Synthesis, antimicrobial and antioxidant activities of sulfone linked bis heterocycles - Pyrazolyl oxadiazoles and pyrazolyl thiadiazole

Article abstract of DOI:10.1248/cpb.57.1376

A new class of bis heterocycles - sulfone linked pyrazolyl oxadiazoles and thiadiazoles were developed from Z-styrylsulfonylacetic acid. The pyrazolyl thiadiazoles exhibited excellent antimicrobial activity whereas pyrazolyl oxadiazoles displayed good antioxidant activity.

Full text of DOI:10.1248/cpb.57.1376

1376
Chem. Pharm. Bull. 57(12) 1376—1380 (2009)
Vol. 57, No. 12
Synthesis, Antimicrobial and Antioxidant Activities of Sulfone Linked Bis
Heterocycles—Pyrazolyl Oxadiazoles and Pyrazolyl Thiadiazole
Venkatapuram PADMAVATHI,* Sanapalli NAGI REDDY, and Konda MAHESH
Department of Chemistry, Sri Venkateswara University; Tirupati-517 502, India.
Received July 12, 2009; accepted September 14, 2009; published online September 24, 2009
A new class of bis heterocycles—sulfone linked pyrazolyl oxadiazoles and thiadiazoles were developed from
Z-styrylsulfonylacetic acid. The pyrazolyl thiadiazoles exhibited excellent antimicrobial activity whereas pyra-
zolyl oxadiazoles displayed good antioxidant activity.
Key words Z-styrylsulfonylacetic acid; pyrazolyl oxadiazole; pyrazolyl thiadiazole; antimicrobial activity; antioxidant property
Five membered heterocycles natural as well as synthetic was treated with two fold excess thiourea in tetrahydrofuran.
are important class of compounds due to their varied biologi- The reaction mixture indicated two spots on TLC which were
cal properties. Pyrazoles show a wide variety of pharmaco- separated and identified as 2-aryl-5-((styrylsulfonyl)methyl)-
logical effects including anti-inflammatory,1) antiobesity2) al- 1,3,4-thiadiazole (5) as major product apart from 4 as minor
1
cohol dehydrogenase inhibitory3) and phosphodiesterase in- one. The H-NMR spectra of 4a and 5a displayed two dou-
hibitory4) activities. Some bis pyrazoline derivatives are also blets at 6.52, 6.48 (HA) and 7.30, 7.34 ppm (HB) for the olefin
found with antimicrobial activity.5) Huisgen’s 1,3-dipolar cy- protons. A singlet at 4.55, 4.49 ppm was observed in both the
cloaddition is a versatile method to synthesize five mem- compounds which was assigned to methylene protons in ad-
bered nitrogen heterocycles.6) Recent synthesis of pyra- dition to signals due to aromatic protons. The coupling con-
zoles via 1,3-dipolar cycloaddition includes reaction of stant value Jꢀ11.7 Hz, indicated the cis geometry. The 13C-
nitrile imines and activated olefins7,8) or enamines,9,10) hydra- NMR spectra of 4a and 5a exhibited signals at 50.8, 48.7
zones and nitroolefins,11,12) diazocompounds and activated (SO2CH2), 130.2, 130.4 (C-HA), 145.0, 142.3 (C-HB), 156.7,
olefins13—17) and azomethine imines and alkynes.18) 1,3,4- 156.8 (C-5), and 165.3, 164.4 ppm (C-2), respectively. The
Thiadiazole nucleus constitutes the active part of several bio- olefin moiety present in 4 and 5 was used to develop pyrazo-
logically active compounds including antibacterial,19—21) an- line ring by 1,3-dipolar cycloaddition of diazomethane.
timycotic,22,23) and anti-inflammatory agents.24—26) There are Treatment of 4 and 5 with diazomethane in the presence of
a large number of methods for the synthesis of 2,5-disubsti- catalytic amount of Et3N at ꢁ20 to ꢁ15 °C for 40 h gave
tuted 1,3,4-thiadiazoles. The most universal is two-stage a solid which was identified as 2-((4ꢂ,5ꢂ-dihydro-4ꢂ-phenyl-
method consisting of acylation of thiosemicarbazide using 1ꢂ-H-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-aryl-1,3,4-oxadiazole
carboxylic acid chlorides and subsequent cyclization of the (6) and 2-((4ꢂ,5ꢂ-dihydro-4ꢂ-phenyl-1ꢂ-H-pyrazol-3ꢂ-ylsul-
1
intermediate acylthiosemicarbazides in the presence of vari- fonyl)methyl)-5-aryl-1,3,4-thiadiazole (7) (Chart 2). The H-
ous dehydrating agents viz., sulfuric acid, phosphorus oxy- NMR spectra of 6a and 7a exhibited an AMX splitting pat-
chloride, benzoyl chloride and acetyl chloride.27) In addition, tern for pyrazoline ring protons at 4.49, 4.47 (HA), 4.08, 4.17
several 1,3,4-oxadiazole derivatives exhibit significant anti- (HM) and 3.69, 3.61 ppm (HX) respectively, in addition to the
bacterial28—32) and anti-inflammatory activities.33—35) One of signals of methylene and aromatic protons. The observed
the popular methods for the synthesis of 1,3,4-oxadiazoles coupling constant values JAMꢀ11.9, 12.6 Hz, JAXꢀ6.1,
involves cyclization of diacylhydrazines prepared by the re- 6.6 Hz, JMXꢀ11.0, 11.5 Hz indicated that HA, HM are cis, HA,
action of acyl chlorides and hydrazine. Several cyclodehy- HX are trans and HM, HX are geminal. The compounds 6 and
drating agents such as Et2O·BF3,36) 1,1,1,3,3,3-hexamethyl- 7 on oxidation with chloranil in xylene gave the correspond-
disilazane,37) triflic anhydride,38) phosphorus pentoxide,39) ing aromatized products, 2-((4ꢂ-phenyl-1ꢂH-pyrazol-3ꢂ-yl-
polyphosphoric acid,40) thionyl chloride,41,42) phosphorus sulfonyl)methyl)-5-aryl-1,3,4-oxadiazole (8) and 2-((4ꢂ-
oxychloride43) and sulfuric acid44) have been used. Recently phenyl-1ꢂH-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-aryl-1,3,4-thia-
we have reported the synthesis, antimicrobial and cytotoxic diazole (9) (Chart 2). The disappearance of AMX splitting
activities of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles.45) In pattern and the appearance of a singlet in the downfield re-
continuation of our interest on the chemical and pharmaco- gion, merged with aromatic protons confirmed their forma-
logical properties of sulfone linked bis heterocycles, we re- tion. The 13C-NMR spectra of 8a and 9a exhibited signals
port herein the synthesis, antimicrobial and antioxidant activ- at 52.3, 49.8 (SO2CH2), 134.9, 133.2 (C-4ꢂ), 139.2, 139.4
ities of pyrazolyl oxadiazoles and thiadiazoles.
