synthesis and antioxidant activity of amidomethane sulfonyl-linked bis heterocycles

ORIGINAL RESEARCH

Synthesis and antioxidant activity of amidomethanesulfonyl-linked bis heterocycles

Bhanu Prakash Talapuru • Lavanya Gopala •

Padmaja Adivireddy • Padmavathi Venkatapuram

Received: 20 September 2013 / Accepted: 22 April 2014

� Springer Science+Business Media New York 2014

Abstract A variety of amidomethane sulfonyl-linked

pyrrolyl oxazoles/thiazoles/imidazoles were prepared from

arylsulfonylethenesulfonyl oxazolyl/thiazolyl/imidazolyl

acetamides and tested for antioxidant activity. The E-(2-(p-

methylphenyl)lsulfonylethenesulfonyl)-N-(4-(p-methylphenyl)

oxazol-2-yl)acetamide (5b) exhibited excellent antioxidant

activity greater than the standard Ascorbic acid.

Keywords Pyrrolyl oxazole/thiazole/imidazole �HATU � DIPEA � Antioxidant activity

Introduction

Polyfunctionalized heterocyclic compounds, particularly

nitrogen-containing heterocycles, have gained importance

in the structural identification of biological macromole-

cules and in the discovery of drugs (Mitchison, 1994; Hung

et al., 1996; Bemis and Murcko, 1996; Nefzi et al., 1997;

Schreiber, 1998; Hinterding et al., 1998; Laet et al., 2000;

Ertl et al., 2006). The azole moiety is a fundamental ring

system for both synthetic and medicinal chemists because

of its presence in a wide range of natural products (Wipf,

1995; Lewis, 2000; Yeh, 2004; Riego et al., 2005; Jin,

2006, 2009) and its pivotal role as synthetic intermediates

(Vedejs and Barda, 2000; Atkins and Vedejs, 2005; Zhang

and Ciufolini, 2009). Several complex natural products

containing oxazole ring such as Diazonamide A, Ulapua-

lide A, Hennoxazole A, Telomestatin, Leucamide A, and

Virginiamycin M1 display significant biological activities

as cytotoxic, antifungal, antibacterial, antitumor, and anti-

viral (Wipf, 1995; Bagley et al., 1998; Lewis, 2000; Yeh,

2004; Riego et al., 2005; Jin, 2006, 2009; Misra and Ila,

2010). Thiazole nucleus is also an integral part of all the

available penicillins which have revolutionized the therapy

of bacterial diseases (Oncu et al., 2004). Imidazole is the

main structure of some well-known components of human

organisms, viz., histidine, Vit-B12, a component of DNA

base structure and purines, histamine and biotin (Lombar-

dino and Wiseman, 1974). Some imidazole-based phar-

maceuticals are Cimetidine, Etomidate, Ketoconazole,

Eprosartan, Losartan, and Metronidazole (Kleeman et al.,

2001; Bellina et al., 2007; Sneyd, 2012; Bhattacharyya and

Bajpai, 2013). Apart from these, pyrrole core can be found

in many natural products such as Lamellarin, Ningalin,

Polycitone, Lukianol, Storniamide (Gupton, 2006), etc., as

well as in agrochemicals and pharmaceuticals. Thus, the

role of azole chemistry has become increasingly important

in designing new class of structural entities of pharmaco-

logical importance. In continuation of our interest to

develop bis heterocycles linked by different pharmaco-

phoric units (Muralikrishna et al., 2012; Reddy et al., 2013;

Basha et al., 2013), the present work has been taken up.

Results and discussion

Chemistry

The multifunctional synthetic intermediate E-arylsulfo-

nylethenesulfonylacetic acid (1) and azole amines, 4-a-

ryloxazol-2-amine (2), 4-arylthiazol-2-amine (3), and

B. P. Talapuru � L. Gopala � P. Adivireddy �P. Venkatapuram (&)

Department of Chemistry, Sri Venkateswara University,

Tirupati 517 502, Andhra Pradesh, India

e-mail: [email protected]

123

Med Chem Res

DOI 10.1007/s00044-014-1022-0

MEDICINALCHEMISTRYRESEARCH

4-aryl-1H-imidazol-2-amine (4) were prepared as per the

literature precedent (Little and Webber, 1994; Reddy

et al., 1999; Potewar et al., 2008; Padmavathi et al.,

2009). The reaction of 1 with 2 in the presence of O-(7-

azabenzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium hexa-

fluorophosphate (HATU), N,N-diisopropylethylamine

(DIPEA) in dimethylformamide (DMF) resulted in E-(2-

arylsulfonylethenesulfonyl)-N-(4-aryloxazol-2-yl)acetam-

ide (5). Similarly, the compounds E-(2-arylsulfonylethe-

nesulfonyl)-N-(4-arylthiazol-2-yl)acetamide (6) and E-(2-

arylsulfonylethene-sulfonyl)-N-(4-aryl-1H-imidazol-2-yl)acet-

amide (7) were prepared by the reaction of 1 with 3 and 4,

respectively (Scheme 1). The 1H NMR spectra of 5a, 6a,

and 7a displayed a singlet at d 4.31, 4.29, and 4.33 due

to methylene protons and a doublet at d 7.98, 7.96, and

8.01 ppm due to olefin proton HA, while the signal of other

olefin proton HB merged with aromatic protons. The coupling

constant value J = 14.6 Hz indicated that they possess trans

geometry. The olefin moiety present in 5, 6, and 7 was used to

develop pyrrole ring. The treatment of 5, 6, and 7 with to-

sylmethyl isocyanide in the presence of NaH and in a solvent

mixture of Et2O and DMSO (2:1) gave 2-(40-arylsulfonyl-10H-

pyrrol-30-ylsulfonyl)-N-(4-aryloxazol-2-yl)acetamide (8), 2-

(40-arylsulfonyl-10H-pyrrol-30-ylsulfonyl)-N-(4-arylthiazol-2-

yl)acetamide (9), and 2-(40-arylsulfonyl-10H-pyrrol-30-ylsulfo-

nyl)-N-(4-aryl-1H-imidazol-2-yl)acetamide (10) (Scheme 1).

