Regioselective synthesis and biological evaluation of bis(indolyl)methane derivatized 1,4-disubstituted 1,2,3-bistriazoles as anti-infective agents

Article abstract of DOI:10.1016/j.bmcl.2009.04.131

The regioselective synthesis of 1,4-disubstituted 1,2,3-bistriazoles from a variety of N-propargyl bis(indolyl)methanes with sodium azide using CuI as the catalyst in polyethyleneglycol-400 is reported. This process is of considerable synthetic advantages

Full text of DOI:10.1016/j.bmcl.2009.04.131

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3611–3614
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Bioorganic & Medicinal Chemistry Letters
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Regioselective synthesis and biological evaluation of bis(indolyl)methane
derivatized 1,4-disubstituted 1,2,3-bistriazoles as anti-infective agents
*
M. Damodiran, D. Muralidharan, Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselective synthesis of 1,4-disubstituted 1,2,3-bistriazoles from a variety of N-propargyl bis(indo-
lyl)methanes with sodium azide using CuI as the catalyst in polyethyleneglycol-400 is reported. This pro-
cess is of considerable synthetic advantages in terms of high atom economy, low environmental impact,
mild reaction condition and good yields. The synthesized compounds have also been screened for their
biological activity.
Received 2 March 2009
Revised 23 April 2009
Accepted 25 April 2009
Available online 3 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Click chemistry
Triazole
Antibacterial activity
Antifungal activity
‘Click chemistry’ has emerged as a fast and efficient approach
for synthesis of novel heterocyclic compounds.1 The Huisgen 1,3-
dipolar cycloaddition of azides and alkynes resulting in 1,2,3-tria-
zoles is one of the most powerful click reactions.2 1,2,3-Triazole
synthesis has been intensively studied, and triazoles are widely
used in pharmaceuticals, agrochemicals, dyes, photographic mate-
rials, and in corrosion inhibitory materials.3 In addition, they pos-
sesses anti-HIV,4 antimicrobial activities5 and selective b3
adrenergic receptor agonism.6 In the absence of a transition-metal
catalyst, these reactions are not regioselective, relatively slow, and
require high temperatures to reach acceptable yields. In early
2002, Meldal and co-workers reported that the use of catalytic
amounts of copper(I), which can bind to terminal alkynes, leads
to fast, highly efficient, and regioselective azide–alkyne cycloaddi-
tions at room temperature in organic medium.7 Recently, Sharpless
and co-workers have reported a high yielding synthesis of triazoles
using a Cu(I) catalyst with an excellent 1,4-regioselectivity.8 The
resulting ‘clicked’ products can even be obtained via in situ gener-
ation of the corresponding organic azides from organic halides–
NaN3 in the presence of an alkyne and a copper catalyst, avoiding
the need to handle organic azides.9
which contain nitrogen heterocyclic nucleus. Since bis(indo-
lyl)methanes possess a wide range of biological activities, their
synthesis has received a paramount interest.12,13
Recently, polyethylene glycols (PEG) as a reaction medium has
received considerable attention in synthetic organic chemistry
and emerged as alternative green reaction media with unique
properties such as thermal stability, commercial availability, non-
volatility, recyclable, non-halogenated, easily degradable, and pos-
sess low toxicity.14 A few reports are available on PEG-40015 for the
synthesis of triazoles with limited and narrow application scope
for different substrates.
As part of our ongoing program directed towards the develop-
ment of new methodologies for the synthesis and biological evalu-
ation of diverse heterocyclic compounds,16 herein we disclose the
synthesis of N-propargylated bis(indolyl)methanes followed by
1,3-dipolar cycloaddition with alkyl azide to form 1,2,3-triazole
R3
R3
R1
R1
R1
Br
R1
Nitrogen heterocycles have received special attention in
pharmaceutical chemistry due to their diverse medicinal poten-
tial.10 The availability of therapeutically important drugs such as
itavastatin, cerivastatin, streptonigrin, sumatriptan, avitriptan,
almotriptan, sumatriptan, pravodoline, remosetron, terconazole,
itraconazole, fluconazole and voriconazole11 are a few examples
CuI, NaN3
+
N
N
R
2 R2
PEG-400,
rt
N
N
R4
2a-c
R2
R2
N
N
N
N
1a-h
N
N
2a = R4 = H,
R1 = H, Br
2b = R4 =OCH3,
R2 = H, CH3
R3 = H, OCH3, Cl
3a-o
2c = R4 = Cl
R4
R4
* Corresponding author. Tel.: +91 44 24913289; fax: +91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
Scheme 1.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.131