Chemistry
The starting material Z-styrylsulfonyl acetic acid 3 was
obtained via the reaction of phenylacetylene with mercap-
toacetic acid followed by oxidation (Chart 1).46) The reaction
of 3 with differently substituted benzoic acid hydrazides in
the presence of phosphorus oxychloride afforded 2-aryl-5-
Chart 1
((styrylsulfonyl)methyl)-1,3,4-oxadiazole (4). Compound 4
© 2009 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: vkpuram2001@yahoo.com

December 2009
1377
Table 1. The in Vitro Antibacterial Activity of 6—9
Zone of inhibition (mm)
Concen-
tration
Compound
Gram (ꢃ)ve
Gram (ꢁ)ve
(mg/ml)
S. aureus B. subtilis
E. coli
K. pneumoniae
6a
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
10
14
8
12
14
10
13
12
14
23
27
19
23
30
32
16
20
16
21
19
22
23
28
25
28
36
38
38
41
7
9
—
8
6b
—
—
8
—
—
—
—
23
24
18
22
23
25
14
17
12
16
15
19
23
25
22
24
29
31
42
45
11
9
6c
12
24
25
19
22
32
34
17
19
15
19
18
21
26
31
23
25
35
37
35
39
10
21
26
17
24
25
26
16
18
14
17
16
18
23
27
22
25
30
32
40
44
7a
7b
7c
8a
8b
8c
Chart 2
9a
(C-5ꢂ), 149.1, 148.9 (C-3ꢂ), 158.7, 157.9 (C-5), 163.9,
164.1 ppm (C-2), besides signals due to aromatic carbons.
Antimicrobial Testing The compounds 6—9 were
tested for antimicrobial activity at two different concentra-
tions 100 and 200 mg/ml. The antibacterial activity was
screened against Staphylococcus aureus, Bacillus subtilis
(Gram-positive bacteria) and Escherichia coli, Klebsiella
pneumoniae (Gram-negative bacteria) on nutrient agar plates
at 37 °C for 24 h using chloramphenicol as reference drug.
The compounds were also evaluated for their antifungal ac-
tivity against Fusarium solani, Curvularia lunata and As-
pergillus niger using ketoconazole as standard drug. Fungi
cultures were grown on potato dextrose agar medium (PDA)
at 25 °C for 3 d. The spore suspension was adjusted to 106
pores/ml at a mg/ml concentration by the Vincent and Vin-
cent method.47)
The results of the compounds of preliminary antibacterial
testing are shown in Table 1. The results revealed that the
compounds 2-((4ꢂ,5ꢂ-dihydro-4ꢂ-phenyl-1ꢂ-H-pyrazol-3ꢂ-yl-
sulfonyl)methyl)-5-aryl-1,3,4-thiadiazole (7) and 2-((4ꢂ-
phenyl-1ꢂH-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-aryl-1,3,4-thia-
diazole (9) exhibited high activity (17—38 mm) on both
Gram-positive and Gram-negative bacteria. In fact, com-
pounds 7c and 9c showed pronounced activity (30—38 mm)
towards Gram-positive bacteria. The compounds 2-((4ꢂ-
phenyl-1ꢂ-H-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-aryl-1,3,4-oxa-
diazole (8) displayed moderate activity towards Gram-posi-
tive bacteria (16—22 mm). On the other hand, 2-((4ꢂ,5ꢂ-dihy-
dro-4ꢂ-phenyl-1ꢂ-H-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-aryl-
1,3,4-oxadiazole (6) exhibited least activity against both bac-
teria. All the test compounds inhibited the spore germination
of tested fungi A. niger, F. solani and C. lunata. Results of
the investigation presented in Table 2 revealed that all the
compounds except 6 showed relatively high inhibitory effect
on F. solani and C. lunata than on A. niger. The compounds
7c and 9c displayed high activity.
