An efficient synthesis of highly functionalized novel chromeno[4,3-b] pyrroles and indolizino[6,7-b]indoles as potent antimicrobial and antioxidant agents

Article abstract of DOI:10.1016/j.bmcl.2011.12.061

A facile and efficient synthesis of novel chromeno[4,3-b]pyrroles has been accomplished by intramolecular 1,3-dipolar cycloaddition which on subsequent Pictet-Spengler cyclisation in presence of p-toluenesulfonic acid yielded indolizino[6,7-b]indoles. The synthesized chromenopyrroles and indolizinoindoles were evaluated for their antimicrobial and antioxidant activities. Compounds 7b, 7e, 7a and 7d exhibited respectively, good antibacterial and antifungal activities against tested pathogens when compared to reference control.

Full text of DOI:10.1016/j.bmcl.2011.12.061

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1375–1379
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
An efficient synthesis of highly functionalized novel chromeno[4,3-b]pyrroles
and indolizino[6,7-b]indoles as potent antimicrobial and antioxidant agents
Natarajan Arumugam a, , Raghavachary Raghunathan b, , Abdulrahman I. Almansour a, Usama Karama a
⇑
⇑
a Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia
b Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and efficient synthesis of novel chromeno[4,3-b]pyrroles has been accomplished by intramolec-
ular 1,3-dipolar cycloaddition which on subsequent Pictet–Spengler cyclisation in presence of p-toluene-
sulfonic acid yielded indolizino[6,7-b]indoles. The synthesized chromenopyrroles and indolizinoindoles
were evaluated for their antimicrobial and antioxidant activities. Compounds 7b, 7e, 7a and 7d exhibited
respectively, good antibacterial and antifungal activities against tested pathogens when compared to ref-
erence control.
Received 13 October 2011
Revised 26 November 2011
Accepted 12 December 2011
Available online 20 December 2011
Keywords:
Azomethine ylide
1,3-DC reaction
Ó 2011 Elsevier Ltd. All rights reserved.
Pictet–Spengler cyclization
Chromenopyrroles
Indolizinoindoles
Antimicrobial activity
HN
X
In the last few decades, the increasing incidence of infection
caused by the rapid development of bacterial resistance to most
of the known antibiotics is a serious health problem.1 While many
factors may be responsible for mutations in microbial genomes, it
has been widely demonstrated that the improper use of antibiotics
can greatly increase the development of resistant genotypes.2 Fur-
ther, the usage of most antimicrobial agents is limited due to the
rapidly developing drug resistance in conjunction with the unsat-
isfactory status of present treatments of bacterial and fungal infec-
tions and drug side effects.3–7 Therefore, the development of novel
antimicrobial drugs possessing new mechanisms of action emerges
as an important objective and much of the research efforts are di-
rected towards the design of new agents comprising chromenopyr-
role moiety.8
Chromeno[4,3-b]pyrrole plays a unique role in medicinal chem-
istry, as its similar structural motif (Fig. 1 X = NH) are found in nat-
urally occurring martinelline or martinellic acid alkaloids and
possess antibacterial activity and act as a bradykinin receptor
antagonist.9 On the other hand, naturally occurring chromene or
chromane derivatives exhibit remarkable physiological properties
and some pyrrolidine annulated benzopyran compounds are
known as selective dopamine D3 receptor antagonist.10 Chro-
meno[4,3-b]pyrrole find utility in other areas of medicinal chemis-
try, in the treatment of impulsive disorders,11 parkinson’s
X = NH, Martinelline or Martinellic acid building blocks
X= O, Chromeneor Chromane derivatives
Figure 1. Representation of the fused pyrrole scaffold.
disease,12 psychoses, memory disorders13 and anxiety.14 Confalone
and co-workers reported15 the synthesis of chromeno[4,3-b]pyr-
role through 1,3-dipolar cycloaddition via deprotonation route.