In the 1H NMR spectra of these compounds, the absence of

doublets corresponding to olefin protons and the presence of

two singlets at d 6.76, 6.82 in 8a, at 6.75, 6.83 in 9a and at 6.82,

6.88 ppm in 10a due to C20–H and C50–H of pyrrole ring

confirmed their formation. The structures of all the

compounds were further established by IR, 13C NMR, and

elemental analysis.

Biological evaluation

Antioxidant activity

The compounds 5–10 were tested for antioxidant property by

2,2,-diphenyl-1-picrylhydrazyl (DPPH) (Cuendet et al., 1997;

Burits and Bucar, 2000), nitric oxide (NO) (Green et al., 1982;

Marcocci et al., 1994), and hydrogen peroxide (H2O2) (Ruch

et al., 1989) methods, and the results are shown in Tables 1, 2,

and 3 and Figs. 1, 2, and 3. The data revealed that the

unsaturated compounds E-(2-arylsulfonylethenesulfonyl)-N-

(4-aryloxazol-2-yl)acetamide (5), E-(2-arylsulfonylethene-

sulfonyl)-N-(4-arylthiazol-2-yl)acetamide (6), and E-(2-aryl-

sulfonylethenesulfonyl)-N-(4-aryl-1H-imidazol-2-yl)acetam-

ide (7) displayed higher antioxidant activity than the

corresponding bis heterocycles 2-(40-arylsulfonyl-10H-pyrrol-

30-ylsulfonyl)-N-(4-aryloxazol-2-yl)acetamide (8), 2-(40-aryl-

sulfonyl-10H-pyrrol-30-ylsulfonyl)-N-(4-arylthiazol-2-yl)acet-

amide (9) and 2-(40-aryl-sulfonyl-10H-pyrrol-30-ylsulfonyl)-

N-(4-aryl-1H-imidazol-2-yl)acetamide (10). This may be

due to effective conjugation in unsaturated systems (5–7). In

fact, the compound E-(2-(p-methyl-phenyl)sulfonylethenesulfo-

nyl)-N-(4-(p-methylphenyl)oxazol-2-yl)acetamide (5b)

exhibited excellent radical scavenging activity greater than

the standard Ascorbic acid. Amongst bis heterocycles,

pyrrolyl oxazoles (8) showed greater activity than pyrrolyl

thiazoles (9) and pyrrolyl imidazoles (10). However,

X

N

SOO

SO O

NH

O

R

R

SOO

SO O

O

OH

R

X

N

NH2

R

X

N

SOO

SOO

NH

NH

O

R

R

+

5 / 6 / 7

8 / 9 / 10

i

ii(i) HATU / DIPEA / DMF(ii) TosMIC / NaH / DMSO / Et2O

2 / 5 / 8 X = O3 / 6 / 9 X = S4 / 7 / 10 X = NH

2 / 3 / 41

1'2'3'4'

5'

123 4

5a: R =H,b: R =Me,c: R = Cl,

1''2''3''

4''5''

6''

1'''2'''3'''4'''

5'''6'''

Scheme 1 Synthesis of amidomethane sulfonyl linked heterocycles

Med Chem Res

123

Table 1 The in vitro antioxidant activity of 5–10 in DPPH method

Compound Concentration IC50 (lmol/ml)

50 (lg/ml) 100 (lg/ml) 150 (lg/ml) 200 (lg/ml)

