Synthesis, characterization and biological studies of some bioactive thiazolotriazole derivatives

Article abstract of DOI:10.1515/znb-2010-1215

The key precursor rac-2-(4-isobutylphenyl)ethyl-1,2,4-triazole-5-thione (3) was synthesized in good yield from Ibuprofen (1). One-pot three-component reactions of 3 with 5-aryl-furan-2-carboxaldehydes/substituted aromatic aldehydes and monochloroacetic acid in acetic acid in the presence of acetic anhydride and anhydrous sodium acetate afforded substituted thiazolo[3,2-b][1,2, 4]triazole derivatives 4 and 5. The structures of the newly synthesized compounds were elucidated by elemental analyses and spectral data. The compounds were tested for their in-vitro antimicrobial activities.

Full text of DOI:10.1515/znb-2010-1215

Synthesis, Characterization and Biological Studies of Some Bioactive
Thiazolotriazole Derivatives
Manjunatha Kumsia, Boja Poojarya, Prajwal Lourdes Loboa, Nalilu Suchetha Kumarib,
and Anoop Chullikanac
a Department of Chemistry, Mangalore University, Mangalagangothri-574 199, Karnataka, India
b Department of Biochemistry, K. S. Hegde Medical Academy, Deralakatte-574 162, Karnataka,
India
c Clinigene International Ltd., Central Laboratory, A Biocon Company, Bangalore-560
100, Karnataka India
Reprint requests to Dr. Boja Poojary. E-mail: bojapoojary@gmail.com
Z. Naturforsch. 2010, 65b, 1509 – 1515; received August 3, 2010
The key precursor rac-2-(4-isobutylphenyl)ethyl-1,2,4-triazole-5-thione (3) was synthesized in
good yield from Ibuprofen (1). One-pot three-component reactions of 3 with 5-aryl-furan-2-carb-
oxaldehydes/substituted aromatic aldehydes and monochloroacetic acid in acetic acid in the presence
of acetic anhydride and anhydrous sodium acetate afforded substituted thiazolo[3,2-b][1,2,4]triazole
derivatives 4 and 5. The structures of the newly synthesized compounds were elucidated by elemental
analyses and spectral data. The compounds were tested for their in-vitro antimicrobial activities.
Key words: Ibuprofen, 1,2,4-Triazole-5-thione, Thiazolo[3,2-b][1,2,4]triazole,
Antimicrobial Activity
Introduction
made them attractive targets for syntheses over many
years. A large number of N-bridged heterocycles de-
rived from 1,2,4-triazoles are important pharmaco-
logical agents, and a significant amount of research
has been directed towards this class of compounds
[18 – 20].
In the light of such observations, we herein re-
port the synthesis of some fused bridgehead nitrogen
heterocyclic systems, viz. substituted thiazolo[3,2-b]-
[1,2,4]triazole derivatives incorporating the Ibuprofen
moiety, and to screen them for antimicrobial activities.
Non-steroidal anti-inflammatory drugs (NSAIDs)
like Ibuprofen are widely used in the treatment of pain
and inflammation, including osteoarthritis and rheuma-
toid arthritis [1 – 3]. The pharmacological activity of
NSAIDs is related to the suppression of prostaglandin
biosynthesis of arachidonic acid by inhibiting the cy-
clooxygenase enzyme (COXs) [4, 5]. Prolonged use of
NSAIDs like ibuprofen has been associated with gas-
trointestinal (GI) complications ranging from stomach
irritation to life-threatening GI ulceration bleeding and
nephrotoxicity [6, 7]. Therefore, synthetic approaches
based on chemical modifications of NSAIDs have been
taken with the aim of improving their safety profile.
Substituted thiazoles have revealed anti-inflamm-
atory, antimicrobial [8, 9], antitumor [10], anticonv-
ulsant [11], analgesic [12], and anticancer [13] prop-
erties. 1,2,4-triazoles represent important pharmaco-
phores and play a vital role as medicinal agents. 1,2,4-
triazole derivatives due to their wide range of biologi-
cal activities such as antimicrobial, anti-inflammatory
[14], anticancer [15], antitubercular [16], and antimy-
cotic [17] properties, have received considerable at-
tention. The structural diversity and biological im-
portance of 1,2,4-triazole-containingheterocycles have
Results and Discussion
The acid hydrazide rac-2 was prepared by esterifica-
tion of Ibuprofen followed by treatment with hydrazine
hydrate in absolute alcohol [21, 22], and 2 converted
into the corresponding thiosemicarbazide by treating
it with potassium thiocyanate followed by cyclization
with 5 % potassium hydroxide solution to yield 2-
(4-isobutylphenyl)ethyl-1,2,4-triazole-5-thione 3 [15].
One-pot three-component condensation reactions [23 –
26] of 3 with monochloroacetic acid and 5-aryl-furan-
2-carbaldehydes or substituted benzaldehydes in acetic
acid in the presence of acetic anhydride and anhy-
drous sodium acetate afforded substituted thiazolo[3,2-
c
0932–0776 / 10 / 1200–1509 $ 06.00 ꢀ 2010 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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M. Kumsi et al. · Bioactive Thiazolotriazole Derivatives
R1 = 4-Cl, 4-NO2, 2-NO2, 4-Br, 2,4,5-Cl3, 3-Cl-4-F, 2-Me-6-NO2, 2-Me-4-NO2, 4-Cl-2-NO2, 3,4-Cl2;
R1 = 3,4-(OCH3)2, 3,4-(OCH3)2-5-NO2, 4-OH, 3,5-F2.
Comp.
