Synthesis and antioxidant activity of a new class of sulfone/sulfonamide-linked bis(oxadiazoles),...

ERRATUM

Erratum to: Synthesis and antioxidant activity of a new class

of sulfone/sulfonamide-linked bis(oxadiazoles), bis(thiadiazoles),

and bis(triazoles)

Adivireddy Padmaja • Devanaboina Pedamalakondaiah •

Gundala Sravya • Guda Mallikarjuna Reddy •

Malaka Venkateshwarulu Jyothi Kumar • Ch. Appa Rao

Published online: 22 November 2014

� Springer Science+Business Media New York 2014

Erratum to: Med Chem Res

DOI 10.1007/s00044-014-1277-5

In the original version of this article, Ch. Appa Rao is

included in the acknowledgements section. He should

instead be credited as the final author of the article. His

name is now included in the author group.

The online version of the original article can be found under

doi:10.1007/s00044-014-1277-5.

A. Padmaja (&) � D. Pedamalakondaiah � G. Sravya �

G. M. Reddy

Department of Chemistry, Sri Venkateswara University,

Tirupati 517502, Andhra Pradesh, India

e-mail: [email protected]

M. V. J. Kumar

Department of Biotechnology, Sri Venkateswara University,


Ch. Appa Rao

Department of Bio-Chemistry, Sri Venkateswara University,


123

Med Chem Res (2015) 24:2021

DOI 10.1007/s00044-014-1301-9

MEDICINALCHEMISTRYRESEARCH

http://dx.doi.org/10.1007/s00044-014-1277-5

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ORIGINAL RESEARCH

Synthesis and antioxidant activity of a new class of sulfone/

sulfonamide-linked bis(oxadiazoles), bis(thiadiazoles),

and bis(triazoles)

Adivireddy Padmaja • Devanaboina Pedamalakondaiah •

Gundala Sravya • Guda Mallikarjuna Reddy •

Malaka Venkateshwarulu Jyothi Kumar

Received: 17 June 2014 / Accepted: 28 September 2014

� Springer Science+Business Media New York 2014

Abstract A new class of sulfone/sulfonamide-linked

bis(oxadiazoles), bis(thiadiazoles), and bis(triazoles) were

prepared from the synthetic intermediates sulfonyldiacetic

acid, arylsulfonylacetic acid hydrazide, and aryl-

aminosulfonylacetic acid hydrazide adopting simple and

versatile synthetic methodologies. All the new compounds

were tested for their antioxidant activity. Amongst all the

tested compounds, methyl-substituted bis(oxadiazoles) (8b

and 11b) were found to be potential antioxidant agents. It

was also observed that sulfonamide-linked bis(oxadiaz-

oles), bis(thiadiazoles), and bis(triazoles) showed compar-

atively higher antioxidant activity than sulfone-linked

bis(oxadiazoles), bis(thiadiazoles), and bis(triazoles).

Keywords Oxadiazole � Thiadiazole � Triazole �

Thiourea � Hydrazine hydrate

Introduction

The five-membered nitrogen-containing heterocycles 1,3,4-

oxadiazoles, 1,3,4-thiadiazoles, and 1,2,4-triazoles have

gained importance in medicinal chemistry as they constitute

the structural features of many bioactive compounds. 1,3,4-

Oxadiazoles exhibit antimicrobial, anticonvulsant, anti-

inflammatory, and analgesic activities (Jha et al., 2010;

Singh and Jangra, 2010) and are known to be mimetics

(Omar et al., 1996; Leung et al., 2005) of ester and amide

groups. Furthermore, 2,5-substituted 1,3,4-oxadiazole

derivatives also have been reported to show broad spectrum

of biological activities including anti-inflammatory, anal-

gesic and ulcerogenicity (Bhandari et al., 2008), and anti-

oxidant (Hamdi et al., 2011). In fact the antioxidants that

scavenge reactive oxygen species are of great value in pre-

venting the onset and propagation of oxidative diseases like

autoimmune, cardiovascular, neurovascular, etc. Literature

survey reveals that 2,5-disubstituted 1,3,4-oxadiazoles have

been synthesized either by thermal/acid catalyzed cycliza-

tion of 1,2-diacylhydrazines (Liras et al., 2000) or by oxi-

dative cyclization of semicarbazone/hydrazone in the

presence of an oxidant (Gaonkar et al., 2006) or by micro-

wave irradiation of hydrazide and carboxylic acid mixture

(Khan et al., 2004). 1,3,4-Thiadiazole derivatives possess

multiple biological activities viz, anticancer (Elson et al.,

1988; Matysiak, 2007; Zou et al., 2011), antibacterial (Du

and Du, 2010), antifungal, and anti-inflammatory (Penning

et al., 1997). Most frequently used methods for the synthesis

of thiadiazoles include the reaction of acylthiosemicarbaz-

ides with acid reagents such as trifluoroacetic acid (Palaska

et al., 2002) andmethanesulfonic acid (Lutwick et al., 1979).

The important chemotherapeutics such as vorozole, letroz-

ole, and anastrozole contain 1,2,4-triazole ring and are cur-

rently being used for the treatment of breast cancer (Clemons

et al., 2004).One of the syntheticmethods for the preparation

of triazoles involves the use of N, N’-dimethyl formamide

dimethyl acetals (Stocks et al., 2004). Replacement of –O–

by –S– or –NH– in some heterocycles was reported viz.,

Bordners (Bordner, 1953) preparation of pyrroles from furan

Electronic supplementary material The online version of thisarticle (doi:10.1007/s00044-014-1277-5) contains supplementarymaterial, which is available to authorized users.