5a 69.63 ± 0.14 73.38 ± 0.11 75.15 ± 0.09 77.56 ± 0.05 0.058 ± 1.09

5b 76.75 ± 0.10 79.16 ± 0.08 80.28 ± 0.06 84.83 ± 0.03 0.054 ± 0.87

5c 44.82 ± 0.34 46.78 ± 0.28 49.71 ± 0.25 51.54 ± 0.23 0.049 ± 0.72

6a 50.16 ± 0.25 53.53 ± 0.21 56.26 ± 0.18 58.48 ± 0.16 0.056 ± 0.61

6b 62.26 ± 0.19 65.42 ± 0.16 68.12 ± 0.12 70.45 ± 0.09 0.052 ± 0.92

6c 31.46 ± 0.39 32.56 ± 0.34 35.85 ± 0.31 37.78 ± 0.26 0.051 ± 1.15

7a – – – –

7b 39.63 ± 0.42 41.34 ± 0.38 43.38 ± 0.35 46.94 ± 0.29 0.057 ± 0.96

7c – – – – –

8a 59.13 ± 0.23 63.24 ± 0.19 65.04 ± 0.15 67.57 ± 0.10 0.053 ± 0.85

8b 64.07 ± 0.18 68.73 ± 0.13 69.27 ± 0.11 72.39 ± 0.06 0.050 ± 0.78

8c 32.11 ± 0.38 34.69 ± 0.32 36.04 ± 0.29 38.85 ± 0.25 0.046 ± 0.53

9a 47.40 ± 0.27 49.64 ± 0.23 51.43 ± 0.21 52.96 ± 0.19 0.051 ± 0.87

9b 55.21 ± 0.24 57.60 ± 0.20 61.51 ± 0.16 63.74 ± 0.12 0.048 ± 0.52

9c 27.93 ± 0.41 29.55 ± 0.41 31.52 ± 0.39 33.28 ± 0.32 0.045 ± 1.23

10a – – – – –

10b 26.54 ± 0.45 29.13 ± 0.36 30.61 ± 0.33 32.02 ± 0.28 0.050 ± 0.82

10c – – – – –

Ascorbic acid 63.45 ± 0.17 66.62 ± 0.15 68.89 ± 0.10 71.23 ± 0.07 0.049 ± 1.12

Blank – – – – –

Values were the means of three replicates ±SD

(–) Showed no scavenging activity

Table 2 The in vitro antioxidant activity of 5–10 in nitric oxide method

Compound Concentration


5a 75.46 ± 0.11 79.62 ± 0.08 82.25 ± 0.09 85.51 ± 0.04

5b 80.13 ± 0.09 83.06 ± 0.05 86.81 ± 0.03 89.17 ± 0.02

5c 49.32 ± 0.25 52.76 ± 0.22 57.26 ± 0.19 58.34 ± 0.19

6a 54.52 ± 0.23 58.21 ± 0.19 62.85 ± 0.16 67.81 ± 0.14

6b 67.37 ± 0.15 71.45 ± 0.12 75.14 ± 0.10 79.28 ± 0.08

6c 36.15 ± 0.28 39.58 ± 0.28 43.58 ± 0.25 45.16 ± 0.25

7a – – – –

7b 43.37 ± 0.27 47.41 ± 0.25 50.73 ± 0.21 54.42 ± 0.21

7c – – – –

8a 64.04 ± 0.18 69.30 ± 0.14 71.45 ± 0.12 76.63 ± 0.10

8b 72.84 ± 0.13 76.03 ± 0.11 78.79 ± 0.06 81.89 ± 0.06

8c 38.43 ± 0.29 41.37 ± 0.26 46.76 ± 0.23 48.55 ± 0.23

9a 51.91 ± 0.24 55.68 ± 0.20 59.02 ± 0.18 63.72 ± 0.17

9b 59.58 ± 0.20 65.76 ± 0.16 68.38 ± 0.14 72.76 ± 0.13

9c 31.71 ± 0.26 34.42 ± 0.30 38.87 ± 0.26 41.41 ± 0.26

10a – – – –

10b 29.30 ± 0.34 32.67 ± 0.29 35.91 ± 0.28 39.69 ± 0.28

10c – – – –

Ascorbic acid 69.52 ± 0.14 74.75 ± 0.11 76.29 ± 0.08 80.31 ± 0.09

Blank – – – –



Med Chem Res

123

Table 3 The in vitro antioxidant activity of 5–10 in H2O2 method

Compound Concentration


5a 71.76 ± 0.10 75.08 ± 0.11 77.26 ± 0.03 83.61 ± 0.05

5b 78.18 ± 0.08 81.54 ± 0.07 83.61 ± 0.05 87.56 ± 0.03

5c 46.83 ± 0.30 48.24 ± 0.23 53.45 ± 0.23 58.67 ± 0.19

6a 52.34 ± 0.23 56.69 ± 0.20 60.92 ± 0.18 65.40 ± 0.15

6b 64.63 ± 0.16 68.38 ± 0.14 71.62 ± 0.12 76.67 ± 0.09

6c 32.43 ± 0.37 35.36 ± 0.31 40.04 ± 0.27 45.62 ± 0.29

7a – – – –

7b 40.80 ± 0.32 43.02 ± 0.28 48.06 ± 0.24 52.96 ± 0.16

7c – – – –

8a 61.71 ± 0.19 65.71 ± 0.15 69.27 ± 0.15 72.02 ± 0.11

8b 69.29 ± 0.12 73.65 ± 0.09 74.38 ± 0.09 79.45 ± 0.07

8c 34.51 ± 0.34 37.21 ± 0.29 44.15 ± 0.26 47.81 ± 0.27

9a 49.85 ± 0.22 52.12 ± 0.21 57.18 ± 0.19 61.52 ± 0.18

9b 57.78 ± 0.21 60.57 ± 0.17 64.51 ± 0.17 68.15 ± 0.12

9c 28.09 ± 0.38 32.19 ± 0.30 36.82 ± 0.28 41.05 ± 0.30

10a – – – –

10b 27.63 ± 0.48 30.13 ± 0.40 33.74 ± 0.36 36.41 ± 0.32

10c – – – –

Ascorbic acid 66.96 ± 0.15 70.25 ± 0.10 72.71 ± 0.12 77.57 ± 0.08

Blank – – – –



Fig. 1 The in vitro antioxidant

activity of 5–10 in DPPH

method

Med Chem Res

123

compounds 9 showed good activity than the compounds 10.

Among imidazole containing compounds, the compound 7b

displayed higher activity than the compound 10b, which

exemplified that the presence of effective conjugation

increases the activity. The presence of electron-donating

methyl substituent on the aromatic ring enhanced the activity.

Conclusion

A variety of amidomethane sulfonyl-linked pyrrolyl oxa-

zoles/thiazoles/imidazoles were prepared from arylsulfo-

nylethenesulfonyl oxazolyl/thiazolyl/imidazolyl acetamides

and tested for antioxidant activity. The arylsulfonylethene-

sulfonyl heterocycles exhibited higher antioxidant activity

than the respective bis heterocycles. In fact, the E-(2-(p-

methylphenyl)sulfonylethene-sulfonyl)-N-(4-(p-methyl-

phenyl)oxazol-2-yl)acetamide (5b) exhibited excellent anti-

oxidant activity greater than the standard Ascorbic acid.

