Design, synthesis and in vitro antibacterial activities of methyl-4-((substituted phenyl) [6H-indolo (2,3-b)quinoxalin-6-yl]methyl-amino) benzoate derivatives

Article abstract of DOI:10.1016/j.cclet.2010.10.055

A series of new methyl-4-((substituted phenyl) [6H-indolo (2,3-b)quinoxalin-6yl]methylamino)benzoate derivatives have been synthesized and assayed for their antibacterial activity on 9 different bacterial strains. Among the screened compounds 2e-2g exhibited potent inhibitory activity compared to standard drug employed, worth further investigation.

Full text of DOI:10.1016/j.cclet.2010.10.055

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 567–570
www.elsevier.com/locate/cclet
Design, synthesis and in vitro antibacterial activities of methyl-4-
((substituted phenyl) [6H-indolo (2,3-b)quinoxalin-6-yl]methyl-
amino)benzoate derivatives
a
Yellajyosula Lakshmi Narasimha Murthy a, , Nagalakshmi Karthikeyan ,
*
Govindh Boddeti a, Bhagavathula S. Diwakar a, E. Rajendra Singh b
a Department of Organic Chemistry, Andhra University, Visakhapatnam 530003, India
b DRDO - HQ, New Delhi 110011, India
Received 13 September 2010
Available online 1 March 2011
Abstract
A series of new methyl-4-((substituted phenyl) [6H-indolo (2,3-b)quinoxalin-6yl]methylamino)benzoate derivatives have been
synthesized and assayed for their antibacterial activity on 9 different bacterial strains. Among the screened compounds 2e–2g
exhibited potent inhibitory activity compared to standard drug employed, worth further investigation.
# 2010 Yellajyosula Lakshmi Narasimha Murthy. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords: Isatin; Schiff base; Mannich base; Antibacterial activity
The synthesis of a newer class of anti-bacterial agents is in need of time, especially against drug-resistant bacteria,
such as Gram-positive and Gram-negative strains, which are responsible for a number of serious infections in the acute
and chronic care units in hospitals.
Isatin (1H-indole-2,3-dione) is a resourceful endogenous heterocyclic molecule identified in human being and
rat tissues. Several of its derivatives were reported to exhibit a wide range of promising pharmacodynamic profile.
Isatin and its derivatives possessing an indole nucleus have arisen great attention in recent years due to their wide
variety of biological activities and pharmacological studies. The literature survey revealed that isatin possesses
diverse chemotherapeutic activities such as antibacterial [1], antifungal [2], antiviral [3], anti-HIV [4], anti-
mycobacterial [5], anti cancer [6], anti-inflammatory [7] and anticonvulsant [8], as well the Mannich bases of
isatin are reported to exhibit broad spectrum of chemotherapeutic properties such as antibacterial [9], antifungal,
and anti-HIV [10]. In view of biological importance of isatins and Mannich bases of isatins, it was planned to
synthesize a new series of compounds containing indole and amino benzoate nucleus, by simple Mannich reaction
using a Schiff’s base, 4-aminobenzoate and substituted aromatic aldehydes. Our research interest was both on the
synthesis and antibacterial evaluation.
* Corresponding author.
E-mail address: murthyyln@gmail.com (Y.L.N. Murthy).
1001-8417/$ – see front matter # 2010 Yellajyosula Lakshmi Narasimha Murthy. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.10.055