9b
9c
Chloramphenicol
Table 2. The in Vitro Antifungal Activity of 6—9
Zone of inhibition (mm)
Concentration
Compound
(mg/ml)
F. solani
C. lunata
A. niger
6a
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
13
15
11
13
15
17
25
28
23
25
30
32
21
24
18
21
24
26
33
36
28
32
30
32
38
42
16
19
14
17
18
21
26
28
25
26
32
34
23
26
17
22
25
28
33
35
27
33
36
39
41
44
12
14
10
12
14
16
21
24
21
22
26
29
19
22
15
19
22
24
29
32
26
30
24
26
36
39
6b
6c
7a
7b
7c
8a
8b
8c
9a
9b
9c
Ketoconazole
The minimum inhibitory concentration (MIC) values were The structure–antimicrobial activity relationship of the syn-
determined as the lowest concentration that completely in- thesized compounds revealed that the compounds having
hibited the visible growth of the microorganisms (Table 3). pyrazoline in combination with oxadiazole (6) exhibited least

1378
Vol. 57, No. 12
Table 3. Minimum Inhibitory Concentration of Compounds 7c and 9c
Minimum inhibitory concentration (MIC), mg/ml
Compound
S. aureus
B. subtilis
E. coli
K. pneumoniae
F. solani
C. lunata
A. niger
7c
9c
100
25
50
25
200
50
200
50
100
50
100
25
100
50
Chloramphenicol
Ketoconazole
6.25
—
6.25
—
6.25
—
12.5
—
—
12.5
—
6.25
—
6.25
zoic acid hydrazide (5 mmol), POCl3 (4 ml) was added and heated under re-
flux for 5—6 h. The excess POCl3 was removed under reduced pressure and
the residue was poured onto crushed ice. The resulting precipitate was fil-
tered, washed with saturated sodium bicarbonate solution and then with
water, dried and recrystallized from ethanol to get 4.
Table 4. Antioxidant Activity of 6—9
% Inhibition at 100 mM
Compound
Nitric oxide method
DPPH method
2-Phenyl-5-((styrylsulfonyl)methyl)-1,3,4-oxadiazole (4a): White solid,
yield 75%, mp 112—114 °C; IR (KBr) cmꢁ1: 1589 (CꢀN), 1542 (CꢀC),
1317, 1135 (SO2); 1H-NMR (CDCl3) d: 4.55 (s, 2H, SO2–CH2), 6.52 (d, 1H,
HA, Jꢀ11.7 Hz), 7.30 (d, 1H, HB, Jꢀ11.7 Hz), 7.22—7.92 (m, 10H, Ar–H);
13C-NMR (CDCl3) d: 50.8 (SO2–CH2), 130.2 (C–HA), 145.0 (C–HB), 156.7
(C-5), 165.3 (C-2), 121.8, 126.1, 127.2, 128.5, 130.1, 130.7, 131.5, 136.2
(aromatic carbons).
6a
6b
6c
7a
7b
7c
8a
8b
8c
9a
9b
9c
69.5
74.1
78.5
45.8
47.3
49.4
74.8
54.3
89.6
46.7
45.5
49.9
70.3
72.5
79.3
46.3
46.8
49.7
75.3
52.5
88.4
46.3
46.9
50.5
2-((Styrylsulfonyl)methyl)-5-p-tolyl-1,3,4-oxadiazole (4b): White solid,
yield 74%, mp 105—107 °C; IR (KBr) cmꢁ1: 1593 (CꢀN), 1546 (CꢀC),
1
1318, 1138 (SO2); H-NMR (CDCl3) d: 2.26 (s, 3H, Ar–CH3), 4.53 (s, 2H,
SO2–CH2), 6.54 (d, 1H, HA, Jꢀ11.8 Hz), 7.31 (d, 1H, HB, Jꢀ11.8 Hz),
7.25—7.94 (m, 9H, Ar–H); 13C-NMR (CDCl3) d: 21.8 (Ar–CH3), 51.1
(SO2–CH2), 129.6 (C–HA), 146.1 (C–HB), 156.1 (C-5), 164.8 (C-2), 121.2,
125.2, 128.2, 128.9, 129.7, 130.9, 131.2, 136.4 (aromatic carbons).
2-(p-Chlorophenyl)-5-((styrylsulfonyl)methyl)-1,3,4-oxadiazole (4c):
White solid, yield 74%, mp 127—129 °C; IR (KBr) cmꢁ1: 1608 (CꢀN),
1559 (CꢀC), 1320, 1143 (SO2); 1H-NMR (CDCl3) d: 4.58 (s, 2H,
activity when compared with compounds having pyrazole
with oxadiazole (8) and pyrazoline/pyrazole with thiadiazole SO2–CH2), 6.56 (d, 1H, HA, Jꢀ12.0 Hz), 7.33 (d, 1H , HB, Jꢀ12.0 Hz),
(7/9) moieties. However, compounds 8 displayed moderate
activity. On the other hand compounds 7 and 9 exhibited
7.27—7.96 (m, 9H, Ar–H); 13C-NMR (CDCl3) d: 51.2 (SO2–CH2), 130.6
(C–HA), 145.2 (C–HB), 156.9 (C-5), 165.6 (C-2), 121.5, 126.3, 128.5, 129.5,
130.2, 130.6, 131.7, 138.6 (aromatic carbons).
General Procedure of Synthesis of 2-Aryl-5-((styrylsulfonyl)methyl)-
high activity. The presence of chloro substituent on the aro-
matic ring enhances the activity of the compounds. The max-
imum activity was observed with the compounds 7c and 9c.
Antioxidant Testing The compounds 6—9 were tested
for antioxidant property by nitric oxide48,49) and 1,1-
diphenylpicrylhydrazyl (DPPH)50) methods. The compounds
6a, 6b, 6c, 8a and 8c exhibited high antioxidant activity in
both nitric oxide and DPPH methods at 100 mM concentration
(Table 4).
1,3,4-thiadiazole (5a—c) In a sealed test tube, a mixture of 4 (5 mmol),
thiourea (20 mmol) dissolved in tertahydrofuran (5 ml) was taken. The con-
tents were heated at 120—150 °C in an oil bath for 22—26 h. After the reac-
tion was completed, it was extracted with dichloromethane. The organic
layer was washed with water, brine solution and dried over anhydrous
Na2SO4. The resultant solid was recrystallized from methanol to obtain 5.