Experimental protocols

Melting points were determined in open capillaries on a

Mel-Temp apparatus and are uncorrected. The purity of

the compounds was checked by TLC (silica gel H, BDH,

ethyl acetate/hexane, 1:3). The IR spectra were recorded

on a Thermo Nicolet IR 200 FT-IR spectrometer as KBr

pellets, and the wave numbers were given in cm-1. The1H NMR spectra were recorded in DMSO-d6 on a

Bruker-400 spectrometer (400 MHz). The 13C NMR

spectra were recorded in DMSO-d6 on a Bruker spec-

trometer operating at 100 MHz. All chemical shifts are

reported in d (ppm) using TMS as an internal standard.

The mass spectra were recorded on Jeol JMS-D 300 and

Finnigan Mat 1210 B at 70 eV with an emission current

of 100 lA. The microanalyses were performed on a

Perkin-Elmer 240C elemental analyzer. The antioxidant

property was carried out by using Shimadzu UV-2450

spectrophotometer.


activity of 5–10 in nitric oxide

method


activity of 5–10 in H2O2 method

Med Chem Res

123

General procedure for the synthesis of E-(2-

arylsulfonylethenesulfonyl)-N-(4-aryloxazol-2-

yl)acetamide (5a–c)/E-(2-arylsulfonylethenesulfonyl)-

N-(4-arylthiazol-2-yl)acetamide (6a–c)/E-(2-

arylsulfonylethenesulfonyl)-N-(4-aryl-1H-imidazol-2-

yl)acetamide (7a–c)

The compound E-arylsulfonylethenesulfonylacetic acid

(1) (10 mmol) was dissolved in 3 ml of DMF. To this

HATU (20 mmol) was added and stirred at room tem-

perature for 15–20 min. Then, DIPEA (20 mmol) fol-

lowed by the compound 2/3/4 (10 mmol) were added and

continued stirring at ambient temperature for 19–22 h.

The reaction mixture was poured onto ice-water, filtered

the separated solid and dried. It was recrystallized from

2-propanol.

E-(2-Phenylsulfonylethenesulfonyl)-N-(4-phenyloxazol-2-

yl)acetamide 5a

Mp 145–147 �C; yield 65 %; IR (KBr) tmax: 3329, 1683,

1634, 1579, 1330, 1132 cm-1; 1H NMR (DMSO-d6,

400 MHz): d = 7.98 (1H, d, J = 14.3 Hz, HA), 7.92 (1H,

bs, CO–NH), 7.21–7.78 (12H, m, HB, Ar–H & C5–H), 4.31

(2H, s, SO2–CH2); 13C NMR (DMSO-d6, 100 MHz,):

d = 172.4 (C, C=O), 149.6 (C, C-2), 145.8 (C, C–HA),

139.0 (C, C-4), 135.8 (CH, C-5), 124.8 (C, C–HB), 56.6

(CH, CH2), 135.9 (C, C-100), 135.2 (CH, C-400), 132.6 (C,

C-1000), 131.4 (CH, C-300, C-500), 130.1 (CH, C-3000, C-5000),128.6 (CH, C-4000), 127.3 (CH, C-200, C-600), 126.8 (CH,

C-2000, C-6000); MS m/z: 432.48 [M?�]; Anal. Calcd. for

C19H16N2O6S2: C, 52.76; H, 3.72; N, 6.47. Found: C,

52.65; H, 3.65; N, 6.56.

E-(2-(p-Methylphenyl)sulfonylethenesulfonyl)-N-(4-(p-

methylphenyl)oxazol-2-yl)acetamide 5b


1632, 1575, 1325, 1128 cm-1; 1H NMR (DMSO-d6,

400 MHz): d = 7.95 (1H, d, J = 14.2 Hz, HA), 7.94 (1H,


(2H, s, SO2–CH2), 2.30 & 2.28 (6H, s, Ar–CH3); 13C NMR

(DMSO-d6, 100 MHz): d = 172.0 (C, C=O), 150.3 (C,

C-2), 145.2 (CH, C–HA), 138.5 (C, C-4), 136.5 (CH, C-5),

124.9 (CH, C–HB), 56.3 (CH, CH2), 22.2 & 21.8 (Ar–

CH3), 134.6 (C, C-100), 131.8 (CH, C-400), 130.9 (C, C-1000),130.4 (CH, C-300, C-500), 129.2 (CH, C-3000, C-5000), 127.8

(CH, C-4000), 127.0 (CH, C-200, C-600), 126.4 (CH, C-2000,C-6000); MS m/z: 460.53 [M?�]. Anal. Calcd. for

C21H20N2O6S2: C, 54.76; H, 3.77; N, 6.08. Found: C,

54.63; H, 4.30; N, 6.00.

E-(2-(p-Chlorophenyl)sulfonylethenesulfonyl)-N-(4-(p-

chlorophenyl)oxazol-2-yl)acetamide 5c


1638, 1580, 1334, 1137 cm-1; 1H NMR (DMSO-d6,

400 MHz): d = 7.99 (1H, d, J = 14.6 Hz, HA), 7.95 (1H,


(2H, m, SO2–CH2); 13C NMR (DMSO-d6, 100 MHz):

d = 172.9 (C, C=O), 150.9 (C, C-2), 146.3 (CH, C–HA),

139.4 (C, C-4), 135.2 (CH, C-5), 125.1 (CH, C–HB), 57.8

(CH, CH2), 136.5 (C, C-100), 134.6 (CH, C-400), 132.2 (C,


C-2000, C-6000); MS m/z: 501.37 [M?�]. Anal. Calcd. for

C19H14Cl2N2O6S2: C, 45.51; H, 2.81; N, 5.58. Found: C,

45.58; H, 2.84; N, 5.65.