568
Y.L.N. Murthy et al. / Chinese Chemical Letters 22 (2011) 567–570
1. Experimental
Melting points were determined by open capillary method and were uncorrected. Purity was confirmed by HPLC.
IR spectra were recorded using KBr on a Shimadzu IR Affinity spectrophotometer. 1H NMR and 13C NMR spectra
were recorded on a Jeol-FT-NMR-90 MHz spectrophotometer using DMSO-d6 as solvents and TMS as an internal
standard. Mass spectra were recorded on a Varian Atlas CH-7 mass spectrometer.
1.1. General procedure for the synthesis of the title compounds 2a–g
Synthetic pathway for the compounds 2a–g and the intermediate 1 was summarized in Scheme 1. The Schiff base,
which was already reported [11] 1 (1 mmol) was dissolved in absolute alcohol (20 mL), and then appropriate aromatic
aldehyde (1 mmol) was added with vigorous stirring. The reaction was further continued with the addition of ethanolic
4-aminobenzoate (1 mmol) solution with constant stirring. Then the reaction mixture was refluxed for about 2–3 h and
allowed to stand overnight, yellow crystallized product was obtained and were collected and recrystallized from
ethanol to yield the title compounds 2a–g. The structures of the product were characterized by melting point, IR, 1H,
13C NMR and MS [12] and elemental analysis [13].
The synthesized compounds were tested for antibacterial activity against some nine bacterial strains. The
determination of antibacterial activity was done using streak plate method. Zone of inhibition (in mm) formed by the
compounds against particular tested bacterial strain determined the antibacterial activity of the synthetic compound.
The zone of inhibition values were compared with Ciprofloxacin. Solvent employed was DMSO (showed no effect on
the tested strains). The in vitro activities of compounds 2e–g against Bacillus sps., P. aeruginosa, S. sonnei, and
Stapylococcus sps. were comparable to or better than Ciprofloxacin. In particular, activity of compound 2g was more
potent than standard against all the tested strains, while the remaining compounds generally showed inferior or equal
activities against all the tested strains.
1.2. Structure–activity relationship (SAR)
In continuation of our investigation, we wish to examine the SAR of the compounds with the increasing donating
groups on the final products viz., 2a–g. From Table 1 the antibacterial activity in vitro of compounds 2a–g
demonstrated that increasing methoxy groups on phenyl ring or with electronic donating substituent on the phenyl ring
resulted in more antibacterial activity.
Due to the electronic donating character of substituents, on phenyl ring in compound 2 could obviously affect on
pharmacological activity and antibacterial spectrum.
[()TD$FIG]
O
N
NH
NH
2
2
a
N
O
+
N
H
N
H
1
N
N
O
H
N
N
b
OH
+
N
N
H
1
R
R
N
N
NH
2
N
NH
CH
O
3
O
R
O
O
2a - g
R = 2a.Cl, 2b.Br, 2c.N02 2d.OH, 2e.4-OH 3-OCH3, 2f.3, 4-OCH3, 2g.2,4,6-OCH3
Scheme 1. Synthetic route of 2a–g. Solvent and conditions: (a) [11]; (b) CH3OH, reflux, 2–3 h.

