic 54
liquids [20], trichloro-1,3,5 triazine [21], PFPAT [22], HFIP [23], 55
*
Corresponding author.
E-mail address: csrsvu@gmail.com (S.R. Cirandur).
http://dx.doi.org/10.1016/j.cclet.2015.08.012
1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: S. Sarva, et al., Synthesis, antibacterial and anti-inflammatory activity of bis(indolyl)methanes, Chin.
Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.08.012

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KHSO4 [24], and molecular iodine [25]. But many of these methods
have several drawbacks such as use of expensive reagents, longer
reaction times, cumbersome workup, and low product yields. All
these procedures involve the use of environmentally toxic solvents
and hazardous chemical substrates. Solvent-free organic reactions
have become the choice in green chemical organic synthesis [26].
Reports on condensation of indoles with carbonyl compounds
under neat conditions are scarce in the literature [27]. Many
synthetic chemists have made alternative sustainable and efficient
heating procedures to replace the classical thermal heating in
synthetic methods. Application of microwave irradiation (MWI) is
one such technique employed in effecting organic reactions [28].
MWI assisted organic synthesis requires mild conditions, short
reaction times and high product yields. In MWI, the chemical
reactions are accelerated because of selective absorption of
microwave energy by polar molecules [29,30].
ether–ethyl acetate mixtures as eluent to obtain known pure 3a,
3b, 3d, 3f, 3i, 3j, 3k, 3l, 3m, 3n and 3a, 3c, 3e, 3g, 3h and 3o new
compounds.
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Spectral data for 3,30-((4-(methylthio)phenyl)methylene) bis(1
H-indole) (3e): Orange solid; isolated yield: (90%); mp 187–189 8C;
IR:
NMR (400 MHz, CDCl3):
H), 5.82 (s, 1H, Ar-CH), 2.43 (s, 3H, S-CH3); 13C NMR (100 MHz,
CDCl3): 141.2, 136.7, 130.1, 129.3, 127.1, 126.79, 123.7, 119.9,
n
= 3401 (NH), 2928, 1684, 1497, 1217, 1085, 1014 cmꢀ1
;
1H
d
7.79 (brs, 2H, NH) 7.37, 6.58 (m, 14H, Ar-
d
53.5, 16.1; MS (LCMS): m/z 391 [M + Na]+; Anal. Calcd. for C24H20N2
S: C, 78.23, H, 5.47, N, 7.60, S, 8.70. Found: C, 78.20, H, 5.44, N, 7.40,
O, 8.66.
The compound 3e was also characterized from its powder XRD
data (Fig. 1).
2.2. Biological assay
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2.2.1. Antibacterial assay
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2. Experimental
Well diffusion method was used to evaluate the antibacterial
activity of BIM’s on bacterial species [31]. Bacterial inoculums are
prepared by growing a single colony overnight in nutrient broth
and adjusting the turbidity to 0.5 McFarland standards. Mueller–
Hinton agar (MHA) plates were inoculated with this bacterial
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Solvents and reagents were procured from Sigma–Aldrich &
Merck and are used as such without further purification. Melting
points were determined using a calibrated thermometer by Guna
Digital Melting Point apparatus. IR spectra of samples were
recorded as potassium bromide pellet on a Bruker Vector 21 FT-IR
spectrophotometer. 1H NMR and 13C NMR spectra were recorded
as solutions in CDCl3 on a Bruker AMX 500 MHz NMR spectrome-
ter operating at 400 MHz for 1H spectra, and 100 MHz for 13C
spectra using tetra methyl silane (TMS) as an internal standard.
LCMS mass spectra were recorded on a Jeol SX 102 DA/600 Mass
spectrometer. Elemental analysis was performed on a Thermo
Finnegan Instrument.
suspension and the compounds (1–15) 100
mg/mL were added to a
center well with a diameter of 8 mm. These plates were incubated
at 37 8C for 24 h. The zone of inhibition (ZOI) was measured by
subtracting the well diameter from the total inhibition zone
diameter. Tetracycline is used as a positive control for bacterial
species. All experiments were done in triplicates, and the results
are consistent.
2.2.2. In vitro anti-inflammatory assay
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Alsever’s solution was prepared by dissolving 2% dextrose, 0.8%
sodium citrate, 0.05% citric acid and 0.42% of sodium chloride in
distilled water followed by sterilization [32]. Blood was collected
from healthy volunteers. The collected blood was mixed in equal
volumes with Alsever’s solution. The mixture was centrifuged at
3000 rpm for 10 min and the packed cells were washed three times
with isosaline (0.85%, pH 7.2) and 10% (v/v) suspension was made.
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2.1. General procedure
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A mixture of indole (2 mmol), aldehyde (1 mmol) is placed in
25 mL conical flask and was irradiated by microwave (CATA.4R,
Catalyst 300 W, 5 min). After completion of the reaction, the
reaction mixture is extracted with ethyl acetate and concentrated
under reduced pressure. The obtained crude product is purified by
column chromatography on silica gel adsorbent using petroleum
Test samples with concentrations of 50
mg/mL and 100 mg/mL
Fig. 1. Powder XRD data of Compound 3e.
Please cite this article in press as: S. Sarva, et al., Synthesis, antibacterial and anti-inflammatory activity of bis(indolyl)methanes, Chin.
Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.08.012