Grigg et al.16 also extensively studied the intramolecular azome-
thine ylide cycloaddition reaction for the synthesis of same type
of compounds. Likewise, indolizinoindole ring systems are of inter-
est to the pharmaceutical industry and have been used as interme-
diates in the preparation of diuretic compounds17 which are also
known to exhibit analgesic and anti-inflammatory activity.18 Its
derivatives act as b-turn mimics and display high binding affinity
and selectivity of CCK1 receptors.19
In this context, we have reported the synthesis of fused pyrrol-
idine and indolizinoindole heterocycles through 1,3-dipolar cyclo-
addition.20 In addition, recently, we have embarked on a program
on the synthesis of structurally diverse novel heterocycles employ-
ing intermolecular 1,3-dipolar cycloadition followed by their
biological screening, which has brought to light various antimicro-
bial leads.21 Our research group reported chromenopyrrole and
⇑
Corresponding authors. Tel.: +966 4675907; fax: +966 4675992 (N. Arumugam).
E-mail addresses: anatarajan@ksu.edu.sa (N. Arumugam), ragharaghunathan@
yahoo.com (R. Raghunathan).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.12.061

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N. Arumugam et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1375–1379
indolizinoindole derivatives derived from electron deficient 4-(2-
formylphenoxy)/4-(1-formylnaphthalen-2-yloxy)but-2-enoate
with tryptophan ester hydrochloride by sequential intramolecular
1,3-dipolar cycloaddition reaction via N-Metalation route followed
by Pictet–Spengler cyclization.22
In continuation of our research in the area of 1,3-dipolar cyclo-
addition reaction and Pictet–Spengler cylisation,20c herein we wish
to report an expeditious and facile protocol for the synthesis of
chromeno[4,3-b]pyrrole and indolizino[6,7-b]indole derivatives
through intramolecular 1,3-dipolar cycloaddition reaction of
azomethine ylide generated from electron rich 2-(allyloxy)benzal-
dehyde/-1-naphthaldehyde with tryptophan methyl ester hydro-
chloride followed by Pictet–Spengler cyclization. Interestingly,
these chromeno[4,3-b]pyrroles and indolizino[6,7-b]indoles dis-
played significantly enhanced in vitro antibacterial, antifungal
and antioxidant activities.
The prerequisite 2-(allyloxy)benzaldehyde/-1-naphthaldehyde
were prepared according to literature procedure23 and were sub-
jected to intramolecular azomethine ylide cycloaddition reaction
with tryptophan methyl ester hydrochloride. Thus, tryptophan
methyl ester hydrochloride 3 and 2-(allyloxy)benzaldehyde 2a/2-
(allyloxy)-1-naphthaldehyde 2b in CH2Cl2 with Et3N stirred over-
night at room temperature to afford imine 4a–b and these were
used for next step without further purification.
The crude imine was refluxed in toluene under Dean–Stark con-
ditions for 12 h yielded chromeno[4,3-b]pyrrole-2-carboxylate
derivatives 5a and 6a in 50–55% as a single diastereoisomer
(Scheme 1). In the infrared (IR) spectrum of cycloadduct 5a, the es-
ring adopts a twist conformation and pyran ring adopts a twist
boat conformation, whilst the molecular structure is stabilized by
intermolecular N–HÁ Á ÁO and C–HÁ Á ÁO hydrogen bonds and also
by week intermolecular p–p interactions.
Next we turned our attention to the synthesis of indolizino[6,7-
b]indole derivatives 7a–e and 8a–e by annulations of chromeno/
benzochromenopyrroles 5a and 6a. The indolizinoindoles are
typically prepared via Pictet–Spengler cyclization reaction of chro-
meno/benzochromenopyrroles 5a/6a with corresponding aromatic
aldehyde in the presence of p-toluenesulfonic acid under thermal
conditions in moderate yield (Scheme 2). The intramolecular cyclo-
addition and Pictet–Spengler cyclization were initially performed
by conventional method under reflux in toluene and were subse-
quently investigated also under microwave irradiation in a focused
microwave synthesizer, as this technique has evolved as a valuable
alternative to conventional heating for the introduction of energy
into reactions and has clear benefits in many chemical transforma-
tions,25 including cycloaddition25b in terms of rate accelerations
and yield enhancements. The reactions under microwave irradia-
tion for 5–10 min afforded better yield of 5, 6, 7 and 8 than conven-
tional heating. The results obtained for both methods are
summarized in Table 1.