3612
M. Damodiran et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3611–3614
in PEG-400 using 10 mol % of CuI. Bis(indolyl)methanes were pre-
pared from N-propargylindoles17 with aldehydes as per the earlier
reported procedure.13
method20 at a concentration of 100 g/mL.22 Out of 15 synthesized
l
compounds 3b, 3e, 3h, 3i, and 3m have shown maximum activity
To begin our study, we carried out the reaction of alkyne 1a,
with 2.4 equiv of sodium azide, 2.6 equiv of triethylamine and
2.2 equiv of benzyl bromide (2a) in the presence of 10 mol % CuI
Table 1
Synthesis of 1,2,3-triazole derivatized bis(indolyl)methanes using PEG-400 as solvent
t
in BuOH. However, the reaction did not proceed at all. Our at-
Entry
Alkyne (1)
R4
Product (3)
Time (h)
Yielda (%)
tempts to carry out the reactions with different solvents such as
H2O, CH3CN, EtOH or mixture of solvents such as CH3CN/H2O
(1:1v/v) did not yield fruitful results. However, the use of a mixture
of EtOH/H2O (1:1v/v) at room temperature drove the reaction to
form the desired bis-triazole product (3a) in 40% yield in 8 h. Sur-
prisingly, when the same reaction was carried out in PEG-400 the
desired product (3a) was obtained in 80% yield at 6 h.18 This may
be due to the hydrophilic and hydrophobic character of the PEG-
400. The reaction took place regioselectively at the alkynes moiety
to produce the corresponding 1,4-disubstituted-1,2,3-triazole. The
generality of this solvent system (PEG-400) was tested with vari-
ous alkynes (1a–1h) and benzyl bromides (2a–c). Under this con-
dition, bistriazoles (3a–3o) were obtained in good to excellent
yields (Scheme 1, Table 1, entries 1–15).
1
H
3a
6
80
N
N
1a
2
3
1a
1a
Cl
OMe
3b
3c
6
24
82
27
OMe
4
H
3d
6
75
The results revealed that the reaction was highly dependent on
the nature of substituents on the aromatic ring of the alkynes (1a–
1h). An evident electronic effect was observed when we compared
the yields of the products (3a–3o). The yield of the products de-
creased when electron-donating groups were present on the phe-
nyl ring of bis(indolyl)methanes (OMe at R3 in entries, 4–6 and
CH3 at R2 in entries 11–15). Indole substrates bearing an elec-
tron-withdrawing group, the Br group at R1 position (entries 8–
10) and Cl group at R3 position (entry 7) afforded higher yields.
In compounds 3j and 3n, the presence of both electron-withdraw-
ing and electron-donating groups competes resulting in more or
less yield. The yields were dramatically decreased when electron-
donating groups present in benzyl bromide and the reaction times
were found to be longer (entries 3 and 6). The structure of the ob-
tained 1,4-disubstituted 1,2,3-triazoles is in good agreement with
those described in the previous reports on the synthesis of substi-
tuted triazoles via three component coupling .19
N
N
1b
5
6
1b
1b
Cl
OMe
3e
3f
6
24
78
32
Cl
7
Cl
3g
8
90
N
N
N
1c
Br
Br
8
H
3h
6
85
1d
All compounds were characterized by 1H, NMR, 13C NMR, IR
spectroscopy and mass spectroscopy. The 1H NMR spectra of com-
pounds (3a–3o) in CDCl3 consist of a characteristic singlet due to
the triazole proton in the region of 7.02–7.25 ppm. Another charac-
teristic feature of the 1H NMR spectra is the appearance of AB quar-
tet at dH 5.26–5.31 ppm, which corresponds to four methylene
protons of triazolyl-CH2-phenyl and appearance of singlet at dH
5.30–5.42 ppm, which corresponds to another four methylene pro-
tons of indolyl-CH2-triazolyl protons. These observations confirm
the formation of bis(indolyl)methane derivatised 1,4-disubstituted
1,2,3-triazole.
N
9
1d
Cl
H
3i
3j
6
6
90
85
OMe
Br
10
Br
1e
N
N
All the newly synthesized compounds (3a-o) were screened for
their in vitro antibacterial and antifungal activities. The in vitro
antibacterial activities of the synthesized compounds were evalu-
ated against Gram-positive bacteria namely Staphylococcus aureus
(ATCC 25923) and Gram-negative bacteria namely Escherichia coli
(ATCC 25922) by disc diffusion method20 using a concentration
11
H
3k
6
72
N
N
1f
of 100 lg/mL. Muller Hinton Agar was employed as culture media
and DMSO was used as solvent control for antibacterial activity.21
The diameter of zone of inhibition was measured in mm. All the
compounds have shown almost comparable activity when com-
pared to the standard drug Ciprofloxacin. Out of 15 synthesized
compounds, 3a, 3g, 3j, 3k and 3n showed maximum activity
(20 mm inhibition) against S. aureus. The compounds are not bio-
logically active against Gram-negative bacteria E. coli.
12
13
1f
Cl
Cl
3l
6
6
78
70
OMe
3m
N
N
1g
The in vitro antifungal activities of the synthesized compounds
were evaluated against Candida albicans (ATCC 10231) by diffusion