2-Phenyl-5-((styrylsulfonyl)methyl)-1,3,4-thiadiazole (5a): White solid,
yield 64%, mp 133—135 °C; IR (KBr) cmꢁ1: 1580 (CꢀN), 1544 (CꢀC),
1318, 1140 (SO2); 1H-NMR (CDCl3) d: 4.49 (s, 2H, SO2–CH2), 6.48 (d, 1H,
HA, Jꢀ11.6 Hz), 7.34 (d, 1H, HB, Jꢀ11.6 Hz), 7.17—7.92 (m, 10H, Ar–H);
13C-NMR (CDCl3) d: 48.7 (SO2–CH2), 130.4 (C–HA), 142.3 (C–HB), 156.8
(C-5), 164.4 (C-2), 121.4, 125.2, 128.4, 128.9, 130.1, 130.3, 131.6, 134.5
(aromatic carbons).
Conclusion
A new and novel bis heterocyclic systems pyrazolyl oxadi-
azoles and thiadiazoles were developed from Z-styrylsul-
fonylacetic acid by appropriate functionalization of acid and
olefin groups. The compounds pyrazolyl thiadiazoles exhib-
ited excellent antimicrobial activity, whereas pyrazolyl oxadi-
azoles showed good antioxidant property.
2-((Styrylsulfonyl)methyl)-5-p-tolyl-1,3,4-thiadiazole (5b): White solid,
yield 69%, mp 147—149 °C; IR (KBr) cmꢁ1: 1594 (CꢀN), 1548 (CꢀC),
1
1324, 1142 (SO2); H-NMR (CDCl3) d: 2.23 (s, 3H, Ar–CH3) 4.46 (s, 2H,
SO2–CH2), 6.51 (d, 1H, HA, Jꢀ11.8 Hz), 7.32 (d, 1H, HB, Jꢀ11.8 Hz),
7.19—7.83 (m, 9H, Ar–H); 13C-NMR (CDCl3) d: 21.9 (Ar–CH3), 49.3
(SO2–CH2), 129.7 (C–HA), 145.3 (C–HB), 155.6 (C-5), 165.7 (C-2), 121.6,
123.4, 125.6, 127.5 , 130.4, 130.5, 130.7, 133.7 (aromatic carbons).
Experimental
2-(p-Chlorophenyl)-5-((styrylsulfonyl)methyl)-1,3,4-thiadiazole (5c):
Melting points were determined in open capillaries on a Mel-Temp appa- White solid, yield 72%, mp 155—157 °C; IR (KBr) cmꢁ1: 1561 (CꢀC),
ratus and are uncorrected. The purity of the compounds was checked by 1603 (CꢀN), 1322, 1144 (SO2); 1H-NMR (CDCl3) d: 4.48 (s, 2H,
TLC (silica gel H, BDH, ethyl acetate/hexane, 1 : 3). The IR spectra were SO2–CH2), 6.53 (d, 1H, HA, Jꢀ12.0 Hz), 7.36 (d, 1H , HB, Jꢀ12.0 Hz),
recorded on a Thermo Nicolet IR 200 FT-IR spectrometer as KBr pellets and 7.23—7.99 (m, 9H, Ar–H); 13C-NMR (CDCl3) d: 48.2 (SO2–CH2), 130.7
the wave numbers were given in cmꢁ1. The H-NMR spectra were recorded (C–HA), 145.7 (C–HB), 147.1 (C-5) 162.8 (C-2), 120.7, 126.4, 127.7, 128.6,
1
in CDCl3/DMSO-d6 on a Bruker spectrospin operating at 400 MHz. The 13C- 130.0, 130.8, 131.9, 134.8 (aromatic carbons).
NMR spectra were recorded in CDCl3/DMSO-d6 on Bruker spectrospin op-
erating at 100 MHz. All chemical shifts are reported in d (ppm) using TMS
General Procedure of Synthesis of 2-((4ꢀ,5ꢀ-Dihydro-4ꢀ-phenyl-1ꢀH-
pyrazol-3ꢀ-ylsulfonyl)methyl)-5-aryl-1,3,4-oxadiazole (6a—c)/2-((4ꢀ,5ꢀ-
as an internal standard. The microanalyses were performed on a Perkin- Dihydro-4ꢀ-phenyl-1ꢀH-pyrazol-3ꢀ-ylsulfonyl)methyl)-5-aryl-1,3,4-thia-
Elmer 240C elemental analyzer. The antioxidant property was carried out by diazole (7a—c) To a cooled solution of 4/5 (2.5 mmol) in dichloromethane
using Shimadzu UV-2450 spectrophotometer. The starting compound Z-
(10 ml), an ethereal solution of diazomethane (20 ml, 0.4 M) and triethy-
lamine (0.06 g) were added. The reaction mixture was kept at ꢁ20 to
styrylsulfonylacetic acid (3) was prepared by the literature procedure.46)
General Procedure of Synthesis of 2-Aryl-5-((styrylsulfonyl)methyl)- ꢁ15 °C for 40—48 h. The solvent was removed under reduced pressure. The
1,3,4-oxadiazole (4a—c) To Z-styrylsulfonylacetic acid (5 mmol) and ben- resultant solid was purified by column chromatography (silica gel (BDH)

December 2009
1379
60—120 mesh, hexane–ethyl acetate, 4 : 1).
2-((4ꢂ,5ꢂ-Dihydro-4ꢂ-phenyl-1ꢂH-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-phenyl-
The resultant solid was purified by recrystallization from 2-propanol.