4a
4-Cl
–
4b
4-NO2
–
4c
2-NO2
–
4d
4-Br
–
4e
4f
4g
R1
R2
2,4-Cl2-5-F
–
3-Cl-4-F 2-Me-6-NO2
–
–
Comp.
4h
4i
4j
5a
–
5b
–
5c
–
5d
–
3,5-F2
R1
R2
2-Me-4-NO2 2-NO2-4-Cl 3,4-Cl2
–
–
–
3,4-(OMe)2 3,4-(OMe)2-2-NO2 4-OH
Scheme 1.
b][1,2,4]triazole derivatives 4 and 5 (Scheme 1). Sub- of signals due to two protons of tautomeric NH/SH
1
stituted 5-aryl-furan-2-carbaldehydes were prepared in the H NMR spectra of 4a – j and 5a – d and the
through Meerwein reaction [23].
The structures of the newly synthesized compounds
were confirmed by elemental analyses, IR, H NMR
presence of a new singlet in the region δ = 7.81 –
8.34 ppm for the exocyclic methine proton of the thi-
azolidinone ring confirmed the transformation of 3 into
the corresponding substituted thiazolo[3,2-b][1,2,4]-
triazole derivatives 4a – j and 5a – d. Two distinct dou-
1
and mass spectra. The data are presented in the Exper-
imental Section. In the IR spectra of 3 the NH, C=S and
C=N units displayed strong absorption bands in the re-
gions around 3285, 1215, and 1608 cm−1, respectively.
The absorption bands associated with other functional
groups appeared in the expected regions. 1H NMR
spectra of 3 showed a down-field D2O-exchangeable
broad singlet at δ = 12.64 ppm for its two tautomeric
NH/SH protons. Further, an LC-MS spectrum of 3
showed the molecular ion peak at m/z = 262 which
corresponds to its molecular formula C14H19N3S.
1
blets observed for 4a – j in their H NMR spectra in
the region δ = 6.82 – 7.00 ppm with J = 3.6 to 4.0 Hz
(β-protons of the furan ring) also confirmed their struc-
tures. Further, in the 13C NMR spectra, 4a – j and 5a –
d showed their characteristic C=O carbon signal in the
region δ = 176.82– 176.98 ppm in addition to other
characteristic signals of the remaining carbon atoms.
The investigation of antibacterial and antifungal
screening data revealed that all the tested com-
The IR spectra of 4a – j and 5a – d displayed strong pounds 4a – j and 5a – d exhibit moderate to good
absorption bands in the regions 1725 – 1738 cm−1 inhibition in DMSO. Compounds 4i and 5c showed
(C=O) and 1598– 1610 cm−1 (C=N), respectively. comparatively good activity against all the bacterial
The absorption bands associated with other functional strains, which can be attributed to the presence of phar-
groups appeared in the expected regions. The absence macologically active 4-chloro-2-nitroarylfuryl and 4-
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M. Kumsi et al. · Bioactive Thiazolotriazole Derivatives
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hydroxy moieties attached to the thiazolotriazole ring. rac-5[2-(4-Isobutyl)phenyl]ethyl-4H-1,2,4-trizole-3-thione
(3)
Compounds 4b, 4c, 4e, 4j, and 5b showed moderate
activity.
Propanehydrazide 2 (22 g, 0.1 mol) was dissolved in
water (100 mL) containing concentrated hydrochloric acid
(10 mL). Potassium thiocyanate (19.4 g, 0.2 mol) was added,
and the mixture was warmed on a water bath for 5 h. The
reaction mixture was cooled. The precipitated solid was fil-
tered, dried and recrystallized from ethanol to get the aroyl
thiosemicarbazide (m. p. 177 ◦C, yield 24.8 g (88 %)). A mix-
ture of this aroyl thiosemicarbazide (27.9 g, 0.1 mol) and
aqueous 5 % potassium hydroxide solution (100 mL) was re-
fluxed 3 h. The reaction mixture was poured into crushed
ice and acidified with dilute hydrochloric acid. The precipi-
tate thus obtained was filtered, dried and recrystallized from
ethanol.
Compounds 4j and 5c showed comparatively good
activity against all the fungal strains, which can be at-
tributed to the presence of 3,4-dichloroarylfuryl and 4-
hydroxy moieties attached to the thiazolotriazole ring.
Compounds 4a, 4b, 4e, 4f, 4h, 5a, and 5b exhibited
moderate antifungal activity.
Conclusion
The present study reports the synthesis of thiazolo-
triazoles derived from Ibuprofen and the evaluation of
their antimicrobial activities. The compounds exhibit
moderate to good activity against all the pathogenic
strains. Compound 5c containing a 4-hydroxyphenyl
M. p. 198 ◦C; yield 22.2 g (85 %). – IR (KBr, cm−1): ν =
3100 (Ar-H), 2972 (C-H), 1215 (C=S) cm−1. – 1H NMR
(CDCl3): δ = 0.85 (d, J = 8 Hz, 6 H, 2× CH3), 1.68 (d,
group attached to the thiazolotriazole unit shows good J = 8 Hz, 3 H, CH3), 1.80 – 1.88 (m, 1 H, CH), 2.45 (d,
J = 4.0 Hz, 2 H, CH2), 4.15 (q, J = 8.0 Hz, 1 H, CH), 697
(d, J = 8 Hz, 2 H, Ar-H), 706 (d, J = 8 Hz, 2 H, Ar-H),
12.64 (br-s, 2 H, NH/SH). – 13C NMR ([D6]DMSO): δ =
18.33, 18.78, 22.42, 30.28, 37.48, 126.13, 126.32, 128.25,
128.43, 136.20, 139.05, 161.05, 167.15. – LC-MS: m/z =
261 [M]+. – C14H19N3S (261.3): calcd. C 64.31, H 7.33,
N 16.08, S 12.27; found C 64.30, H 7.33, N 16.09, S 12.27.
antimicrobial activity.