M. Damodiran et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3611–3614
3613
Chem. Commun. 2007, 1453; (d) Munteanu, M.; Choi, S. W.; Helmut Ritter, H.
Macromolecules 2008, 41, 9619.
Table 1 continued
Entry
Alkyne (1)
R4
Product (3)
Time (h)
Yielda (%)
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Cl
14
H
3n
8
75
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N
N
1h
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15
1h
Cl
3o
8
75
a
Isolated yields.
Table 2
The antibacterial and antifungal screening data
S. No
Compound
Zone of inhibition (in mm)
Antibacterial activity
S. aureus
Antifungal activity
C. albicans
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
20
17
18
19
16
18
20
16
16
20
20
17
16
20
19
22
—
16
20
16
17
21
16
16
21
21
16
16
19
20
18
18
—
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Ciprofloxacin
Ketoconazole
24
against C. albicans. The antibacterial and antifungal screening data
are recorded in Table 2.
In conclusion a safe and efficient method for the generation of
1,4-disubstituted 1,2,3-bis-triazole in a complete regioselective
manner has been developed. This method avoids isolation and han-
dling of potentially unstable organic azide and provides triazole
product in pure form. The operational simplicity of this method
and the high yields of the product make it attractive for the synthe-
sis of this class of potential biologically active molecules.
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Chem. Sci. 2009, 121, 65; (b) Sujatha, K.; Shanmugam, P.; Perumal, P. T.;
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Sridhar, R.; Perumal, P. T.; Etti, S.; Shanmugam, G.; Ponnuswamy, M. N.;
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Acknowledgements
One of the authors M.D. thanks UGC and CSIR (New Delhi) for
the award of Senior Research Fellowship (SRF). The authors are
thankful to SAIF, IIT Madras for recording 13C NMR spectra.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.04.131.
References and notes
17. To
a mixture of indole (8.5 mmol), propargyl bromide (12.8 mmol) and
50 mol % Tetrabutylammonium bromide in 12 mL of toluene at room
temperature, 12 mL of 50% NaOH was added dropwise. Stirring was
continued until completion of the reaction as evidenced by TLC analysis. The
products were separated by column chromatography using silica gel with
petroleum ether and ethyl acetate as the eluents and characterized by 1H,
NMR, 13C NMR, IR spectroscopy and mass spectroscopy.
1. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004;
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E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249; (d) Hein, C. D.; Liu, X.-M.;
Wang, D. Pharm. Res. 2008, 25, 2216; (e) Tron, G. C.; Pirali, T.; Billington, R. A.;
Canonico, P. L.; Sorba, G.; Genazzani, A. A. Med. Res. Rev. 2008, 28, 278.
2. (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley:
New York, 1984; p 1; (b) Ming, X.; Leonard, P.; Heindl, D.; Seela, F. Nucleic Acids
Symp. Ser. 2008, 52, 471; (c) Zeng, Q.; Li, T.; Cash, B.; Li, S.; Xie, F.; Wang, Q.
18. A typical experimental procedure for synthesis of 1,4-disubstituted 1,2,3-bistriazole
for compound 3a. N-propargylbis(indolyl)methane 1a (0.501 mmol, 200 mg),
sodium azide 2a (1.204 mmol, 78 mg) and benzylbromide (1.104 mmol,