2-((4ꢂ-Phenyl-1ꢂH-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-phenyl-1,3,4-oxadia-
1,3,4-oxadiazole (6a): Yellow solid, yield 62%, mp 136—138 °C; IR (KBr) zole (8a): Yellow solid, yield 64%, mp 157—159 °C; IR (KBr) cmꢁ1: 3341
cmꢁ1: 3338 (NH), 1582 (CꢀN), 1331, 1130 (SO2); 1H-NMR (DMSO-d6) d: (NH), 1584 (CꢀN), 1331, 1136 (SO2); 1H-NMR (DMSO-d6) d: 4.74 (d, 1H,
3.69 (dd, 1H, HX, JAXꢀ6.1 Hz, JMXꢀ11.0 Hz), 4.74 (d, 1H, SO2–CH2, SO2–CH2, Jꢀ14.6 Hz), 4.98 (d, 1H, SO2–CH2, Jꢀ14.6 Hz), 6.52 (br s, 1H,
Jꢀ14.6 Hz), 4.08 (dd, 1H, HM, JAMꢀ11.9 Hz, JMXꢀ11.0 Hz), 4.49 (dd, 1H,
NH) 6.84—7.78 (m, 11H, C5ꢂ–H, Ar–H); 13C-NMR (DMSO-d6) d: 52.3
HA, JAMꢀ11.9 Hz, JAXꢀ6.1 Hz ) 5.03 (d, 1H, SO2–CH2, Jꢀ14.6 Hz), 7.20— (SO2–CH2), 134.9 (C-4ꢂ), 139.2 (C-5ꢂ), 149.1 (C-3ꢂ), 158.7 (C-5), 163.9 (C-
7.94 (m, 10H, Ar–H), 8.87 (br s, 1H, NH); 13C-NMR (DMSO-d6) d: 48.6 2), 122.1, 127.6, 128.4, 129.1, 129.8, 137.2, 140.1 (aromatic carbons). Anal.
(C-4ꢂ), 51.6 (SO2–CH2), 59.1 (C-5ꢂ), 149.4 (C-3ꢂ), 156.6 (C-5), 165.5 (C-2),
123.2, 125.6, 127.5, 129.1, 129.8, 137.2, 138.9 (aromatic carbons). Anal.
Calcd for C18H16N4O3S: C, 58.68; H, 4.38; N, 15.21; Found: C, 58. 81; H,
4.43; N, 15.32.
Calcd for C18H14N4O3S: C, 59.01; H, 3.85; N, 15.29; Found: C, 59.09; H,
3.90; N, 15.35.
2-((4ꢂ-Phenyl-1ꢂH-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-p-tolyl-1,3,4-oxadia-
zole (8b): Yellow solid, yield 69%, mp 163—165 °C; IR (KBr) cmꢁ1: 3342
2-((4ꢂ,5ꢂ-Dihydro-4ꢂ-phenyl-1ꢂH-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-p-tolyl- (NH), 1596 (CꢀN), 1332, 1138 (SO2); 1H-NMR (DMSO-d6) d: 2.32 (s, 3H,
1,3,4-oxadiazole (6b): Yellow solid, yield 72%, mp 112—114 °C; IR (KBr) Ar–CH3), 4.71 (d, 1H, SO2–CH2, Jꢀ14.2 Hz), 5.04 (d, 1H, SO2–CH2,
cmꢁ1: 3341 (NH), 1592 (CꢀN), 1334, 1131 (SO2); 1H-NMR (DMSO-d6) d: Jꢀ14.2 Hz), 6.56 (br s, 1H, NH), 6.81—7.75 (m, 10H, C5ꢂ–H, Ar–H); 13C-
2.32 (s, 3H, Ar–CH3), 3.66 (dd, 1H, HX, JAXꢀ6.2 Hz, JMXꢀ11.1 Hz), 4.06
(dd, 1H, HM, JAMꢀ12.1 Hz, JMXꢀ11.1 Hz), 4.47 (dd, 1H, HA, JAMꢀ12.1 Hz, (C-5ꢂ), 148.7 (C-3ꢂ), 157.8 (C-5), 164.2 (C-2), 122.3, 127.8, 128.6, 128.9,
AXꢀ6.2 Hz), 4.72 (d, 1H, SO2–CH2, Jꢀ14.2 Hz), 5.04 (d, 1H, SO2–CH2, 130.2, 135.4, 138.8 (aromatic carbons). Anal. Calcd for C19H16N4O3S: C,
Jꢀ14.2 Hz), 7.21—7.85 (m, 9H, Ar–H), 8.95 (br s, 1H, NH); 13C-NMR 59.99; H, 4.24; N, 14.73; Found: C, 60.07; H, 4.30; N, 14.80.
(DMSO-d6) d: 21.8 (CH3–Ar), 47.7 (C-4ꢂ), 51.8 (SO2–CH2), 58.2 (C-5ꢂ), 2-((4ꢂ-Phenyl-1ꢂH-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-(p-chlorophenyl)-
NMR (DMSO-d6) d: 22.5 (CH3–Ar), 51.5 (SO2–CH2), 135.2 (C-4ꢂ), 141.4
J
148.6 (C-3ꢂ), 157.8 (C-5), 164.6 (C-2), 122.1, 127.7, 128.3, 129.4, 130.1, 1,3,4-oxadiazole (8c): Yellow solid, yield 72%, mp 181—183 °C; IR (KBr)
137.4, 140.2 (aromatic carbons). Anal. Calcd for C19H18N4O3S: C, 59.67; H, cmꢁ1: 3344 (NH), 1602 (CꢀN), 1334, 1142 (SO2); 1H-NMR (DMSO-d6) d:
4.74; N, 14.65; Found: C, 59.73; H, 4.68 ; N, 14.71.
