Synthesis and bioassay of pyrrolyl oxazolines and thiazolines

Article abstract of DOI:10.1016/j.ejmech.2010.04.010

A new class of sulfone linked pyrrolyl oxazolines and thiazolines were synthesized from E-arylsulfonylethenesulfonylacetic acid methyl ester and studied their antimicrobial and antioxidant activities.

Full text of DOI:10.1016/j.ejmech.2010.04.010

European Journal of Medicinal Chemistry 45 (2010) 3178e3183
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and bioassay of pyrrolyl oxazolines and thiazolines
*
V. Padmavathi , K. Mahesh, G. Dinneswara Reddy, A. Padmaja
Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of sulfone linked pyrrolyl oxazolines and thiazolines were synthesized from E-arylsulfonyl-
ethenesulfonylacetic acid methyl ester and studied their antimicrobial and antioxidant activities.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Received 22 January 2010
Received in revised form
25 March 2010
Accepted 8 April 2010
Available online 14 April 2010
Keywords:
2-Oxazolines
2-Thiazolines
Pyrroles
1,3-Dipolarcycloaddition
Antimicrobial activity
Antioxidant property
1. Introduction
on pyrrole nitrogen or 3,4-silylated precursors [23]. Pyrroles have
also been prepared from Michael acceptors and tosylmethyl iso-
Oxazolines, thiazolines and pyrroles are important naturally
occurring five membered heterocycles. The 2-oxazoline ring system
[1], a simple cyclic imino ester, is of great interest in modern
organic chemistry because it can be used as a masked carboxylic
acid [2], versatile synthetic intermediate [3], and therapeutic agent
[4]. A number of reliable preparative methods are known in the
literature which includes cyclodehydration of carboxylic acids and
cyanide (TosMIC) [24,25]. Recently we have reported the synthesis,
antimicrobial and cyctotoxic activities of a variety of bis heterocy-
cles pyrrolyl oxadiazoles, thiadiazoles and triazoles [26]. In
continuation of our interest on the synthesis and pharmacological
properties of sulfone linked bis heterocycles, the present work has
been taken up.
b-amino alcohol, treatment of b-hydroxyamide with suitable
2. Chemistry
cyclization reagents such as thionyl chloride [5], phosphorotris-
(1,2,4)-triazolide [6], Mitsunobu conditions (DEAD/PPh3) [7] and
phosphorous mediated Appel reaction conditions [8]. In addition,
thiazoline derivatives possess anti HIV-1 [9], antimitotic [10] and
bioluminescent activities and have recently found applications as
building blocks in pharmaceutical drug discovery [11e13]. Thiazo-
lines have been prepared by the condensation of aminothiols with
nitriles [9], esters [14], iminoethers [15] or iminotriflates [16]
and also by cyclization of N-acyl-2-aminoethanols [17,18] or
The synthetic method involves the articulation of pyrrole in
combination with oxazoline and thiazoline rings from an inter-
mediate trans-arylsulfonylethenesulfonyl-acetic acid methyl ester
(1). This compound was prepared by the reaction of 1-arylsulfonyl-
2-chloroethene with mercaptoacetic acid followed by oxidation
and esterification [26]. Earlier we have reported the synthesis of
2-arylsulfonylmethyl oxazolines/thiazolines and 2-arylmethane-
sulfonylmethylsulfonyl oxazolines/thiazolines by the traditional
four-step three-intermediate route from arylsulfonylacetic acid
methyl ester [27]. We have also reported one pot methodology to
develop these heterocycles exploiting lanthanide amino alkoxide
complexes as reagents [28]. Encouraged by the results, the ester
and olefin functionalities in 1 were appropriately functionalized to
develop bis heterocycles. The reaction of compound 1 with
2-aminoethanol and n-butyllithium complexed with a suspension
of 5e10% mol. equivalents of anhydrous SmCl3 in toluene resulted
b-hydroxythioamides [19e21]. Netropsin and distamycin are
pyrrole polyamides and are naturally occurring anticancer antibi-
otics [22]. Multistep synthetic routes for 3,4-disubstituted pyrroles
have been reported either by coupling of imines and nitroalkanes or
using FriedeleCraft’s acylation with an electron withdrawing group
* Corresponding author. Tel.: þ91 877 2289303; fax: þ91 877 2249532.
E-mail address: vkpuram2001@yahoo.com (V. Padmavathi).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.04.010

V. Padmavathi et al. / European Journal of Medicinal Chemistry 45 (2010) 3178e3183
3179
in 2-(arylsulfonylethenesulfonylmethyl)-4,5-dihydrooxazole (2).
3.2. Antioxidant testing
Adopting similar methodology, 2-(arylsulfonylethenesulfonyl-
methyl)-4,5-dihydrothiazole (3) was prepared by treating 1 with
2-aminoethanethiol and n-butyllithium in the presence of anhy-
drous SmCl3 in toluene (Scheme 1). The olefin moiety in 2 and 3
was used to develop pyrrole ring. Treatment of 2 and 3 with TosMIC
in the presence of sodium hydride in a solvent mixture of ether and
DMSO produced 2-(40-arylsulfonyl-10H-pyrrol-30-sulfonylmethyl)-
4,5-dihydrooxazole (4) and 2-(40-arylsulfonyl-10H-pyrrol-30-sulfo-
nylmethyl)-4,5-dihydrothiazole (5) (Scheme 1).