The Pictet–Spengler cyclized product was confirmed by spectral
and elemental analysis. The cyclized product 7a gave a singlet for
Hc proton at d 5.24 ppm and the trans-stereochemistry was con-
firmed by NOE studies. Irradiation of the benzylic proton (Hc) of
7a at d 5.24 did not cause any enhancement of the signal for the
Ha proton, which appeared as a doublet at d 3.97 (J = 4.4 Hz)
(Fig. 3). A peak at m/z 450.84 (M+) in the mass spectrum of the
compound 7a confirmed the formation of Pictet–Spengler cyclized
product.
The synthesized compounds 5, 6, 7 and 8 were evaluated for
their in vitro antibacterial activity against four bacterial strains
Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeroginosa
and Klebsiella pneumonia and in vitro antifungal activity against
Fusarium oxysporum and Macrophomenaphaseolina by agar diffu-
sion method in dublicate, using tetracycline and carbendazim as
reference control for antibacterial and antifungal activities, respec-
tively. Further, these compounds were also studied for their anti-
oxidant property.
Antibacterial activity of chromeno[4,3-b]pyrroles and indolizi-
no[6,7-b]indoles (agar diffusion assay): The antibacterial activity of
the synthesized twelve compounds against human bacterial patho-
gens as determined by agar diffusion method with tetracycline as
reference control was investigated. Analysis of antimicrobial
ter carbonyl group exhibited
a strong absorption band at
1730 cmÀ1 and the indole NH appeared at 3292 cmÀ1. The fusion
at the ring junction was found to be cis from the spectroscopic data
of the cycloadduct 5a, the Ha proton appeared as a doublet at d
4.36 ppm (J = 4.3 Hz) and Hb proton resonated as a multiplet in
the region d 2.39–2.42 ppm. The H1 proton exhibited a doublet of
doublet in the region d 4.01–4.05 ppm (J = 10.6, 4.2 Hz) and H2 pro-
ton appeared as multiplet at d 3.60–3.67 ppm. The indole adjacent
methylene protons resonated as two doublets at d 3.21 and
3.38 ppm with geminal coupling constant (J = 14.2 Hz). The 13C
NMR spectrum of compounds 5a showed
a singal at d
176.84 ppm due to ester carbonyl carbon. The presence of molecu-
lar ion peak at m/z 362.52 (M+) in the mass spectrum of 5a
confirms the formation of cycloadduct.
Finally, the structure of cycloadduct was unambiguously ascer-
tained by single crystal X-ray diffraction analysis24 of the cycload-
duct 6a (Fig. 2). In the molecular structure of 6a, the pyrrolidine
CHO
O
H3COOC
N
O
2a-b
Et3N, Dry DCM
rt, 12 hr
CHO
K2CO3, acetone
Reflux
N
Andyd. MgSO4
COOCH3
NH2 HCl
OH
4a-b
H
1a-b
.
Toluene
Reflux
12 h
3
N
H
Br
O
O
H1
Hb
H2
O
O
H3COOC
HN
HN
Ha
N
H
N
H
5a
6a
a = Salicylaldehyde
b = 2-hydroxy-1-naphthaldehyde
Scheme 1. Synthesis of chromeno[4,3-b]pyrroles.

N. Arumugam et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1375–1379
1377
Figure 2. ORTEP diagram of 6a.
groups in enhancing the antimicrobial activity is supported by P.
Sharma et al.26 Antimicrobial results revealed that the maximum
antibacterial activity was observed for compounds 7b and 7e
against all the tested pathogens at low concentration. Compounds
5a, 6a, 8b and 8e showed good antibacterial activity compared to
reference control tetracycline. Compounds 7c, 7d, 8c and 8d exhib-
ited moderate activity against all the tested antibacterial patho-
gens. Compounds 7a and 8a showed good activity at higher
concentration level. The above antimicrobial results demonstrate
that all the synthesized compounds showed good antibacterial
activity, which are comparable to the reference control. It was ob-
served that all the antibacterial activities of the present studied
compounds are dose dependant. Further clinical studies are re-
quired to validate the effective compounds of the present study
as an antimicrobial agent. The results are summarized in Table 2.