4.80 (d, 1H, SO2–CH2, Jꢀ14.9 Hz), 5.06 (d, 1H, SO2–CH2, Jꢀ14.9 Hz) 6.53
2-((4ꢂ,5ꢂ-Dihydro-4ꢂ-phenyl-1ꢂH-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-(p- (br s, 1H, NH), 6.87—7.78 (m, 10H, C5ꢂ–H, Ar–H); 13C-NMR (DMSO-d6)
chlorophenyl)-1,3,4-oxadiazole (6c): Yellow solid, yield 74%, mp 148— d: 52.6 (SO2–CH2), 135.4 (C-4ꢂ), 141.5 (C-5ꢂ), 149.7 (C-3ꢂ) 158.9 (C-5),
1
150 °C; IR (KBr) cmꢁ1: 3343 (NH), 1606 (CꢀN), 1336, 1134 (SO2); H-
164.4 (C-2), 122.5, 127.4, 128.8, 129.5, 130.4, 137.6, 140.5 (aromatic car-
NMR (DMSO-d6) d: 3.68 (dd, 1H, HX, JAXꢀ6.3 Hz, JMXꢀ11.3 Hz), 4.13
bons). Anal. Calcd for C18H13ClN4O3S: C, 53.94; H, 3.27; N, 13.98; Found:
(dd, 1H, HM, JAMꢀ12.2 Hz, JMXꢀ11.3 Hz), 4.54 (dd, 1H, HA, JAMꢀ12.2 Hz, C, 54.02; H, 3.31; N, 14.07.
J
AXꢀ6.3 Hz), 4.77 (d, 1H, SO2–CH2, Jꢀ14.9 Hz), 5.06 (d, 1H, SO2–CH2,
2-((4ꢂ-Phenyl-1ꢂH-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-phenyl-1,3,4-thiadia-
Jꢀ14.9 Hz), 7.23—7.98 (m, 9H, Ar–H), 8.97 (br s, 1H, NH); 13C-NMR
zole (9a): Yellow solid, yield 68%, mp 168—170 °C; IR (KBr) cmꢁ1: 3346
(DMSO-d6) d: 48.9 (C-4ꢂ), 51.9 (SO2–CH2), 59.3 (C-5ꢂ), 146.6 (C-3ꢂ), (NH), 1587 (CꢀN), 1336, 1139 (SO2); 1H-NMR (DMSO-d6) d: 4.62 (d, 1H,
158.0 (C-5), 164.8 (C-2), 122.2, 127.9, 128.8, 129.2, 130.2, 137.6, 140.4 SO2–CH2, Jꢀ14.3 Hz), 4.89 (d, 1H, SO2–CH2, Jꢀ14.3 Hz), 6.55 (br s, 1H,
(aromatic carbons). Anal. Calcd for C18H15ClN4O3S: C, 53.67; H, 3.75; N, NH), 6.76—7.71 (m, 11H, C5ꢂ–H, Ar–H); 13C-NMR (DMSO-d6) d: 49.8
13.91; Found: C, 53.60; H, 3.82; N, 14.00.
(SO2–CH2), 133.2 (C-4ꢂ), 139.4 (C-5ꢂ), 148.9 (C-3ꢂ), 157.9 (C-5), 164.1 (C-
2-((4ꢂ,5ꢂ-Dihydro-4ꢂ-phenyl-1ꢂ-H-pyrazol-3ꢂ-ylsulfonyl)methyl)-5- 2), 124.3, 125.7, 126.5, 129.3, 129.9, 137.4, 138.2 (aromatic carbons). Anal.
phenyl-1,3,4-thiadiazole (7a): Yellow solid, yield 70%, mp 145—147 °C; IR Calcd for C18H14N4O2S2: C, 56.53; H, 3.69; N, 14.65; Found: C, 56.45; H,
(KBr) cmꢁ1: 3339 (NH), 1583 (CꢀN), 1332, 1132 (SO2); 1H-NMR 3.74; N, 14.55.
(DMSO-d6) d: 3.61 (dd, 1H, HX, JAXꢀ6.6 Hz, JMXꢀ11.5 Hz), 4.17 (dd, 1H,
HM, AMꢀ12.6 Hz, MXꢀ11.5 Hz), 4.47 (dd, 1H, HA,
AMꢀ12.6 Hz, zole (9b): Yellow solid, yield 73%, mp 181—183 °C; IR (KBr) cmꢁ1: 3341
AXꢀ6.6 Hz), 4.61 (d, 1H, SO2–CH2, Jꢀ14.7 Hz), 5.15 (d, 1H, SO2–CH2,
2-((4ꢂ-Phenyl-1ꢂH-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-p-tolyl-1,3,4-thiadia-
J
J
J
J
(NH), 1595 (CꢀN), 1334, 1138 (SO2); 1H-NMR (DMSO-d6) d: 2.23 (s, 3H,
Jꢀ14.7 Hz), 7.25—7.84 (m, 10H, Ar–H), 8.91 (br s, 1H, NH); 13C-NMR Ar–CH3), 4.67 (d, 1H, SO2–CH2, Jꢀ14.5 Hz), 4.90 (d, 1H, SO2–CH2,
(DMSO-d6) d: 48.8 (C-4ꢂ), 49.3 (SO2–CH2), 59.3 (C-5ꢂ), 149.4 (C-3ꢂ), Jꢀ14.5 Hz), 6.52 (br s, 1H, NH), 6.84—7.76 (m, 10H, C5ꢂ–H, Ar–H); 13C-
157.8 (C-5), 164.7 (C-2), 122.8, 127.7, 128.5, 129.0 129.7, 134.6, 137.2 NMR (DMSO-d6) d: 22.4 (CH3–Ar), 48.1 (SO2–CH2), 134.3 (C-4ꢂ), 141.5
(aromatic carbons). Anal. Calcd for C18H16N4O2S2: C, 56.23; H, 4.19; N, (C-5ꢂ), 147.9 (C-3ꢂ), 159.7 (C-5), 164.3 (C-2), 122.4, 127.9, 128.7, 129.5
14.57; Found: C, 56.17; H, 4.11 ; N, 14.63.