Experimental Section
Instruments
The melting points were determined by an open capillary
method and are uncorrected. The IR spectra (in KBr pellets)
were recorded on a Shimadzu FT-IR 157 spectrophotome-
ter. The 1H NMR and 13C NMR spectra were recorded on a
Bruker Avance II-400 (400 MHz) spectrometer using TMS
as an internal standard. Mass spectra were recorded on a
Agilent Technology LC-mass spectrometer. Elemental anal-
yses (CHNS) were performed on an CHNS Elementar Vario
EL III. The progress of the reaction was monitored by thin-
layer chromatography (TLC) on silica gel plates.
Procedure for the preparation of rac-2-(4-isobutylphenyl)-
ethyl-5-[aryl/(5-arylfuran-2-yl)-methylidene]-[1,3]thi-
azolo[3,2-b][1,2,4]triazol-6(5H)-ones 4a – j and 5a – d
A mixture of the mercaptotriazole 3 (2.61 g, 0.01 mol),
monochloroacetic acid (1.41 g, 0.015 mol), anhydrous
sodium acetate (2 g, 0.024 mol), glacial acetic acid (20 mL),
acetic anhydride (15 mL) and a 5-aryl-furan-2-carbaldehyde
or substituted benzaldehyde (0.01 mol) was heated to reflux
for 6 – 8 h. The reaction mixture was cooled and poured into
crushed ice with vigorous stirring. The solid obtained was
filtered, washed with water, dried and recrystallized from a
mixture of ethanol and dimethyl formamide.
rac-2-[4-Isobutylphenyl]propanehydrazide (2)
A
mixture of ethyl 2-(4-isobutylphenyl)propanoate
(23.4 g, 0.1 mol) and hydrazine hydrate (9.3 mL, 0.2 mol)
was refluxed in absolute alcohol (50 mL) for 8 h. The excess
solvent was then distilled off under reduced pressure, and
the concentrated solution was poured into ice cold water.
The separated solid was filtered, washed and dried. The
crude product was purified by recrystallization from ethanol.
rac-2-(4-Isobutylphenyl)ethyl-5-[(5-(4-chlorophenyl)furan-
2-yl)methylidene]-[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-
one (4a)
◦
M. p. 243 C; yield 4.0 g (82 %). – IR (KBr, cm−1): ν =
3028 (Ar-H), 2955 (C-H), 1726 (C=O), 162 (C=N), 839 (C-
M. p. 71 ◦C; yield 85 %. – IR (KBr, cm−1): ν = 3449 (NH, Cl). – 1H NMR ([D6]DMSO): δ = 0.88 (d, 6 H, 2× CH3,
NH2), 3275 (NH2), 2972 (C-H), 1695 (CO-NH) cm−1. – 1H J = 6.4 Hz), 1.52 (d, 3 H, CH3, J = 7.6 Hz), 1.75 – 1.85 (m,
NMR (CDCl3): δ = 0.85 (d, J = 8 Hz, 6 H, 2× CH3), 1.68 1 H, CH), 2.43 (d, 2 H, CH2, J = 7.2 Hz), 4.31 – 4.33 (q,
(d, J = 8 Hz, 3 H, CH3), 1.80 – 1.88 (m, 1 H, CH), 2.45 (d, 1 H, CH, J = 7.2 Hz), 6.85 (d, 1 H, furan H, J = 4.0 Hz),
J = 4 Hz, 2 H, CH2), 4.14 (q,J = 8 Hz, 1 H, CH), 4.0 (s, 7.01 (d, 1 H, furan H, J = 4.0 Hz), 7.11 (d, 2 H, ArH, J =
2 H, NH2), 7.5 (br s, 5 H, C6H4 and NH). – LC-MS: m/z = 8.4 Hz), 7.31 (d, 2 H, ArH, J = 8.4 Hz), 7.41 (d, 2 H, ArH, J =
220 [M]+. – C13H20N2O (220.3): calcd. C 70.87, H 9.15, 8.0 Hz), 7.66 (d, 2 H, ArH, J = 8 Hz), 7.86 (s, 1 H, exocyclic
N 12.72; found C 70.85, H 9.13, N 12.70.
vinylic H). – 13C NMR ([D6]DMSO): δ = 20.27, 22.84,
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M. Kumsi et al. · Bioactive Thiazolotriazole Derivatives
30.65, 40.58, 45.54, 109.88, 121.48, 123.16, 124.89, 126.48, 881 (C-Br). – 1H NMR ([D6]DMSO): δ = 0.88 (d, 6 H,
127.63, 127.79, 129.93, 136.01, 139.94, 140.96, 149.24, 2× CH3, J = 6.4 Hz), 1.76 (d, 3 H, CH3, J = 7.2 Hz), 1.80 –
156.75, 158.62, 160.79, 176.82. – LC-MS: m/z = 490 [M]+, 1.87 (m, 1 H, CH), 2.44 (d, 2 H, CH2, J = 7.2 Hz), 4.30 –
492 [M+2]+ in 3:1 ratio. – C27H24N3O2ClS (489.12): calcd. 4.35 (q, 1 H, CH, J = 7.2 Hz), 6.87 (d, 1 H, furan H, J =
C 66.18, H 4.94, N 8.58, S 6.54; found C 66.20, H 4.96, 3.6 Hz), 7.00 (d, 1 H, furan H, J = 3.6 Hz), 7.10 (d, 2 H,
N 8.59, S 6.52.