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Scheme 1. Synthesis of bis(indolyl)methanes.
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were prepared by suspending in DMSO. The assay mixture
contained the sample, 1 mL phosphate buffer (pH 7.2, 0.1 mol/
L), 2 mL hyposaline (0.36%), and 0.5 mL human red blood cells
suspension. Hydrocortisone sodium was used as the reference drug
and 2 mL of distilled water as control. All the assay mixtures were
incubated at 37 8C for 30 min and centrifuged. The hemoglobin
content in the supernatant solution was estimated using a
spectrophotometer at 560 nm. The percentage hemolysis was
calculated by assuming the hemolysis produced in the presence of
distilled water was 100%.
microwave conditions. Under the same neat condition, 92% 153
product yield is obtained within 5 min. The scope of application 154
of this method is found by reacting different substituted aromatic 155
and heteroaromatic aldehydes. In all cases, corresponding BIM’s 156
were obtained in 90% yields for heteroaromatic aldehydes while 157
homoaromatic aldehydes afforded poor yields. Among the 158
heteroaromatic aldehydes, six membered derivatives gave higher 159
yields when compared to that of five membered ones.
160
3.2. Pharmacology
161
The percentage of hemolysis and stabilization of HRBC
membrane are calculated from the following equations:
The antibacterial activity of 3a–o is investigated by screening 162
them against the gram positive bacterium S. aureus by well 163
ꢀ
ꢁ
141
ODT
ODC
ODT
ODC
% Hemolysis ¼
ꢁ 100; % Protection ¼ 100 ꢀ
ꢁ 100
diffusion technique (Fig. 2) with reference to Tetracycline.
164
The inhibition zone values are summarized in Table 1. The 165
results showed that 3o showed good antibacterial activity whereas 166
3i, 3j showed moderate activity compared to that of the standard 167
1423
144
where ODT = optical density of the test sample and ODC = optical
density of the control.
drug.
All the title compounds are also subjected to in vitro anti- 169
inflammatory activity using two different concentrations, 50 g/ 170
mL and 100 g/mL. Diclofenac is used as the standard. All the 171
168
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3. Results and discussion
m
m
3.1. Chemistry
tested compounds showed excellent anti-inflammatory activity 172
when compared to their diclofenac except 3m. Interestingly, 173
3j, 3i, 3k, 3g exhibited remarkably higher anti-inflammatory 174
activity than that of the standard drug and thus qualifies 175
for further clinical tests to on them so that they can be used 176
as anti-inflammatory agents. The results are summarized in 177
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A facile and clean one pot two component reaction of an
aldehyde and indole in 1:2 molar ratio is described for the
synthesis of bis(indolyl)methanes under microwave irradiation
and catalytic free condition (Scheme 1). To optimize the solvent
requirements, ethanol, toluene, acetonitrile and THF are used and
obtained in 70, 62, 58, 43% yields respectively in 15 min under
Table 2.
178
Fig. 2. The antibacterial activity of 3a–o by well diffusion analysis.
Please cite this article in press as: S. Sarva, et al., Synthesis, antibacterial and anti-inflammatory activity of bis(indolyl)methanes, Chin.
Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.08.012

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Table 1
Anti-bacterial activity of bis(indolyl)methanes.
Research Fellowship (SRF) to Ms. S. Santhisudha under UGC-RGNF
(Rajiv Gandhi National Fellowship) scheme and for providing
financial assistance through a Major Research Project (F. No. 42-
281/2013 (SR), Dated: 12-03-2013).
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Compounds
Zone of inhibition (mm)a
3a
–
3b
–
3c
2.7
6.6
7.2
–
3d
Appendix A. Supplementary data
200
3e
3f
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2015.08.012.
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3g
–
3h
3.4
9.1
9.3
–
3i
3j
References
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3k
3l
–
3m
4.5
7.8
16.2
18.0
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3o
Tetracycline
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a
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Table 2
In vitro anti-inflammatory activity of bis(indolyl)methanes.
Entry
% Hemolysis
50a
% Protection
50a
100a
100a
3a
3b
3c
3d
3e
3f
69.44
47.22
52.77
55.83
79.72
63.88
33.33
66.66
41.60
30.55
44.44
72.22
94.40
86.10
77.77
75.00
58.33
30.55
38.8
30.6
41.67
69.45
61.2
52.78
47.3
45.55
67.50
55.55
27.77
52.77
25.00
22.22
27.70
52.77
80.55
66.66
58.33
66.60
44.17
20.28
36.12
66.67
33.34
58.40
69.45
55.56
27.78
5.60
54.45
32.50
44.45
72.23
47.23
75.00
77.78
72.30
47.23
19.45
33.40
41.67
33.40
3g
3h
3i
3j
3k
3l
3m
3n
3o
13.90
22.23
25.00
Diclofenac
a
Concentration in
m
g/mL.
179
4. Conclusion
180
181
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183
184
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187
188
189
Green synthesis of bis(indolyl)methanes by microwave irradi-
ation condition of indole with aldehydes under solvent free
conditions is reported. This procedure has short reaction time and
affords high product yields. Compound 3o showed good antibac-
terial activity against S. aureus. The anti-inflammatory activity
revealed almost all title compounds except 3m exhibited good
anti-inflammatory activity. Compounds 3j, 3i, 3k and 3g showed
much higher anti-inflammatory activity than the standard
diclofenac drug and thus qualifying for further clinical evaluation
so that they can be used as effective anti-inflammatory agents.
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We thank Prof. C.D. Reddy, Department of Chemistry, S.V.
University, Tirupati for his helpful discussions and University
Grants Commission (UGC), New Delhi, India for providing Senior
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