The structure activity relationship demonstrates that indolizinoin-
doles 7b, 7e, 8a and 8e showed excellent to good activity at low
O
O
Hb
O
H
O
CHO
R
H
O
N
PTSA, toluene
reflux, 4-6 h
O
Ha
N
H
HN
Hc
N
H
R
5a
6a
7a-e
8a-e
R = a) p-H, b) p-Cl, c) p-CH3, d) p-OCH3, e) m-NO2
Scheme 2. Synthesis of indolizino[6,7-b]indoles.
results indicated that the presence of electron withdrawing groups
attached to the phenyl ring were generally more active than the
other derivatives and the importance of electron withdrawing
Table 1
Comparison of the reaction times and yields for the conventional and microwave-assisted 1,3-dipolar cycloaddition and Pictet–Spengler cyclization
Entry
Compounds
R
Conventional method toluene, reflux
Microwave assisted (100 °C, 100 W)
Yield
Time (hr)
Yield
Time (min)
1
2
3
4
5
6
7
8
9
5a
6a
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
Chromenopyrrole
Benzochromenopyrrole
H
Cl
CH3
OCH3
3-NO2
H
50
55
65
68
70
65
72
66
78
76
74
75
12
12
6
4
5
5
4
5
4
78
81
85
88
92
83
86
79
84
83
86
90
10
9
6
5
7
9
5
7
6
Cl
10
11
12
CH3
OCH3
3-NO2
5
5
4
8
10
6

1378
N. Arumugam et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1375–1379
2.10-2.14 dd, J = 11.6, 7.2 Hz
2, 29-2.32, dd, J = 11.6, 4.4 Hz
2.45-2.48, m, 1H
52.6
O
3.19, d, 1H, J = 15.0 Hz
3.28, d, 1H, J = 15.0 Hz
O
H
H
176.3
4.06-4.11 dd, 1H, J = 10.3, 4.2 Hz
3.68-3.74, dd, 1H, J = 10.3, 8.0 Hz
6H7.2
O
32.9
30.7
40.6
55.7
108.4
N
H 126.3
65.2
152.8
N133.7
H
H
5.24, S, 1H
3.97, d, 1H, J = 4.4 Hz
Figure 3. Selected 1H and 13C NMR chemical shifts of 7a.
Table 2
Effect of chromno[4,3-b]pyrroles 5a, 6a and indolizino[6,7-b]indoles 7(a–e) and 8(a–e) on the growth of human pathogens Bacillus subtilis, Staphylococcus aureus, Pseudomonas
areoginosa and Klebsiella pneumonia
S. No
Compounds
Concentration of compounds(
lg/ml) Zone of inhibition (nm)
Bacillus subtilis
Staphylococcus aureus
Pseudomonas aeroginosa
Klebsiella pneumonia
25
50
75
100
25
50
75
100
25
50
75
100
25
50
75
100
1
2
3
4
5
6
7
8
9
5a
6a
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
11
10
9
13.5
9
8
14
9
12
9
9
12
15
15
15
11
21
12
11
21
12
18
14
12
19
24
20
19
20
26
15
18
28
20
21
16
17
24
29
26
24
25
36
20
19
40
24
26
20
20
29
40>
10
9
9
20
9
-
20
9
14
9
9
19
22
15
13
11
21
13
12
22
13
17
12
11
20
24
20
18
18
24
17
16
24
18
20
17
18
24
29
23
24
25
29
18
18
36
26
28
19
20
28
40>
10
9
9
16
8
7
17
9
12
8
10
14
20
15
14
12
22
12
11
24
13
16
14
12
20
26
21
20
20
25
16
15
26
18
20
17
16
24
28
23
21
24
36
19
20
40
25
26
20
19
30
40>
11
10
9
16
8
15
14
11
20
13
11
20
12
15
12
11
18
22
21
20
19
25
18
19
25
17
22
17
18
22
28
23
23
26
30
19
20
36
24
25
21
20
27
40>
8
15
10
11
9
9
13
18
10
11
12
Tetracycline
Table 3
concentration presumably ascribable to the presence of both ind-
olizinoindole nucleus and electron withdrawing group (–Cl, –
NO2) substituted in the phenyl ring and in compounds 5a and 6a,
the presence of chromeno[4,3-b]pyrrole unit may be responsible
for their activity. From overall antibacterial activity results
(Table 2), it was observed that indolizinoindoles 7b and 7e were
the effective inhibitors against all the bacterial pathogens at lower
concentration comparable to standard drug tetracycline.