ArH, J = 5.6 Hz), 7.22 (d, 2 H, ArH, J = 5.6 Hz), 7.32 –
7.61 (m, 4 H, ArH-NO2), 7.86 (s, 1 H, exocyclic vinylic
H). – 13C NMR ([D6]DMSO): δ = 20.26, 22.84, 30.65,
40.58, 45.54, 109.10, 121.42, 123.12 124.74, 126.54, 127.72,
127.82, 129.96, 136.74, 140.02, 141.46, 149.84, 157.06,
159.64, 160.80, 176.86. – LC-MS: m/z = 534 [M]+, 536
[M+2]+ in 1:1 ratio. – C27H24N3O2BrS (533.07): calcd.
C 64.78, H 4.83, N 1.19, S 6.41; found C 64.77, H 4.85,
N 11.16, S 6.39.
rac-2-(4-Isobutylphenyl)ethyl-5-[(5-(4-nitrophenyl)furan-2-
yl)-methylidene]-[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-
one (4b)
M. p. 256 ◦C; yield 3.8 g (76 %). – IR (KBr, cm−1):
ν = 3102 (Ar-H), 2957 (C-H), 1729 (C=O), 1604 (C=N)
–
1H NMR ([D6]DMSO): δ = 0.88 (d, 6 H, 2× CH3, J =
6.4 Hz), 1.74 (d, 3 H, CH3, J = 7.6 Hz), 1.79 – 1.86 (m,
1 H, CH), 2.43 (d, 2 H, CH2, J = 7.2 Hz), 4.31 – 4.33 (q,
1 H, CH, J = 7.2 Hz), 6.86 (d, 1 H, furan H, J = 3.6 Hz),
7.02 (d, 1 H, furan H, J = 3.6 Hz), 7.10 (d, 2 H, ArH,
J = 8.0 Hz), 7.28 (d, 2 H, ArH, J = 8.4 Hz), 7.50 (d, 2 H,
ArH, J = 8.0 Hz), 7.64 (d, 2 H, ArH, J = 8.0 Hz), 7.87 (s,
1 H, exocyclic vinylic H) – 13C NMR ([D6]DMSO): δ =
20.28, 22.86, 30.66, 40.54, 45.58, 113.87, 122.38, 123.26,
124.769, 126.58, 127.52, 127.64, 129.62, 136.0, 139.94,
140.15, 145.20, 157.07, 159.46, 161.04, 176.92 – LC-MS:
m/z = 501 [M+1]+. – C27H24N4O4S (500.5): calcd. C 64.78,
H 4.83, N 1.19, S 6.41; found C 64.76, H 4.85, N 11.15,
S 6.39.
rac-2-(4-Isobutylphenyl)ethyl-5-[(5-(2,4-dichloro-5-fluoro-
phenyl)furan-2-yl)methylidene]-[1,3]thiazolo [3,2-b]-
[1,2,4]triazol-6(5H)-one (4e)
M. p. 258 ◦C; yield 4.4 g (79 %). – IR (KBr, cm−1):
ν = 3062 (Ar-H), 2986 (C-H), 1728 (C=O), 1599 (C=N). –
1H NMR ([D6]DMSO): δ = 0.88 (d, 6 H, 2× CH3, J =
6.4 Hz), 1.76 (d, 3 H, CH3, J = 7.2 Hz), 1.80 – 1.87 (m, 1 H,
CH), 2.44 (d, 2 H, CH2, J = 7.2 Hz), 4.30 – 4.35 (q, 1 H,
CH, J = 7.2 Hz), 6.87 (d, 1 H, furan H, J = 3.6 Hz), 7.00 (d,
1 H, furan H, J = 3.6 Hz), 7.10 (d, 2 H, ArH, J = 6.8 Hz),
7.22 (d, 2 H, ArH, J = 6.8 Hz), 7.41 (s, 1 H, ArH), 7.62 (s,
1 H, ArH), 7.89 (s, 1 H, exocyclic vinylic H). – 13C NMR
([D6]DMSO): δ = 20.32, 22.88, 30.68, 40.76, 45.60, 112.36,
122.67, 125.54, 125.96, 127.68, 128.24, 129.93, 140.14,
141.48, 151.62, 157.80, 159.84, 161.42, 176.96. – LC-MS:
m/z = 542 [M]+, 544 [M+2]+, 546 [M+4]+ in 9:6:1 ratio. –
C27H22N3O2Cl2FS (541.07): calcd. C 59.78, H 4.09, N 7.75,
S 5.91; found C 59.80, H 4.10, N 7.76, S 5.93.
rac-2-(4-Isobutylphenyl)ethyl-5-[(5-(2-nitrophenyl)furan-2-
yl)methylidene]-[1,3]thiazolo[3,2-b] [1,2,4]triazol-6(5H)-
one (4c)
M. p. 227 ◦C; yield 3.5 g (71 %). – IR (KBr, cm−1):
ν = 3082 (Ar-H), 2954 (C-H), 1731 (C=O), 161 (C=N). –
1H NMR ([D6]DMSO): δ = 0.88 (d, 6 H, 2× CH3, J =
6.4 Hz), 1.74 (d, 3 H, CH3, J = 7.6 Hz), 1.79 – 1.86 (m,
1 H, CH), 2.43 (d, 2 H, CH2, J = 7.2 Hz), 4.31 – 4.33 (q,
1 H, CH, J = 7.2 Hz), 6.86 (d, 1 H, furan H, J = 3.6 Hz),
7.02 (d, 1 H, furan H, J = 3.6 Hz), 7.10 (d, 2 H, ArH, J =
8.0 Hz), 7.28 (d, 2 H, ArH, J = 8.4 Hz), 7.5 – 7.8 (m, 4 H,
ArH-NO2), 7.87 (s, 1 H, exocyclic vinylic H). – 13C NMR
([D6]DMSO): δ = 20.28, 22.86, 30.66, 40.54, 45.58, 113.89,
122.48, 123.50, 124.69, 125.12, 125.76, 127.79, 129.85,
129.95, 130.63, 132.99, 137.70, 139.86, 140.97, 141.25,
148.17, 150.38, 153.95, 156.64, 160.90, 176.97 – LC-MS:
m/z = 501 [M+1]+. – C27H24N4O4S (500.5): calcd. C 64.78,
H 4.83, N 11.19, S 6.41; found C 64.77, H 4.85, N 11.16,
S 6.39.