E-(2-Phenylsulfonylethenesulfonyl)-N-(4-phenylthiazol-2-

yl)acetamide 6a


1631, 1574, 1328, 1130 cm-1; 1H (DMSO-d6, 400 MHz):

d = 7.96 (1H, d, HA, J = 14.2 Hz), 7.88 (1H, bs, CO–

NH), 7.15–7.70 (11H, m, HB & Ar–H), 6.40 (1H, s, C5–H),

4.29 (2H, s, SO2–CH2); 13C NMR (DMSO-d6, 100 MHz):

d = 172.2 (C, C=O), 156.2 (C, C-2), 145.5 (CH, C–HA),

138.2 (C, C-4), 124.2 (CH, C–HB), 123.2 (CH, C-5), 56.4

(CH, CH2), 134.9 (C, C-100), 134.2 (CH, C-400), 133.2 (C,



C19H16N2O5S3: C, 50.87; H, 3.59; N, 6.24. Found: C,

50.78; H, 3.53; N, 6.12.


methylphenyl)thiazol-2-yl)acetamide 6b


1628, 1572, 1322, 1125 cm-1; 1H NMR (DMSO-d6,

400 MHz): d = 7.93 (1H, d, J = 14.1 Hz, HA), 7.87 (1H,

bs, CO–NH), 7.12–763 (9H, m, HB & Ar–H), 6.35 (1H, s,

C5–H), 4.30 (2H, s, SO2–CH2), 2.28 & 2.24 (6H, s, Ar–

CH3); 13C NMR (DMSO-d6, 100 MHz): d = 171.6 (C,

C=O), 156.0 (C, C-2), 145.2 (CH, C–HA), 137.9 (C, C-4),

124.7 (CH, C–HB), 124.1 (CH, C-5), 55.2 (CH, CH2), 21.8

& 21.6 (Ar–CH3), 134.1 (C, C-100), 133.8 (CH, C-400), 132.6

(C, C-1000), 131.2 (CH, C-300, C-500), 129.2 (CH, C-3000,C-5000), 128.8 (CH, C-4000), 127.4 (CH, C-200, C-600), 125.8

(CH, C-2000, C-6000); MS m/z: 476.60 [M?�]. Anal. Calcd. for

C21H20N2O5S3: C, 52.92; H, 4.22; N, 5.87. Found: C,

53.02; H, 4.27; N, 5.93.

Med Chem Res

123


chlorophenyl)thiazol-2-yl)acetamide 6c


1633, 1577, 1330, 1133 cm-1; 1H NMR (DMSO-d6,

400 MHz): d = 8.00 (1H, d, J = 14.4 Hz, HA), 7.94 (1H,

bs, CO–NH), 7.20–7.82 (9H, m, HB, Ar–H), 6.38 (1H, m,

C5–H), 4.32 (2H, s, SO2–CH2); 13C NMR (DMSO-d6,

100 MHz): d = 172.7 (C=O), 157.4 (C, C-2), 145.9 (CH,

C–HA), 138.6 (C, C-4), 124.8 (C, C–HB), 123.5 (CH, C-5),

56.9 (CH, CH2), 135.9 (C, C-100), 135.2 (CH, C-400), 132.8

(C, C-1000), 131.2 (CH, C-300, C-500), 130.2 (CH, C-3000,C-5000), 128.7 (CH, C-4000), 127.8 (CH, C-200, C-600), 126.8

(CH, C-2000, C-6000); MS m/z: 489.43 [[M?�]. Anal. Calcd.

for C19H14Cl2N2O5S3: C, 46.62; H, 2.88; N, 5.72. Found:

C, 46.55; H, 2.93; N, 5.79.

E-(2-Phenylsulfonylethenesulfonyl)-N-(4-phenyl-1H-

imidazol-2-yl)acetamide 7a


1640, 1583, 1335, 1138 cm-1; 1H NMR (DMSO-d6,

400 MHz): d = 12.34 (1H, bs, C5–NH), 8.01 (1H, d,

J = 14.5 Hz, HA), 7.95 (1H, bs, CO–NH), 7.23–7.85 (12H,

m, HB, Ar–H & C5–H), 4.33 (2H, s, SO2–CH2); 13C NMR

(DMSO-d6, 100 MHz): d = 172.6 (C=O), 146.2 (CH, C–

HA), 139.8 (C, C-4), 137.2 (C, C-2), 135.2 (CH, C-5),

124.9 (CH, C–HB), 57.0 (CH, CH2), 134.8 (C, C-100), 133.2

(CH, C-400), 132.2 (C, C-1000), 131.0 (CH, C-300, C-500),130.6 (CH, C-3000, C-5000), 129.2 (CH, C-4000), 128.1 (CH,

C-200, C-600), 127.8 (CH, C-2000, C-6000); MS m/z: 431.49

[M?�]. Anal. Calcd. for C19H17N3O5S2: C, 52.88; H, 3.96;

N, 9.73. Found: C, 52.96; H, 4.02; N, 9.80.