The compounds 2aec to 5aec were tested for antioxidant
property by nitric oxide [31,32] and DPPH [33] methods. The
observed data on the antioxidant activity is given in Table 4.
4. Results and discussion
We have synthesized a new class of heterocycles, 2-(arylsulfo-
nylethenesulfonylmethyl)-4,5-dihydrooxazole (2) 2-(arylsulfonyl-
ethenesulfonylmethyl)-4,5-dihydrothiazole (3), 2-(40-arylsulfonyl-
10H-pyrrol-30-sulfonylmethyl)-4,5-dihydrooxazole (4) and 2-(40-
arylsulfonyl-10H-pyrrol-30-sulfonylmethyl)-4,5-dihydrothiazole (5)
as depicted in Scheme 1. Structures of all the compounds were
3. Biology
3.1. Antimicrobial activity
established on the basis of elemental analyses, IR, 1H NMR and 13
NMR spectral data.
C
The compounds 2aec to 5aec were tested for in vitro antimi-
crobial activity against the Gram-positive bacteria Staphylococcus
aureus (NCIM No. 5021), Bacillus subtilis (NCIM No. 2063), the
Gram-negative bacteria Klebsiella pneumoniae (NCIM No. 2957),
Proteus vulgaris (NCIM No. 2027) and fungi Fusarium solani (NCIM
No. 1330), Curvularia lunata (NCIM No. 716) and Aspergillus niger
(NCIM No. 596). The preliminary screening was carried out by agar
disc-diffusion method [29] using nutrient agar medium. The
minimum inhibitory concentration for the most active compounds
3c, 5a, and 5c against the same microorganisms used in the
preliminary screening was carried out using microdilution
susceptibility method [30]. Chloramphenicol and Ketoconazole
were used as control drugs. The observed data on the antimicro-
bial activity of the compounds and control drugs are given in
Tables 1e3.
4.1. Biological results
The results ofpreliminaryantimicrobialtestingof thecompounds
are shown in Tables 1e3. The results revealed that, the inhibitory
activity against Gram-positive bacteria was higher than Gram-
negative bacteria. The oxazoline derivatives 2aec were displayed
least activity. Thecompounds 3c, 5a and 5c showed excellent activity
against Gram-positive (inhibitory zone > 27 mm) and good activity
against Gram-negative (inhibitory zone > 20 mm) bacteria. The
compounds having pyrrole in combination with oxazoline unit
displayed moderate activity 4aec when compared with compounds
having only oxazoline moiety 2aec. All the test compounds showed
moderateto high inhibitoryeffect towardstested fungi. The presence
HA
O
O
S
CO2Me
S
O
O
HB
R
1
ii
i
O
O
N3
O
O
N3
4
5
S
4
5
S
2
S
2
1
S
1
O
O
O
S
O
O
O
R
R
3
2
iii
iii
N3
2
N3
2
4
5
4
5
O
O
O
O
O
O
O
S
S
1
O
S
S
1
S
3'
4'
4'
5'
3'
2'
2'
5'
1'
1'
R
N
R
N
H
H
5
4
a: R = H
b: R = 4- Me
c: R = 4-Cl
i. NH2CH2CH2OH / Sm(III)Cl3 / n-BuLi / Toluene
ii. NH2CH2CH2SH / Sm(III)Cl3 / n-BuLi / Toluene
iii. TosMIC / NaH / Et2O+DMSO
Scheme 1.

3180
V. Padmavathi et al. / European Journal of Medicinal Chemistry 45 (2010) 3178e3183
Table 1
Antibacterial activity of 5e8.
Compound
Concentration
g/disc)
Zone of inhibition (mm)
(
m
Gram-positive bacteria
Gram-negative bacteria
Staphylococcus aureus
Bacillus subtilis
Klebsiella pneumoniae
Proteus vulgaris
2a
100
200
11
13
10
12
e
e
e
e
2b
100
200
10
13
9
11
e
e
e
e
2c
100
200
13
15
12
14
10
12
9
10
3a
100
200
21
24
22
23
19
21
17
18
3b
100
200
20
23
19
21
17
20
15
18
3c
100
200
27
28
29
31
22
23
21
22
4a
100
200
15
19
16
18
14
17
13
15
4b
100
200
12
15
13
14
10
13
11
13
4c
100
200
17
19
16
19
15
17
12
14
5a
100
200
29
30
30
32
23
25
24
28
5b
100
200
23
26
22
24
20
21
17
19
5c
100
200
32
34
33
35
27
29
29
30
Chloramphenicol
100
200
35
41
38
44
37
42
42
45
of chloro substituent in the aromatic ringenhances the antimicrobial
activity.
30-sulfonylmethyl)-4,5-dihydrooxazole (4) and 2-(40-arylsulfonyl-
10H-pyrrol-30-sulfonylmethyl)-4,5-dihydrothiazole (5) were devel-
oped by functionalization of ester and olefin moieties in E-aryl-
sulfonylethenesulfonylacetic acid methyl ester (1) exploiting
lanthanide chemistry and 1,3-diploar cycloaddition methodology.
The antimicrobial testing showed that the compounds having
pyrrole with thiazoline possess excellent antimicrobial activity.
However, the compounds having pyrrole with oxazoline showed
good antioxidant property.