Y.L.N. Murthy et al. / Chinese Chemical Letters 22 (2011) 567–570
569
Table 1
Antibacterial activities of the compounds 2a–g (in mm)a.
2a 2b 2c
2d
9.4
2e
2f
2g
Ciprofloxacin
B. subtilis
B. cereus
8.5 8.7 9.1
10.2
15.3
11.2
12.3
14.3
9.0
10.8
15.6
11.5
12.5
14.7
9.5
11.2
16.2
12.0
12.8
15.2
10.0
10.5
11.0
11.6
10.0
15.0
10.5
12.0
14.0
9.0
7.5
7.2
7.0
8.0
6.7
8.2
11.0
9.6
5.2
5.5
5.0
8.5
10.0
10.0
11.4
13.0
8.5
P. aureginosa
S. aureus
10.0
12.2
8.2
10.6
11.2
7.5
S. sciuri
S. pneumonia
P. vulgaris
K. pneumonia
S. sonnei
7.3
5.0
7.8
8.7
9.0
8.0
6.6
7.0
7.0
10.0
10.5
10.6
11.0
9.0
6.8
6.0
7.2
10.0
a
The concentration of compounds is 20 mg/mL. Bacillus subtilis (MTCC-441), Bacillus cereus (MTCC-430), Pseudomonas aeruginosa (MTCC-
424), Staphylococcus aureus (MTCC-3160) Staphylococcus sciuri, Streptococcus pneumonia, Proteus vulgaris (NCTC-8313) Klebsiella pneumonia
(ATCC-4352), and Shigella sonnei.
The conclusions made were just preliminarily, further studies on their synthesis and nonlinear optical (NLO)
properties are in progress.
Acknowledgments
The authors are thankful to DRDO, India for their financial support and also to the COSIST labs, School of
Chemistry, Andhra University for providing spectral data.
References
[1] S.N. Pandeya, D. Sriram, G. Nath, E. De Clercq, Il Farmaco 54 (1999) 624.
[2] A. Amal Raj, R. Raghunathan, M.R. SrideviKumari, N. Raman, Bioorg. Med. Chem. 11 (2003) 407.
[3] C.Q. Debra, A.K. Kathy, E.R. Kern, Antiviral Res. 71 (2006) 24.
[4] S.N. Pandeya, D. Sriram, G. Nath, E. De Clercq, Pharmac. Acta Helv. 74 (1999) 11.
[5] N. Karal, A. Gursoy, F. Kandemirli, et al. Bioorg. Med. Chem. 15 (2007) 5888.
[6] A. Gursoy, N. Karal, Eur. J. Med. Chem. 38 (2003) 633.
[7] S.K. Sridhar, A. Ramesh, Biol. Pharm. Bull. 24 (10) (2001) 1149.
[8] K. Singh, M. Verma, S.N. Pandeya, J.P. Stable, Acta Pharm. 54 (2004) 49.
[9] B.S. Holla, B.S. Rao, K. Shridhara, P.M. Akberali, Farmaco 55 (2000) 338.
[10] S.N. Pandeya, D. Sriram, G. Nath, E. De Clercq, Eur. J. Med. Chem. 35 (2000) 249.
[11] K. Niume, F. Toda, K. Uno, et al. J. Polym. Sci.: Polym. Chem. Ed. 21 (2) (2008) 615.
[12] Methyl-4-((4-chlorophenyl)(6H-indolo(2,3-b)quinoxalin-6-yl)methylamino)benzoate (2a): Yield 75%; mp: 270–273 8C; IR (KBr) vmax in
cmÀ1: 1125.96 (C–Cl), 3334.95 (N–H), 1584.05 (C N), 1616.84 (C 0); 1H NMR (DMSO-d6, 90 MHz): d 7.36–8.39 (Ar, H), 3.14 (s, 1H),
3.88 (s, 3H), 11.92 (s, 1H); 13C NMR (DMSO-d6, 90 MHz): d 42.29, 111.93, 118.95, 120.63, 122.15, 125.87, 127.40, 128.97, 131.22, 138.55,
140.11, 143.96, 145.82, 161.63, EI-MS (m/z) 492. Methyl-4((4-bromo phenyl)(6H-indolo(2,3b)quinoxalin-6-yl)methyl amino) benzoate
(2b): Yield 72%; mp: 283–287 8C; IR (KBr) vmax in cmÀ1: 1472.23 (C–Br), 3120.36 (N–H), 1680.37 (C N), 1726.56 (C O); 1H NMR
(DMSO-d6, 90 MHz): d 7.42–8.38 (Ar, H), 3.08 (s, 1H), 3.82 (s, 3H), 11.93 (s, 1H); 13C NMR (DMSO, 90 MHz): d 51.37, 72.84, 114.92,
119.56, 125.71, 128.39, 130.68, 131.18, 131.02, 137.82, 143.23, 144.52, 154.26, 166.45. Methyl-4((4-nitrophenyl)(6H-indolo(2,3b)qui-
noxalin-6-yl)methylamino) benzoate (2c): Yield 70%; mp: 272–275 8C; IR (KBr) vmax in cmÀ1: 1520.52 (C–N), 3252.27 (N–H), 1684.26
(C N), 1732.12 (C O); 1H NMR (DMSO-d6, 90 MHz): d 7.46–8.28 (Ar, H), 3.12 (s, 1H), 3.72 (s, 3H), 11.90 (s, 1H); 13C NMR (DMSO-d6,
90 MHz): d 52.46, 75.32, 114.84, 119.45, 120.98, 130.02, 131.18, 132.12, 135.54, 140.50, 143.53, 142.13, 147.32, 152.11, 167.34. Methyl-4-
((4-hydoxyphenyl)(6H-indolo(2,3-b)quinoxalin-6-yl)methylamino)benzoate (2d): Yield 72%; mp: 279–282 8C; IR (KBr) vmax in cmÀ1
:
3334.95 (N–H), 1584.05 (C N), 1616.84 (C 0); 1H NMR (DMSO-d6, 90 MHz): d 7.36–8.38 (Ar, H), 3.12 (s, 1H), 3.83 (s, 3H), 11.92 (s,
1H); 13C NMR (DMSO-d6, 90 MHz): d 36.70, 42.35, 111.72, 118.97, 120.61, 122.15, 125.84, 128.63, 131.20, 138.57, 140.12, 143.98,
145.83, 160.45, EI-MS (m/z) 518. Methyl-4((4-hydoxy,3-methoxy phenyl)(6H-indolo-(2,3b)quinoxalin-6-yl)methylamino)benzoate (2e):
Yield 77%; mp: 283–285 8C; IR (KBr) vmax in cmÀ1: 1192.02 (C–O), 3134.83 (O–H), 1576.34 (C N), 1635.65 (C O); 1H NMR (DMSO-d6,
90 MHz): d 7.28–8.39 (Ar, H), 3.05 (s, 1H), 3.84 (s, 3H), 4.12 (s, 1H), 11.99 (s, 1H); 13C NMR (DMSO-d6, 90 MHz): d 36.70, 42.30, 111.85,
120.54, 122.07, 125.78, 127.35, 128.56, 128.91, 131.12, 138.50, 140.04, 143.90, 162.03, EI-MS (m/z) 504. Methyl-4((3,4dimethoxy(6H-
indolo(2,3b)quinoxalin-6-yl)methylamino)benzoate (2f): Yield 69%; mp: 267–269 8C; IR (KBr) vmax in cmÀ1: 3123.26 (N–H), 1684.35
(C N), 1717.62 (C O); 1H NMR (DMSO-d6, 90 MHz): d 7.35–8.38(Ar, H), 3.16 (s, 1H), 3.77 (s, 3H), 11.97 (s, 1H); 13C NMR (DMSO-d6,
90 MHz): d 42.29, 111.87, 118.90, 120.56, 122.09, 125.79, 127.35, 128.56, 128.92, 131.15, 138.52, 140.06, 143.06, 143.91, 145.77, 161.25,