methylphenyl)-1H-imidazol-2-yl)-acetamide 7b

Mp 170-172 �C; yield 65 %; IR (KBr) tmax: 3327, 1677,

1636, 1578, 1331, 1133 cm-1; 1H NMR (DMSO-d6,

400 MHz): d = 12.28 (1H, bs, C5–NH), 7.97 (1H, d,

J = 14.2 Hz, HA), 7.93 (1H, bs, CO–NH), 7.18–7.78 (10H,

m, HB, Ar–H & C5–H), 4.29 (2H, s, SO2–CH2), 2.29 &

2.26 (6H, s, Ar–CH3); 13C NMR (DMSO-d6, 100 MHz):

d = 172.2 (C, C=O), 147.0 (CH, C–HA), 139.2 (C, C-4),

136.8 (C, C-2), 134.8 (CH, C-5), 123.4 (CH, C–HB), 56.8

(CH, CH2), 22.3 & 22.0 (Ar–CH3), 134.2 (C, C-100), 133.8


C-200, C-600), 127.2 (CH, C-2000, C-6000); MS m/z: 459.55


N, 9.14. Found: C, 54.77; H, 4.57; N, 9.19.


chlorophenyl)-1H-imidazol-2-yl)-acetamide 7c


1644, 1588, 1340, 1142 cm-1; 1H NMR (DMSO-d6,

400 MHz): d = 12.38 (1H, bs, C5–NH), 8.00 (1H, d,

J = 14.7 Hz, HA), 7.98 (1H, bs, CO–NH), 7.26–7.88 (10H,

m, HB, Ar–H & C5–H), 4.34 (2H, s, SO2–CH2); 13C NMR

(DMSO-d6, 100 MHz): d = 173.8 (C, C=O), 146.6 (CH,

C–HA), 140.9 (C, C-4), 137.8 (C, C-2), 135.8 (CH, C-5),

125.4 (CH, C–HB), 57.1 (CH, CH2), 135.2 (C, C-100), 133.3


C-200, C-600), 128.2 (CH, C-2000, C-6000); MS m/z: 500.39

[M?�]. Anal. Calcd. for C19H15Cl2N3O5S2: C, 45.60; H,

3.02; N, 8.39.; Found: C, 45.68; H, 3.07; N, 8.30.

General procedure for the synthesis of 2-(40-arylsulfonyl-10H-pyrrol-30-ylsulfonyl)-N-(4-aryloxazol-

2-yl)acetamide (8a–c)/2-(40-arylsulfonyl-10H-pyrrol-30-ylsulfonyl)-N-(4-aryl-thiazol-2-yl)acetamide (9a–c)/2-

(40-arylsulfonyl-10H-pyrrol-30-ylsulfonyl)-N-(4-aryl-

1H-imidazol-2-yl)acetamide (10a–c)

A mixture of tosylmethyl isocyanide (1 mmol) and 5/6/7

(1 mmol) in diethyl ether–DMSO (2:1) was added drop

wise to a stirred slurry of sodium hydride (0.05 g) in dry

diethyl ether (10 ml) at room temperature, and stirring

was continued for 12–14 h. Then, it was diluted with

water and extracted with ether. The ethereal layer was

dried over an Na2SO4, and the solvent was removed under

reduced pressure. The resultant solid was purified by

passing through a column of silica gel (hexane–ethyl

acetate 3:1).

2-(40-Phenylsulfonyl-10H-pyrrol-30-ylsulfonyl)-N-(4-

phenyloxazol-2-yl)acetamide 8a


1639, 1584, 1333, 1136 cm-1; 1H NMR (DMSO-d6,

400 MHz): d = 9.78 (1H, bs, C20–NH), 7.96 (1H, bs, CO–

NH), 7.16–7.90 (11H, m, Ar–H & C5–H), 6.82 (1H, s, C50–

H), 6.76 (1H, s, C20–H), 4.35 (2H, s, SO2–CH2); 13C NMR

(DMSO-d6, 100 MHz): d = 172.6 (C, C=O), 149.9 (C,

C-2), 139.0 (C, C-4), 136.8 (CH, C-5), 133.8 (C, C-40),127.2 (CH, C-20), 121.2 (CH, C-50), 116.4 (C, C-30), 57.2

(CH, CH2), 135.8 (C, C-100), 134.8 (CH, C-400), 132.2 (CH,

C-300, C-500), 130.6 (CH, C-3000, C-5000), 129.2 (CH, C-4000),127.9 (CH, C-200, C-600), 127.0 (CH, C-2000, C-6000); MS m/z:

471.51 [M?�]. Anal. Calcd. for C21H17N3O6S2: C, 53.49;

H, 3.63; N, 8.91. Found: C, 53.58; H, 3.60; N, 8.97.

Med Chem Res

123

2-(40-(p-Methylphenyl)sulfonyl-10H-pyrrol-30-ylsulfonyl)-

N-(4-(p-methylphenyl)oxazol-2-yl)-acetamide 8b


1635, 1579, 1329, 1131 cm-1; 1H NMR (DMSO-d6,


NH), 7.12–7.82 (9H, m, Ar–H & C5–H), 6.84 (1H, s, C50–H),

6.74 (1H, s, C20–H), 4.38 (2H, s, SO2–CH2), 2.28 & 2.26 (6H,

s, Ar–CH3); 13C NMR (DMSO-d6, 100 MHz): d = 172.2

(C, C=O), 149.8 (C, C-2), 138.6 (C, C-4), 136.2 (CH, C-5),

133.4 (C, C-40), 126.8 (CH, C-20), 120.8 (CH, C-50), 116.0

(C, C-30), 57.8 (CH, CH2), 22.3 & 21.9 (Ar–CH3), 134.9 (C,

C-100), 134.5 (CH, C-400), 132.7 (C, C-1000), 131.3 (CH, C-300,C-500), 130.2 (CH, C-3000, C-5000), 129.9 (CH, C-4000), 128.4