The minimum inhibitory concentration (MIC) values were
determined as the lowest concentration that completely inhibited
visible growth of the microorganisms (Table 3). The structure-
antimicrobial activity relationship of the synthesized compounds
revealed that the compounds having oxazoline (2aec) showed
least activity. However, the compounds having thiazoline (3aec)
exhibited good activity when compared with compounds having
oxazoline and pyrrole units (4aec). On the other hand, compounds
with thiazoline and pyrrole rings (5aec) displayed excellent
activity. The maximum activity was observed with the compounds
3c, 5a and 5c.
6. Experimental
6.1. Chemistry
4.2. Antioxidant testing
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
acetateehexane, 0.5:2). The IR spectra were recorded on a Thermo
Nicolet IR 200 FT-IR spectrometer as KBr pellets and the wave
numbers were given in cmꢀ1. The 1H NMR spectra were recorded
The compounds 2aec to 5aec were tested for antioxidant
property by nitric oxide, DPPH and reducing power methods. The
compounds 2a, 2c, 4a and 4c exhibited high antioxidant property in
all the three methods at 100 mM concentration (Table 4). In fact, the
in CDCl3/DMSO-d6 on a Jeol JNM
were recorded in CDCl3/DMSO-d6 on a Jeol JNM spectrometer
operating at 75.5 MHz. All chemical shifts are reported in (ppm)
l
-300 MHz. The 13C NMR spectra
compounds having oxazoline and pyrrole units displayed high
antioxidant property. The maximum activity was observed with the
compound 4c.
d
using TMS as an internal standard. The microanalyses were
performed on Perkin-Elmer 240C elemental analyzer. The anti-
oxidant property was carried out by using Shimadzu UV-2450
spectrophotometer. The starting compound trans-arylsulfonyl-
ethenesulfonylacetic acid methyl ester (1) was prepared according
to literature procedure [26].
5. Conclusion
A
new class of heterocycles 2-(arylsulfonylethenesulfo-
nylmethyl)-4,5-dihydrooxazole (2), 2-(arylsulfonylethenesulfo-
nylmethyl)-4,5-dihydrothiazole (3), 2-(40-arylsulfonyl-10H-pyrrol-

V. Padmavathi et al. / European Journal of Medicinal Chemistry 45 (2010) 3178e3183
3181
Table 2
Table 4
Antifungal activity of 5e8.
Antioxidant property of 2e5.
Compound
Concentration
g/ml)
Zone of inhibition (mm)
Compound
% Inhibition at 100 mM
(
m
Fusarium
solani
Curvularia
lunata
Aspergillus
niger
Nitric oxide
method
DPPH
method
Reducing
power
2a
100
200
14
15
16
18
17
19
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
82.12
74.23
85.54
30.42
21.74
32.28
87.68
78.54
92.11
34.61
23.74
41.42
96.90
e
83.72
73.88
86.61
29.31
22.18
33.46
88.32
76.14
91.46
33.84
23.21
40.51
95.37
e
79.45
73.51
82.68
29.28
21.21
28.31
86.81
77.31
89.41
32.41
22.89
40.35
e
2b
100
200
14
17
18
19
14
16
2c
100
200
16
19
18
20
17
20
3a
100
200
26
29
24
26
26
28
3b
100
200
22
25
21
24
20
23
Ascorbic acid
Butylated hydroxy
toluene (BHT)
3c
100
200
29
31
24
28
27
29
92.34
4a
100
200
18
22
19
23
20
22
(CDCl3 þ DMSO-d6)
d
3.62 (t, 2H, C-4, J ¼ 5.5 Hz), 4.24 (s, 2H,
4b
100
200
18
20
17
21
17
21
SO2CH2), 4.65 (t, 2H, C-5, J ¼ 5.5 Hz), 7.28 (d, J ¼ 14.1 Hz, 1H, HB),
7.66 (d, J ¼ 14.1 Hz, 1H, HA), 7.32e7.83 (m, 5H, Ar-H) ppm; 13C NMR
4c
100
200
21
23
20
23
21
22
(CDCl3 þ DMSO-d6)
d 51.4 (C-4), 57.6 (SO2CH2), 59.4 (C-5), 137.4
(SO2CH), 143.9 (CHSO2), 161.8 (C-2), 127.4, 129.4, 130.7, 131.5 ppm
(aromatic carbons). Anal. Calcd. for C12H13NO5S2: C, 45.70; H, 4.15;
N, 4.44; Found: C, 45.79; H, 4.19; N, 4.50.
5a
100
200
34
37
32
35
30
33
5b
100
200
29
31
28
32
31
35
6.1.1.2. 2-(p-Methylphenylsulfonylethenesulfonylmethyl)-4,5-dihy-
5c
100
200
35
38
36
41
34
38
drooxazole 2b. White solid (0.2173 g, 66 %); m.p. 152e154 ꢁC; IR
(KBr): 1138, 1336 (SO2), 1580 (C]C), 1595 (C]N) cmꢀ1 1H NMR
;
Ketoconazole
100
200
38
42
41
44
36
39
(CDCl3 þ DMSO-d6)
d 2.23 (s, 3H, Ar-CH3), 3.71 (t, 2H, C-4,
J ¼ 5.7 Hz), 4.28 (s, 2H, SO2CH2), 4.71 (t, 2H, C-5, J ¼ 5.7 Hz), 7.32 (d,
J ¼ 14.3 Hz, 1H, HB), 7.69 (d, J ¼ 14.3 Hz, 1H, HA), 7.36e7.74 (m, 4H,
Ar-H) ppm; 13C NMR (CDCl3 þ DMSO-d6)
d 22.1 (Ar-CH3), 51.9 (C-4),
6.1.1. General procedure for the synthesis of 2-
(arylsulfonylethenesulfonylmethyl)-4,5-dihydrooxazole 2aec/2-
(arylsulfonylethenesulfonylmethyl)-4,5-dihydrothiazole 3aec
58.2 (SO2CH2), 60.2 (C-5), 138.7 (SO2CH), 142.6 (CHSO2), 160.1 (C-2),
128.6, 129.9, 130.2, 132.4 ppm (aromatic carbons). Anal. Calcd. for
C13H15NO5S2: C, 47.40; H, 4.59; N, 4.25; Found: C, 47.32; H, 4.64; N,
4.29.