2-((4ꢂ,5ꢂ-Dihydro-4ꢂ-phenyl-1ꢂH-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-p-tolyl- 57.56; H, 4.07; N, 14.13; Found: C, 57.63; H, 4.02; N, 14.18.
1,3,4-thiadiazole (7b): Yellow solid, yield 66%, mp 156—158 °C; IR (KBr) 2-((4ꢂ-Phenyl-1ꢂH-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-(p-chlorophenyl)-
130.3, 137.5, 138.5 (aromatic carbons). Anal. Calcd for C19H16N4O2S2: C,
cmꢁ1: 3342 (NH), 1592 (CꢀN), 1334, 1133 (SO2); 1H-NMR (DMSO-d6) d: 1,3,4-thiadiazole (9c): Yellow solid, yield 66%, mp 194—196 °C; IR (KBr)
2.35 (s, 3H, Ar–CH3), 4.64 (d, 1H, SO2–CH2, Jꢀ14.8 Hz), 4.97 (d, 1H,
SO2–CH2, Jꢀ14.8 Hz), 3.67 (dd, 1H, HX, JAXꢀ6.8 Hz, JMXꢀ11.2 Hz), 4.11
cmꢁ1: 3345 (NH), 1604 (CꢀN), 1336, 1141 (SO2); 1H-NMR (DMSO-d6) d:
4.72 (d, 1H, SO2–CH2, Jꢀ14.9 Hz), 5.03 (d, 1H, SO2–CH2, Jꢀ14.9 Hz),
(dd, 1H, HM, JAMꢀ12.1 Hz, JMXꢀ11.2 Hz), 4.50 (dd, 1H, HA, JAMꢀ12.1 Hz, 6.58 (br s, 1H, NH), 6.89—7.78 (m, 10H, C5ꢂ–H, Ar–H); 13C-NMR (DMSO-
J
AXꢀ6.8 Hz), 7.25—7.97 (m, 9H, Ar–H), 8.94 (br s, 1H, NH); 13C-NMR d6) d: 48.7 (SO2–CH2), 132.6 (C-4ꢂ), 139.7 (C-5ꢂ), 148.7 (C-3ꢂ) 159.2 (C-5),
(DMSO-d6) d: 22.1 (CH3–Ar), 50.2 (SO2–CH2), 49.1 (C-4ꢂ), 59.4 (C-5ꢂ), 165.6 (C-5), 125.4 127.2, 128.9, 129.5, 129.7, 134.8, 139.7 (aromatic car-
147.9 (C-3ꢂ), 158.1 (C-5), 163.9 (C-2), 124.3, 127.3 128.7, 129.1, 130.2, bons). Anal. Calcd for C18H13ClN4O2S2 : C, 51.86; H, 3.13; N, 13.44; Found:
137.5, 139.4 (aromatic carbons). Anal. Calcd for C19H18N4O2S2: C, 57.27; C, 51.78; H, 3.16; N, 13.52.
H, 4.55; N, 14.06; Found: C, 57.35; H, 4.49; N, 14.00.
Antimicrobial Testing The compounds 6—9 were dissolved in DMSO
2-((4ꢂ,5ꢂ-Dihydro-4ꢂ-phenyl-1ꢂH-pyrazol-3ꢂ-ylsulfonyl)methyl)-5-(p- at different concentrations of 100, 200 and 800 mg/ml.
chlorophenyl)-1,3,4-thiadiazole (7c): Yellow solid, yield 73%, mp 172—
Antibacterial and Antifungal Assays Preliminary antimicrobial activ-
ity of compounds 6—9 was tested by agar disc-diffusion method. Sterile fil-
1
174 °C; IR (KBr) cmꢁ1: 3344 (NH), 1602 (CꢀN), 1337, 1135 (SO2); H-
NMR (DMSO-d6) d: 3.69 (dd, 1H, HX, JAXꢀ6.6 Hz, JMXꢀ11.8 Hz), 4.19
ter paper discs (6 mm diameter) moistened with the test compound solution
(dd, 1H, HM, JAMꢀ12.8 Hz, JMXꢀ11.8 Hz), 4.49 (dd, 1H, HA, JAMꢀ12.8 Hz, in DMSO of specific concentration 100 mg and 200 mg/disc were carefully
JAXꢀ6.6 Hz), 4.69 (d, 1H, SO2–CH2, Jꢀ14.4 Hz), 5.01 (d, 1H, SO2–CH2,
placed on the agar culture plates that had been previously inoculated sepa-
rately with the microorganisms. The plates were incubated at 37 °C and the
Jꢀ14.4 Hz), 7.26—8.01 (m, 9H, Ar–H), 8.96 (br s, 1H, NH); 13C-NMR
(DMSO-d6) d: 49.6 (C-4ꢂ), 50.7 (SO2–CH2), 59.7 (C-5ꢂ), 148.2 (C-3ꢂ), diameter of the growth inhibition zones were measured after 24 h in case of
158.3 (C-5), 164.9 (C-2), 122.4, 128.1, 128.9, 129.4, 130.4, 137.7, 140.6 bacteria and after 48 h in case of fungi.
(aromatic carbons). Anal. Calcd for C18H15ClN4O2S2: C, 51.61; H, 3.61; N,
13.37; Found: C, 51.50; H, 3.65; N, 13.47.