A. Padmaja (&) � D. Pedamalakondaiah � G. Sravya �G. M. Reddy

Department of Chemistry, Sri Venkateswara University,


e-mail: [email protected]

M. V. J. Kumar

Department of Biotechnology, Sri Venkateswara University,


123

Med Chem Res

DOI 10.1007/s00044-014-1277-5

MEDICINALCHEMISTRYRESEARCH

http://dx.doi.org/10.1007/s00044-014-1277-5

and the transformation of epoxide to episulfides by the action

of thiocyanates or thiourea (Van Tamelen, 1951; Price and

Kirk, 1953; Culvenor, 1952). However, reports about the

conversion of 1,3,4-oxadiazoles to 1,3,4-thiadiazoles, and

1,2,4-triazoles are relatively less (Linganna and Lokanatha

Rai, 1998; Kiyoshi and Senji, 1960). The compounds with

good antioxidant activity are expected to possess anti-

inflammatory activity (Maheshwari et al., 2011). As such the

development of effective methods for the synthesis of a

variety of heterocycles and modification of oxadiazole motif

is of considerable importance in heterocyclic arena. Indeed,

we have synthesized a new class of bisheterocycles having a

variety of functional groups and studied their antioxidant

activity (Padmaja et al., 2011a, b; Padmavathi et al., 2011;

Padmaja et al., 2013; Padmavathi et al., 2009a, b). Prompted

by these observations and our continued interest in the

development of bioactive heterocycles, it is planned to

synthesize hitherto unknown sulfone/sulfonamide-linked

bis(oxadiazoles), bis(thiadiazoles), and bis(triazoles) and to

study their antioxidant activity.

Results and discussion

Chemistry

The synthetic scheme involves the preparation of target bis-

heterocycles from the synthetic intermediates arylsulfonyl-

acetic acid hydrazide (3)/arylaminosulfonylacetic acid

hydrazide (6), and sulfonyldiacetic acid (7). The compounds

3/6 were prepared by the reaction of arylsulfonylacetic acid

methyl ester (2)/arylaminosulfonylacetic acidmethyl ester (5)

with hydrazine hydrate in the presence of pyridine. The

compounds 2/5 were in turn obtained by the esterification of

arylsulfonylacetic acid (1)/arylaminosulfonylacetic acid (4)

with methanol in the presence of concentrated sulfuric

acid (Scheme 1). The cyclocondensation of 2 mol of

arylsulfonylacetic acid hydrazide (3)/arylaminosulfonylace-

tic acidhydrazide (6)with1 mol of sulfonyldiacetic acid (7) in

the presence of POCl3 resulted in bis((5-arylsulfonylmethyl)-

1,3,4-oxadiazolylmethyl)sulfone (8)/bis((5-arylaminosulfo-

nylmethyl)-1,3,4-oxadiazolylmethyl)sulfone (11). Moreover,

bis((5-arylsulfonylmethyl)-1,3,4-thiadiazolylmethyl)sulfone

(9)/bis((5-arylaminosulfonylmethyl)-1,3,4-thiadiazolylmeth-

yl)sulfone (12) were synthesized by the treatment of com-

pounds 8/11 with thiourea in THF. However, bis(5-

arylsulfonylmethyl(4-amino)-1,2,4-triazol-3-ylmethyl)sulfone

(10)/bis(5-arylaminosulfonylmethyl(4-amino)-1,2,4-triazol-

3-ylmethyl)sulfone (13) were obtained by the conversion of

compounds 8/11 with hydrazine hydrate in n-butanol

(Scheme 2). The 1HNMRspectra of 8a and 9a displayed two

singlets at d 4.55, 4.51 and 5.57, 5.43 due to methylene

protons attached to C-2 and C-5, whereas 10a presented two

singlets at 4.42 and 5.39 due tomethylene protons attached to

C-3 and C-5. In addition to these, a broad singlet was

observed at 5.69 ppm in compound 10a due to NH2. The

signal due to highly acidic protons disappeared when D2O

was added

On the other hand, the 1H NMR spectra of 11a and 12a

exhibited two singlets at d 4.86, 5.09 (CH2-(C-2)) and 5.11,

5.35 (CH2-(C-5)), in addition to these, a broad singlet was

observed at 10.45 and 10.34 ppm (NH),whereas 13a furnished

two singlets at 5.19 (CH2-(C-3)) and 5.43 (CH2-(C-5)). More-

over, two broad singlets observed at 5.68, 10.37 ppm were

assigned to NH2 and NH which disappeared on deuteration.

The structures of all the newly synthesized compounds were

further established by IR, 13C NMR, and elemental analyses.

Biological evaluation

Antioxidant activity

The compounds 8–13 were tested for antioxidant property

by DPPH, nitric oxide (NO), and hydrogen peroxide

SOO

R

O

OMeS

OO

R

OH

O

SOO

R

NH

O

NH2

SOO

NH

O

OMe

R

SOO

NH

OH

OR

SOO

NH

NH

O

NH2

R

21 3

MeOH / H2NNH2.H2O /

546

Pyridine / MeOH

(i)(ii)

Conc. H2SO4

i ii

i ii

R = a) H

b) Me

c) Cl

Scheme 1 Synthesis of arylsufonylacetic acid hydrazide and arylaminosufonylacetic acid hydrazide

Med Chem Res

123

R

SOO

SOO

S

NN

SOO

S

NN

R R

SOO

SOO

N

NN

SOO

N

NN

RNH

2NH

2

1 2

45 3

SOO

OH

O

OH

O

12

453

SOO

OH

O

OH

O

NH

SOO

SOO

O

NN

SOO

O

NN

NH

R R

NH

SOO

SOO

S

NN

SOO

S

NN

NH

R R

NH

SOO

SOO

N

NN

SOO

N

NN

NH

NH2

NH2

R R

1 2

45 312

453

1 24

53

12 5

3 4

NH2NH2.H2O/ n-Butanol

NH2CSNH2 / THF

POCl3(i)(ii)(iii)