rac-2-(4-Isobutylphenyl)ethyl-5-[(5-(3-chloro-4-fluoro-
phenyl)furan-2-yl)methylidene]-[1,3]thiazolo [3,2-b]-
[1,2,4]triazol-6(5H)-one (4f)
M. p. 249 ◦C; yield 4.3 g (85 %). – IR (KBr, cm−1):
ν = 3078 (Ar-H), 2983 (C-H), 1731 (C=O), 1599 (C=N). –
1H NMR ([D6]DMSO): δ = 0.88 (d, 6 H, 2× CH3, J =
6.4 Hz), 1.76 (d, 3 H, CH3, J = 7.2 Hz), 1.80 – 1.87 (m, 1 H,
CH), 2.44 (d, 2 H, CH2, J = 7.2 Hz), 4.30 – 4.35 (q, 1 H, CH,
J = 7.2 Hz), 6.87 (d, 1 H, furan H, J = 3.6 Hz), 7.00 (d, 1 H,
furan H, J = 3.6 Hz), 7.08 (d, 2 H, ArH, J = 8.0 Hz), 7.12
(d, 2 H, ArH, J = 8 Hz), 7.35 – 7.58 (m, 3 H, ArH), 7.84 (s,
1 H, exocyclic vinylic H). – 13C NMR ([D6]DMSO): δ =
20.27, 22.84, 30.65, 40.58, 45.54, 109.91, 121.54, 123.32,
124.90, 126.72, 127.91, 129.64, 136.82, 139.98, 140.64,
149.02, 156.82, 158.94, 160.57, 176.83. – LC-MS: m/z =
508 [M]+, 510 [M+2]+ in 3:1 ratio. – C27H23N3O2ClFS
rac-2-(4-Isobutylphenyl)ethyl-5-[(5-(4-bromophenyl)furan-
2-yl)methylidene]-[1,3]thiazolo [3,2-b][1,2,4]triazol-
6(5H)-one (4d)
M. p. 233 ◦C; yield 4.1 g (78 %). – IR (KBr, cm−1): (507.11): calcd. C 63.84, H 4.56, N 8.27, S 6.31; found
ν = 3025 (Ar-H), 2954 (C-H), 1733 (C=O), 1611 (C=N), C 63.88, H 4.57, N 8.25, S 6.33.
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rac-2-(4-Isobutylphenyl)ethyl-5-[(5-(2-methyl-6-nitro-
phenyl)furan-2-yl)methylidene]-[1,3]thiazolo[3,2-b]-
[1,2,4]triazol-6(5H)-one (4g)
(s, 1 H, exocyclic vinylic H). – 13C NMR ([D6]DMSO): δ =
20.28, 22.86, 30.64, 40.60, 45.58, 110.20, 122.34, 123.95,
124.37, 126.84, 127.86, 137.06, 139.25, 140.50, 150.48,
156.84, 159.62, 160.92, 176.84. – LC-MS: m/z = 535 [M]+,
537 [M+2]+ in 3:1 ratio. – C27H23N4O4ClS (534.11): calcd.
C 60.61, H 4.33, N 10.47, S 5.99; found C 60.63, H 4.36,
N 10.49, S 5.97.
M. p. 239 ◦C; yield 4.4 g (87 %). – IR (KBr, cm−1):
ν = 3090 (Ar-H), 2978 (C-H), 1728 (C=O), 161 (C=N). –
1H NMR ([D6]DMSO): δ = 0.88 (d, 6 H, 2× CH3, J =
6.4 Hz), 1.36 (s, 3 H, CH3), 1.76 (d, 3 H, CH3, J = 7.2 Hz),
1.80 – 1.87 (m, 1 H, CH), 2.14 (s, 3 H, CH3), 2.36 (d, 2 H,
CH2, J = 7.2 Hz), 2.61(s, 3 H, Ar-CH3), 4.24 – 4.26 (q, 1 H,
CH, J = 8.0 Hz), 6.86 (d, 1 H, furan H, J = 4.0 Hz), 7.02 –
7.05 (m, 3 H, 2 ArH and furan H), 7.23 (d, 2 H, ArH, J =
8.0 Hz), 7.41 (d, 2 H, ArH, J = 8.4 Hz), 7.87 (s, 1 H, exo-
cyclic vinylic H), 8.08 (dd, 2 H, ArH, J = 8.4 Hz), 8.55 (d,
2 H, ArH, J = 8 Hz). – LC-MS: m/z = 514 (M+). – 13C NMR
([D6]DMSO): δ = 20.27, 20.68, 22.84, 30.68, 40.60, 45.60,
110.08, 121.26, 123.54, 124.90, 126.86, 127.08, 137.64,
139.74, 140.26, 149.68, 156.72, 159.68, 160.28, 176.88. –
LC-MS: m/z = 515 [M+1]+. – C28H26N4O4S (514.16):
calcd. C 65.35, H 5.09, N 10.89, S 6.23; found C 65.37,
H 5.07, N 10.91, S 6.25.