(CH, C-200, C-600), 127.0 (CH, C-2000, C-6000); MS m/z: 499.57

[M?�]. Anal. Calcd. for C23H21N3O6S2: C, 55.29; H, 4.23; N,

8.41. Found: C, 55.37; H, 4.28; N, 8.49.

2-(40-(p-Chlorophenyl)sulfonyl-10H-pyrrol-30-ylsulfonyl)-

N-(4-(p-chlorophenyl)oxazol-2-yl)-acetamide 8c


1642, 1587, 1338, 1140 cm-1; 1H NMR (DMSO-d6,


NH), 7.24–7.92 (9H, m, Ar–H & C5–H), 6.85 (1H, s, C50–


(DMSO-d6, 100 MHz): d = 173.8 (C, C=O), 150.3 (C,


(CH, CH2), 136.3 (C, C-100), 135.2 (CH, C-400), 134.8 (C,




46.55; H, 2.73; N, 7.82.


phenylthiazol-2-yl)acetamide 9a


1637, 1577, 1332, 1135 cm-1; 1H NMR (DMSO-d6,


NH), 7.18–7.80 (11H, m, Ar–H & C5–H), 6.83 (1H, s, C50–


(DMSO-d6, 100 MHz): d = 172.1 (C, C=O), 157.8 (C,

C-2), 144.2 (C, C-4), 133.2 (C, C-40), 127.0 (CH, C-20),122.6 (CH, C-5), 120.6 (CH, C-50), 116.3 (C, C-30), 56.7

(CH, CH2), 134.3 (C, C-100), 133.7 (CH, C-400), 132.4 (C,



C21H17N3O5S3: C, 51.73; H, 3.51; N, 8.61. Found: C,

51.83; H, 3.56; N, 8.69.


N-(4-(p-methylphenyl)thiazol-2-yl)-acetamide 9b


1634, 1575, 1327, 1127 cm-1; 1H NMR (DMSO-d6,


NH), 7.12–7.78 (9H, m, Ar–H & C5–H), 6.85 (1H, s, C50–

H), 6.73 (1H, s, C20–H), 4.37 (2H, s, SO2–CH2), 2.27 &

2.24 (6H, s, Ar–CH3); 13C NMR (DMSO-d6, 100 MHz):

d = 171.8 (C, C=O), 157.2 (C, C-2), 144.0 (C, C-4), 132.8

(C, C-40), 126.4 (CH, C-20), 121.8 (CH, C-5), 120.8 (CH,

C-50), 56.3 (CH, CH2), 22.1 & 21.8 (Ar–CH3), 115.4 (C,

C-30), 134.2 (C, C-100), 131.5 (CH, C-400), 130.3 (C, C-1000),129.1 (CH, C-300, C-500), 128.3 (CH, C-3000, C-5000), 127.9

(CH, C-4000), 126.3 (CH, C-200, C-600), 125.8 (CH, C-2000,C-6000); MS m/z: 515.64 [M?�]. Anal. Calcd. for

C23H21N3O5S3: C, 53.57; H, 4.10; N, 8.14. Found: C,

53.48; H, 4.05; N, 8.07.


N-(4-(p-chlorophenyl)thiazol-2-yl)-acetamide 9c


1585, 1643, 1337, 1139 cm-1; 1H NMR (DMSO-d6,


NH), 7.22–7.84 (9H, m, Ar–H & C5–H), 6.84 (1H, s, C50–


(DMSO-d6, 100 MHz): d = 172.6 (C, C=O), 158.2 (C,

C-2), 144.8 (C, C-4), 132.6 (C, C-40), 127.3 (CH, C-20),122.9 (CH, C-5), 121.5 (CH, C-50), 116.6 (C, C-30), 57.9

(CH, CH2), 135.8 (C, C-100), 134.2 (CH, C-400), 133.6 (C,




45.46; H, 2.77; N, 7.62.


phenyl-1H-imidazol-2-yl)acetamide 10a

Mp 184–186 �C, yield 68 %; IR (KBr) tmax: 3341, 1687,

1589, 1646, 1339, 1144 cm-1; 1H NMR (DMSO-d6,

400 MHz): d = 12.48 (1H, bs, C5–NH), 9.80 (1H, bs, C20–

NH), 7.98 (1H, bs, CO–NH), 7.20–7.94 (11H, m, Ar–H &

C5–H), 6.88 (1H, s, C50–H), 6.82 (1H, s, C20–H), 4.42 (2H,

s, SO2–CH2); 13C NMR (DMSO-d6, 100 MHz): d = 172.8

(C, C=O), 143.8 (C, C-4), 138.2 (C, C-2), 135.2 (CH, C-5),

133.9 (C, C-40), 127.5 (CH, C-20), 121.6 (CH, C-50), 116.6

(C, C-30), 57.5 (CH, CH2), 134.9 (C, C-100), 134.6 (CH,

C-400), 133.2 (C, C-1000), 132.6 (CH, C-300, C-500), 131.7

(CH, C-3000, C-5000), 130.1 (CH, C-4000), 128.8 (CH, C-200,C-600), 128.1 (CH, C-2000, C-6000); MS m/z: 470.53 [M?�].

Med Chem Res

123

Anal. Calcd. for C21H18N4O5S2: C, 53.60; H, 3.85; N,

11.90. Found: C, 53.69; H, 3.90; N, 11.99.


N-(4-(p-methylphenyl)-1H-imidazol-2-yl)acetamide 10b


1641, 1583, 1336, 1137 cm-1; 1H NMR (DMSO-d6,

400 MHz): d = 12.42 (1H, bs, C5–NH), 9.76 (1H, bs, C20–

NH), 7.94 (1H, bs, CO–NH), 7.13–7.88 (9H, m, Ar–H &

C5–H), 6.86 (1H, m, C50–H), 6.79 (1H, s, C20–H), 4.41 (2H,

s, SO2–CH2), 2.30 & 2.28 (6H, s, Ar–CH3); 13C NMR

(DMSO-d6, 100 MHz): d = 173.4 (C, C=O), 137.8 (C,


(CH, CH2), 22.1 & 22.4 (Ar–CH3), 133.7 (C, C-100), 132.9


C-200, C-600), 127.4 (CH, C-2000, C-6000); MS m/z: 498.58


N, 11.23. Found: C, 55.47; H, 4.40; N, 11.15.