To
a flask charged with anhydrous samarium chloride
(0.1 mmol), dry toluene (10 ml) and aminoethanol/amino-
ethanethiol (2 mmol) followed by n-butyllithium (2.2 mmol) were
added at 0 ꢁC. The reaction mixture was stirred at 0 ꢁC for 30 min.
Then the contents were refluxed to 120 ꢁC. To this, arylsulfonyl-
ethenesulfonylacetic acid methyl ester (1) (1 mmol) was added and
continued refluxion for an additional period of 12e14 h. The
suspension was cooled to room temperature and filtered. The
filtrate was extracted with chloroform, washed with water
followed by brine solution. The solvent was removed in vacuo. The
product was purified by column chromatography [silica gel
(60e120 mesh), EtOAcehexane 1:3].
6.1.1.3. 2-(P-Chlorophenylsulfonylethenesulfonylmethyl)-4,5-dihy-
drooxazole 2c. White solid (0.2413 g, 69 %); m.p. 166e168 ꢁC; IR
(KBr): 1134, 1332 (SO2), 1577 (C]C), 1587 (C]N) cmꢀ1 1H NMR
;
(DMSO-d6)
d
3.65 (t, 2H, C-4, J ¼ 5.2 Hz), 4.31 (s, 2H, SO2CH2), 4.62
(t, 2H, C-5, J ¼ 5.2 Hz), 7.41 (d, J ¼ 14.6 Hz, 1H, HB), 7.73 (d,
J ¼ 14.6 Hz, 1H, HA), 7.45e7.79 (m, 4H, Ar-H) ppm; 13C NMR (DMSO-
d6)
d 52.2 (C-4), 58.9 (SO2CH2), 59.7 (C-5), 138.1 (SO2CH), 143.1
(CHSO2), 159.6 (C-2), 129.2, 130.4, 131.8, 132.6 ppm (aromatic
carbons). Anal. Calcd. for C12H12ClNO5S2: C, 41.20; H, 3.46; N, 4.00;
Found: C, 41.26; H, 3.49; N, 4.06.
6.1.1.1. 2-(Phenylsulfonylethenesulfonylmethyl)-4,5-dihydrooxazole
6.1.1.4. 2-(Phenylsulfonylethenesulfonylmethyl)-4,5-dihydrothiazole
2a. White solid (0.2239 g, 71%); m.p. 125e127 ꢁC; IR (KBr): 1128,
3a. White solid (0.2518 g, 76 %); m.p. 114e116 ꢁC; IR (KBr): 1130,
1334 (SO2), 1572 (C]C), 1581 (C]N) cmꢀ1
;
1H NMR
1339 (SO2), 1573 (C]C), 1594 (C]N) cmꢀ1 1H NMR (DMSO-d6)
;
Table 3
Minimum inhibitory concentration (MIC,
m
g/ml) of 3c, 5a and 5c.
Compound
Minimum inhibitory concentration, MIC, mg/ml
S. aureus
B. subtilis
K. pneumoniae
P. vulgaris
F. solani
C. lunata
A. niger
2c
5a
5c
200
100
25
6.25
e
100
50
12.5
6.25
e
200
100
50
6.25
e
200
100
50
12.5
e
100
100
50
200
100
12.5
e
100
100
25
Chloramphenicol
Ketoconazole
e
e
12.5
6.25
6.25

3182
V. Padmavathi et al. / European Journal of Medicinal Chemistry 45 (2010) 3178e3183
d
3.37 (t, 2H, C-5, J ¼ 7.3 Hz), 3.76 (t, 2H, C-4, J ¼ 7.3 Hz), 4.27 (s, 2H,
carbons). Anal. Calcd. for C15H16N2O5S2: C, 48.90; H, 4.38; N, 7.60;
Found: C, 48.86; H, 4.43; N, 7.55.
SO2CH2), 7.37 (d, J ¼ 14.3 Hz, 1H, HB), 7.68 (d, J ¼ 14.1 Hz, 1H, HA),
7.39e7.73 (m, 5H, Ar-H) ppm; 13C NMR (DMSO-d6)
d 36.9 (C-5), 51.7
(C-4), 58.0 (SO2CH2), 136.9 (SO2CH), 143.6 (CHSO2), 157.7 (C-2),
128.2, 129.7, 130.2, 131.9 ppm (aromatic carbons). Anal. Calcd. for
C12H13NO4S3: C, 43.49; H, 3.95; N, 4.23; Found: C, 43.54; H, 3.91;
N, 4.28.