rac-2-(4-Isobutylphenyl)ethyl-5-[(5-(3,4-dichlorophenyl)-
furan-2-yl)methylidene]-[1,3]thiazolo[3,2-b][1,2,4]triazol-
6(5H)-one (4j)
M. p. 265 ◦C; yield 3.9 g (76 %). – IR (KBr, cm−1):
ν = 3073 (Ar-H), 2963 (C-H), 1726 (C=O), 1605 (C=N). –
1H NMR ([D6]DMSO): δ = 0.88 (d, 6 H, 2× CH3, J =
6.4 Hz), 1.76 (d, 3 H, CH3, J = 7.2 Hz), 1.80 – 1.87 (m,
1 H, CH), 2.44 (d, 2 H, CH2,J = 7.2 Hz), 4.30 – 4.35 (q,
1 H, CH, J = 7.2 Hz), 6.87 (d, 1 H, furan H, J = 3.6 Hz),
7.00 (d, 1 H, furan H, J = 3.6 Hz), 7.14 (d, 2 H, ArH, J =
8.0 Hz), 7.16 (d, 2 H, ArH, J = 8.0 Hz), 7.41 – 7.63 (m,
3 H, ArH), 7.86 (s, 1 H, exocyclic vinylic H). – 13C NMR
([D6]DMSO): δ = 20.26, 22.84, 30.66, 40.61, 45.58, 110.24,
122.36, 124.42, 125.70, 126.80, 127.94, 137.74, 139.46,
140.84, 150.62, 156.92, 159.84, 160.28, 176.92. – LC-MS:
m/z = 524 [M]+, 526 [M+2]+, 526 [M+4]+ in 9:6:1 ratio. –
C27H23N3O2Cl2S (523.08): calcd. C 61.83, H 4.42, N 8.01,
S 6.11; found C 61.85, H 4.45, N 8.02, S 6.09.
rac-2-(4-Isobutylphenyl)ethyl-5-[(5-(2-methyl-4-nitro-
phenyl)furan-2-yl)methylidene]-[1,3]thiazolo[3,2-b]-
[1,2,4]triazol-6(5H)-one (4h)
M. p. 263 ◦C; yield 3.7 g (72 %). – IR (KBr, cm−1):
ν = 3086 (Ar-H), 2985 (C-H), 1725 (C=O), 1602 (C=N). –
1H NMR ([D6]DMSO): δ = 0.88 (d, 6 H, 2× CH3, J =
6.4 Hz), 1.76(d, 3 H, CH3, J = 7.2 Hz), 1.80 – 1.87 (m, 1 H,
CH), 2.24 (s, 3 H, CH3), 2.44 (d, 2 H, CH2, J = 7.2 Hz),
4.30 – 4.35 (q, 1 H, CH, J = 7.2 Hz), 6.87 (d, 1 H, fu-
ran H, J = 3.6 Hz), 7.00 (d, 1 H, furan H, J = 3.6 Hz),
7.14 (d, 2 H, ArH, J = 8.0 Hz), 7.16 (d, 2 H, ArH, J =
8.0 Hz), 7.41 – 7.63 (m, 3 H, ArH), 7.86 (s, 1 H, exocyclic
vinylic H). – 13C NMR ([D6]DMSO): δ = 20.27, 20.64,
22.84, 30.68, 40.60, 45.60, 110.14, 121.36, 123.60, 124.84,
126.53, 127.28, 137.56, 139.80, 140.32, 150.16, 156.78,
159.74, 160.72, 176.86. – LC-MS: m/z = 515 [M+1]+. –
C28H26N4O4S (514.16): calcd. C 65.35, H 5.09, N 10.89,
S 6.23; found C 65.36, H 5.10, N 10.91, S 6.25.
rac-2-(4-Isobutylphenyl)ethyl-5-(3,4-dimethoxybenzyl-
idene)-[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-one (5a)
M. p. 158 ◦C; yield 3.5 g (80 %). – IR (KBr, cm−1):
ν = 3048 (Ar-H), 2924 (C-H), 173 (C=O), 1600 (C=N). –
1H NMR ([D6]DMSO): δ = 0.81 (d, 6 H, 2× CH3, J =
6.4 Hz), 1.68 (d, 3 H, CH3, J = 7.6 Hz), 1.71 – 1.79 (m, 1 H,
CH), 2.36 (d, 2 H, CH2, J = 7.2 Hz), 3.86 – 3.87 (2s, 6 H,
2× OC H 3), 4.11 – 4.17 (q, 1 H, CH, J = 7.2 Hz), 6.92 (d,
2 H, ArH, J = 8.4 Hz), 6.99 (d, 2 H, ArH, J = 8.4 Hz), 7.03 (d,
2 H, ArH, J = 8.0 Hz), 7.01 – 7.04 (dd, 2 H, ArH, J = 8.4 Hz),
7.22 (d, 2 H, ArH, J = 8.4 Hz), 8.05 (s, 1 H, exocyclic vinylic
H). – 13C NMR ([D6]DMSO): δ = 20.31, 22.89, 30.65,
40.63, 45.54, 56.48, 56.65, 112.08, 113.57, 121.5, 125.83,
125.95, 127.74, 129.92, 139.90, 140.94, 141.94, 141.05,
150.04, 152.84, 156.97, 160.12, 176.84. – LC-MS: m/z =
449 [M+]. – C25H27N3O3S (449.56): calcd. C 66.79, H 6.05,
N 9.35, S 7.13; found C 66.80, H 6.08, N 9.37, S 7.11.