3614
M. Damodiran et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3611–3614
0.131 mL) were suspended in polyethylene glycol-400 (5 mL). To this copper
19. (a) Sreedhar, B.; Reddy, P. S.; Krishna, V. R. Tetrahedron Lett. 2007, 48, 5831; (b)
Chandrasekhar, S.; Basu, D.; Rambabu, Ch. Tetrahedron Lett. 2006, 47, 3059; (c)
Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Eycken, E. V. Org. Lett. 2004, 6, 4223.
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21. Experimental for antibacterial activity: 1000 mL of media was prepared using
agar (2%) with beef extract (30 g), casein hydrolysate (17.5 g), soluble starch
(1.5 g) and sodium hydroxide (5 g) in distilled water. The pH of the media was
set to 7.4 0.2 at 25 °C. The The standard drug ciprofloxacin disc was placed on
the media and the Whatmann No. 2 filter disc (5 mm diameter) were cut and
fitted in to vials plugged with cotton. These vials were kept in hot air oven at
160 °C for 30 min for sterilization. The synthesized compounds are dissolved in
iodide (10 mol %) was added and the reaction mixture was stirred for 6 h. After
completion of the reaction (monitored by TLC), the product was extracted with
EtOAc (3 Â 15 mL) and the organic extract was dried. The crude product was
subjected to column chromatography to yield the desired product that was
characterized by 1H NMR, 13C NMR, IR spectroscopy, mass spectroscopy and
elemental analysis. Pink solid; mp 55–57 °C; Rf 0.46 (60% EtOAc/petroleum
ether); IR (KBr): 2929, 1610, 1462, 1330 cmÀ1 1H NMR (500 MHz, CDCl3): d
;
5.27 (AB quartet, 4H, J = 11.6 Hz, –triazolyl-CH2-Ar), 5.38 (s, 4H, –indolyl-CH2-
triazolyl), 5.81 (s, 1H, –CH), 6.59 (s, 2H, –Indolyl-H), 6.92 (t, 2H, J = 6.9 Hz, –Ar-
H), 7.04 (s, 2H, –triazolyl-H), 7.11–7.23 (m, 9H, –Ar-H), 7.28–7.33 (m, 12H, –Ar-
H); 13C NMR (125 MHz, CDCl3): 40.1, 42.0, 54.2, 109.6, 119.1 (2C), 120.0, 121.7,
121.8, 126.2, 127.2, 127.9 (3C), 128.0, 128.2, 128.3, 128.6, 128.7, 128.9, 129.0
(3C), 129.1 (3C), 131.2, 134.5, 136.6, 136.8, 143.7, 145.2; MS (EI) m/z 665
[M++H+]; Anal. Calcd for C43H36N8: C, 77.69; H, 5.46; N, 16.85. Found: C, 77.77;
H, 5.43; N, 16.79. Spectral data for compound 3b: Pink solid; mp 95–97 °C; Rf
DMSO solution at 100 lg/10 ll. With the help of micro pipette the test solution
was added over the paper disc and dried. After drying, discs were placed over
solid agar media and kept in the refrigerator for 1 h to facilitate uniform
diffusion of the drug and later kept in the incubator for a period of 24 h at
37 °C. Observations were made for the zone of inhibition around the
synthesized compounds and compared with standard. Each experiment was
performed for three times. Observations were made as an average of three
works performed.
0.48 (60% EtOAc/petroleum ether); IR (KBr): 2918, 1610, 1330, 1462 cmÀ1 1H
;
NMR (500 MHz, CDCl3): d 5.28 (AB quartet, 4H, J = 10.4 Hz, –triazolyl-CH2-Ar),
5.35 (s, 4H, –indolyl-CH2-triazolyl), 5.81 (s, 1H, –CH), 6.59 (s, 2H, –indolyl-H),
6.92 (t, 2H, J = 7.6 Hz, –Ar-H), 7.04 (s, 2H, –triazolyl-H), 7.09 (d, 4H, J = 8.4 Hz, –
Ar-H), 7.13 (t, 2H, J = 7.6 Hz, –Ar-H), 7.19–7.23 (m, 3H, –Ar-H), 7.26–7.35 (m,
10H, –Ar-H); 13C NMR (125 MHz, CDCl3): 40.0, 42.0, 53.3, 109.5, 119.1 (2C),
120.0, 121.5, 121.8, 122.9, 127.7, 128.2, 128.3, 128.5, 128.7, 129.2 (3C), 129.3
(3C), 129.4, 129.5, 129.6, 132.9, 134.7, 136.6, 136.8, 143.6, 145.4; MS (EI) m/z
733 [M++H+], 735 [M+2+H+], 737 [M+4+H+]; Anal. Calcd for C43H34Cl2N8: C,
70.39; H, 4.67; N, 15.27. Found: C, 70.51; H, 4.64; N, 15.24.
22. Experimental for antifungal activity: The media was prepared using agar with
glucose (<10 g), peptone (10 g) and sabouroud dextrose agar (15 g) in distilled
water. The pH of the media was set to 5.5 0.2 at 25 °C. The same procedure
employed for the evaluation of antibacterial activities was followed for
antifungal evaluation also.