R

SOO

SOO

O

NN

SOO

O

NN

R

1 24

53

12 53 4

+3

7

9 10

11

1213

+

7

R = a) H

b) Me

c) Cl

6

8

i

ii iii

i

ii iii

Scheme 2 Synthesis of sulfonyl- and sulfonamide-linked bis heterocycles

Table 1 The in vitro

antioxidant activity of 8–13 in

DPPH method

Values were the means of three

replicates ±SD

(–) Showed no scavenging

activity

Compounds Concentration

50 (lg/ml) 75 (lg/ml) 100 (lg/ml) IC50 (lg/ml)

8a 67.21 ± 0.14 69.34 ± 0.11 72.54 ± 0.19 37.19 ± 0.05

8b 76.91 ± 0.10 79.05 ± 0.28 81.43 ± 0.33 32.51 ± 0.03

8c 36.22 ± 0.34 38.24 ± 0.21 42.29 ± 0.39 69.02 ± 0.23

9a 42.22 ± 0.25 44.16 ± 0.08 47.82 ± 0.16 59.21 ± 0.12

9b 46.72 ± 0.17 48.95 ± 0.15 51.32 ± 0.21 53.51 ± 0.19

9c 22.29 ± 0.45 24.14 ± 0.36 26.40 ± 0.29 112.15 ± 0.25

10a 51.93 ± 0.41 54.26 ± 0.41 57.42 ± 0.11 48.14 ± 0.06

10b 58.94 ± 0.24 61.20 ± 0.20 64.07 ± 0.15 42.42 ± 0.10

10c 29.20 ± 0.27 30.12 ± 0.23 32.56 ± 0.35 85.61 ± 0.29

11a 70.45 ± 0.38 74.05 ± 0.32 76.91 ± 0.31 61.80 ± 0.26

11b 77.12 ± 0.18 80.41 ± 0.13 83.62 ± 0.12 32.42 ± 0.09

11c 39.14 ± 0.23 41.62 ± 0.19 45.90 ± 0.18 63.87 ± 0.16

12a 45.42 ± 0.42 47.14 ± 0.38 52.23 ± 0.25 54.92 ± 0.23

12b 50.35 ± 0.31 53.01 ± 0.34 55.46 ± 0.06 49.65 ± 0.03

12c 23.40 ± 0.19 25.39 ± 0.16 29.14 ± 0.09 106.83 ± 0.05

13a 55.14 ± 0.11 59.15 ± 0.25 62.81 ± 0.04 45.34 ± 0.78

13b 61.15 ± 0.20 64.27 ± 0.14 68.73 ± 0.25 40.88 ± 0.13

13c 31.29 ± 0.40 33.14 ± 0.19 36.32 ± 0.19 79.89 ± 0.41

Ascorbic acid 76.18 ± 0.17 78.29 ± 0.15 80.14 ± 0.10 32.82 ± 0.12

Blank – – – –

Med Chem Res

123

(H2O2) methods at 50, 75, and 100 lM concentration

(Tables 1, 2 and 3; Figs. 1, 2 and 3). The structure–activity

relationship of the tested compounds revealed that the

compounds having oxadiazole moieties (8 and 11) showed

higher radical scavenging activity when compared with

those having thiadiazole (9 and 12) and triazole (10 and 13)