rac-2-(4-Isobutylphenyl)ethyl-5-[(5-(4-chloro-2-nitro-
phenyl)furan-2-yl)methylidene]-[1,3]thiazolo[3,2-b]-
[1,2,4]triazol-6(5H)-one (4i)
M. p. 230 ◦C; yield 4.3 g (82 %). – IR (KBr, cm−1):
ν = 3072 (Ar-H), 2964 (C-H), 1727 (C=O), 1602 (C=N)
rac-2-(4-Isobutylphenyl)ethyl-5-(3,4-dimethoxy-5-nitrobenz-
ylidene)-[1,3]thiazolo[3,2-b][1,2,4] triazol-6(5H)-one (5b)
–
1H NMR ([D6]DMSO): δ = 0.88 (d, 6 H, 2× CH3,J =
6.4 Hz), 1.76 (d, 3 H, CH3, J = 7.2 Hz), 1.80 – 1.87 (m, 1 H,
CH), 2.44 (d, 2 H, CH2, J = 7.2 Hz), 4.30 – 4.35 (q, 1 H, CH,
M. p. 165 ◦C; yield 3.8 g (78 %). – IR (KBr, cm−1):
J = 7.2 Hz), 6.87 (d, 1 H, furan H, J = 3.6 Hz), 7.00 (d, 1 H, ν = 3051 (Ar-H), 2966 (C-H), 1727 (C=O), 1602 (C=N). –
furan H, J = 3.6 Hz), 7.14 (d, 2 H, ArH, J = 8.0 Hz), 7.16 1H NMR ([D6]DMSO): δ = 0.81 (d, 6 H, 2× CH3,J =
(d, 2 H, ArH, J = 8.0 Hz), 7.41 – 7.63 (m, 3 H, ArH), 7.86 6.4 Hz), 1.68 (d, 3 H, CH3, J = 7.6 Hz), 1.71 – 1.79 (m,
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1514
M. Kumsi et al. · Bioactive Thiazolotriazole Derivatives
Table 1. Antibacterial activitya
MIC (µgmL−1) and zone of inhibition (mm) in parentheses
of 4a – j and 5a – d.
Compound
S. aureus
E. coli
P. aeruginosa
25 (< 10)
12.5 (11 – 15)
12.5 (11 – 15)
25 (< 10)
K. pneumoniae
25 (< 10)
12.5 (11 – 15)
12.5 (11 – 15)
25 (< 10)
4a
25 (< 10)
25 (< 10)
4b
12.5 (11 – 15)
12.5 (11 – 15)
25 (< 10)
12.5 (11 – 15)
12.5 (11 – 15)
25 (< 10)
4c
4d
4e
12.5 (11 – 15)
25 (< 10)
25 (< 10)
12.5 (11 – 15)
25 (< 10)
25 (< 10)
12.5 (11 – 15)
25 (< 10)
25 (< 10)
12.5 (11 – 15)
25 (< 10)
25 (< 10)
4f
4g
4h
25 (< 10)
25 (< 10)
25 (< 10)
25 (< 10)
4i
6.25 (20 – 26)
12.5 (11 – 15)
25 (< 10)
6.25 (16 – 20)
12.5 (11 – 15)
25 (< 10)
6.25 (16 – 20)
12.5 (11 – 15)
25 (< 10)
6.25 (16 – 20)
12.5 (11 – 15)
25 (< 10)
4j
5a
5b
12.5 (11 – 15)
6.25 (20 – 26)
25 (< 10)
12.5 (11 – 15)
6.25 (16 – 20)
25 (< 10)
12.5 (11 – 15)
6.25 (16 – 20)
25 (< 10)
12.5 (11 – 15)
6.25 (16 – 20)
25 (< 10)
a
5c
The MIC values were evaluated
5d
in the concentration range, 1.56 –
25 µg mL−1
.
Ampicillin (Standard)
1.56 (22 – 30)
6.25 (30 – 40)
6.25 (25 – 33)
6.25 (23 – 27)
Table 2. Antifungal activitya
MIC (µg mL−1) and zone of inhibition (mm) in parentheses
of 4a – j and 5a – d.
Compound
A. flavus
A. fumigatus
12.5 (11 – 15)
12.5 (11 – 15)
25 (< 10)
P. marneffei
12.5 (11 – 15)
12.5 (11 – 15)
25 (< 10)
T. mentagrophytes
12.5 (11 – 15)
12.5 (11 – 15)
25 (< 10)
4a
12.5 (11 – 15)
12.5 (11 – 15)
25 (< 10)
4b
4c
4d
25 (< 10)
25 (< 10)
25 (< 10)
25 (< 10)
4e
12.5 (11 – 15)
12.5 (11 – 15)
25 (< 10)
12.5 (11 – 15)
25 (< 10)
12.5 (11 – 15)
12.5 (11 – 15)
25 (< 10)
12.5 (11 – 15)
25 (< 10)
12.5 (11 – 15)
12.5 (11 – 15)
25 (< 10)
12.5 (11 – 15)
25 (< 10)
12.5 (11 – 15)
12.5 (11 – 15)
25 (< 10)
12.5 (11 – 15)
25 (< 10)
4f
4g
4h
4i
4j
6.25 (22 – 28)
12.5 (11 – 15)
12.5 (11 – 15)
6.25 (20 – 26)
25 (< 10)
6.25 (16 – 20)
12.5 (11 – 15)
12.5 (11 – 15)
6.25 (16 – 20)
25 (< 10)
6.25 (16 – 20)
12.5 (11 – 15)
12.5 (11 – 15)
6.25 (16 – 20)
25 (< 10)
6.25 (16 – 20)
12.5 (11 – 15)
12.5 (11 – 15)
6.25 (16 – 20)
25 (< 10)
5a
5b
a
5c
The MIC values were evaluated
5d
in the concentration range, 1.56 –
25 µg mL−1
.