6.1.2.3. 2-(40-P-Chlorophenylsulfonyl-10H-pyrrol-30-sulfonylmethyl)-
4,5-dihydrooxazole 4c. Yellow solid (0.2916 g, 75 %); m.p.
221e223 ꢁC; IR (KBr): 1142, 1345 (SO2), 1566 (C]N), 3220 (NH)
cmꢀ1; 1H NMR (DMSO-d6)
d
3.68 (t, 2H, C-4, J ¼ 5.4 Hz), 4.24 (s, 2H,
0
SO2-CH2), 4.68 (t, 2H, C-5, J ¼ 5.4 Hz), 6.93 (s, 1H, C2 -H), 7.13 (s, 1H,
C5 -H), 7.32e7.81 (m, 4H, Ar-H), 10.21 (bs, 1H, NH) ppm; 13C NMR
0
6.1.1.5. 2-(P-Methylphenylsulfonylethenesulfonylmethyl)-4,5-dihy-
drothiazole 3b. White solid (0.2693 g, 78 %); m.p. 125e127 ꢁC; IR
(DMSO-d6) d
52.2 (C-4), 58.9 (SO2-CH2), 60.9 (C-5), 105.7 (C-30),
(KBr): 1136, 1343 (SO2), 1579 (C]C), 1583 (C]N) cmꢀ1
;
1H NMR
108.1 (C-40), 114.8 (C-20), 115.6 (C-50), 159.4 (C-2), 128.7, 129.2, 130.2,
131.4 ppm (aromatic carbons). Anal. Calcd. for C14H13ClN2O5S2:
C,43.24; H, 3.37; N, 7.20; Found: C, 43.18; H, 3.33; N, 7.26.
(DMSO-d6)
d
2.21 (s, 3H, Ar-CH3), 3.33 (t, 2H, C-5, J ¼ 7.0 Hz), 3.69
(t, 2H, C-4, J ¼ 7.0 Hz), 4.34 (s, 2H, SO2CH2), 7.35 (d, J ¼ 13.7 Hz, 1H,
HB), 7.61 (d, J ¼ 13.7 Hz, 1H, HA), 7.44e7.76 (m, 4H, Ar-H) ppm; 13C
NMR (DMSO-d6)
d
21.6 (Ar-CH3), 37.3 (C-5), 52.5 (C-4), 59.9
6.1.2.4. 2-(40-Phenylsulfonyl-10H-pyrrol-30-sulfonylmethyl)-4,5-dihy-
(SO2CH2), 136.2 (SO2CH), 142.9 (CHSO2), 159.3 (C-2), 128.6, 129.9,
130.6, 131.2 ppm (aromatic carbons). Anal. Calcd. for C13H15NO4S3:
C, 45.20; H, 4.38; N, 4.05; Found: C, 45.14; H,; 4.35 N, 4.08.
drothiazole 5a. Yellow solid (0.2852 g, 77 %); m.p. 176e178 ꢁC; IR
(KBr): 1148, 1330 (SO2), 1570 (C]N), 3228 (NH) cmꢀ1 1H NMR
;
(DMSO-d6)
d
3.34 (t, 2H, C-5, J ¼ 7.1 Hz), 3.71 (t, 2H, C-4, J ¼ 7.10Hz),
0
4.26 (s, 2H, SO2-CH2), 6.88 (s, 1H, C2 -H), 7.09 (s, 1H, C5 -H),
6.1.1.6. 2-(P-Chlorophenylsulfonylethenesulfonylmethyl)-4,5-dihy-
7.26e7.71 (m, 5H, Ar-H), 9.59 (bs, 1H, NH) ppm; 13C NMR (DMSO-
drothiazole 3c. White solid (0.2561 g, 70 %); m.p. 133e135 ꢁC; IR
d6) d
37.4 (C-5), 52.8 (C-4), 58.4 (SO2CH2), 106.4 (C-30), 107.8 (C-40),
(KBr): 1129, 1345 (SO2), 1574 (C]C), 1588 (C]N) cmꢀ1
;
1H NMR
114.2 (C-20), 115.0 (C-50), 160.4 (C-2), 128.1, 129.8, 130.9, 131.9 ppm
(aromatic carbons). Anal. Calcd. for C14H14N2O4S3: C, 45.39; H, 3.81;
N, 7.56; Found: C, 45.43; H, 3.75; N, 7.52.
(DMSO-d6)
4.32 (s, 2H, SO2CH2), 7.47 (d, J ¼ 14.2 Hz, 1H, HB), 7.72 (d, J ¼ 14.2 Hz,
1H, HA), 7.49e7.79 (m, 4H, Ar-H) ppm; 13C NMR (DMSO-d6)
36.8
(C-5), 51.9 (C-4), 59.2 (SO2CH2), 137.7 (SO2CH), 143.2 (CHSO2), 158.7
(C-2), 128.1, 129.7, 130.4, 131.6 ppm (aromatic carbons). Anal. Calcd.
for C12H12ClNO4S3: C, 39.39; H, 3.31; N, 3.83; Found: C, 39.43; H,
3.28; N, 3.87.
d
3.39 (t, 2H, C-5, J ¼ 7.5 Hz), 3.73 (t, 2H, C-4, J ¼ 7.5 Hz),
d
6.1.2.5. 2-(40-P-Methylphenylsulfonyl-10H-pyrrol-30-sulfonylmethyl)-
4,5-dihydrothiazole 5b. Yellow solid (0.2845 g, 74 %); m.p.