NO method


replicates ±SD


activity



8a 70.61 ± 0.11 73.24 ± 0.08 76.0 ± 0.04 35.40 ± 0.22

8b 80.05 ± 0.09 82.14 ± 0.05 84.26 ± 0.02 31.23 ± 0.36

8c 39.32 ± 0.25 40.27 ± 0.22 43.48 ± 0.19 63.58 ± 0.47

9a 45.41 ± 0.23 48.12 ± 0.19 50.59 ± 0.14 55.05 ± 0.15

9b 51.17 ± 0.15 53.23 ± 0.12 56.45 ± 0.08 48.86 ± 0.69

9c 25.91 ± 0.28 29.90 ± 0.28 31.15 ± 0.25 96.49 ± 0.58

10a 59.13 ± 0.27 61.85 ± 0.25 64.02 ± 0.21 42.28 ± 0.67

10b 63.09 ± 0.18 65.72 ± 0.14 68.12 ± 0.10 39.63 ± 0.49

10c 32.20 ± 0.13 34.72 ± 0.11 37.08 ± 0.06 76.64 ± 0.28

11a 74.21 ± 0.29 77.08 ± 0.26 79.61 ± 0.23 33.68 ± 0.47

11b 82.55 ± 0.24 85.62 ± 0.27 87.34 ± 0.17 30.28 ± 0.98

11c 42.76 ± 0.20 46.11 ± 0.16 48.20 ± 0.13 58.47 ± 0.75

12a 50.07 ± 0.26 52.76 ± 0.30 54.23 ± 0.26 49.93 ± 0.66

12b 55.38 ± 0.34 58.72 ± 0.29 60.40 ± 0.28 45.15 ± 0.55

12c 29.66 ± 0.14 30.82 ± 0.10 34.19 ± 0.09 84.28 ± 0.43

13a 60.15 ± 0.08 64.29 ± 0.09 66.20 ± 0.03 41.56 ± 0.91

13b 66.80 ± 0.05 69.22 ± 0.03 71.47 ± 0.08 37.42 ± 0.37

13c 36.09 ± 0.22 39.18 ± 0.18 41.50 ± 0.12 69.27 ± 0.48

Ascorbic acid 79.42 ± 0.14 80.98 ± 0.11 83.42 ± 0.07 31.47 ± 0.88

Blank – – – –



H2O2 method


replicates ±SD


activity



8a 69.54 ± 0.18 73.91 ± 0.21 75.11 ± 0.29 35.95 ± 0.29

8b 78.15 ± 0.30 80.33 ± 0.19 82.09 ± 0.27 31.98 ± 0.36

8c 37.28 ± 0.34 40.02 ± 0.02 44.31 ± 0.34 67.06 ± 0.58

9a 44.16 ± 0.28 46.80 ± 0.04 49.27 ± 0.39 56.61 ± 0.47

9b 48.30 ± 0.11 50.22 ± 0.23 56.05 ± 0.04 52.05 ± 0.31

9c 25.10 ± 0.20 27.54 ± 0.08 30.01 ± 0.28 99.60 ± 0.48

10a 56.11 ± 0.29 59.31 ± 014 62.10 ± 0.12 44.55 ± 0.71

10b 60.62 ± 0.17 62.04 ± 0.13 67.98 ± 0.10 41.24 ± 0.18

10c 31.66 ± 0.13 33.19 ± 0.12 36.42 ± 0.44 78.96 ± 0.95

11a 72.12 ± 0.11 76.06 ± 0.03 79.23 ± 0.32 34.66 ± 0.86

11b 80.71 ± 0.23 83.20 ± 0.18 86.57 ± 0.21 30.97 ± 0.79

11c 41.07 ± 0.29 43.53 ± 0.16 47.01 ± 0.15 60.87 ± 0.65

12a 47.72 ± 0.26 49.17 ± 0.25 53.30 ± 0.23 52.39 ± 0.98

12b 52.13 ± 0.09 55.70 ± 0.28 59.21 ± 0.07 47.95 ± 0.70

12c 26.85 ± 0.24 30.60 ± 0.10 32.37 ± 0.13 93.11 ± 0.69

13a 59.05 ± 0.30 61.24 ± 0.09 64.81 ± 0.33 42.34 ± 0.59

13b 62.29 ± 0.26 67.35 ± 0.07 70.42 ± 0.41 40.13 ± 0.37

13c 33.29 ± 0.12 35.16 ± 0.18 39.43 ± 0.28 75.09 ± 0.51

Ascorbic acid 77.42 ± 0.06 79.69 ± 0.26 81.49 ± 0.17 32.29 ± 0.19

Blank – – – –

Med Chem Res

123

units in all the three methods. Further, it was noticed that

methyl substituted and unsubstituted compounds displayed

higher antioxidant activity than the corresponding chloro-

substituted compounds. In fact, the compounds 8b, 11b

exhibited antioxidant activity greater than the standard

Ascorbic acid. It was also observed that the compounds 8a,

9a, 9b and 10a, 10b, 11a, 12a, 12b, 13a, 13b exhibited

good antioxidant activity, whereas other compounds dis-

played low activity. Besides, the perusal of Tables 1, 2, 3

and Figs. 1, 2, 3 indicated that radical scavenging activity

increases with increase in concentration in all the three

methods. It was also observed that sulfonamide-linked bis

Fig. 1 The in vitro antioxidant

activity of 8–13 in DPPH

method


activity of 8–13 in NO method


activity of 8–13 in H2O2 method

Med Chem Res

123

heterocycles showed comparatively higher antioxidant

activity (11–13) than sulfone-linked bis heterocycles (8–

10).

Conclusion

A new class of sulfone/sulfonamide-linked bis(oxadiaz-

oles), bis(thiadiazoles), and bis(triazoles) were prepared

from the synthetic intermediates sulfonyldiacetic acid,

arylsulfonylacetic acid hydrazide, and arylaminosulfonyl-

acetic acid hydrazide. All the synthesized compounds were

evaluated for antioxidant activity. Amongst all the tested

compounds methyl-substituted bis(oxadiazoles) exhibited

excellent antioxidant activity. It was observed that com-

pounds having oxadiazole moiety displayed higher radical

scavenging activity than those having thiadiazole and tri-

azole units. Further, it was noticed that sulfonamide-linked

bis heterocycles showed comparatively higher antioxidant

activity than sulfone-linked bis heterocycles.

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, 1:4). The IR spectra were run on a Thermo

Nicolet IR 200 FT-IR spectrometer as KBr pellets and the

wave numbers were given in cm-1. The 1H NMR spectra

were determined in CDCl3/DMSO-d6 on a Jeol JNM

operating at 400 MHz. The 13C NMR spectra were recor-

ded in CDCl3/DMSO-d6 on a Jeol JNM spectrometer

operating at 100 MHz. All chemical shifts are reported in d

(ppm) using TMS as an internal standard. The High-Res-

olution mass spectra were recorded on Micromass Q-TOF

micromass spectrometer using electrospray ionization. The

microanalyses were performed on Perkin-Elmer 240C

elemental analyzer. The antioxidant property was deter-

mined using Shimadzu UV-2450 spectrophotometer. The

starting compound 3 and 6 were prepared as per literature

procedure (Padmavathi et al., 2009a, b; Padmaja et al.,

2011a, b).