Itraconozole (Standard)
1.56 (22 – 30)
6.25 (30 – 40)
6.25 (25 – 33)
6.25 (23 – 27)
1 H, CH), 2.36 (d, 2 H, CH2, J = 7.2 Hz), 3.86 – 3.87 (2s, 8.92 (s, Ar-OH), 8.05 (s, 1 H, exocyclic vinylic H). – LC-
6 H, 2× OCH3), 4.11 – 4.17 (q, 1 H, CH, J = 7.2 Hz), 6.96 MS: m/z = 406 [M++1]. – C23H23N3O2S (405.51): calcd.
(d, 2 H, ArH, J = 8.4 Hz), 7.00 (d, 2 H, ArH, J = 8.4 Hz), C 68.12, H 5.72, N 10.36, S 7.91; found C 68.14, H 5.75,
7.4 – 7.7 (m, 2 H, ArH), 8.25 (s, 1 H, exocyclic vinylic H). – N 10.39, S 7.93.
13C NMR ([D6]DMSO): δ = 20.31, 22.88, 30.64, 40.63,
rac-2-(4-Isobutylphenyl)ethyl-5-(3,5-difluorobenzylidine)-
[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-one (5d)
45.54, 56.55, 56.72, 113.23, 115.64, 122.06, 126.96, 128.08,
130.62, 140.68, 142.62, 142.42, 151.12, 153.32, 158.28,
161.26, 176.88. – LC-MS: m/z = 494 [M]+. – C25H26N4O5S
(494.56): calcd. C 60.71, H 5.30, N 11.33, S 6.48; found
C 60.73, H 5.32, N 11.36, S 6.51.
M. p. 154 ◦C; yield 3.2 g (76 %). – IR (KBr, cm−1):
ν = 3074 (Ar-H), 2979 (C-H), 1728 (C=O), 161 (C=N). –
1H NMR ([D6]DMSO): δ = 0.81 (d, 6 H, 2× CH3, J =
6.4 Hz), 1.68 (d, 3 H, CH3, J = 7.6 Hz), 1.71 – 1.79 (m, 1 H,
CH), 2.36 (d, 2 H, CH2, J = 7.2 Hz), 4.11 – 4.17 (q, 1 H, CH,
J = 7.2 Hz), 6.94 (d, 2 H, ArH, J = 8.4 Hz), 6.98 (d, 2 H, ArH,
rac-2-(4-Isobutylphenyl)ethyl-5-(4-hydroxy-5-nitrobenzyl-
idene)-[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-one (5c)
M. p. 135 ◦C; yield 3.3 g (82 %). – IR (KBr, cm−1): J = 8.4 Hz), 7.03 (d, 2 H, ArH, J = 8.0 Hz), 7.01 – 7.04 (dd,
ν = 3034 (Ar-H), 2957 (C-H), 1736 (C=O), 164 (C=N). – 2 H, ArH, J = 8.4 Hz), 7.22 (d, 2 H, ArH, J = 8.4 Hz), 8.05
1H NMR ([D6]DMSO): δ = 0.81 (d, 6 H, 2× CH3, J = (s, 1 H, exocyclic vinylic H). – 13C NMR ([D6]DMSO): δ =
6.4 Hz), 1.68 (d, 3 H, CH3, J = 7.6 Hz), 1.71 – 1.79 (m, 1 H, 20.32, 22.82, 30.64, 40.65, 45.52, 112.25, 113.62, 121.47,
CH), 2.36 (d, 2 H, CH2, J = 7.2 Hz), 4.11 – 4.17 (q, 1 H, CH, 125.92, 125.92, 127.64, 139.76, 141.02, 149.88, 151.64,
J = 7.2 Hz), 6.94 (d, 2 H, ArH, J = 8.4 Hz), 6.98 (d, 2 H, 156.06, 159.04, 176.86. – LC-MS: m/z = 426 [M+1]+. –
ArH, J = 8.4 Hz), 7.03 (d, 2 H, ArH, J = 8.0 Hz), 7.01 – 7.04 C23H21N3OF2S (425.13): calcd. C 64.92, H 4.97, N 9.88,
(dd, 2 H, ArH, J = 8.4 Hz), 7.22 (d, 2 H, ArH, J = 8.4 Hz), S 7.54; found C 64.94, H 4.99, N 9.89, S 7.57.
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M. Kumsi et al. · Bioactive Thiazolotriazole Derivatives
1515
Antimicrobial activity
Aspergillus fumigatus (NCIM No. 902), Penicillium marn-
effei (recultured), and Trichophyton mentagrophytes (recul-
tured) in DMSO by the serial plate dilution method [31, 32].
The antifungal activity was determined by measuring the di-
ameter of the inhibition zone. The activity of each compound
was compared with itraconozole as standard. Zones of inhi-
bition were determined for 4a – n and 5a – d, and the results
are summarized in Table 2.
The newly synthesized compounds were screened for
their antibacterial activity against Staphylococcus aureus
(ATTC-25923), Escherichia coli (ATTC-25922), Pseu-
domonas aeruginosa (ATTC-27853), and Klebsiella pneu-
moniae (recultured) bacterial strains by the serial plate dilu-
tion method [27, 28]. Antibacterial activity was determined
by measuring the diameter of the inhibition zone. The activ-
ity of each compound was compared with ampicillin as stan-
dard [29, 30]. The zone of inhibition was determined for 4a –
Acknowledgements
We gratefully acknowledge IISC Bangalore and CDRI
j and 5a – d. The results are summarized in Table 1. The Lucknow for the spectroscopic analysis. M. K. is thankful to
newly prepared compounds were also screened for their an- UGC for providing financial assistance under UGC-RFSMS
tifungal activity against Aspergillus flavus (NCIM No. 524), and also under the UGC-SAP program of the department.
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