182e184 ꢁC; IR (KBr): 1132, 1334 (SO2), 1565 (C]N). 3226 (NH)
cmꢀ1 1H NMR (DMSO-d6)
; d 2.26 (s, 3H, Ar-CH3), 3.39 (t, 2H, C-5,
J ¼ 7.4 Hz0), 3.78 (t, 2H, C-4, 0J ¼ 7.4 Hz), 4.22 (s, 2H, SO2-CH2), 6.94
6.1.2. General procedure for the synthesis of 2-(40-arylsulfonyl-10H-
pyrrol-30-sulfonylmethyl)-4,5-dihydrooxazole 4aec/2-(40-
arylsulfonyl-10H-pyrrol-30-sulfonylmethyl)-4,5-dihydrothiazole
5aec
An equimolar mixture of TosMIC and 2-(arylsulfonylethene-
sulfonylmethyl)-4,5-dihydrooxazole/2-(arylsulfonylethenesulfonyl-
methyl)-4,5-dihydrothiazole (2/3) (1 mmol) in Et2O/DMSO (2:1) was
added dropwise to a stirred contents of NaH (50 mg) in dry Et2O
(10 ml) at room temperature and stirring was continued for 12e14 h.
Then thereaction mixturewasdiluted withwaterandextracted with
ether. The ethereal layer was dried over anhydrous Na2SO4 and the
solvent was removed under reduced pressure. The resultant solid
was purified by column chromatography using silica gel (60e120
mesh) and EtOAcehexane (1.5:3) as eluent.
(s, 1H, C2 -H), 7.15 (s, 1H, C5 -H), 7.31e7.78 (m, 4H, Ar-H), 9.68 (bs,
1H, NH) ppm; 13C NMR (DMSO-d6)
d 21.4 (Ar-CH3), 36.7 (C-5), 51.6
(C-4), 59.1 (SO2CH2), 105.9 (C-30), 108.7 (C-40), 113.5 (C-20), 114.7
(C-50),161.2 (C-2),126.7,128.9, 130.5, 132.4 ppm (aromatic carbons).
Anal. Calcd. for C15H16N2O4S3: C, 46.86; H, 4.19; N, 7.29; Found: C,
46.92; H, 4.24; N, 7.34.
6.1.2.6. 2-(40-P-Chlorophenylsulfonyl-10H-pyrrol-30-sulfonylmethyl)-
4,5-dihydrothiazole 5c. Yellow solid (0.2955g, 73 %); m.p.
193e195 ꢁC; IR (KBr): 1140, 1340 (SO2), 1576 (C]N), 3231 (NH)
cmꢀ1; 1H NMR (DMSO-d6)
d
3.32 (t, 2H, C-5, J ¼ 7.2 Hz), 3.73 (t, 2H,
0
C-4, J ¼ 7.2 Hz), 4.28 (s, 2H, SO2-CH2), 6.99 (s, 1H, C2 -H), 7.12 (s, 1H,
C5 -H), 7.16e7.87 (m, 4H, Ar-H), 9.77 (bs, 1H, NH) ppm; 13C NMR
0
(DMSO-d6) d
37.2 (C-5), 52.3 (C-4), 58.7 (SO2CH2), 105.2 (C-30), 107.5
(C-40), 112.9 (C-20), 115.3 (C-50), 160.8 (C-2), 127.7, 128.1, 133.3,
134.2 ppm (aromatic carbons). Anal. Calcd. for C14H13ClN2O4S3: C,
41.53; H, 3.24; N, 6.92; Found: C, 41.47; H, 3.28; N, 6.85.
6.1.2.1. 2-(40-Phenylsulfonyl-10H-pyrrol-30-sulfonylmethyl)-4,5-dihy-
drooxazole 4a. Yellow solid (0.2374 g, 67 %); m.p. 202e204 ꢁC; IR
(KBr): 1139, 1342 (SO2), 1576 (C]N), 3224 (NH) cmꢀ1 1H NMR
;
(DMSO-d6)
d
3.67 (t, 2H, C-4, J ¼ 5.6 Hz), 4.21 (s, 2H, SO2-CH2), 04.61
6.2. Biological assays
0
(t, 2H, C-5, J ¼ 5.6 Hz), 6.89 (s, 1H, C2 -H), 7.11 (s, 1H, C5 -H),
7.31e7.72 (m, 5H, Ar-H), 9.98 (bs,1H, NH) ppm; 13C NMR (DMSO-d6)
6.2.1. Compounds
The compounds 2aec to 5aec were dissolved in DMSO at
different concentrations of 100, 200 and 800 mg/ml.
d
52.1 (C-4), 58.8 (SO2-CH2), 60.2 (C-5), 106.4 (C-30), 109.3 (C-40),
114.9 (C-20), 117.8 (C-50), 160.1 (C-2), 128.4, 129.7, 131.2, 131.9 ppm
(aromatic carbons). Anal. Calcd. for C14H14N2O5S2: C, 47.45; H, 3.98;
N, 7.90; Found: C, 47.50; H, 4.04; N, 7.96.
6.2.2. Cells
Bacterial strains S. aureus, B. subtilis, K. pneumonie, P. vulgaris and
fungi F. solani, C. lunata and A. niger were obtained from National
Collection of Industrial Microorganisms (NCIM), National Chemical
Laboratory, Pune, India.