General method for preparation of bis((5-

arylsulfonylmethyl)-1,3,4-oxadiazolylmethyl) sulfone

(8a–c)/bis((5-arylaminosulfonylmethyl)-1,3,4-

oxadiazolylmethyl)sulfone (11a–c)

A mixture of arylsulfonylacetic acid hydrazide (3a–c)/a-

rylaminosulfonylacetic acid hydrazide (6a–c) (0.002 mol),

sulfonyldiacetic acid (7) (0.001 mol) and POCl-3 (5 mL)

were refluxed on a heating mantle for 6–9 h. The excess

POCl-3 was removed under vacuum and the residue was

poured onto crushed ice. The separated solid was filtered,

washed with saturated sodium bicarbonate solution, and

then with water. It was dried and recrystallized from ethanol.

Bis((5-phenylsulfonylmethyl)-1,3,4-oxadiazolylmethyl)

sulfone 8a

White solid, mp 173–175 �C, yield 67 %; IR (KBr)

(cm-1): 1572 (C=N), 1320, 1136 (SO2);1H NMR

(400 MHz, DMSO-d6): d 7.31–7.92 (m, 10H, Ar–H), 5.57

(s, 4H, CH2-(C-5)), 4.55 (s, 4H, CH2-(C-2));13C NMR

(100 MHz, DMSO-d6): d 158.3 (C-5), 157.2 (C-2), 54.8

(CH2-(C-5)), 52.4 (CH2-(C-2)), 139.8 136.9, 130.6, 129.9,

(aromatic carbons). HRMS: (m/z) 561.0184 [M?Na]. Anal.

Calcd for C20H18N4O8S-3: C, 44.60; H, 3.36; N, 10.40 %.

Found: C, 44.68; H, 3.40; N, 10.55 %.

Bis((5-(4-methylphenylsulfonylmethyl)-1,3,4-

oxadiazolylmethyl)sulfone 8b

White solid, m.p. 182–184 �C, yield 65 %; IR (KBr)

(cm-1): 1577 (C=N), 1315, 1134 (SO2);1H NMR

(400 MHz, DMSO-d6): d 7.26–7.86 (m, 8H, Ar–H), 5.51

(s, 4H, CH2-(C-5)), 4.49 (s, 4H, CH2-(C-2)), 2.52 (s, 6H,

Ar–CH3);13C NMR (100 MHz, DMSO-d6): d 157.8 (C-5),

156.4 (C-2), 53.5 (CH2-(C-5)), 51.8 (CH2-(C-2)), 23.9 (Ar–

CH3), 138.7, 136.5, 130.1, 129.4 (aromatic carbons);

HRMS: (m/z) 589.0497 [M?Na]. Anal. Calcd for

C22H22N4O8S-3: C, 46.63; H, 3.91; N, 9.88 %. Found: C,

46.58; H, 3.89; N, 10.00 %.

Bis((5-(4-chlorophenylsulfonylmethyl)-1,3,4-

oxadiazolylmethyl)sulfone 8c


(cm-1): 1583 (C=N), 1324, 1140 (SO2);1H NMR

(400 MHz, DMSO-d6): d 7.56–7.97 (m, 8H, Ar–H), 5.65

(s, 4H, CH2-(C-5)), 4.64 (s, 4H, CH2-(C-2));13C NMR

(100 MHz, DMSO-d6): d 159.7 (C-5), 158.4 (C-2), 55.2

(CH2-(C-5)), 52.9 (CH2-(C-2)), 140.2, 137.1, 132.9, 130.8


Calcd for C20H16Cl2N4O8S3: C, 39.54; H, 2.65; N, 9.22 %.

Found: C, 39.61; H, 2.67; N, 9.39 %.

Bis((5-phenylaminosulfonylmethyl)-1,3,4-

oxadiazolylmethyl)sulfone 11a


(cm-1): 3227 (NH), 1572 (C=N), 1315,1160 (SO2);1H

NMR (400 MHz, DMSO-d6): d 10.31 (bs, 1H, NH),

7.11–7.69 (m, 10H, Ar–H), 5.11 (s, 4H, CH2-(C-5)), 4.86

(s, 4H, CH2-(C-2));13C NMR (100 MHz, DMSO-d6): d

158.0 (C-5), 157.3 (C-2), 49.7 (CH2-(C-5)), 44.3 (CH2-(C-

Med Chem Res

123

2)), 135.6, 129.4, 120.5, 117.9 (aromatic carbons). HRMS:

(m/z) 591.0402 [M?Na]. Anal. Calcd for C20H20N6O8S3:

C, 42.25; H, 3.55; N, 14.78 %. Found: C, 42.20; H, 3.59;

N, 14.94 %.

Bis((5-(4-methylphenylaminosulfonylmethyl)-1,3,4-

oxadiazolylmethyl)sulfone 11b

White solid, m.p. 156–158 �C, yield 65 %; IR (KBr) (cm-1):

3224 (NH), 1565 (C=N), 1312, 1155 (SO2);1H NMR

(400 MHz, DMSO-d6): d 10.02 (bs, 1H, NH), 7.03–7.59 (m,

8H,Ar–H), 5.06 (s, 4H, CH2-(C-5)), 4.69 (s, 4H, CH2-(C-2)),

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

155.1 (C-5), 154.5 (C-2), 48.4 (CH2-(C-5)), 42.8 (CH2-(C-

2)), 21.9 (Ar–CH3), 134.2, 128.2, 120.1, 117.1, (aromatic

carbons). HRMS: (m/z) 619.0715 [M?Na]. Anal. Calcd for

C22H24N6O8S3: C, 44.29; H, 4.05; N, 14.09 %. Found: C,

44.38; H, 4.08; N, 14.27 %.