570
Y.L.N. Murthy et al. / Chinese Chemical Letters 22 (2011) 567–570
EI-MS (m/z) 548. Methyl-4((2,4,6-dimethoxyquinoxalin-6-yl)methylamino)benzoate (2g): Yield 75%; mp: 273–276 8C; IR (KBr) vmax in
cmÀ1: 3735 (O–H), 3170.03 (N–H), 1558.50 (C N), 1616.84 (C O); 1H NMR (DMSO-d6, 90 MHz): d 7.308.34(Ar, H), 2.94 (s, 1H), 3.40
(s, 3H), 3.52 (s, H), 11.95(s, 2H); 13C NMR (DMSO-d6, 90 MHz): d 42.32, 111.90, 118.92, 120.59, 122.10, 124.76, 125.82, 127.37, 128.60,
128.94, 131.19, 138.53, 140.06, 143.93, 145.78, 162.28, EI-MS (m/z) 474.
[13] Elemental analysis: calculated (Found) C, H, N; 70.66 (70.61), 4.29 (4.33), 11.37 (11.39), (2a); 64.81 (64.78), 3.94 (3.90), 10.43 (10.39), (2b);
69.18 (69.14), 4.20 (4.16), 13.91 (13.88), (2c); 73.40 (73.37), 4.67 (4.61), 11.81 (11.81) (2d), 71.42 (71.47), 4.79 (4.82), 11.10 (11.14), (2e);
71.80 (71.84), 5.05 (5.11), 10.80 (10.78), (2f); 70.06 (70.12), 5.14 (5.13), 10.21 (10.24), (2 g).