6.1.2.2. 2-(40-P-Methylphenylsulfonyl-10H-pyrrol-30-sulfonylmethyl)-
4,5-dihydrooxazole 4b. Yellow solid (0.2652 g, 72 %); m.p.
197e199 ꢁC; IR (KBr): 1135, 1338 (SO2), 1568 (C]N), 3227 (NH)
cmꢀ1 1H NMR (DMSO-d6)
; d 2.24 (s, 3H, Ar-CH3), 3.65 (t, 2H, C-4,
J ¼ 5.2 Hz), 4.25 (s, 2H, SO20-CH2), 4.65 (t, 2H, C-5, J ¼ 5.2 Hz), 6.91
6.3. Antibacterial and antifungal assays
0
(s, 1H, C2 -H), 7.17 (s, 1H, C5 -H), 7.35e7.68 (m, 4H, Ar-H), 10.06 (bs,
1H, NH) ppm; 13C NMR (DMSO-d6)
d
22.4 (Ar-CH3), 51.8 (C-4), 58.2
Preliminary antimicrobial activities of compounds 2aec to 5aec
were tested by agar disc-diffusion method. Sterile filter paper discs
(6 mm diameter) moistened with the test compound solution in
(SO2-CH2), 59.4 (C-5), 106.1 (C-30), 108.9 (C-40), 115.1 (C-20), 116.4
(C-50), 160.6 (C-2), 128.1, 128.9, 129.6, 130.7 ppm (aromatic

V. Padmavathi et al. / European Journal of Medicinal Chemistry 45 (2010) 3178e3183
3183
DMSO of specific concentration 100
m
g and 200
m
g/disc were
potassium ferricyanide [K3Fe (CN)6 (2.5 ml, 1%). The mixture was
incubated at 50 ꢁC for 20 min and 2.5 ml of trichloroacetic acid
(10%) was added to the mixture, which was then centrifuged at
3000 rpm for 10 min. The upper layer of the solution (2.5 ml) was
mixed with distilled water (2.5 ml) and FeCl3 (0.5 ml, 0.1%) and the
absorbance was measured at 700 nm. Increased absorbance of the
reaction mixture indicated increased reducing power. In this
method also the compound 4c showed the highest reducing power.
carefully placed on the agar culture plates that had been previously
inoculated separately with the microorganisms. The plates were
incubated at 37 ꢁC and the diameter of the growth inhibition zones
were measured after 24 h in case of bacteria and after 48 h in case
of fungi.
The MICs of the compound assays were carried out using
microdilution susceptibility method. Chloramphenicol was used as
reference antibacterial agent. Ketoconazole was used as reference
antifungal agent. The test compounds, chloramphenicol and keto-
Acknowledgements
conazole were dissolved in DMSO at concentration of 800
and two-fold dilution of the solution was prepared (400, 200,
100,., 6.25 g/ml). The microorganism suspensions were inocu-
mg/ml
The authors are grateful to University Grants Commission (UGC),
New Delhi, for financial assistance under major research project.
One of the authors K. Mahesh is thankful to Council of Scientific and
Industrial Research (CSIR), New Delhi, India for the sanction of
Senior Research Fellowship.
m
lated to the corresponding wells. The plates were incubated at
36 ꢁC for 24 and 48 h for bacteria and fungi, respectively. The
minimum inhibitory concentrations of the compounds were
recorded as the lowest concentration of each chemical compounds
in the tubes with no turbidity (i.e. no growth) of inoculated
bacteria/fungi.
References
[1] T.G. Gant, A.I. Meyers, Tetrahedron 50 (1994) 2297e2360.
[2] T.W. Green, P.G.M. Wuts, Protective Groups in Organic Synthesis, second ed.
John Wiley & Sons Inc., 1991, pp. 265e266 and 433e436.
[3] D.A. Evans, S.J. Miller, T. Lectka, J. Am. Chem. Soc. 115 (1993) 6460e6461.
[4] E.J. Corey, K. Ishihara, Tetrahedron Lett. 33 (1992) 6807e6810.
[5] E.M. Fry, J. Org. Chem. 14 (1949) 887e894.
6.3.1. Antioxidant testing
The compounds 2aec to 5aec were tested for antioxidant
property by nitric oxide, DPPH and reducing power methods.
[6] C. Sund, J. Ylikoski, M. Kwiatkowski, Synthesis (1987) 853e855.
[7] N. Galeotti, C. Montagne, J. Poncet, P. Jouin, Tetrahedron Lett. 33 (1992)
2807e2810.
6.3.2. Assay for nitric oxide (NO) scavenging activity
Sodium nitroprusside (5
mM) in phosphate buffer pH 7.4 was
[8] M.J. Miller, P.G. Mattingly, M.A. Morrison, J.F. Kerwin, J. Am. Chem. Soc. 102
(1980) 7026e7032.
[9] R.J. Boyce, G.C. Mulqueen, G. Pattenden, Tetrahedron Lett. 35 (1994)
5705e5708.
[10] J.D. White, T.S. Kim, M. Nambu, J. Am. Chem. Soc. 117 (1995) 5612e5613.
[11] J. Einsiedel, H. Hubner, P. Gmeiner, Bioorg. Med. Chem. Lett. 11 (2001)
2533e2536.