Bis((5-(4-chlorophenylaminosulfonylmethyl)-1,3,4-

oxadiazolylmethyl)sulfone 11c


(cm-1): 3235 (NH), 1580 (C=N), 1318,1169 (SO2);1H


7.17–7.71 (m, 8H, Ar–H), 5.25 (s, 4H, CH2-(C-5)), 5.02 (s,

4H, CH2-(C-2));13C NMR (100 MHz, DMSO-d6): d 159.7

(C-5), 158.1 (C-2), 50.9 (CH2-(C-5)), 47.6 (CH2-(C-2)),

137.6, 130.2, 122.4, 118.4 (aromatic carbons). HRMS: (m/

z) 658.9623 [M?Na]. Anal. Calcd for C20H18Cl2N6O8S3:

C, 37.68; H, 2.85; N, 13.18 %. Found: C, 39.95; H, 2. 89;

N, 14.02 %.

General method for preparation of bis((5-arylsulfonylm-

ethyl)-1,3,4-thiadiazolylmethyl) sulfone (9a–c)/Bis((5-ary-

laminosulfonylmethyl)-1,3,4-thiadiazolylmethyl)sulfone

(12a–c)

The compound 8a–c/11a–c (0.001 mol), thiourea

(0.004 mol), and tetrahydrofuran (8 mL) were taken in a

sealed tube and heated at 120–150 �C in an oil bath for

18–23 h. After the reaction was completed, it was extracted

with dichloromethane. The organic layer was washed with

water, brine solution, and dried over anhydrous Na2SO4.

The solvent was removed on a rotary evaporator and the

resultant solid was recrystallized from 2-propanol.

Bis((5-phenylsulfonylmethyl)-1,3,4-

thiadiazolylmethyl)sulfone 9a


(cm-1): 1574 (C=N), 1315, 1138 (SO2);1H NMR

(400 MHz, DMSO-d6): d 7.29–7.88 (m, 10H, Ar–H), 5.43

(s, 4H, CH2-(C-5)), 4.51 (s, 4H, CH2-(C-2)),;13C NMR

(100 MHz, DMSO-d6): d 157.9 (C-5), 156.8 (C-2), 53.7

(CH2-(C-5)), 51.5 (CH2-(C-2)), 138.4 134.5, 129.9, 129.2


Calcd for C20H18N4O6S5: C, 42.09; H, 3.18; N, 9.82 %.

Found: C, 42.20; H, 3.20; N, 9.95 %.

Bis((5-(4-methylphenylsulfonylmethyl)-1,3,4-

thiadiazolylmethyl)sulfone 9b


(cm-1): 1571 (C=N), 1323, 1135 (SO2);1H NMR

(400 MHz, DMSO-d6): d 7.22–7.84 (m, 8H, Ar–H), 5.34

(s, 4H, CH2-(C-5)), 4.38 (s, 4H, CH2-(C-2)), 2.49 (s, 6H,

Ar–CH3);13C NMR (100 MHz, DMSO-d6): d 156.5 (C-5),

155.6 (C-2), 53.4 (CH2-(C-5)), 50.8 (CH2-(C-2)), 24.2 (Ar–

CH3), 135.2, 133.7, 129.6, 128.4 (aromatic carbons).

HRMS: (m/z) 628.0041 [M?Na]. Anal. Calcd for

C22H22N4O6S5: C, 44.13; H, 3.70; N, 9.36 %. Found: C,

44.07; H, 3.69; N, 9.46 %.

Bis((5-(4-chlorophenylsulfonylmethyl)-1,3,4-

thiadiazolylmethyl)sulfone 9c


(cm-1): 1578 (C=N), 1330, 1142 (SO2);1H NMR

(400 MHz, DMSO-d6): d 7.35–7.84 (m, 8H, Ar–H), 5.61

(s, 4H, CH2-(C-5)), 4.62 (s, 4H, CH2-(C-2));13C NMR

(100 MHz, DMSO-d6): d 158.5 (C-5), 157.2 (C-2), 54.6

(CH2-(C-5)), 51.9 (CH2-(C-2)), 139.5, 137.2, 132.9, 129.8


Calcd for C20H16Cl2N4O6S5: C, 37.55; H, 2.52; N, 8.75 %.

Found: C, 37.65; H, 2.57; N, 8.91 %.

Bis((5-phenylaminosulfonylmethyl)-1,3,4-

thiadiazolylmethyl)sulfone 12a


3228 (NH), 1575(C=N), 1305, 1162 (SO2);1H NMR

(400 MHz, DMSO-d6): d 10.39 (bs, 1H, NH), 7.14–7.68 (m,

10H, Ar–H), 5.35 (s, 4H, CH2-(C-5)), 5.09 (s, 4H, CH2-(C-

2)); 13C NMR (100 MHz, DMSO-d6): d 158.8 (C-5), 157.7

(C-2), 51.8 (CH2-(C-5)), 43.5 (CH2-(C-2)), 138.4, 128.5,

119.2, 116.5 (aromatic carbons). HRMS: (m/z) 622.9946

[M?Na]. Anal. Calcd for C20H20N6O6S5: C, 39.99; H, 3.36;

N, 13.99 %. Found: C, 39.95; H, 3.38; N, 14.20 %.

Bis((5-(4-methylphenylaminosulfonylmethyl)-1,3,4-

thiadiazolylmethyl)sulfone 12b


(cm-1): 3236 (NH), 1559 (C=N), 1324, 1139 (SO2);1H


7.11–7.62 (m, 8H, Ar–H), 5.27 (s, 4H, CH2-(C-5)), 5.07 (s,

Med Chem Res

123

4H, CH2-(C-2)), 2.29 (s, 6H, Ar–CH3);13C NMR

(100 MHz, DMSO-d6): d 159.6 (C-5), 158.2 (C-2), 50.7

(CH2-(C-5)), 42.8 (CH2-(C-2)), 21.9 (Ar–CH3), 132.3,

129.5, 126.9, 116.1 (aromatic carbons). HRMS: (m/z)

651.0251 [M?Na]. Anal. Calcd for C22H24N6O6S5: C,

42.02; H, 3.85; N, 13.37 %. Found: C, 42.13; H, 3.90; N,

13.54 %.