Effect of chromno[4,3-b]pyrroles 5a, 6a and indolizino[6,7-b]indoles 7(a–e) and 8(a–
e) on mycelia growth of plant fungal pathogens Fusarium oxysporum and
Macrophomenaphaseolina
S. No
Compounds
Minimum Inhibitory Concentration (lg/ml)
F. oxysporum
M. phaseolina
1
2
3
4
5
6
7
8
9
5a
6a
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
75
85
30
70
110
35
90
30
90
85
60
60
40
20
80
50
25
85
105
30
95
90
15
Antifungal activity of chromeno[4,3-b]pyrroles and indolizino[6,7-
b]indoles (Minimum Inhibitory Concentration): The minimum inhib-
itory concentration (MIC) of the tested compounds against plant
fungal pathogens ranged from 20 to 110
and 7d were effective in controlling both fungal pathogens namely
F. oxysporum and M. phaseolina with MIC values of (30 and 40 g/
ml) and (35 and 50 g/ml), respectively. Compounds 8a and 8e
effectively inhibited fungal pathogen F. oxysporum with MIC (30
and 85 g/ml) and (35 and 90 g/ml), respectively. Similarly, com-
pounds 7b, 7e and 8c effectively inhibited fungal pathogens M.
phaseolina with MIC (70 and 20 g/ml), (90 and 25 g/ml) and
(85 and 30 g/ml), respectively, and other compounds 5a, 6a, 7c,
8b and 8d inhibited mycelial growth at higher concentration
between 60 and 110 g/ml, compared to the reference control
carbendazim ranged 15 and 20 g/ml. In general most of the syn-
thesized compounds inhibited mycelial growth at higher concen-
tration (50–125 g/ml). The results are summarized in Table 3.
lg/ml. Compound 7a
l
10
11
12
l
100
35
20
Carbendazim
l
l
l
l
studies and facilitate rapid screening for radical scavenging activ-
ity. DPPH (1,1-diphenyl-2-picryl-hydrazyl) radical scavenging
activity27 of chromenopyrroles and indolizinoindoles were deter-
mined by spectrophotometrically28 according to Blois’s method.29
All the 12 compounds were tested for their interaction with the
stable free radical DPPH and this interaction, in turn, indicates their
radical scavenging activity. The percentage of inhibition was com-
l
l
l
l
Antioxidant activity of chromeno[4,3-b]pyrroles and indolizi-
no[6,7-b]indoles: In the present antioxidant study, DPPH radical
scavenging method was chosen to evaluate antioxidant potential
of chromenopyrroles and indolizinoindoles. DPPH radical scaveng-
ing activity evaluations are standard assays in antioxidant activity
pared with respective standard drug L-ascorbic acid. The results in
percentage are expressed as the ratio of absorbance decrease at
517 nm and the absorbance of DPPH solution in the absence of
chromenopyrrole and indolizinoindoles. The analysis of Table 4

N. Arumugam et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1375–1379
1379
Table 4
DPPH radical scavenging activity of chromno[4,3-b]pyrroles 5a, 6a and indolizino[6,7-b]indoles 7(a–e) and 8(a–e)
S. No
Compounds
Concentration (lg/mL)
Absorbance (50
0.037
lg)
%
Absorbance (500
0.025
lg)
%
Absorbance (1000
0.007
lg)
%
L
-Ascorbic acida
95
97
99
1
2
3
4
5
6
7
8
9
5a
6a
7a
7b
7c
7d
7e
8a
8b
0.626
0.596
0.635
0.702
0.668
0.638
0.722
0.731
0.650
0.658
0.721
0.621
0.8897
29
33
28
21
24
28
18
17
26
26
18
30
0.430
0.427
0.410
0.505
0.446
0.444
0.513
0.596
0.498
0.410
0.462
0.415
51
52
53
43
49
50
42
33
44
53
48
53
0.350
0.302
0.262
0.282
0.236
0.282
0.264
0.268
0.222
0.110
0.168
0.285
64
66
70
68
73
68
70
69
75
87
81
67
10
11
12
8c
8d
8e
Control
a
Reference drug used for antioxidant evaluation
6. Macchiarulo, A.; Constantino, G.; Fringuelli, D.; Vecchiarelli, A.; Schiaffella, F.;
Fringuelli, R. Bioorg. Med. Chem. 2002, 10, 3415.