The MIC’s of the compound assays were determined using micro dilution
susceptibility method. Chloramphenicol was used as reference antibacterial
General Procedure of Synthesis of 2-((4ꢀ-Phenyl-1ꢀH-pyrazol-3ꢀ-ylsul- agent. Ketoconazole was used as reference antifungal agent. The test com-
fonyl)methyl)-5-aryl-1,3,4-oxadiazole (8a—c)/2-((4ꢀ-Phenyl-1ꢀH-pyrazol- pounds, chloramphenicol and ketoconazole were dissolved in DMSO at con-
3ꢀ-ylsulfonyl)methyl)-5-aryl-1,3,4-thiadiazole (9a—c) A solution of 6/7 centration of 800 mg/ml. The two-fold dilution of the solution was prepared
(1 mmol) and chloranil (1.4 mmol) in xylene (10 ml) was refluxed for 24— (400, 200, 100, …, 6.25 mg/ml). The microorganism suspensions were incu-
25 h. Then, the reaction mixture was treated with a 5% NaOH solution. The
bated at 36 °C for 24 and 48 h for bacteria and fungi, respectively. The mini-
organic layer was separated and repeatedly washed with water. It was dried mum inhibitory concentrations of the compounds were recorded as the low-
over anhydrous Na2SO4 and the solvent was removed on a rotary evaporator. est concentration of each chemical compound in the tubes with no turbidity

1380
Vol. 57, No. 12
(i.e., no growth) of inoculated bacteria/fungi.
Antioxidant Testing The compounds 6—9 are tested for antioxidant
property by nitric oxide and DPPH methods.
Assay for Nitric Oxide (NO) Scavenging Activity Sodium nitroprus-
side (5 mM) in phosphate buffer pH 7.4 was incubated with 100 mM concen-
tration of test compounds dissolved in a suitable solvent (dioxane/methanol)
17) Aggarwal V. K., de Vicente J., Bonnert R. V., J. Org. Chem., 68,
5381—5383 (2003).
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(2006).
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and tubes were incubated at 25 °C for 120 min. Control experiment was con- 20) Thomasco L. M., Gadwood R. C., E. Weaver A., Ochoada J. M., Ford
ducted 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
C. W., Zurenko G. E., Hamel J. C., Stapert D., Moerman J. K., Schaadt
R. D., Agi B. H., Bioorg. Med. Chem. Lett., 13, 4193—4196 (2003).
reagent (1% sulfanilamide, 0.1% N-naphthylethylenediamine dihydrochlo- 21) Karaku S., Rollas S., Il Farmaco, 57, 577—581 (2002).
ride and 2% o-phosphoric acid dissolved in distilled water). The absorbance 22) Dogan H. N., Duran A., S. Rollas., Sener G., Uysal M. K., Gülen D.,
of the chromophore formed during diazotization of nitrite with sulfanil-
Bioorg. Med. Chem., 10, 2893—2898 (2002).
amide and subsequent N-naphthylethylenediamine dihydrochloride was read 23) Mamolo M. G., Vio L., Banfi E., Il Farmaco, 51, 71—74 (1996).
at l 546 nm. The experiment was repeated in triplicate.
Reduction of 1,1-Diphenyl-2-picrylhydrazyl (DPPH) Free Radical
(DPPH Method) The nitrogen centered stable free radical 1,1-diphenyl-2-
24) Schenone S., Brullo C., Bruno O., Bondavalli F., Ranise A., Filippelli
W., Rinaldi B., Capuano A., Falcone G., Bioorg. Med. Chem., 14,
1698—1705 (2006).
picrylhydrazyl (DPPH) has often been used to characterize antioxidants. It is 25) Santagati M., Modica M., Santagati A., Russo F., Amico-Roxas M.,
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 spectrophotometric studies. A radical scaveng-
Pharmazie, 49, 880—884 (1994).
26) Palaska E., Sahin G., Kelecin P., Durlu N. T., Altinok G., Il Farmaco,
57, 101—107 (2002).
ing antioxidant reacts with DPPH stable free radical and converts into 1,1- 27) Matysiak J., Niewiadomy A., Synth. Commun., 31, 2537—2547
diphenyl-2-picrylhydrazine. The resulting decolorization is stoichiometric (2001).
with respect to the number of electrons captured. The change in the ab- 28) Sxahin G., Palaska E., Ekizoˇglu M., Zalp M. O., Il Farmaco, 57,
sorbance produced in this reaction has been used to measure antioxidant
properties.
The solutions of test compounds (100 mM) were added to DPPH (100 mM)
in dioxane/methanol. The tubes were kept at an ambient temperature for 30) Macaev F., Rusu G., Bogrebnoi S., Gudima A., Stingaci E., Vlad L.,
539—542 (2002).
29) Sx. G. Kuc. u kgu zel., E. E. Oruc., Rollas S., Sxahin. F., Ozbek. A.,
Eur. J. Med. Chem., 37, 197—206 (2002).
20 min and the absorbance was measured at l 517 nm. The difference be-
tween the test and the control experiments was taken and expressed as the
per cent scavenging of the DPPH radical.
Shvets N., Kandemirli F., Dimoglo A., Reynolds R., Bioorg. Med.
Chem., 13, 4842—4850 (2005).
31) Zitouni G. T., Kaplancikli Z. A., Yildiz. M. T., Chevallet P., Kaya D.,
Eur. J. Med. Chem., 40, 607—613 (2005).
Acknowledgements The authors are grateful to Council of Scientific
and Industrial Research (CSIR), New Delhi, for financial assistance under
major research project.
32) Mamolo M. G., Zampieri D., Vio L., Fermeglia M., Ferrone M., Pricl
S., Scialino G., Banfi E., Bioorg. Med. Chem., 13, 3797—3809 (2005).
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