Bis((5-(4-chlorophenylaminosulfonylmethyl)-1,3,4-

thiadiazolylmethyl)sulfone 12c


(cm-1): 3250 (NH), 1573 (C=N), 1336,1151 (SO2);1H

NMR (400 MHz, DMSO-d6): d 10.42 (bs, 1H, NH), 6.81 (m,

8H, Ar–H), 5.41 (s, 4H, CH2-(C-5)), 5.18 (s, 4H, CH2-(C-

2)); 13C NMR (100 MHz, DMSO-d6): d 159.5 (C-5), 158.6

(C-2), 51.5 (CH2-(C-5)), 44.2 (CH2-(C-2)), 129.8, 128.1,


[M?Na]. Anal. Calcd for C20H18Cl2N6O6S5: C, 35.87; H,

2.71; N, 12.55 %. Found: C, 35.92; H, 2.74; N, 12.70 %.

General method for preparation of bis(5-arylsulfonylmethyl

(4-amino)-1,2,4-triazol-3-ylmethyl)sulfone (10a–c)/

Bis(5-arylaminosulfonylmethyl(4-amino)-1,2,4-

triazol-3-ylmethyl)sulfone (13a–c)

To a solution of compound 8a–c/11a–c (0.001 mol) in n-

butanol (5 mL), hydrazine hydrate (0.004 mol) was added

and refluxed for 7–10 h. Then KOH (0.002 mol) was added

to the reaction media and the precipitate formed was fil-

tered. The solid obtained was acidified with conc. HCl to

pH 3 and washed with water. It was dried and recrystallized

from ethanol.

Bis(5-phenylsulfonylmethyl(4-amino)-1,2,4-triazol-3-

ylmethyl)sulfone 10a


3332, 3441 (NH2), 1575 (C=N), 1327,1137 (SO2);1H NMR

(400 MHz, DMSO-d6): d 7.24–7.42 (m, 10H, Ar–H), 5.69

(bs, 4H, NH2), 5.39 (s, 4H, CH2-(C-5)), 4.42 (s, 4H, CH2-(C-

3)); 13C NMR (100 MHz, DMSO-d6): d 156.2 (C-5), 155.3

(C-3), 53.5 (CH2-(C-5)), 51.2 (CH2-(C-3)), 138.8, 134.6,



N, 19.78 %. Found: C, 42.48; H, 3.93; N, 19.98 %.

Bis(5-(4-methyl)phenylsulfonylmethyl(4-amino)-1,2,4-

triazol-3-ylmethyl)sulfone 10b


(cm-1): 3326, 3433 (NH2), 1570 (C=N), 1322,1130 (SO2);

1H NMR (400 MHz, DMSO-d6): d 7.21–7.59 (m, 8H, Ar–

H), 5.62 (bs, 4H, NH2), 5.31 (s, 4H, CH2-(C-5)), 4.32 (s, 4H,

CH2-(C-3)), 2.45 (s, 6H, Ar–CH3);13C NMR (100 MHz,

DMSO-d6): d 154.9 (C-5), 153.8 (C-3), 52.4 (CH2-(C-5)),

50.7 (CH2-(C-3)), 23.6 (Ar–CH3), 137.6, 135.9, 130.2, 128.6


Calcd for C22H26N8O6S3: C, 44.43; H, 4.41; N, 18.84 %.

Found: C, 44.51; H, 4.40; N, 18.94 %.

Bis(5-(4-chloro)phenylsulfonylmethyl(4-amino)-1,2,4-

triazol-3-ylmethyl)sulfone 10c


(cm-1): 3335, 3446 (NH2), 1580 (C=N), 1334,1145 (SO2);1H NMR (400 MHz, DMSO-d6): d 7.36–7.98 (m, 8H, Ar–

H), 5.74 (bs, 4H, NH2), 5.47 (s, 4H, CH2-(C-5)), 4.49 (s,

4H, CH2-(C-3));13C NMR (100 MHz, DMSO-d6): d 158.1

(C-5), 157.5 (C-3), 53.8 (CH2-(C-5)), 51.6 (CH2-(C-3)),

139.5, 137.1, 130.4, 128.9, (aromatic carbons). HRMS: (m/

z) 656.9943 [M?Na]. Anal. Calcd for C20H20Cl2N8O6S3:

C, 37.80; H, 3.17; N, 17.63 %. Found: C, 37.92; H, 3.23;

N, 17.86 %.

Bis(5-phenylaminosulfonylmethyl(4-amino)-1,2,4-triazol-

3-ylmethyl)sulfone 13a


(cm-1): 3433, 3445 (NH2), 3230 (NH), 1570 (C=N),

1318,1144 (SO2);1H NMR (400 MHz, DMSO-d6): d

5.19 (s, 4H, CH2-(C-3)), 5.43 (s, 4H, CH2-(C-5)), 5.75

(bs, 4H-NH2), 7.19–7.72 (m, 10H, Ar–H), 10.37 (bs, 1H,

NH); 13C NMR (100 MHz, DMSO-d6): d 159.6 (C-5),

158.2 (C-3), 52.0 (CH2-(C-5)), 47.2 (CH2-(C-3)), 129.1,

127.4, 118.2, 116.9 (aromatic carbons). HRMS: (m/z)

619.0940 [M?Na]. Anal. Calcd for C20H24N10O6S3: C,

40.26; H, 4.05; N, 23.47 %. Found: C, 40.32; H, 4.08; N,

23.66 %.