7. Hatya, S. A.; Aki-Sener, E.; Tekiner-Gulbas, B.; Yildiz, I.; Temiz-Arpaci, O.;
Yalcin, I.; Altanlar, N. Eur. J. Med. Chem. 2006, 41, 1398.
discloses that the radical scavenging activity of chromenopyrroles
and indolizinoindoles on DPPH radicals increases with the increas-
ing concentration. It was observed that all the compounds showed
8. Purushothaman, S.; Prasanna, R.; Niranjana, P.; Raghunathan, R.; Nagaraj, S.;
Rengasam, R. Bioorg. Med. Chem. Lett. 2010, 20, 7288.
9. Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard, A. M.; Salvatore, M. J.;
Lumma, W. C.; Anderson, P. S.; Pitzenberger, S. M.; Varga, S. L. J. Am. Chem. Soc.
1995, 117, 6682.
10. (a) Dubuffet, T.; Newman-Tancerdi, A.; Cussac, D.; Audinot, V.; Loutz, A.;
Millan, M. J.; Lavielle, G. Bioorg. Med. Chem. Lett. 1999, 9, 2059; (b) Dubuffet, T.;
Muller, O.; Simonef, S. S.; Descomhes, J.-J.; Laubie, M.; Verheuren, T. J.; Lavielle,
G. Bioorg. Med. Chem. Lett. 1996, 6, 349.
11. Caine, B. Science 1993, 260, 1814.
12. Carlson, J. Neurol. Transm. 1993, 94, 11.
13. Sokoloff, P.; Giros, B.; Martres, M. P.; Bouthenet, M. L.; Schwartz, J. C. Nature
(London) 1990, 347, 147.
14. Wilner, P. Clin. Neuropharm. 1985, 18, 549.
15. (a) Confalone, P. N.; Huie, E. M. J. Org. Chem. 1983, 48, 2994; (b) Confalone, P.
N.; Huie, E. M. J. Am. Chem. Soc. 1984, 106, 7175.
16. (a) Grigg, R.; Aly, M. F.; Sridharan, V.; Thianpatanagul, S. J. Chem. Soc., Chem.
Commun. 1984, 182; (b) Grigg, R.; Donegan, G.; Gunaratne, H. Q. N.; Kennedy,
D. A.; Malone, J. F.; Sridharan, V.; Thianpatanagul, S. Tetrahedron 1989, 45,
1723.
good antioxidant activity at 1000
showed maximum activity at a concentration of 1000
l
g/mL. Compounds 8c and 8d
lg/mL.
In conclusion, we have synthesized a series of novel chro-
meno[4,3-b]pyrroles and indolizino[6,7-b]indoles by sequential
intramolecular 1,3-dipolar cycloaddition and subsequent Pictet-
Spengler cyclization. Four leads compounds 7b, 7e, 8b and 8e, dis-
played the potent activity against four selected bacterial pathogens
and two compounds 7a and 7d exhibited good activity against two
fungal organisms. Compounds 8c and 8d showed good antioxidant
potential. The quantitative structure–activity relationship (QSAR)
demonstrates that indolizino[6,7-b]indole with electron withdraw-
ing groups (–NO2, –Cl) attached directly to the phenyl ring were
essential for activity. Further studies on the activity of these com-
pounds in an expanded panel of organisms and in vivo efficacy
models will be reported in due course.
17. (a) Herbst, D. R.; Smith, H. Chem. Abstr. 1971, 75, 118297d; (b) Herbst, D. R.;
Smith, H. Chem. Abstr. 1972, 77, 34373d.
Acknowledgements
18. Herbst, D. R.; Smith, H. Chem. Abstr. 1972, 76, 113061h.
19. (a) De La Figuera, N.; Alkorta, I.; Garcia-Lopez, M. T.; Herranz, R.; Gonzalez-
Muniz, R. Tetrahedron 1995, 51, 7841; (b) Martin-Martinez, M.; De La Figuera,
N.; Latorre, M.; Herranz, R.; Garcia-Lopez, M. T.; Cenarruzabeitia, E.; Del Rio, J.;
Gonzalez-Muniz, R. J. Med. Chem. 2000, 43, 3770.