N-(4-(p-chlorophenyl)-1H-imidazol-2-yl)acetamide 10c


1652, 1596, 1346, 1147 cm-1; 1H NMR (DMSO-d6,

400 MHz): d = 12.49 (1H, bs, C5–NH), 9.82 (1H, bs, C20–

NH), 7.80 (1H, bs, CO–NH), 7.24–7.96 (9H, m, Ar–H &

C5–H), 6.92 (1H, s, C50–H), 6.84 (1H, s, C20–H), 4.45 (2H,

s, SO2–CH2); 13C NMR (DMSO-d6, 100 MHz): d = 173.2

(C, C=O), 144.4 (C, C-4), 138.8 (C, C-2), 136.8 (CH, C-5),

134.0 (C, C-40), 127.9 (CH, C-20), 122.4 (CH, C-50), 116.9

(C, C-30), 57.9 (CH, CH2), 135.2 (C, C-100), 134.8 (CH,

C-400), 134.0 (C, C-1000), 133.1 (CH, C-300, C-500), 132.5

(CH, C-3000, C-5000), 130.3 (CH, C-4000), 129.1 (CH, C-200,C-600), 128.6 (CH, C-2000, C-6000); MS m/z: 539.43 [M?�].

Anal. Calcd. for C21H16Cl2N4O5S2: C, 46.75; H, 2.99; N,

10.38. Found: C, 46.81; H, 3.05; N, 10.46.

Antioxidant activity

The compounds 5–10 were tested for antioxidant property

by DPPH, NO, and H2O2 methods.

DPPH radical scavenging activity

The hydrogen atom or electron donation ability of the

compounds was measured from the bleaching of the purple

colored methanol solution of 2,2,-diphenyl-1-picrylhy-

drazyl radical (DPPH). This property makes it suitable for

spectrophotometric studies. 1 ml of various concentrations

of the test compounds (50, 100, 150 and 200 lg/ml) in

methanol were added to 4 ml of 0.004 % (w/v) methanol

solution of DPPH. After a 30 min incubation period at

room temperature, the absorbance was read against blank at

517 nm. Ascorbic acid was used as the standard. The

percent of inhibition (I %) of free radical production from

DPPH was calculated by the following equation

I % ¼ Acontrol�Asample

� �=Ablank

� �� 100;

where Acontrol was the absorbance of the control reaction

(containing methanolic DPPH and Ascorbic acid), Asample

was the absorbance of the test compound (containing

methanolic DPPH and test compound), and Ablank was the

absorbance of the blank (containing only methanolic

DPPH). Tests were carried out in triplicate. The IC50 values

of all the tested compounds can be calculated in DPPH

method.

Nitric oxide (NO) scavenging activity

Nitric oxide scavenging activity was measured by slightly

modified methods of Green et al. 1982 and Marcocci et al.

1994. Nitric oxide radicals (NO) were generated from

sodium nitroprusside. 1 ml of sodium nitroprusside

(10 mm) and 1.5 ml of phosphate buffer saline (0.2 M, pH

7.4) were added to different concentrations (50, 100, 150,

and 200 lg/ml) of the test compounds and incubated for

150 min at 25 �C. After incubation 1 ml of the reaction

mixture was treated with 1 ml of Griess reagent (1 %

sulfanilamide, 2 % H3PO4 and 0.1 % naphthylethylene-

diamine dihydrochloride). The absorbance of the chro-

matophore was measured at 546 nm. Ascorbic acid was

used as standard. Nitric oxide scavenging activity was

calculated by the following equation

% of scavenging ¼ Acontrol�Asample

� �=Ablank

� �� 100;


(containing all reagents and Ascorbic acid), Asample was the

absorbance of the test compound (containing all reagents

and test compound), and Ablank was the absorbance of the

blank (containing only reagents). Tests were carried out in

triplicate.

Hydrogen peroxide (H2O2) scavenging activity

The H2O2 scavenging ability of the test compound was

determined according to the method of Ruch et al. 1989. A

solution of H2O2 (40 mm) was prepared in phosphate

buffer (pH 7.4). 50, 100, 150, and 200 lg/ml concentra-

tions of the test compounds in 3.4 ml phosphate buffer

were added to H2O2 solution (0.6 ml, 40 mm). The

absorbance value of the reaction mixture was recorded at

230 nm. The percent of scavenging of H2O2 was calculated

by the following equation

Med Chem Res

123

% of scavenging ¼ Acontrol�Asample

� �=Ablank

� �� 100;


(containing all reagents and Ascorbic acid), Asample was the

absorbance of the test compound (containing all reagents

and test compound), and Ablank was the absorbance of the

blank (containing only reagents). Tests were carried out in

triplicate.

Acknowledgments The authors, B. P. Talapuru and L. Gopala, are

thankful to University Grants Commission (UGC), New Delhi for the

sanction of UGC-BSR fellowship. The authors are grateful to Council

of Scientific and Industrial Research (CSIR), New Delhi for financial

assistance under major research project.

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synthesis and antioxidant activity of amidomethane sulfonyl-linked bis heterocycles

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