Bis(5-(4-methyl)phenylaminosulfonylmethyl(4-amino)-

1,2,4-triazol-3-ylmethyl)sulfone 13b


3427, 3436 (NH2), 3225 (NH), 1566 (C=N), 1314, 1141

(SO2);1H NMR (400 MHz, DMSO-d6): d 10.40 (bs, 1H,

NH), 7.28–7.94 (m, 8H, Ar–H), 5.38 (s, 4H, CH2-(C-5)), 5.20

(s, 4H, CH2-(C-3)), 2.40 (s, 6H, Ar–CH3),;13C NMR

(100 MHz, DMSO-d6): d 160.8 (C-5), 159.6 (C-3), 51.6

(CH2-(C-5)), 45.3 (CH2-(C-3)), 22.8 (Ar–CH3), 134.1, 130.6,

128.4, 116.2, (aromatic carbons). HRMS: (m/z) 647.1253


N, 22.42 %. Found: C, 42.37; H, 4.47; N, 22.54 %.

Med Chem Res

123

Bis(5-(4-chloro)phenylaminosulfonylmethyl(4-amino)-

1,2,4-triazol-3-ylmethyl)sulfone 13c


(cm-1): 3437, 3449 (NH2), 3239 (NH), 1576 (C=N),

1326,1155 (SO2);1H NMR (400 MHz, DMSO-d6): d 10.43

(bs, 1H, NH), 7.29–7.89 (m, 8H, Ar–H), 5.81 (bs, 4H-NH2),

5.41 (s, 4H, CH2-(C-5)), 5.12 (s, 4H, CH2-(C-3));13C

NMR (100 MHz, DMSO-d6): d 159.5 (C-5), 158.6 (C-3),

51.9 (CH2-(C-5)), 44.8 (CH2-(C-3)), 134.7, 129.2, 124.5,

118.8 (aromatic carbons). HRMS: (m/z) 687.0161

[M?Na]. Anal. Calcd for C20H22Cl2N10O6S3: C, 36.09; H,

3.33; N, 21.04 %. Found: C, 37.20; H, 3.36; N, 21.20 %.

Antioxidant activity

The compounds 8–13 were evaluated for antioxidant

property by DPPH (Burits and Bucar, 2000; Cuendet et al.,

1997), nitric oxide (Green et al., 1982; Marcocci et al.,

1994), and H2O2 (Ruch et al., 1989) methods.

2,2-Diphenyl-1-picrylhydrazyl (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). The spectrophotometric assay uses

the stable radical DPPH as a reagent. To 4 ml of 0.004 %

w/v methanol solution of DPPH, 1 ml of various concen-

trations of the test compounds (50, 75, and 100 lg/ml) in

methanol were added. After 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 DPPHwas

calculated by the following equation

I% ¼ Acontrol�Asample

� �

=Ablank

� �

� 100;

where Acontrol is the absorbance of the control reaction

(containing methanolic DPPH and Ascorbic acid), Asample

is the absorbance of the test compound (containing meth-

anolic DPPH and test compound), and Ablank is the absor-

bance of the blank (containing only methanolic DPPH).

Tests were carried out in triplicate.

The IC50 was calculated by the following equation

IC50 in l g =ml ¼ 50 � 100 =% Inhibition,

IC50 in lmol =ml ¼ % of the IC50=

M:Wt: of the compound:

Nitric oxide (NO) scavenging activity

Sodium nitroprusside (5 lM) in phosphate buffer pH 7.4

was incubated with different concentrations (50, 75, and

100 lg/ml) of test compounds dissolved in a suitable sol-

vent (dioxane/methanol) and tubes were incubated at 25 �C

for 120 min. Control experiment was conducted with equal

amount of solvent in an identical manner. At intervals,

0.5 ml of incubation solution was taken and diluted with

0.5 ml of Griess reagent (1 % Sulfanilamide, 0.1 % N-

naphthylethylenediamine dihydrochloride and 2 % o-

phosphoric acid dissolved in distilled water). The absor-

bance of the chromophore formed during diazotization of

nitrite with sulfanilamide and subsequent N-naphthylethy-

lenediamine dihydrochloride was read at 546 nm. The

experiment was repeated in triplicate. Nitric oxide scav-

enging activity was calculated by the following equation

% of scavenging ¼ ðAcontrol� Asample½ Þ =Ablank�� 100;

where Acontrol is the absorbance of the control reaction (con-

taining all reagents and Ascorbic acid), Asample is the absor-

bance of the test compound (containing all reagents and test

compound), and Ablank is the absorbance of the blank (con-

taining 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 A solution of H2O2

(40 mm) was prepared in phosphate buffer (pH 7.4). 50,

75, and 100 lg/ml concentrations 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. Ascorbic acid was used

as the standard. The percent of scavenging of H2O2 was

calculated by the following equation

% of scavenging ¼ Acontrol�Asample

� �

=Ablank

� �

� 100;

where Acontrol is the absorbance of the control reaction (con-

taining all reagents and Ascorbic acid), Asample is the absor-

bance of the test compound (containing all reagents and test

compound), and Ablank is the absorbance of the blank (con-

taining only reagents). Tests were carried out in triplicate.

Acknowledgments The authors are grateful to Council of Scientific

and Industrial Research (CSIR), New Delhi for financial assistance

under major research project. One of the authors G. Sravya is thankful

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

of UGC-BSR fellowship. The authors are also thankful to Prof. Ch.

Appa Rao, Department of Bio-Chemistry, S.V.University, Tirupati,

for providing facilities to carry out the antioxidant activity.

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