[12] P. Zarantonello, C.P. Leslie, R. Ferritto, W.M. Kazmierski, Bioorg. Med. Chem.
Lett. 12 (2002) 561e565.
[13] P. Wipf, J.T. Reeves, R. Balachandran, B.W. Day, J. Med. Chem. 45 (2002)
1901e1917.
[14] C.A. Busacca, Y. Dong, E.M. Spinelli, Tetrahedron Lett. 37 (1996) 2935e2938.
[15] C.D.J. Boden, G. Pattenden, T. Ye, Synlett (1995) 417e419.
[16] A.B. Charette, P. Chua, J. Org. Chem. 63 (1998) 908e909.
[17] H. Wenker, J. Am. Chem. Soc. 57 (1935) 9e15.
incubated with 100 M concentration of test compounds dissolved
m
in a suitable solvent (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 dihy-
drochloride and 2% o-phosphoric acid dissolved in distilled water).
The absorbance of the chromophore formed during diazotization of
nitrite with sulfanilamide and subsequent N-naphthylethylenedi-
amine dihydrochloride was read at
repeated in triplicate.
l 546 nm. The experiment was
[18] T. Nishio, Tetrahedron Lett. 36 (1995) 6113e6116.
[19] P. Wipf, P.C. Fritch, Tetrahedron Lett. 35 (1994) 5397e5400.
[20] P. Lafargue, P. Guenot, J.P. Lellouche, Synlett (1995) 171e173.
[21] S.G. Mahler, G.L. Serra, D. Antonow, E. Manta, Tetrahedron Lett. 42 (2001)
8143e8146.
[22](a) S. Neidle, Nat. Prod. Rep. 18 (2001) 291e309.
[22](b) D.E. Wemmer, Biopolymers 52 (2001) 197e211.
[23](a) H. Shiraish, T. Nishitani, T. Nishihara, S. Sakaguchi, Y. Ishii, Tetrahedron 55
(1999) 13957e13964.
6.3.3. Reduction of 1,1-diphenyl-2-picrylhydrazyl (DPPH) free
radical (DPPH method)
The nitrogen centered stable free radical 1,1-diphenyl-2-pic-
rylhydrazyl (DPPH) has often been used to characterize antioxi-
dants. It is reversibly reduced and the odd electron in the DPPH free
radical gives a strong absorption maximum at
l 517 nm, which is
purple in color. This property makes it suitable for spectrophoto-
metric studies. A radical scavenging antioxidant reacts with DPPH
stable free radical and converts into 1,1-diphenyl-2-picrylhy-
drazine. The resulting decolorization is stoichiometric with respect
to the number of electrons captured. The change in the absorbance
produced in this reaction has been used to measure antioxidant
properties.
[23](b) A. Zelikin, V.R. Shastri, R. Langer, J. Org. Chem. 64 (1999) 3379e3380.
[23](c) J.H. Liu, H.W. Chan, H.N.C. Wong, J. Org. Chem. 65 (2000) 3274e3283.
[24](a) A.M. Van Leusen, H. Siderius, B.E. Hoogenboom, D. Van Leusen, Tetrahedron
Lett. 13 (1972) 5337e5340.
[24](b) N.P. Pavri, M.L. Trudell, J. Org. Chem. 62 (1997) 2649e2651.
[25] V. Padmavathi, B. Jagan Mohan Reddy, M. Rajagopal Sarma, P. Thriveni,
J. Chem. Res. (2004) 79e80.
[26] V. Padmavathi, A.V. Nagendra Mohan, P. Thriveni, Ali-Shazia, Eur. J. Med.
Chem. 44 (2009) 2313e2321.
[27] V. Padmavathi, B.C. Obula Reddy, D.R.C.V. Subbaiah, Indian J. Chem. 43B
(2004) 2456e2458.
[28] V. Padmavathi, B.C. Obula Reddy, P. Thriveni, A.V. Nagendra Mohan, Synth.
Commun. 37 (2007) 3127e3142.
The solutions of test compounds (100
(100 M) in dioxane/ethanol. The tubes were kept at an ambient
temperature for 20 min. and the absorbance was measured at
mM) were added to DPPH
m
l
517 nm. The difference between the test and the control experi-
ments was taken and expressed as the per cent scavenging of the
DPPH radical.
[29] National Committee for Clinical Laboratory Standards (NCCLS) Approved
Standard Document M-7A, Villanova, PA (1985).
[30] P.R. Murray, E.J. Baron, M.A. Pfaller, F.C. Tenover, R.H. Yolken, in: G.L. Wood,
J.A. Washington (Eds.), Manual of Clinical Microbiology, Am. Soc. Microbiol.
(1995) Washington DC.
[31] A. Shirwaiker, K. Rajendran, C. DineshKumar, Indian J. Exp. Biol. 42 (2004)
803e807.
[32] B.H. Babu, B.S. Shailesh, J. Paddikala, Fitotherapia 72 (2001) 272e279.
[33] K. Kato, S. Terao, N. Shimamoto, M. Hirata, J. Med. Chem. 31 (1988) 793e798.
[34] M. Oyaizu, Jpn. J. Nutr. 44 (1986) 307e315.
6.3.4. Reducing power
The reducing power was determined according to the method of
Oyaizu [34]. The 100
mM concentration was prepared in methanol
were mixed with phosphate buffer (2.5 ml, 0.2M, pH 6.6) and