20. (a) Arumugam, N.; Jayashankaran, J.; Rathna Duraga, R. S. M.; Raghunathan, R.
Tetrahedron 2005, 61, 8512; (b) Arumugam, N.; Raghunathan, R. Synth.
Commun. 2011, 41, 2747; (c) Arumugam, N.; Raghunathan, R. Tetrahedron
2010, 66, 969.
21. (a) Arumugam, N.; Raghunathan, R.; Shanmugaiah, V.; Mathivanan, R. Bioorg.
Med. Chem. Lett. 2010, 20, 3698; (b) Arumugam, N.; Periyasami, G.;
Raghunathan, R.; Kamalraj, S.; Muthumary, J. Eur. J. Med. Chem. 2011, 46, 600.
22. Subramaniyan, G.; Jayashankaran, J.; Rathna Duraga, R. S. M.; Raghunathan, R.
Synlett 2005, 1167.
NA, AIM and UK gratefully acknowledge Deanship of Scientific
Research at King Saud University and this work funded through
the research grant RGP-VPP-128. Also, the authors thank King Saud
University for providing lab facilities.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.12.061.
23. Majumdar, K. C.; Taher, A.; Ray, K. Tetrahedron Lett. 2009, 50, 3889.
24. Karthick, S.; Selvanayagam, S.; Velmurugan, D.; Ravikumar, K.; Arumugam, N.;
Raghunathan, R. Acta Crystallogr. 2005, E61, o1780.
References and notes
25. For representative reviews and books on the use of microwave irradiation in
synthetic organic chemistry, see: (a) Caddick, S. Tetrahedron 1995, 38, 10403;
(b) de la Hoz, A.; Díaz-Ortiz, A.; Moreno, A.; Langa, F. Eur. J. Org. Chem. 2000, 22,
3659; (c) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199; (d) Lidstrom, P.;
Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225; (e) Varma, R. S.
Advances in green chemistry: chemical synthesis using microwave irradiation;
Astra Zeneca Research Foundation: Malleswaram (Bangalore), India, 2002; (f)
Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
26. Sharma, P.; Rane, N.; Gurram, V. K. Bioorg. Med. Chem. Lett. 2004, 14, 4185.
27. Brand-Williams, W.; Cuvelier, M. E.; Berst, C. Lebensm.-Wiss. u.-Technol. 1995,
28, 250.
28. Hatano, T.; Kagawa, H.; Yasuhara, T.; Okuda, T. Chem. Pharm. Bull. 1988, 36,
2090.
1. (a) Chu, D. T. W.; Plattner, J. J.; Katz, L. J. Med. Chem. 1996, 39, 3853; (b) Beovic,
B. Int. J. Food Microbiol. 2006, 112, 280; (c) Finch, R.; Hunter, P. A. J. Antimicrob.
Chemother. 2006, 58, i3; (d) Suree, N.; Jung, M. E.; Clubb, R. T. Mini-Rev. Med.
Chem. 2009, 7, 991.
2. (a) Clark, A. M. Pharm. Res. 1996, 13, 1133; (b) Cowan, M. M. Clin. Microbiol. Rev.
1999, 12, 564; (c) Rex, J. H.; Walsh, T. J.; Sobel, J. D.; Filler, S. G.; Pappas, P. G.;
Dismukes, W. E.; Edwards, J. E. Clin. Infect. Dis. 2000, 30, 662; (d) Sanglard, D.;
Odds, F. C. Lancet Infect. Dis. 2002, 2, 73; (e) Buzzini, P.; Arapitsas, P.; Goretti,
M.; Branda, E.; Turchetti, B.; Pinelli, P.; Ieri, F.; Romani, A. Mini-Rev. Med. Chem.
2008, 8, 1179.
3. Fidler, D. F. Emerg. Infect. Dis. 1998, 4, 169.
4. Oren, I.; Temiz, O.; Yalcin, I.; Aki-Sener, E.; Altanlar, N. Eur. J. Pharm. Sci. 1998, 7,
153.
29. Blois, M. S. Nature 1958, 26, 1199.
5. Hong, C. Y. J. Farmaco 2001, 56, 41.